PETITION UNDER ARTICLE 32 OF THE CONSTITUTION

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PETITION UNDER ARTICLE 32 OF THE CONSTITUTION
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RF_DR_26_SUDHA CONTRAC I P HON

PLASMA LEVELS OF NORETHISTERONE AFTER SINGLE AND
MULTIPLE
INJECTIONS OF NORETHISTERONE
OENANTHATE
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K. Fotherby-, Geraldine Howard , K. Shrimanker ,
M. Elder2 and P.G.T. Bye3
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Royal Postgraduate Medical School, Ducane Road, London Wlc OHS;

Department of Obstetrics and Gynaecology, Charing Cross Hospital,
3
London W6 and Schering Chemicals Ltd., Burgess Hill, Sussex, England

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ABSTRACT

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Plasma norethisterone levels were measured in 15 women at
varying times after the first injection of rorethisterone/Jenar.thate
and in a group of 15 women who had received multiple injections of
the gestagen. % There was no difference between the two groups of
women in respect of age, height and weight. There was a significant
difference in the rate of metabolism of norethisterone oenanthate
between the two groups and the results suggest that some
accumulation of norethisterone occurs in women receiving multiple
injections at intervals of ten or twelve weeks.

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Accepted for publication June 1, 1978

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CONTRACEPTION

CONTRACEPTION

large individual variation in the levels of norethisterone attained in
blood.
When the values from the analysis of 133 samples of blood
collected between days 28 and 90 after injection were plotted semilogarithmically (Figure),the mean values fell approximately on a
straight line, the regression equation for which was
Y « -0.01378X + 3.479, where Y is the logarithm of the norethisterone
concentration and X the number of days after injection.
From the
regression equation it can be calculated that the mean time required
for the concentration of norethisterone to reach undetectable levels
(< 100 pg/ml) was 107 days.

* *

The figure also shows the values for 56 samples obtained between days
28 - 90 after injection from the 15 subjects who had received multiple
injections.
For these values the equation of the regression line
was Y = -0.01036X + 3.569.
From this equation it can be calculated
that time required for the plasma norethisterone levels to reach
undetectable values was 152 days.
There was a statistically
significant difference (T = 4.5, p < 0.01) between the slopes of the
two regression lines, tested as described by Armitage (6), showing
that plasma levels of norethisterone decreased significantly more
slowly in women receiving multiple injections than in those
receiving only a single injection.

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The women who received one injection of 200 mg norethisterone
oenanthate ranged in age from 21 to 46 years (mean 30.7 years) and
those receiving multiple injections from 20 to 36 years (mean 28.4
years).
There was no significant difference between the two groups
of women in respect of height, weight and ponderal index.

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Ovulation returns within eight weeks of the injection in some
subjects (1, 2) so it is now recommended that tne first three
injections of norethisterone oenanthate should be given at intervals

There was no significant difference between the mean ponderal index
of the two groups studied, suggesting that a possible storage of
norethisterone in a secondary fat depot is not responsible for the
finding of higher circulating levels in women receiving multiple
injections.
The long-term clinical significance of hi ch circulating levels, of
norethisterone is not known.
There is sqrre evidence that multiple
injections of norethisterone do not cause significant changes in tne
intravenous glucose tolerance test or affect pre-existing
hypertension (Howard et aj. unpublished).
The fact that circulating
norethisterone persists at higher levels than expected might
predispose to amenorrhoea in some cases.
Further studies are
required to exclude long-term clinical and metabolic effects of
raised circulating norethisterone levels due to multiple injections.

DISCUSSION

The results illustrated in Figure show that of the 15 women
receiving five or more injections of norethisterone oenanthate,twelve
had levels of norethisterone in plasma, during the period from 28 to
90 days after injection, higher than the mean levels obtained in the
group of women receiving their first injection.
In addition, tne
rate of decline of circulating norethisterone in patients having
multiple injections was significantly slower, suggesting a decrease
in the rate of metabolism of the steroid.
The nature of this
alteration in metabolism is obscure.' It is not known after how long
the change to a slower metabolism occurs.
Provided that the rate
of absorption of the gestagen from the injection site remains constant
and that the metabolism of norethisterone by tne liver is not
increased by serial injections, then the total amount of
norethisterone in tne body will progressively increase with each'
st^sequent injection.

of 60 days.
After the first injection of norethisterone oenanthate,
plasma levels of norethisterone have decreased by this time below
400 pg/ml in 12 of the 15 subjects (80") whereas plasma levels of
norethisterone had decreased to this value in only 2 of the 14
subjects (14X) receiving multiple injections.
Thus our results
provide some rationale for the now-suggested use of norethisterone
oenanthate by giving the first three injections at intervals of 60
days and later injections at intervals of 90 days.
In this way
the accumulation of norethisterone in the body would be minimised
while still maintaining an antiferti1ity effect.
There was a wide range between individuals in the rate at which
norethisterone oenanthate was metabolised.
We have shown
previously that the time taken to reach undetectable plasma levels
of norethisterone after a single injection of- norethisterone
oenanthate varies from 7 to 16 weeks (7).
This range is similar to
that observed in the present study for women receiving a single
injection of norethisterone oenanthate.

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WHO symposium
-geneva 1979

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Endometrial Bleeding
and
Steroidal Contraception
Proceedings of a Symposium on

Steroid Contraception and Mechanisms
of Endometrial Bleeding

organized by

the World Health Organization

in Geneva
on 12-14 September 1979

IlDITORS

C
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E. Diczfalusy
WHO Collaborating Centre for Research and Training in Human Reproduction,
Stockholm

IS. Fraser
Department of Obstetrics and Gynaecology. University of Sydney, Sydney
F. I'. G. Webb
WHO Special Programme of Research, Development and Research Training in
Human Reproduction. Geneva

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Pitman Press Ltd
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WHO SYMPOSIUM ON STEROID CONTRACEPTION AND MECHANISMS

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OF ENDOMETRIAL BLEEDING

Geneva. 12-14 September 1979
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VASCULAR AND PBRIVASCU! AR CHANCiRS IN THE

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endoml:trium of women using steroidal

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CONTRACEP I IVES

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I NTRODUCTION

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I he morphology of the ciulomeliium of women receiving dill’crenl steroid
therapies has been reviewed in many publications such as Obei (1966).

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Maqueo el al. (1970a), Jackson and Linn, ( 1964). Stamp (1967) and many
others. 1 he main emphasis has been on the changes that the glands and

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stroma undergo in the norma! or hyperplastic endometrium. All the authors
have shown that in women using combined oestrogen progestogen oral

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contraceptives, there is endometrial involution in the lirst days of treatment,
manifested as early irregular secretory endometrium with moderately under­

developed glands. After seven to twelve days the endometrium still shows
secretory activity but the glands are very irregularly developed and the
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stroma may show varying degrees of oedema and occasional small, irregular
patches of predecidual reaction. In the last week of treatment there is

marked glandular involution with the glands becoming small or very small,
exhausted of secretions and lined with eosinophilic, low columnar
epithelium. The stroma shows varying degrees of oedema and sometimes
predecidual reaction that is usually discrete and irregular, but rarely may be
intense or quite diffuse. Minor variations have been seen with the different

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compounds, and some authors claim that they can distinguish differences in
the endometrial pattern in relation to the drugs used. (Jackson and Linn.

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1964). I he endometrial pattern also varies in relation to the duration of
drug use; usually the secretory changes arc less intense and shorter in

women that have been under therapy for several months (Maqueo et al..
1970a). Several terms have been used to describe this ty|x* of endometrium.

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Whilst this report is limited to changes in the endometriuin. it is important
to remember that vascular changes have been described in the vessels of
many organs of women receiving oral contraceptives, as well as in those that
have physiologically high levels of steroidal hormones, as in pregnancy. Ten
Berge (In: Maxwell. 1968) reported thickening of the arterioles of the
ovaries and uterus in women using oral contraccptixcs and Laufcr (In:
Maxwell, 1968) has reported similar changes in multiparous women.
Schwarz and Hawker (1950) made a detailed dcsciiplion of the changes of
the uterine vessels during pregnancy.
Lipschutz (1950) has reported that steroids can induce proliferation of the
endothelium in several animal species. Danforth el al. (1964) saw. in the
aortac of rabbits receiving progestogens, a decrease of the acid
mucopolysaccharides, fragmentation of the reticular fibres and loss of the
normal structure of the elastic layers. Similar changes were reported
(Manalo-listrclla and Barker, 1977), in the aortac of pregnant women. Irey et
al. ( 1970) and Irey and Norris (1973) reported intimal proliferation, with or
without thrombosis, in the vessels of several organs from women using oral
contraceptives, as well as in pregnant or postpartum patients; they suggested
that endogenous and exogenous female reproductive steroids could be the
common hormonal factor producing vasctilai lesions and that these steroids
should be listed as agents with which intimal prolilciation could be as
sociatcd. Blaustein et al. (1968) and Blauslcin and Schenker (197(1) also
reported vascular lesions in several organs and hyperplasia of the en­
dothelium of the endometrial vessels in 31% of their specimens. This
hyperplasia was substantial in 5% of cases. They also reported hyperplasia
of the muscle in 82%, which was prominent in 3.4%. rhev found no
correlation with duration of therapy and saw no progression.
In ultrastructural studies of endometrial capillaries, I riedrich (1967)
reported that “endothelial cells and pericytes showed evidence of
growth as well as changes suggestive of synthesis of molecular complexes
destined to be secreted, such as mucopolysaccharides, mucoproteins or
collagen”.
Song et al. (1970) have described capillary proliferation, with lymphatic
dilatation and even formation of microcysts; they also noted thrombosis of
the capillaries and endothelial proliferation, but no changes in the pericytes.
Grant (1969) reported changes in the venules of the endometrium and even
attempted to correlate such lesions with clinical manifestations such as leg
cramps or tenderness of the legs. Other authors, such as Laufcr (In:
Maxwell, 1968), have been unable to confirm such lesions in women
receiving oral contraceptives. Feria-Valasco et al. (1972), in ultrastructural
studies, did not sec any changes in the vascular epithelium excepting
plaque-like aggregates that, in their opinion, did not represent thrombus
formation.
Maqueo et al. (1970b) reported the morphology of endometrial \enules
in biopsies taken from women using steroidal contraceptive preparations in
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cyclic, continuous or injectable regimens, as well as control groups of

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biopsies taken from postmenopausal patients and normal cyclic women.

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With the oral combination agents ami the injectables, a large percentage of
the specimens showed venule dilatation which was more frequent and

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marked in the last ten days of treatment, it was observed with all the drugs
used, with different dose levels ol the same progestogen and in the first or
subsequent cycles of treatment. In the last ten days of treatment such venule

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dilatation was seen in 30-57% ol the specimens, while in the first ten days
of treatment it was seen in only 8-20%.
Based on these various reports, there appears to he agreement that
steroidal contraceptives cause important vascular changes in the human

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endometrium, manifested mainly as underdevelopment of the arterioles and
degenerative changes in the venules. In a small number of cases, there are

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lesions of the vascular endothelium or the vascular wall that have also been

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noted in several other organs.
1 he significance of such lesions has been variously interpreted. Those of

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the vascular wall and endothelium have been correlated with thromboem­
bolic changes by several investigators Grey and Words, 1973). The changes

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in the venules, although widely mentioned, arc not easily correlated with

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bleeding and. even if some authors claim them to be the cause of irregular
bleeding (Ober. 1970), it should be remembered that their frequency is
much higher than that of irregular bleeding. Therefore the presence of

venule dilatation bv itself does not necessarily mean that the patient will
have irregular bleeding.

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In a recent study we look

100(1 endometrial biopsies at random from

women who were rcceix ing dillcrcnl oral combination and sequential steroi­
dal cootiaccplivcs and JO specimens from women who underwent hysterec­
tomy lor reasons olhei than cndomeliial pathology. The latter group had all
shown a normal endometrial pattern before treatment. Prior to surgery, (hey

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were Heated with iioicthistcronc 2 mg plus mcstranol 80 /ig for I 3 months.
1 he different combinations of steroids were always carefully recorded for
comparison with the histological findings.
Control biopsies were taken from 60 postmenopausal women with diag­

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noses of resting or atrophic endometrium. 60 normal women showing
proliferative endometrium. 60 showing early secretory endometrium (days

16 20) and 60 showing late secretory endometrium (days 21-28 of cycle),

according to the criteria of Noves el al. (1950).
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Ol the 40 hysterectomy specimens, al least 10 blocks were made from
each specimen. All were sectioned at 6/zm and stained with haematoxylin

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and eosin. In classilying these biopsies the billowing terms were used:

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Resting or inactive endometrium: I-ndometrium having small glands with
cuboidal or low columnar epithelium and absence of mitoses. 'The stroma

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was usually dense and had a fibrous appearance. More rarely it was loose,
but it always lacked signs of proliferative activity.

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WHO SYMPOSIUM ON STEROID CONTiiACEPTlON AND MECHANISMS

OF ENDOMETRIAL BLEEDING

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Geneva. 12-14 September 1979

Frauciikiinik Mannheitn, Lakulliit fiir
Klinische Medizin dcr Universitiil Heidelberg

THE INFLUENCE OF CONTRACEPTIVE STEROIDS ON THE

HISTOLOGICAL APPEARANCE OF THE ENDOMETRIUM
By

(i. I )(dlcnb(U h -1 Icllwcn,

The eflecls of many of the synthetic oestrogens and progestogens differ from
their natural counterparts, depending on their chemical structure and
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biological potency. To understand their combined action, the isolated effects

of both hormones have to be considered first.

I. ()cs(rogefis alone
The hormones grou|K‘d together and referred to as oestrogens, although
similar in their action, are chemically heterogeneous. The group includes

various milurallv occurring hormones, some of which are unique to certain
species of animals, as well as synthetic steroids and non-steroidal agents.
Although the oestrogens do show line distinctions in their effects that are

of clinical importance, most of these hormones are extremely potent, even in
tiny doses, since the target cells they stimulate are exquisitely responsive to
low concentrations and promptly react by characteristic changes. On the
other hand, prolonged high doses seem to overwhelm the receptors of the

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target cells and apparently exhaust the cytoplasmic structures that produce
them (Nordquist, 1970) so that specific enzyme systems become blocked

(Villee, 1961). and the cells may become unable to respond to further
oestrogen. For example, in monkeys very high doses of oestrogen mav lead
io endometrial atrophy (Hartmann et al., 1941) or hyperplasia, whereas in
other animals such, as rabbits and mice, prolonged treatment with small

doses may induce carcinoma (Allen, 1940; Lipschiitz, 1950; Meissner el al..

1957; Graham et al . 1980).
The oral or parenteral administration of oestradiol alone from the lirsi

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day of a menstrual cycle prolongs the proliferative phase and suppresses the
secretion of gonadotrophins by the pituitary, especially FSH. Ovulation and
the development of a corpus luteum is inhibited until the oestrogen is
discontinued. Menstruation consequently is delayed (Zondek. 1940). Treat­
ment with high doses of oestradiol during the secretory phase results in
severe stromal oedema (Egger and Kindermann. 1974), delay in secretory
transformation of glands and stroma and a disruption of the nucleolar
channel-system, an organelle normally found in the glandular cell nuclei of
the secretory endometrium (Gordon et al.. 1973). If the oestrogen is
discontinued after prolonged therapy, an oestrogen “withdrawal bleeding”
ensues; if the oestrogen is given over a long period in consistently small
doses, a spontaneous “breakthrough bleeding" may occur. Short-term treat­
ment with progesterone prevents these two types of bleeding. The haemor­
rhage that follows after the progesterone is discontinued (“progesterone
withdrawal bleeding ’) is not usually as profuse as with the oestrogen
withdrawal bleeding . which is probably due to tissue necrosis without
dissociation of intercellular bonds. Persistent follicular activity (Schriider.
I Z54) oi prolonged administration ol small to mode rale doses of some
oestrogens (Grccnblatl and Zarate. 1967; Obci ami Bronstein. 1967) can
lead to (he development of cystic glandular hyperplasia of the endometrium.
However, oestriol seems to have a different elfccl on the endometrium.
Horn lime to time portions of these hyperplastic emlomcliia may undergo
haemorrhagic necrosis and be discharged, but when the oestrogen stimulus
continues, unopposed by progcsteione, they may progress to prccancerous
adenomatous hyperplasias (Riehm and Stoll. 1952; Jensen ami Ostergaard.
1954; Wallach and Hcnncmann. 1959; Gusbcrg and Hall. 1961; Hertz.
1967; Laufer. 1968) (Fig. 1). Droplets of fat appear in stromal cells of the
upper layers of the endometrium (Black et al., 1941) and lipid-laden foam
cells eventually develop, which could store oestrogen metabolites or related
substances (Dallcnbach and Rudolph. 1974). The activity of alkaline phos­
phatase is increased, that of the acid phosphatase decreased.

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1 he synthetic progestogens used clinically differ both chemically and
metabolically from natural progesterone. Most arc derivatives of 17hydroxyprogesterone or 19-nortestosterone. Although their progcstogenic
potencies vary considerably, most are more potent than natural proges­
terone (Suchowski and Baldratti. 1964). Norgestrel, which in its laevorolatory-form is the most active progestogen in clinical use at present, is
eighty times more active than progesterone (Fig. 2). Its high potency may be
due in part to its selective uptake by the endometrium for. as autoradio­
graphic studies have shown (Zaldivar and Gallegos, 1971), more norgestrel
localizes in the endometrium than docs progesterone or chlormadinonc
acetate. I he endometrial effects produced by the synthetic progestogens
depend closely on dosage and potency of the progestogen used.

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Adenomatous hy|x;rplasia following therapy with conjugated oestrogens.

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The administration of progesterone alone during the proliferative phase

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depresses the maturation of Graafian follicles, arrests endometrial prolifera­

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tion.

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progesterone piolongs the menstrual cycle. When progesterone is discon­

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low' doses, breakthrough bleeding may develop during therapy. If doses of

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5-6 mg chlormadinonc acetate are given daily for four weeks or longer, then

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the secretory change is abolished anti the endometrium remains in a state ol
“arrested proliferation” (Bayer.

1965). With treatment beyond six weeks,

the arrested proliferation gives way It) progressive atiophy of the glands and

decidualization of the stroma. After three months of continuous therapy,

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wdth large doses of progesterone, decidualized stroma develops with extreme
or complete atrophy of the glands: “arrested secretion” (Winter and Pots,

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1956) (Fig. 3).

I hc same picture can be protlucctl experimentally in cas­

trated monkess after priming with ocstiogcn (llisaw anti llisaw, 1961). Jf
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treatment is continued it may lead to atrophy or, rarely, an apparently

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irreversible atrophy with hyalinization of the stroma (Charles, 1964; Bayer.

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1965).

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dosage required to produce a transformation of the endometrium varies

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TC'^r

ily the glands. Following therapy with derivatives ol 19-nortestosterone,.
ilccidualizalion is more pronounced and the subsequent atrophy more
extreme than with derivatives of progesterone^ Fried rich. 1967). Since the
glandular epithelial cells arc more sensitive to progesterone and react to it

K.:- •
dw
zyrn<

earlier than do the stromal cells, the epithelium usually becomes refractory
sooner to abnormal stimulation by progestogens. whereas the stroma begins

to atrophy only after a prolonged deciduali/alion (I )allcnbach-l lellweg.
1972).
I he elfect on the endometrium of progestational agents alone may he
more intense than that of combined preparations. Even during the first
cycles after onset of therapy the progestational agent severely retards the
growth of the endometrium. A discordance in the development of the glands

and stroma appears that varies in extent and quality depending on the dose
and perhaps tv|K‘ of progestogen given, ami leads to various degrees of

arrested secretion.
With daily small doses of progesterone alone (thc’ miiiipill”). abortive
secretion of glands may be seen as early as the 7th day of the cycle. I he

x ■

secretion of glycoprotein is diminished and spiral arterioles remain under­

developed. The reticular network appears fragmented or may not be visible at

fK;®
■ 4*

w
.

pF? ■

h

■

■

F

al! (Kiihne cl al., 1972).
After treatment with quingestanol acetate, piofound histochemical altera­
tions were observed during all phases of the menstrual cycle (f lowers et al.,

LL

thest

III. <
The ;
prog;

tions
Fo
prog<
its m

longt
hornt
Still J;
togcn
wind

On
initiocomp

YamI 966

1974): the secretory process was altered by accumulation of diastaseresistant mucopolysaccharides at the apical cell border of the glands, in the
base of the gland cells, small foci of glycogen persisted throughout the
secretory phase. The activities of succinic dehydrogenase, alkaline and acid

progv

phosphatases were not altered, suggesting that the transport ability ol the
epithelial cells was not seriously affected. Also, the cyclic variations in acid

Wt
III St I

mucosubslanccs were unchanged. Sulfomucins predominated during the

slrom
appc;
slrom
lilitx
prcm
•<irl\

proliferative phase and carboxylmucins in the secretory phase. The en­
dometrial blood vessels contained platelet aggregates which were PAS
positive and diastase resistant. Many cells showed abundant tonofilaments

ami microtubules which were likely to have resulted from an increase in
ribosomes and granular endoplasmic reticulum, indicating that the mechan­
isms were present for glycogen synthesis and transport, but the actual

i

'

E
-

II

■ WI
I

*

!fe

■-

amount of glycoprotein and the transport systems within the cells were

altered (Flowers el al.. 1974).
Pronounced changes also became apparent in the ultrastructurc of glandu­
lar cells, which reveal elongated mitochondria and loss of the nucleolar

patic!
physn

pre\ c
Anol

inters
of wL
the c

channel system during the secretory phase (Feria-Valasco cl al., 1972).

sin l’a<

Endometrial atrophy usually ensues earlier during treatment with injecta­
ble progestational agents than with the combination type of contraceptives

In >
cvck •

(Lee, 1969; Kh<x) cl al.. 1971).
I he contraceptive steroid, R 2323, which competes for the progcstcione

(a) 7/

I5S

mem.

WHO SYMPOSIUM ON STEROID CONTRACEPTION AND MECHANISMS

i • silastic

OF ENDOMETRIAL BLEEDING

Con

i

Geneva. 12-14 September 1979

'jand

:> ‘-tsteinic
(

University Department of Medicine
’The General Infirmary, Leeds, U.K.

tllliv<li

tbMvronc
> f.ivpdon

i
HAEMOSTATIC MECHANISMS IN THE NORMAL
ENDOMETRIUM AND ENDOMETRIUM EXPOSED TO

I

CONTRACEPTIVE STEROIDS

By
R. ( . Paion. Hilary Tindall. M^Zuzel. and Ci. P. McNicol.

I

ti

I N I RODUCTION

I

When a blood vessel is damaged, the injured vessel wall, the platelets and
the coagulation and fibrinolytic systems combine in a scries of interrelated
events. An initial period of vasoconsiriction is followed by adherence of

platelets to the vessel wall, and activation of the coagulation system is
followed by activation and aggregation of more platelets; the resulting
haemostatic plug is stabilized by fibrin. Bleeding is arrested and finally,

during the repair process, the plug is gradually resorbed by the fibrinolytic
enzyme svslcm and othci proteolytic enzymes (Macfarlane, 1976; Mustard

anil Packham, 1977).
Tor manv years it has been recognised that defects in the haemostatic
system, such as thrombocytopenia and certain specific coagulation factor
deficiencies, arc associated with increased menstrual blood loss (Quick,
1966). However, the means whereby platelets and the coagulation and

fibrinolytic systems interact within the endometrium to regulate menstrua­
tion arc poorly understood and although many changes in systemic haemo­
static function have been attributed to oral contraceptive steroids, there is
vcr\ little inhumation on the cllccl ol such drugs on endomet i ial haemosta­

tic function. This paper will attempt to summarize what is known about the
involvement of the haemostatic system in normal menstruation, and what
little is known about the modifying effect of oral contraceptive steroids
Information may be obtained from three sources: studies of endometrial

1

pathology, an examination of the menstrual fluid and measurement of

I

changes in haemostatic factors in the circulating blood.

1

325
I

i
----l’.■

.IL'j- 4 >’
.:y,

■ ■Hr

*

v

■

70

t
1

60

50

- •->

f 40
o
® 30

20

%
Q

O

io

^'4

O

Q.

XT

o
0

20

10

30

40

PG 6 keto Fja nanograms/ml-----■

Mg. 7
Rclalionship <»f platelet letention and b-kcto-prostaglandin 1
concentrations in 6
paired samples horn pcriphcial and uterine hlootl. (Paton cl al., unpublished data).

i
CONCLUSIONS
mwiici)

’tirai

-er of
ifecr
isStgV

.'Mem
rntal
llirrc
.«.M Uhc
..Mil’!

1

Our knowledge of how the haemostatic system operates in the uterus at the
time of menstruation is very incomplete. To date, histological studies have
shown a paucity of haemostatic plugs in the menstruating endometrium. It
niay be that haemostasis in the uterus is temporarily less effective during
menstruation, but an alternative interpretation of the facts is possible.
Bleeding may be initiated by the appearance of gaps in the endometrial
blood vessels, platelct-librin thrombi subsequently securing partial haemo­
stasis shortly after the onset of menstruation. Owing to the active fibrinolytic
system in the endometrium, fibrin is lysed and some platelets which have
undergone the release reaction, but not irreversible membrane damage, may
be returned to the systemic circulation. 'This hypothesis requires confirma­
tion, including fui lhei histological studies to search for platelets and fibrin in
the earliest stages of menstruation.
The balance of evidence suggests that oral contraception with a combina­
tion of oestrogens and-progestogens results in an overall increase in coagula­
bility. though how far such changes arc reflected locally in the uterus is

'i

1

!
337

>

!

u

I

Bo
:

fci

if;

I ■

j .

,

x ■

Ct;. ■ ■

v\’ ■'.-M. ''.t..

4 nH

/q

Ji
uncertain. Many of these clfcets mirror those found in pregnancy, where

Li-?

presumably they help to maintain the integrity of the vascular compartment
before and during labour. Fibrinogen and factors VII, VIII. X. and possibly

tj?

IX. increase throughout pregnancy though, unlike with oral contraception,

i

levels of factors II, V and antithrombin ill remain unaltered (Bonnar,
1973). In the context of uterine haemostasis, oral contraception with

I
I E

oestrogen-progestogen preparations might predispose to reduced menstrua)
blood loss. Since progestogen-only contraceptives, and possibly also low-*
oestrogen preparations, have less effect on coagulability, it is possible that
(his might partly explain the prolonged intcrmcnstrual bleeding which is

4

sometimes a problem with these formulations. However, without further
information on the effects of oral and other steroid contraceptives on the
endometrial haemostatic system these conclusion:, remain speculative.

i!

acknowledgements

I

The unpublished work from Tindall cl al. was supported by a grant from
Boehringer Ingelheim. We thank Miss (. . Jackson and Mis A. Spcncct foi

?

their skilled technical assistance.

I
j

REI l.REN('ES

f••

Alhrcchtsen, (). K (1956) The fibrinolytic activity of menstrual blood. Acta Endoclinol. (Gopcnh) 2.». 219- 226.
Apaiicio, S. R.. Bradbury. K.. Bird. ( . (
I'olcy. M. I ... Jenkins, 1). M.. < layton. J
K . Scott. .1. S.. Rajah. S M. and McNicol, (i. I’ (1979) Effect of intraulcime
contraceptive devices on uterine haemostasis: a morphological study. Br. .1 Obstel
Gynaecol. X6, 314 324.
Basu. H. K. (197(1) f ibrin degradation products in sera of women with normal

menstruation and menorrhagia. Br. Med. J. /. 74 75.
Bonnar. J. (1973) Blood coagulation and fibrinolysis in obstetrics. Clin. Haematol. 2,

2 13 233.
Bonnar. J.. Prentice. C. R. M.. McNicol. G. P. and Douglas A. S. (197(1) Haemosta­
tic mechanism in the uterine circulation during placental separation. Br. Med. J. 2.

BSLui;i

if 'i

Ilf

564 567.
Brakman, I’ . Albrcchlscn. O K. ami Aslrup. T. (1967) Blood coagulation, lib
rinolvsis and contraceptive hormones. JAMA /99, 69 74.
( allcmlcr, S I .. Warner. G. I . and Cope, I- (197(1) Treatment of menorrhagia uilh
tranexamic acid. A double blind trial. Br. Med. J 4. 214 216.
( aspary. E. A. and Peberdy. M. (1965) Oral contraception and blood-platelet
adhesiveness. Lancet I. 1142- 1143.
Cole, S. K. and Clarkson, A. R. (1972) Menstrual blood loss aud fibrin degradation
products. Br. Med. .1. /. 78 79.
Davies, T.. Fieldhouse. G. and McNicol. G. P. (1976) The effects of thcrapv with
ocsliiol succinate ami ethinyl oestradiol on the haemostatic mechanism in posi
menopausal women. Thromh. llacmosl. 55, 403 414.

3 LS

t

4''-‘

■-S

e;

IS1

■“

B

Dugdale.
disease
of the !
Egeberg. •
Rr K4»_*z^
Eerc- '•
tk
Feri;
tuns
contr;
Foley, M
( lax ton.
I lepaui.
Ireidrich.
struct ur«
Grant. I. I
Hahn, L. I
Acta Ob'
Hahn. I.. ( •
Blooei o.
with cxcv
Hilden. M
con tract i
Hirsh. J.. F
I Johnsen
I )epar ttn<
Washingr
I lohman, V.
hemostas
endomet i
Howie. I*. T
G P. (I
oestrogen
1329 13Jetfeoate. i
of (iynat.
I .udlam.. <
.!.. Horm
I Jcparlm
Washingt
Macfai lane
/memos/ti
lions. OxMackav. A
cotnponc
227-239
Marutlo. <
the hum.
l ei til Si

i

• 1 .a

■

I
>

>7

ination of

S'MPOSiM'.l 01% STTR04O CO.%TRA.CfFrx)i% AND MECHANISMS

ithdrawal.

i

•

OF ENDOMETRIAL BLEEDING

the price

Geneva. 12-14 September 1979

< ■ *uid und a

WHO Collaborating Centre for Research and

en this would

Training in Human Reproduction, Stixkholm. Sweden

ibicms is that

. a.enorrhocic
:! is still not
; ptescnl with

•

in ethnic

-

• maccptivc
Hiiplc

liist-

CLOSING REMARKS
By
;•! Icrbmulinc

£

E. Dii zfalusy

tmg vasoLadies and gentlemen, in his book entitled “Science and the safe pericxl'*

.d activity in

( arl Hartman ( 1962) quotes a famous statement made by Professor Ludwig

ao/ogy (iiui
<ew York.

dictum:

during oral

Unregelmassigkeit", or-in Hartman’s translation - “The only regular fea­

I racnkcl ol Vienna some 70 years ago, which became known as Fraenkel's

“Das

einzig

Regelmassigc

an

der

Rcgel

ihre

ist

ture of the menstrual cycle is its lack of regularity". It is an unfortunate
I

W. (1967)

i\«;aecoi. Hr.

of steroidal

dictum, not only because it is untrue, but also because it

represents a

pessimistic, almost defeatist philosophy, a kind of “ignoramus, ergo ig-

norabimus".

ds Eniiomel-

< onsider now, just for a moment, the difference between this and another

■ \ mposium.

famous dictum; the favourite motto of Albert Einstein, which he used to

i%v late in the

aber boshaft ist er nicht”. In A. L. Mackay’s (1977) translation: “God is

• 283 285

subtle but he is not blocxly-minded". Einsteins own translation: “God is

have on the wall of his office in Princeton: “Raffiniert ist der Herr Gott,

'!!'■ of protein

i<-chn:

J.

slick, but he ain’t meun". In my interpretation. Mother Nature is basically

prepared to reveal her secrets to us, provided we are willing to apply the
scientific

i« ‘.-bclsinann,

DR. cds.
i ial biopsy.

realizing, of course,

method

that

those secrets arc extremely

complicated and that perhaps nothing is so diflicult to establish as a fact. In
terms of

the

normal

tesearchable and

menstrual

that

cycle,

is possible

it

this

means

that

the

problem

is

to delineate the limits of variation

between subjects and those within the individual subject, if we arc willing to

itc.itincnt of
-lud\

Bi

.1

invest the clfort and time.

Ibis symposium

was

organized

because

bleeding

abnormalities

were

found to constitute a major obstacle interfering with the prolonged and

widespread use ol certain types of steroidal contraceptives. During the past
three days we have examined in detail a large variety of factors which might
influence normal and abnormal bleeding. It became evident that our data

423

»

®L
I
...I”

I•%

i

I’

'd

fl

F

•IT

W
r!
I

F

I
•i

I
’>!

II

MM

I

I

Ll

i yV .

base is meagre, confusing and sometimes controversial and that we cannot,
as vet, relate bleeding to well-defined morphological, biochemical and
endocrinological variables. The “bleeding problem appears to be complex
and no simple solution is in sight. Under such circumstances, there may be a
temptation to succumb to Fraenkel’s dictum and believe that “I he only
regular feature of intermenstrual bleeding is its lack of regularity . This,
however, could be a major mistake, and we should remember that Sir
Francis Bacon, in 1605, said: “T hey arc ill discoverers that think there is no
land, when lhev can sec nothing but sea.”
Women do exhibit bleeding abnorm alities when using steroidal contracep­
tives of the “progestogen only” type, and the problem becomes worse with
long-acting injectable progestogens. Can we prevent and/or treat these
abnormalities? Can we do this without learning a great deal more about the
nature of the abnormalities caused by various agents? I doubt it. To
complicate the issue further, we have to realize that various agents given in
different doses may produce different effects, and that an in-deplh study of
normal menstruation may, or may not produce results relevant to inlcnncnstrual bleeding. Hence, we are facing a difficult task because of the extreme
paucity of information. However, this problem is also rescarchable. In
addition, it offers a major intellectual challenge. Moreover, I firmly believe,
that a systematic and sustained research effort simply cannot fail to unravel
new horizons in any field of research. In short, the time has come when we
must find out our facts.
This is by no means a unique situation. Scientists of other disciplines have
faced it frequently, as suggested by the tombstone ol the physicist, David
Hilbert in Gottingen. There arc six words chiselled in the stone: “Wir
nnissen wissen. Wir werden wissen". We must know. We will know. Please
note that the language of science is always We, and not I.
Ladies and gentlemen, with your kind permission, I would like to thank
our secretaries, Jennifer Bayley, Jenny Darmody and Anne Porter who
worked long hours Io make all the necessary arrangements and to provide us
so promptly with the transcripts of the discussions. Also, on behalf ol my
colleagues, Drs 1 Fraser and F. Webb, 1 would like to express our indebted­
ness that you accepted the invitation to attend this Symposium. You worked
very hard indeed to make this Symposium an important first contribution
towards a better understanding ol a problem of great practical importance.
We hope that you will be willing to assist this Organization again in the
future to achieve its major objective: to improve the human condition.

REFERENCES

I

ji JK

Hartman, C. G. (1962) Science and the Safe Period, p. 126. The Williams and
Wilkins Company. Baltimore.
Mackay, A. I (1977) Scientific quotations: The harvest of a quiet eye. p. 52. Crane.
Russak and Company Inc., New York.

424

■

-

..r

Sr;

;

<

AND WITHOUT INTERMENr*t”JAL BLEEDING DURING CONTRACEPTION WITH rut
300 ug NOAETHISTERONu ..NET) MINIPILL

E. Johannisson, B.-M. Landgren and E. Diczfalusy

I

Department of Obstetrics and Gynecology, University of Geneva,
Geneva, Switzerland
and

j-

Reproductive Endocrinology Research Unit, Institute of Obstetrics
Stockholm, Sweden

and Gynecology, Karolinska Institute,»

I
ABSTRACT
■

The peripheral levels of estradiol and progesterone were anar, '
in blood samples withdrawn three times a week (Mondays, Wednesday
and Fridays) from 24 normally menstruating volunteers during a pie­
treatment (control) cycle and then every day during the second me ■ ’■
of administration of daily oral doses of 300 pg norethisterone (NF’
An endometrial biopsy was also taken on days 23-25 of the control • •
for morphometric , microf 1 uorometric and ul tramicroscopic quantit ••' ■

i
-

-

J

Intermenstrual bleeding occurred in 12 subjects during the
month of NET administration; the number of days with bleeding and
spotting (13.4 i 5.1 days) in this group significantly exceeded thv
found in their control cycle (6.3 i 1.2), or in the group of "non­
bleeders” (6.0 t 1.2) taking the same dose of NET.

T

I

I

>

Within 6 hours after the onset of intermenstrual bleeding, another
endometrial biopsy was taken, after which the subjects were allocated
at random to two types of treatments subjects were given daily oral
doses of 50 ug of ethinylestradiol for 7 days and 6 subjects receivedplacebo for the same period of time. Daily blood samples were withdrawn
during this period.

Daily blood samples were also withdrawn from "non-bleeders"
during the second month of NET administration and an endometrial
was taken between days 23 and 25 of this month.
Submitted for publication September 2, 1981
Accepted for publication December 8, 1981
JANUARY 19.82 VOL. 25 NO 1

13

DISCUSSIO*.

the
- -t
association with NET administration S-b
spotting in
of women with regular bleeding episodes an^toX d’ffe^ed from that
ethinylestradiol theraov h^d
d t0 assess whether or not
ing episodes and the Xphoiooic ? nnn" 0" th6 durati°" of the f eed­
view of the variable effect offhe da iTv
the endometrium. In
on the ovarian function, the circula? no fdm’stnation of 300 i.g NET
progesterone were assessed dai XdX9 ’ev®!s.of estradiol and
changes. An essential prerequisite forWlth the morPhological
Quantitative assessment of the roroholnn^f cornD3rative study is a
endometrium that would allow
™,ph u ?
Events occurring in the
by established statisticalfXthods XfXLXX ,to be assessed
microscopic and microfluorometric quantif t
under’*in9 the electron
indices measured were randomly, dis
‘
WaS that the
differences due to the treatment
1Dured and that, therefore, the
statistically. Recently cond^rtn^ var(!ous SubJ'ects could be evaluated
difference w^s fou£Tin biopsie
’h which no
endometrium seem to favour fis approach™)
erent SiteS of the same

i
i
I

h

3
3 I'Vq

bleeding episfdesXlfbe’attributedXX1 the.Dresenc:e
.4

a

H

I

Furthermore, since estradiol receptors have been reported to be
present in endothelial cell cultures (18), it is not unlikely that norethisterone could inhibit the estradiol binding in the endothelial cell:
of the endometrium. Whether or not such a suppression of the est’-v;-’
binding interferes with the function of the endothelial cells of the
human endometrium is not known.

It has been suggested by several investigators (7,19) that the use
of progestogens with or without estrogens is associated with a frequent
dilatation of the endometrial venules. The findings of the present study
indicate no difference in this respect between control and treated endometria or between endometria obtained in the presence or absence of ar.
intermenstrual bleeding.
The significant increase in the number of plasmolemmal vesicles
following NET administration seems to deserve some comments. The pr««^-t
study has shown a significant increase in the number of plasmolemma
vesicles per u2 following the administration of norethisterone. This
increase has been shown in the biopsies obtained in relation to bleeding
episodes as well as in biopsies obtained during bleeding-free periods.
There is considerable evidence in the literature that the plasmolnirr.-1
vesicles take part in active transport of various molecules (20). A
number of animal experiments have confirmed this mechanism of vesicular
transport by using particular tracers, such as ferritin or hemopeptides
(20,21). Continuous endothelial plasmolemmal vesicles are also considered
as the only structure capable of accepting molecules 100-300 A ir* diampte*
(22) and consequently an important factor in endothelial permeability.
It would seem to be logical that an increased number of pla$mok<*sr.af
vesicles reflects an increased vascular permeability. However, the in­
creased number of vesicles may also be compatible with an inhibited
transport (22). Hence, a direct link between intermenstrual bleeding,
increased capillary permeability and an increased number of plasmolemal
vesicles cannot as yet be postulated. This is underlined by the lack of
any difference in this respect between women with intermenstrual bleed t. -.
and women with more regular bleedings (cf. Table II).

™re regular

normal secretory changes of the endometf
>7 fre9uent occurrence of
of studies carried out in women
S J?
Nevertheless, the results
amounts of norethisterone (15) or lX.r-.5''13 rlngs releasing small
ant y higher frequency of inteXn Lua^XX1 (16) have Sbow" significovulation than in women with normal lu?L? 7d 7 ld women w’th sup
suppressed
morphologic events assessedb ™ t
function. No correlation
to
m these studies. Therefore X presen
nvfo X5 WaS’ however.w.)
- dMe
siderably expanded before definite conclusionf9at’°h ou9ht to be conrelationship between soecifir mnrnhn? c!usi°n can be drawn as to the
the occurrence of intermenstrual Xed?ngSC a"565 °f the endometrium and
administration^ norethisteronX■Ve ?f the ovar’an function - the
endometnal glands , dfminlshed XX277Xred“Ced the number of
of double-stranded ’polynucleotides fndndp?r d|j3rnet^r’ red“ced the amount
nucleus and increased the number of ntX^Xf
acid. per cel 1
portion of venular endothelial celR^
onmal vesicles and the orofindings indicate that the nrnlifl J'owln9.contraction. All these
was significantly suppressed Normal secret^V1
•the Wh°le endonetrium
m 3 out of 7 cases with normal
J
°7 actlv1tY was found only
administration (D) and in 1 ou*
Cycl®s fo11°wing the NET
activity (C). The rise in PndnL f 6 ?SeS W1th SuPPressed corpus luteum
women belonging to group B was^insuf*?-1
®stradiol values present in
activity
of
the
endometrium
and
nn
L°
the prolgroup
iferative
A and B as to the ^rnhom^ir e ° dl fference
tound between

action of synthet.c progestogens onXXex sXoid^ re2eCt ' deDressive

?•

An interesting finding in the present study was the increased
frequency of contracted endothelial cells in the endometrial capillary
venules following the administration of NET. Endothelial contraction
in the venules of other tissues has been described as a result of
histamine-type mediators (23). The mechanism which operates to inert-isc
the vascular contractility associated with the histamine release is a
partial dissociation of the endothelial sheet, with erythrocytes leakin:
out into the pericapi11 ary spaces and the surrounding stroma. It is
noteworthy that the presence of mast cells and histamine release has
been reported as responsible for irregular endometrial bleeding in
IUD users (24). Hence a detailed quantitative study of endometrial mast
cells in connection with steroid-induced intermenstrual bleedinj would
be of considerable interest.

The most popular treatment of intermenstrua 1 bleeding is still
the administration of estrogens (25,26). In the present study, the
administration of 50 pg ethinylestradiol for 7 days exhibited no effect
on the frequency of endometrial bleeding and did not influence any nf

■

26

JANUARY 1982 VOL. 25 NO. ’

JANUARY 1982 VOL. 25 NO. 1

2?

the usefulness of estrogen therapy in^ntn crltlcal re-evaluation of
S’nce significantly more inte^enstrua n^™nstrual b’eeding. However,
compared to ovulatory cycles in wnmpr
• eedln9 occurs in anovulatory
°r levonor9estrel (15,16) it may be’niV?-1 "*1 devices ^leasing
attributable
to the sieroid
lack of ch a V rrh^'
quest10n
whether
thisbfis
Of
another ovarian
Or P°ed
SSibly
to the
^t

1

I

!

4.

Israel, R., Mishell, D.R.
Labudovitch, M. Mechanism of normal
and dysfunctional uterine bleedina
Cl in.Obstet.Gynec. 13:386-399
(1970).
y

5.

Johannissdn, E. & Landgren, B.-M. Bleeding irregularities with
steroidal contraceptives in relation to changes in circulating
hormones . In: Diczfalusy, E., Fraser, I.S. &' Webb, F.T.G. (Eds
Endometrial Bleeding and Steroidal Contraception. Pitman Press i
Bath, England (1980) pp. 291-317.

6.

Flowers, C.E., Wilborn, W.H. & Enger, J. Effects of quingestanol
acetate on the histology, histochemistry and ultrastructure of the
human endometrium. Amer.J.Obstet.Gynec. l_20:589-610 (1974).

7.

Maqueo, M. Vascular and perivascular changes in the endometrium
of women using steroidal contraception. In: Diczfalusy, E.
& Webb, F.T.G. (Eds.) Endometrial Bleeding and
5ter?nnaLAOntraceptinn- pitman press Ltd-‘ Bath» England (1980)
pp. 138-149.
'
’

8.

Aso, T., Guerrero, R., Cekan, S. & Diczfalusy, E. A rapid 5-hour
radioimmunoassay of progesterone and oestradiol in human plasma.
Clin.Endocr. 4:173-182 (1975).

9.

Johannisson, E. & Engstrom, L. CCytological diagnosis of endometrial
disorders with a brush technique.. Acta Obstet.Gynec.Scand. 50•.
141-148 (1971).

progesterone or even prooesterone n,
K°T''?r°9esterone • 20p-dihydro.
significant effect of endooenous
urJnat”’’ty to detect ary
7
indices underlines
o'f’I
endometrial

.hlth „ght

’Stic changes in the infrastructure of
1=terone induces character- '
these changes may represent a potential ln' HU™n ?ndometriom. Any of
menstrual bleeding and spotting Studies of Jhe°S1?9 f3CtOr for interusing steroid contraceptive formulations
endometr’om in women
intermenstrua 1 bleeding may provide Jal. aM2 i""5® ittle or no
significance of the alterations obL^Jd
atlOn re9ardin9 the
menstrual bleeding.
observed in the present study to inter■

acknowledgments

I
«*

I

M.S!

H.« «<. stw. <;

M,7* Karine .aurnier,

Britt Masironi
i2Sd,.y-8r,tt

The norethisterone minipill (Mini
-Pe) was generously provided
by Astra-syntex, Sddertalje, Sweden

WorldTHJalthVnSti9at’°n rTceived financial f
support from the
from the
? on Human Reproduction and
(Grant No. 3.917-0.80).

REFERENCES
1.

:1

1 in intra*
Carnegie
2.
for menstrual bleeding,
of bleeding.

24:253-268 (1948).

3.

w

a

28

Wallach, E.E. r:
17
Physiology
of mens trua t ion.
]_3:366-385 (1970' .

Cl in.Obstet.Gynec.

JANUARY 1982 VOL. 25 NO. 1

10. Johannisson, E. The influence of contraceptive steroids on the
histochemistry and cytochemistry of the normal endometrium
In: Diczfalusy, E., Fraser, I.S. b Webb, F.T.G. (Eds.) Endometrial
bleeding and Steroidal Contraception. Pitman Press Ltd., Bath,
England"(1980) pp. 174-187.

11. Reynolds, E.S. The use of lead citrate at high pH as an electron­
opaque stain in electron microscopy. J.Cell.Biol. 17:208-212 (1963'
12. Landgren, B.-M. & Diczfalusy, E. Hormonal effects of the 300 uq
norethisterone (NET) minipill. 1. Daily steroid levels in 43 subjects
during a pretreatment cycle and during the second month of NET ’
administration. Contraception 21:87-113 (1980).

13. Landgren, B.-M., Und§n, A.-L. & Diczfalusy, E. Hormonal profile
of the cycle in 68 normally menstruating women. Acta Endocr. (Kbh. :•
94:89-98 (1980).
14. Johannisson, E., Parker, R.A., Landgren, B.-M. & Diczfalusy, E.
Morphometric analysis of the human endometrium in relation to
peripheral hormone levels. A reassessment of the histological
dating of endometrial biopsies. Ferti1.Steri1., submitted for
publication.

JANUARY 1982 VOL. 25 NO. 1

29

4A-'/V L(

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Indian Council of Medical Research

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President
Dr. KARAN SINGH M.A., Ph.D.
Minister tor Health and Family Planning

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D.Sc. (Lond.). F.R.C P. (£), F.A.M.S.. F.N.A., F.A.Sc.

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id women >»*»«
who were not on the oral pills.

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d,fferent fr<’m those

Synthesis of Steroids for Oral Pills

her of
etween
.c one
limize
io use
s. In
dc\e•ype
onths

Ccc
jll’cct,

ihinyl
There
ised.

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> in
elate
lipid
omainhon

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demand for covering target populations hl0 S1Cr°'ds rcc)uired “> meet the
present, steroids for oral pihs^re beinn '
InCrjaSed substan|ially. At
steps be taken at this stage for the d
imPorled- K is necessary that
to achieve self-reliance in the production of0^")
!nd'8enous technology
;bo ..
lb. couurr,
to ensure that adequate cultivation .,r n
LAR’ ,aken slePs
will be maintained for the extraction of ,'<Wt"'ra species (Indian yams)
strains of Triyone/la foetnon-^^
^te.n
sated as ..possible alternate sourcX th
r <'''W‘U bc cu,li-

IS
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ther, the possibility of using sisal waste for the
d'0"
d‘OSSenin' Furthe possibility of obtaining cholesterol fr
producll0n of hecogenin, and
woo! fat for the manufa ureXX
th°USeS and
of steroids is also being attempted n t be,ng explored- Total synthesis
£ empted in collaboration with CORI, Lucknow
and other laboratories in ;
the country. Partial synthesis of steroids based
on 16-DPA obtained from__
diosgenm or solasodine is another important
area of research that is bcing^Explored.

S'■

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Inject a bits
While oral pills are
popular and extensively used i;
their wide acceptance in our
poor socio-economic gr
groups.
ere is thus a need for constant efforts to
develop methods which will obviate
the need for
—
motivation for daily pill
intake.

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of
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3-nionth Schedule
Clinical evaluation of
medroxyprogesterone acetate (depo-provera)
and norethindrone enanthate in <
different dose regimens as monthly and threemonthly injections continued during the year
• A total of 131 women were
given 150 mg. depo-provera
every three months. Data collected over a
period of eight months
heavy ai ’
occurrence
(quinestrol 0’5 mg.)

«y signili J,

•ill. ibis drug »„e. ,h„crore.

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Clinical trials with 200 mg. norethindrone enanthate given every three
months were initiated and 225 women were enrolled. Preliminary data
have shown that breakthrough bleeding, menorrhagia and amenorrhoea
occurred in approximately 50 per cent of cycles. A great majority of women
discontinued the method due to menstrual irregularities. There was, thus,
very little difference between depo-provera and norethindrone enanthate
when administered in high doses once every three months. Both pre­
parations, at these dose levels^ inhibited ovulation by disrupting the normal
pituitary-hypothalamic endocrine relationship. Atrophy of the endo­
metrium was a common feature in these women.

menstr
with n
rods w
and ar
of the
Nas»!

g
ed the
through
intrana
directh
steroid
amoun
approa
histoio
The ei
lished.

“Mini-Injection" Schedule
Since injection is still the method of choice for many women, phase II
trials were initiated with “mini-injection . Dcpo-provera (15 mg.) and norethindronc enanthate (20 mg.) were injected once a month. At this dose
level of dcpo-provera it was found that ovulation was not inhibited while
preliminary results with 20 mg. norethindrone enanthate are encouraging.
Detailed studies on endocrine profiles are now
now' in progress.
Biodegradable Materials

Bioava
One of the major disadvantages of using oily preparations is the
need for relatively frequent administrations of the drug. The use of bio­
degradable polymers incorporating steroids has been suggested as a method
by which the release of the drug from the injection site could be slowed down
and if successful, could also considerably reduce the frequency of injections.
In collaboration with the Sriram Institute, polymers based on lactic acid
and glycolic acid have been developed on a laboratory scale. It is now
proposed to incorporate steroids in these polymers and investigate the rate
of biodegradation of these compounds in vivo.

I
k nown
It is a
influen
In the
determ
toxic s
has it
malnut
drugs
Hyder.

Subdermal Implants
The microdose concept in combination with silastic has led to the appli­
cation of a system which could provide long term contraception without
inhibiting ovulation. Phase II clinical trials with norethindrone silastic
subdermal rods were carried out in three groups of women to evaluate their
long term effectiveness.
In a group of women in whom 40 mg. rods were implanted, although
the cycle control was good, pregnancy rate was unacceptably high. In an­
other group of women in whom 80 mg. rods were implanted, pregnancy
rate was low but the incidence of menstrual disturbances was high during the
nine months of use. Reducing the quantity to 65 mg. did not improve the

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GOODMAN and OILMAN’S

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The
Pharmacological
Basis of
Therapeutics

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MACMILLAN PUBLISHING COMPANY
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COLLIER MACMILLAN CANADA, INC .

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COLLIER MACMILLAN PUBLISHERS

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Copyright O 1985. Macmillan Publishing Company,
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Division ol Macmillan. Inc.

PR I N I I I) IN

I HL UNITED STA IES OI

'W
;

All lights reserved. No part of this book may be reproduced or
transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and
retrieval system, without permission in writing from the Publisher.
Earlier editions entitled The Pharmacological Basis of Therapeutics
copyright 1941 and 1955. © copyright 1965. copyright © 1970. and
copyright © 1975 by Macmillan Publishing Company. Earlier edition
entitled Goodman and Gilman's The Pharmacological Basis oj
Therapeutics copyright © 1980 by Macmillan Publishing Company.

*

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AMERICA

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Ma< mii pan Publishing Company
866 Third Avenue • New York. N.Y. 10022

< oi i ilk Mac mii i an Canada. Inc.
Coi i ii k Mai Mil l an Publishi rs • London
l ibrary aj Congress culalux curd number M-ISJSb

I

Year: 5 6 7 8 9 0 1

I’riniiiig: I 2 3 4 5 6 7 8

In this textbook, reference to proprietary names of drugs is ordinar­
ily made only in chapter sections dealing with preparations. Such
names arc given in smaI I -Cap f YPL. usually immediately following
the otTicial or nonproprietary titles. Proprietary names of drugs also
appear in the Index.

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CHAPTER

61 ESTROGENS AND PROGESTINS

Ferid Murad and Robert C. Haynes, Jr.
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The controlled and cyclic formation of
estrogens and progesterone is unique to the
ovary These hormones play a vital role
preparing the female reproductive tract for
he reception of sperm and ^plantation o
' fertilized ovum H is of course also well
recogm/ed that many features ol the female
habitus are also influenced by these aget ,
Current knowledge of the synthesis and
action of the ovarian hormones has peimit
ted rational therapeutic intervention m cer­
tain diseases. Much more clmical use how­
ever has been made of agents that can
mimic the ellects of these hormones and
that act as contraceptives.
History. It has long been known that removal of
the ovaries results in uterine atrophy and a loss t
sexual functions. The hormonal nature ol the ovar
control of the female reproductive system was
establ.shed in 1900 by Knauer when he found Ih.^
ovarian transplants picvcntcd the .y
gonadectomy. This observation
^md^ were
Halban (1900). who showed that. ,f
‘‘n n
.,
transplanted even in immature animals, no ma
sexual development and function were ^sured. In
Allen and Doisy devised a simple, ouantit
,7ve bmassay method tor ovarian extracts based
upon changes produced in the
S l. ‘ cx horiat Loewe (1925) first reported a ,cmdlt?e*i ‘ v
mone in the blood of various species and. shot I y
thereafter, f rank and associates (1925) detected ar
.clive sex principle in the blood of sows in cstit
Of even greater significance was the discoveiy
oewc andI Lange <1926) of a female sex hormm e
in the urine of menstruatrng women and the obsc
tond. the concentration of the hormone in the
ur^ va^d with the phase of the menstrual eye e^
I he excretion of large amounts ol estrogen m the
urine during pregnancy was also r^P0,.1Cl ■
^3
I92X). 1 his finding was a boon to the Uiun'v u
soon isolated an active substance
form(Butenandt. 1929: Doisy etui.. 192>. I9.H . a
few years later its chemical structure was cluci-

d The results of early investigations indeed that
the ovary secretes two substances. Beard (189/)
tl;,d postulated that the corpus luleum serves, a
essary luncuon during pregnancy, and ui2P<><«• «
evidence was offered by braenkel (IX). ). wi o
showed that destruction of the corpora lutca in
pregnant labbits causes abortion. I he contnbu-

ESTROCiKNS

.5°»s=xs..-=
of esirogens by ovarian follicles is.^l11-'’^

through the formation and subsequent
action of adenosine 3'.5'-monophosphaR
(cyclic AMP). While the actions ol this cy
chc nucleotide ultimately result in en­
hanced cleavage of the side ^am of choles­
terol to yield pregnenolone, the precise
mechanism for stimulation ol the synthesis
of estrogen, as well as other steroids,
unknown. In men. the testis can also pro­
duce and secrete small amounts of estradiol
and estrone (sec Chapter 62).
'Hie estrogens are ultimately tormei tom
either androstenedione or testosterone as
immediate precursors. The react.on of cen­
tral importance is the aromatization ol ting
A The first step in this reaction involves
hydroxylation of C 19. the angular methyl
Xp Liding on C 10 of the precursm.
Then the newly formed hydioxymeltnl
group is lost from the nucleus, and nngA is
aromatized to yield a phenohe hydioxyI .
C 3 In certain pathological conditions this
reaction appears to be defective and the
androgenic precursor escapes into the cii
culation. Some cases of hirsutism and vm ism are thought to be caused by this defect
Of the three main estrogens of human
beings. estradiol-W is the most potent and
the maior secretory product of the ovaiy.
is readily oxidized to estrone, which in turn

1412

*
i

2'i

j1 -iI

1431

Oral Coniracliiivls
nancy is POAS.NC duruw...Kir adn—.on.P..
ol;ll contraceptives. However, beea sc of
tienu should discontiiu v 1
M J , ;ind t|K>
have amenorrhea lor " “ru
^.y i.ikewr-c. .1
reports suggesting an increased inc d^
should be exanuned for P,L‘’" ‘n V j||s .,nd h.oe
of endometrial tumors and a owe t^ —
patients have missed one or mt r
|k
sequential preparations oi th s type ha
amenorrhea for more than 45 days.
been removed from the marKel. .he, h-..ee replaced by products that contain rOuively low amounts of a progesun and with

i

which the amount of progestin taken is
creased during the monthly cye.e
Smcle-entitJ preparations are also avail

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and jfw*ubhon <- n rc
cthindrone uun^ier^
ministered mt.amuseulatly_ m od

uhen ..a
Jo^.
........

!

.............. •'
cepuon. AUnouLn ivit,
n.linbci » couniiK^
progestin arc emp oyt wJchio |y7bl sUCh

,„ jcl l,.eh,»u.aleriscM<..W.■ H

Br^

re
f™X
of oral contraceptives. Smcc the co

c*

.we efficacy of the' m.niiul.
9X'..;. which IS somewhat cs

of

‘

Jays in suite ol mrnseu

d somi.uin

should be ,'erl’ormed >1 diethylst.lbestrol is not elfectivc.

the United Stales because ol the develop
mem of breast and uterme b'^rs ",[ |.

use It
be
danthis purpose is unpleasant and may
wilh
un
gerotis. postcoital contraception
estrogen can be useful when the: desirability
cc
obvious, as in
of avoiding pregnancy is <......
<uses of iape or incest.

eom.accptive. Although Us

I’u-paratioiis and Dosage.

I

0

in |able

l.eiicr (IW).

. ...........
„,■.......... ;.nd a J™

.1 ' the nusltire inhibits ovulation. I he

t, | „>gof etlmiyl esUadml m
lt)| 20 ol 2|
amounts ol a pror.cstm. a L *
n }
ncl ||u''"'’rLosZi'n. m^vtiun--!'-'
iml'^Xuld h-tJ Um. e.lmul ..................

ft.5

gpprovunalely mice as ruieul ■<>; '^YJ'cbspenscJ

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^muting bTincorpmiumg ^

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Pi'C,i:,S.H lAPpmHs^day- reg.udless of
"hen menstruamm Marts or sums. Im» p metuded

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f' S rouen is to inhibit the secretion of
i-SH. while continued action ol
'
one serves to inhibit the release oi l.l • > •
cleat That ovulation could be prevented e
inhibiting, he ovulaurrysinindustn
by preventing the giovU

"' .".'c
kon^k and NOR-tM’.. conlhC ((‘""'mg <>f norethmdrone. anti ovki iii.
75
of norgestrel) are taken daily eon- alceuve and nreg-

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(Chap. 611

Estrogens and Progestins
1432

1

r
---------- tSTROGEN

PROGESTIN

Combinations 2
0.02 Ethinyl estradiol
0 03 Ethinyl estradiol
0.03 Ethinyl estradto
0.03 Ethinyl estradiol
0.035 Ethinyl estradiol
0.035 Ethinyl estradiol
0.035 Ethinyl estradiol
0.035 Ethinyl estradiol

I

hi? ’

POTENCY_________ ___________

_______ —----- ----- —---------

(ms)

(mu)

Medium
Medium
Medium
Medium
Low
Low
High
Low

I Norethindrone acetaie
^5 NoSdrone acetate
0.15 Levonorgestrel
0 4 Norethindrone
0.5 Norethindrone
I Ethynodiol diacetatc
I Norethindrone

Low

1 Norethindrone
0.05 Mestranol

i ■

0 OS Ethinyl estradiol
0.05 Ethinyl estradio
0.05 Ethinyl estradio
0.05 Ethinyl estradio
0.05 Ethinyl estradiol
0.075 Mestranol
O.OK Mestranol

OL'ib

Medium

K-':
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Sec/aential 3
0.035 Ethinyl estradiol

■

Low

0.5 Norethindrone. then
1 Norethindrone

Low
Low

0 35 Norethindrone
0.075 Norgestrel

DEMULEN 1/35
norinyl 1+35;
OR I HO-NOVUM 1/35
NORINYL 1 + 50;
OR I HO-NOVUM 1/50
OVRAL
DEMULEN
OVCON-50

i

norlestrin 1/50

NORLESTRIN 2-5/50
ENOVID 5 MG
NORINYL 1 + 80;
ORTHO-NOVUM I/KO

OVULEN
NORINYL 2 MG.
OR I HO-NOVUM 2 Mli
ENOVID-E

ORTHO-NOVUM 10/11

mu honor; nor-q o.

OVRETFL

. and the other progestins
TTTuongly androgenic.
______
)
is
indicated.
in older of
norcthynodicl has
listed in older
1 Of the progestins used,
K days. I hoe preparations arc
lhe
iclalivc
pioges.y
■jl days a..d ;..e
lo‘ 7
—
have modeiale andiogenie activity
lakenlo' Iddays
laken loi 20 or -• —■
the lirsl is
■' Ctmihiiiaiion lablcls aic I.....
^..Mhyont.™^
......
.........
..................
Ihc sainv
conicnl
*>l
csliogcn
inuicasing
.wMlixcd
dose lablcl
........piepai
:..r .i.ition includes two
I
’ .| his
text lol
s. |O||oucd by 7 days ol no> medication.
sexual inictciHiixc.
and ihc sec mid loi 11 Uay\ “
within 72 houis altci
animually.
daily foi 5 days
* Muupdls 4K taken daily
IS uken ... ;. Uow of 25 ...» t-ec
' picihylstilbcsiiol
indications-

---------------

"

One .night reasonably conclude that^e
The orally active
gesterone given singly
be equated as a group
progestins cannot
because some arc mheiwith progesterone
enUy,est;og^^--^X1X-

most widely used
ovu|ation to
their cHcctivenus.
he p|O_
lhe estrogen.c co,nponcnt .u d th.|
E^S^Eing w.ll be Pronwt.

some ate Pu^,y ^jon-inhibiling po-

brief, and essentially Phy^'^nted. it
Even if ovulation
^‘^traceptive
is easy to tmagme that
nation by
agents could ,n.lerfer
h genital tract. It
lhei;dirEu?XX- -"nra! experi-

ZX ~ '

different ways.
Measurements
LH show that
lions suppress b
concentrations ot

..ircuiating FSH and
nmizestin combina-

>

stable;
,nidcycle FSH and
,Swc,‘"‘’tT ‘"’d

Odell. 1%9’. Briggs. 1976).
iL

brevicon: modicon

0.10 Mestranol

posit oitai 5
Dicthylsiilbcsuol

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2.5 Norcthynodrel

"Mitupills" 4

$

High
Medium

1 Ethynodiol diacetatc
2 Norethindrone

0.10 Mestranol
0.10 Mestranol

I I
Pl ■

High
High
Low
Medium
Medium
Medium
Low

0.5 Norgestrel
1 Ethynodiol diacetate
| Norethindrone
I Norethindrone accla^
2.5 Norethindrone acetate
5 Norcthynodrel
1 Norethindrone

I:

LOESTRtN 1/20
lo/ovral
LOESTRtN 1.5/30
NORDETTE
ovcon-35

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place. Il seems unlikely that implantation
would be possible in the altered endome­
trium developed under the influence of
most of the suppressants. Similarly, the
abundant watery secretion of the cervix at
the time of ovulation has always been re­
garded as essential to the well-being of the
sperm and the thick tenacious mucus se­
creted* under the influence of progesterone
to be a hostile environment. Little is known
of the coordinated contractions of the cer­
vix, uterus, and Fallopian tubes that are
presumed to be essential for the transport
ol spermatozoa to the egg and the precisely
timed conveyance of the blastocyst to the
uterine lumen, but probably the correct
hormonal environment is essential for the
execution of these important maneuvers.
Although it can easily be imagined that estrogen-progestin mixtures could interfere
with impregnation in these ways, there has
been no opportunity to find out. because
ovulation is almost always prevented when
the agents are used in the usual way.
7 he fear that estrogen may have deleteri­
ous effects prompted the use of a proxeslin
alone in various ways. Cohlinuous adminis-

and leads, to ovarian and endometrial atro­
phy. Very small doses may alter the struc­
ture of the endometrium and the consist­
ency of the cervical mucus without
disrupting the cycle or inhibiting ovulation.
As currently administered, oral contracep­
tives that contain only a progestin cause
variable suppression of FSH. LH, and ovu­
lation. which may explain their lower de­
gree of efficacy (see Briggs. 1976). With
continued daily administration, menstrua­
tion occurs but the length of the cycle and
the duration ol bleeding arc quite variable,
laclois that have inllticnced their populai ity.
Long-acting progestins, given by intra­
muscular injection. 4ue also effective, as
noted above. For example. 150 mg of
medroxyprogesterone acetate, adminis­
tered every 3 months starting just after par­
turition, prevents pregnancy in all; irregular
bleeding, troublesome al Lirst, gives way (o *
amenorrhea and an atrophic endometrium
in most cases? 1 his form of contraception
also utilizes the highly active, purely pro­
gestational compounds by incorporating

1433

them in pessaries to provide vaginal ab­
sorption, in intrauterine devices, or in plas­
tic capsules for subcutaneous application.
An intrauterine device containing a reser­
voir of 38 mg of progesterone is available
(see above) and releases progesterone con­
tinuously into the uterine cavity for I year.
It is about as effective as other intrauterine
devices (97 to 98%), and the side effects are
also similar except that the incidence of ec­
topic pregnancies may be greater (I DA
Drug Bulletin, 1978a).
The development of postco'ual conn a
ceptives is an intriguing subject. A \.i>i
number of hormones and other agents aic
effective* in this regard in ajiimals. It has
long been known that the use of large doses
of estrogen in women is effective in pre­
venting implantation, but such doses are
tolerated only in cases of single or very in­
frequent exposure. There is a rough coirel­
ation between the contraceptive potency of
these substances and their estrogenic ac­
tivity.
Large doses of estrogens used as postcoilal contraceptives may act by inhibiting fer­
tilization and nidation in several ways. The
motility of the oviduct may be altered, the
endometrium is changed, and withdrawal
from the large doses of estrogens induces
bleeding.
Antiprogestational agents could prove to
be effective when administered postcoitally
or monthly to induce progesterone with­
drawal bleeding and abortion. Such drugs
are not currently available. The use of pros­
taglandins to promote abortion is discussed
in Chapter 39.
Undesirable Effects. A variety of major
and minor side effects have been attributed
to the use of oral contraceptives. In some
instances the undesirable effects ate well
documented and their incidence has been
determined. Of most concern are cardio­
vascular side effects and the induction or
promotion of tumors. However, a number
of possible side effects are not well substan­
tiated. Furthermore, the incidence of some
disorders has been lowered by the use of
oral contraceptives. An assessment ui
of mu
the
risk-to-benefit ratio is essentiaffor 'each

I

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V

patient in order to provide the most effica­
cious method of contraception with the
least possible risk.

r.,

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Wld Hith Org. techn. Rep. Ser., 1971, No. 473

„ _____ ...Ji.,..

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WORLD HEALTH ORGANIZATION
No. 473

TECHNICAL REPORT SERIES

I

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’1
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■

S' T

Methods of Femiity
Regulation:
Advances in Research
and Clinical Experience

;4
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■I.
Report of a
WHO Scientific Group

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GENEVA
197 1
■

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This report contains the collective views of
an international group of experts and docs not necessarily
represent the decisions or the stated policy of the
World Health Organization.

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7

REPORT OF A WHO SCIENTIFIC GROUP

true when progestogens alone are administered orally in a continuous
fashion. These data suggest that in order to reach definite conclusions
concerning the hormonal parameters mentioned above, a large number
of women need to be studied; such studies have not been published.
Limited knowledge of processes such as sperm function and transport,
fertilization, ovum and zygote transport, and implantation represent
other obstacles to the understanding of the mechanisms of action of
hormonal contraceptives. With these limitations in mind, the most
probable mechanisms of action of the different types of contraceptive
steroids may be characterized as follows :

2.1.2.1

J
d'
T.
■s

3

Combined oral formulations

The balance of evidence indicates that the combined oral formula­
tions at present in use interfere with ovulation and ovarian steroidogenesis
in an overwhelming majority of cases. This result is secondary to sup­
pression of the hypothalamo-hypophyseal system for production and
release of gonadotrophins. This conclusion has been arrived at chiefly
by study of various parameters indicated above. Evidence for suppression
of ovulation is also provided by inspection of the ovaries at laparotomy.
Combined oral contraceptives, apart from suppressing ovulation, also
induce histological and biochemical changes in the endometrium, physico­
chemical changes in the cervical mucus, and changes in tubal physiology
and uterine motility. It is not known, however, whether these changes
are involved in the antifertility effect of the combined preparations.

2.1.2.2

Sequential formulations

Available evidence indicates that inhibition of ovulation and of
ovarian steroid production occurs in a majority of women taking sequential
formulations, and that it is due mainly to the feedback action of oestrogens
during the first phase of the treatment. Sperm penetration occurs readily
and has been shown not to be altered until the progestational phase of
the regimen.

2.1.2.3

(

Oral progestagens administered continuously

Hormonal studies have been carried out in subjects taking various
types of continuous oral progestogens. As had been stated by a previous
WHO Scientific (iioup1 such formulations do not consistently inhibit
ovulation although they offer a high degree of protection against concep­
tion. This has been further substantiated by recent long-term studies
on plasma and urinary LH, plasma progesterone, and urinary pregnanediol.
These studies reveal that the mid-cycle LH peak is often reduced, and
1 B lit Ulth Org. techn. Rep. Ser., 1968, No. 386.

I

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Mt

33
8

>

METITOHS OF FERTILITY REGULATION

that such a reduction may or may not be associated with absence of the
nost-ovulatory rise in plasma progesterone and urinary pregnanediol.
In other subjects, plasma progesterone levels showed a definite post­
ovulatory rise, although this was somewhat lower than in the preceding
or subsequent untreated cycle. It is therefore not always possible to
define the exact relationship of plasma or urinary LH, plasma proges­
terone, or urinary pregnanediol levels to ovulatory or non-ovulatory
cycles. In addition to their effect on the hypothalamo-pituitary axis,
certain oral progestogens have been shown to interfere with the normal
steroidogenic process in the corpus luteum.
Oral progestogens administered continuously arc Known to induce
changes in the physico-chemical properties of the cervical mucus, but the
significance of these changes js unclear as these changes arc also brought
about by dose levels that do not have an antifertility effect. Oral pro­
gestogens also influence both the histological and biochemical characte­
ristics of the endometrium, and it has been suggested that the endometrium
exposed to the continuous use of progestogens becomes unsuitable for
implantation. Since continuous oral progestogens given only during
the second part of the cycle have little if any contraceptive effect, their
antifertility effect cannot be attributed only to an action on the endometrium.
Whether such formulations affect other functions, such as sperm transport,
capacilation, fertilization, and ovum transport, in the human remains
to be investigated further.
2.1.2.4

1

Slow-release preparations

Injectable combined ocstrogcn-progestogen preparations interfere
with ovulation in the majority of women studied, as evidenced by urinary
and plasma gonadotrophin levels and by the inspection of ovaries at
laparotomy. Injectable preparations of progestogens alone also inhibit
ovulation, as indicated by the same criteria. The administration of
injectable progestogen results most frequently in endometrial atrophy
resulting from continuous progestogen stimulation in the absence of
sufficient ovarian oestrogen production to provide adequate endometrial
priming.

2.2 Mechanism of Action of Intrauterine Devices

r*

2.2.1

Antifertility effects

Since the last report on intrauterine devices,1 relatively little informa­
tion has been published on studies in man. This section, therefore,
refers mainly to data published on experiments in animals.
1 \V!d illth Org. techn. Rep. Ser.t 1968, No. 397.

I

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34
.rV;;'

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Thirteenth
■t-

■ '*W

Annual Report

I 1984
—

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Special Programme of
Research, Development
and Research Training
in HUMAN REPRODUCTION

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WORLD HEALTH ORGANIZATION

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Research and development
This section is devoted to a technical review of the activities and plans of the various

Task Forces.
It should be noted that all activities relating to the development and evaluation ol
jone-actine steroidal methods for women, including vaginal rings, are incorporated into
onercpotmThe work on prostaglandins has been included under the report on post-ovulatorv methods. In addition, activities related to improving current technology and to develop­
ing new methods have been combmed under the title "New- and unproved methods ol

lerlilily regulation’’.

M.W AND IMPROVED METHODS OK FERTILITY REGULATION

Upjohn trade name lor DM PA) as a con­
traceptive in (he UK, reported its opinion
in April 1984. A licence was subsequently
granted for the long-term use of DcpoProvcra, but its use was recommended
only in women in whom other contracep­
tives arc contra-indicated or have caused
unacceptable side effects or arc otherwise
unsatisfactory. The report of the panel
concluded that: “Depo-ProvcraR offers an
alternative and highly elfcctive method ol
contraception and its mode ol administra­
tion would make it uniquely valuable for
some women. The evidence at present d< )CS
not support suggestions ol major or life
(lircalcning risks to women using the

Long-acting systemic methods

I

The debate on the scientific and politi­
cal concerns relating to injectable con­
traceptives and particularly to depot med­
roxyprogesterone acetate (DMPA) con­
tinued during the past year and several
important decisions relating to licensing
their use as contraceptives have been
made.

The Bundcsgcsundhcitsamt of the
1-ederal Republic of Germany reduced res­
trictions it had imposed on DM PA and
norelhisleronc enanlale (Nl.l-I.N) and
deleted the u< ml ra-indica I ions ol use in
diabetic or lactating women. I he panel ol
experts appointed by the UK Department
of Health and Social Security, following an
appeal by the Upjohn Company at the
Minister of Health’s refusal to accept the
Conimitiuc on the Safely ol Medicines ap­
proval of the use of Dcpo-ProveraK (the

dl Ug".

The l ood and Drug Administration of
the Philippines has approved the use ol
DM PA as a contraceptive and NET-LN
has been approved for marketing in India.
A I'orum on Depo-Proverau was held by

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34
THIRTEENTH ANNUAL REPORT
Post-ovulatory methods

also needed to evaluate the overall net risk

Ov

of oral contraceptive use. Some important

demonstrated in de­

One way to attain a greater degree of

veloped countries, but little information is

safety in fertility regulation for women is

available

to limit as much as possible the amount

benefits have been

from

developing

countries.

A

UCS
ca­
sl I

consultation on (he subject was convened

of coniraccptive drugs to which they arc

by the Programme in November 1983 in

exposed during their reproductive \cars.

Bethesda. Results from developed coun­

Because conception

av­

w In

tries were reviewed for their potential ap­

erage only once every 3-4 months in sexu­

;k r

to

plication

ami

countries.

Some of I he benefits demon­

relevance

place

on

lioi

con

o\.

Iraccplion. the greatest reduction m h<>i

imj

active

ally

developing

lakes

women

not

practising

i n x.

strated in developed countries were con

monc intake could be achieved b\ the use

sidered to be of likely importance in de­

of

compounds

den

menses-inducing

agents,

veloping countries, such as prevention of

that only need to be taken after missed

me

iron deficiency anemia, pelvic inflammat­

menses and are capable of inducing men

kv

ory disease, and endometrial and ovarian

slruation. Next in let ins of hormone ex­

I 01

cancer. Other beneficial effects were con­

posure would be once a-month drugs, ag­

sc.r

sidered to be of considerably less impor­

ents that will reliably prevent picgn.incy

con

as

when taken for a brief period al a specific

prevention of benign breast disease, rheu­

stage of the menstrual cycle. I inally, some

A<h

matoid arthritis, and benign ovarian cysts.

reduction in hormone exposure could also

sHi.

post-coital drugs dial

I <H

Pelvic inllamatory disease (PID) is an

arc taken after intercourse, allhough not

gl V <

tance

in

developing

countries,

such

be expected

from

following

coital

every

act.

women of reproductive age in a number of

since the woman max be aware when she

Opt
hor

developing countries, and contributes sub­

is not fertile.

h< •.

important

public

health

problem

necessarily

for

stantially to another major problem, infer­

tility. The Programme conducted a case­

(iiven the complexity ol the pmccsscs

control study of PI I) and contraception in

involved in establishing a siiccessliil piep

sh!,

1978 and 1979. The primary focus of the

nancy and the inadequate imdcistanding

an.l

study was the risk of PI I) associated with

of them, the piohlems of developing ellec-

IllCi

the use of IUD’s but oral contraception

(ivc post-ovulatory drugs arc formidable.

noi

was also included in the analyses. How­

Unlike oral combined pills or inlrannis-

the

ever. in the developing count l ies included

cular

winch

llki

a nr.

in the study, only 27 cases and 59 controls,

alamic-piluilarx oxaiian

contraceptive use, thus limiting the inter­

post-ovulatory drug would be a delicate

p<^

pretation of the results. Nevertheless, al­

precision tool, uniquely designed and ad­

an;i

though no significant protective eirect of

apted to interfere with a very limited num

. i

axis

the

ideal

oral contraceptives was seen with regard to

bcr of selected reproductive events in such

nb-

the first episode of PI I). there was evidence

a way that the inliinsic rhythm of the men

()in

that oral contraceptives did provide some

slrual cycle is minimally disturbed

against

recurrent

PH).

I he

( )b

ar I

viously this appioach icquiies a piolound

am!

Task l orce on the Safely and Idllcacy of

understanding

reproductive

la. :

Fertility Regulating Methods will be ad­

processes in oidet to identify those critical

slci

dressing this issue as it plans its research

events that can serve as potential targets

strategy.

for contraceptive attack.

IDO!
imp

26

t

preparations

or about 7" i. of the subjects, reported oral

protection

I -

long acting

grossly disturb the function of the hxpoth-

of

basic

NORISTERAT
Depot Progestagen for hormonal contraception

37

Composition
1 ml contains 200 mg Norethisterone in oily solution.

Indications for use
fLong-term contraceptive (2-3 months) only for women who cannot
use other methods of contraception, or who cannot take oral
.contraceptives (the ’Pill’).
Special notice
Only women with normal menstrual cycle should use'Noristerat.
E ford the use of Noristerat one should have a thorough medical
as well as
gynaecological examination. Pregnancy must be ruled
out, generally on the basis of a hormonal pregnancy test.
During the period Noristerat is used, one should have a general
medical and gynaecological examination, the first one two months
after starting usage, from then on once every six months, in
order to detect unwanted side effects ( see Side effects) at
an early stage.

(

Counter indications
^Noristerat must not be used
- in case of oregnancy
- during breast feeding
- in case of diabetes (mellitus)
- in case of thrombophlebitis (thrombo-embolic disorders)
- in case of high blood pressure (disorder)
- during acute or severe chronic disorders of the liver, with
or without jaundice (especi ally in the case of primary biliary
cirrhosis of the liver)
in case of breast cancer or cervical cancer ( also after treatment)
- in case of disorders of lipid metabolism
- in case of enzyme disorders, such as Dubin-Johnson or Rotor
syndrome as well as sickle cell anemia
- whenever, during previous pregnancies, one has had jaundice,
continuous itching, herpes gestationes or otosclerosis.
- 12 weeks before a scheduled surgery and during long periods
of bed rest (for instance after an accident).

2

3^

*

Noristerat should not or only after careful consideration
of the advantages and risks be used
- in case of porphyria
- in all cases of reduced liver functions
- in case of a history of thrombophlebitis (thrombo-embolic
disorders)

* One should refrain from another injection, if during usage
the' following occurs:
- for the first time migraine or recurrent unusually severe
headaches, acute visual disturbances, first signs of thrombo­
phlebitis ( for example unusual pains or swelling of the legs),
acute pains while breathing or coughing of indeterminate cause,
pain or pressure in the chest ( in all these cases there is
an'increased danger of thrombosis)
■ significant increase of blood pressure
depressions
- medically significant changes on the liver functions or in
the hormonal level.
The same applies to cases in which, due to simultaneous use of
different drugs ( see Interaction of different drugs)pregnancy
may have occured. One should contact the physician when one believes
to be pregnant.

Attention

c

In connection with the androgenic after effects of estran derivatives
it must be noted that in earlier years, while the substances
were used in very high doses for contraception, also with preparations
containing Noristerat, there have been repcTts on a few single
cases of female new-born children with male external genital
characteristics. In the few cases of pregnancy that have occured
during the period of diminishing after effects of Noristerat,
however, no such effectshave been observed.

Side effects
The most common side effects are spotting or breakthrough bleeding
and also the absence of menstruation (Amenorrhea). After discontiauarion
of the preparation the return of regular ovulation can be seriously
retarded and in certain conditions be ds long as six months.

■

37
3

Occasionally headaches, nervousness, dizziness, depressions,
allergic reactions and heavy weight increase
acne, temporary nausea
have been observed. Only in the case of long bleeding it can
-CEstrogen preparation,
be advisable to give an- additional Progestagen
for ten days, for example 1 tablet of Prosiston per day, after
a
which within from 1 to 4 days after taking the last

withdrawal bleeding will commence.
; stopped ( see Directions
When usage is stopped because the period has
for dosage) further diagnostic measures to
t. clarify the cause
have to be taken.
Vuien the possibility of a pregnancy has been eliminate
amenorrhea still continues, a special treatment is advi-a

e,

especially in the case of younger women.

A decrease of glucose tolerance has been diagnosed
during the use Tf progestagen. Therefore women who have
a tendency toward diabetes (mellitis) (pre diabetics) should
be carefully monitored when Noristerat is used.
With the current state of knowledge the possibility_^tha£^he

hormonal coriHacent^AlJ^1!^^^035^. ^S- , H
pf veinous and arteric thrombo-embolic disorders , ^nnot^sJ±_±_

out.

(

Warning
.
. ,
Smokers who use hormonal contraceptives j^lj^
oTdisorders caused ^the^nartl^
Changes ( heart attack, stroke). The risk increases witn age
and with the quantity of cigarettes smoked. Women over 30 should

therefore refrain from smoking while using hormonal contrac p
When smoking is not .given up, other contraceptives should
used, especially when further risk factors are present.
In these cases the advice of the physician should be sought.

Intcraction of different drugs.
physician should be told about^^reg^
dT^ITT^Tse various'"substances can influence_the_etfe£ts.o
^7i s t e r a t: f orexatnple barbiturates-J^<ifarnpicir.^Ainpicil 1 in,
and drugs for epilepsy (such as Barbexaclon, Garbamazepin,

Phenytoin, Primidon).

■**i*-.*' »■ ■’ ’ 5

■

■

'

4

Directions for dosage
The first injection should take place within the first five days
of the cycle. The next three injections must, independent of
the cycle, be administered at 8-week intervals.

After that a further injection is needed once every 12 weeks
(84 days). Otherwise tnere is insufficient protection from pregnancy
from the 13th week onwards. Under special circumstances ( for
example travel, holidays) the period between injections can be
reduced by one week.
The next injection then should only be administered when within
the previous ten weeks a period-like bleeding has o'cured. Otherwise
Noristerat must be stopped and a pregnancy must be ruled out.
Manner of usage
oily^solutions such as Noristerat must be injected intermvscularly
only: an injection into blood vessels must be avoided. It is
advisable to seal the injected place with a bandage immediately
afterwards, to prevent the fluid from flowing back.

Medicine I
Keep away from children!

Characteristics
The effect of Noristerat rests in first instance in the changedin thd iint^.g of the cervix, which is in effect during the entire
period of usage, and is such that male semen can not penetrate
deeply enough. Hormone research has furthermore shown that within
the first 5 to 7 weeks after the injection the maturation of
the ovum is repressed due to the’high plasma level of florethisteron2.
Furthermore the lining of the uterus is not sufficiently prepared
for the onset of a pregnancy. The protection against pregnancy
begins at .the day of the first injection when administered •
according to the instructions.
During clinical tests Noristerat was generally injected at 12
week intervals . The protective effect was thereby not as reliable
as that of the 'Pill'. The failure rate lies between 0 and 3.6
pregnancies for 100 women using Noristerat for 1 year. The majority
of observed pregnancies occured in the period after the first

'll

5
I

two injections.
With the increase of the duration of usage and from the moment
when the intervals beween the injections had been reduced to
8 weeks,.the safety increased noticeably.

Special notice

i

^■n YSH, rare,cases after long periods of using hormones, among
which the active substance^used in Noristerat, changes of the
liver__have been observed, which could mahe the discontinuation
of the preparation necessary. Therefore the physician should
be informed when unusual complaints of the stomach occur, that
dp not quickly disappear by themselves.
<

Packing
Ready-filled syringe 1 ml.

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Noristerat’

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Depot Gestagen
2vr hcrmoca'cn Enipfingnisverhutung

werden. m dcr Regel mit etnem inniunbiologischen Schwangerschaltstest.
Wahtend der Anwendung von Noristerat i$t zu"ach 2 M,5nalen ur.d spater in halbjahrigen
Abslanden eine allgemeinarzlliche und gynakoloq sche Untcrsuthung durchzufiihren. um unerwunschte Wirkungen (siehe .Nebenwirkunaen")
fruhzcit.g erfassen zu kbnnen

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Zuwmmer.seUung
LclTngh&n 200 m9 NorethlstefO^nantat in bl-ger

i

'3
1
E
£

- wenn truher cinmal Venenentzundungen oder
Blulpf.-opfbiloung in Arterien odor Voncn
(Ihromboembolische Krankheiten) bestanden
haben.

Gegenanzeigen

Schering Aktie'-gesellschaft
Fharma
0-1000 fierhn 65

I

- be: Porphyrie.
" tional,en F°rrnCn cin9escbrankter Leberfunk-

Aawendung $ g e b i e t e
Scf^-angerschattsverhutung von lingerer Dauer
(2 3 Monale) nur bei Frauen, die andere Metho­
den der Kcntrazeptfon nicht vertragen odcr orale
Kontrazepbva (Anlibaby-Pillen) nicht einnehmen
konnen.
Bescndere Hinweise:
Nur Frauen rmt normalem Zyklusverlauf durfen
Nomterat erhalten. Vor Anwendung von Noristerat
set! eine griindliche allgemefnarztliche sowie gynakologische Untersuchung durchgefuhrt werden.
tine Schwangerschaft mu8 ausgeschlossen

• Noristerat darf nicht angewendet werden
~ bci Schwangcrschaft,
- wahrend der Stillzeit.
- bei Diabetes (meilitus).
- bei Ver.enenlzundungen c J
-• - Oder Blulpfropfbildung m Arterien odcr Venen (thrornboembolischen Krankheitcn).
- be: krunknaft
Bluidr.ick.
- be- akuten ur.d schweren chronischen Leberkrankheiten rmt und ohne Gefbsucht (insbesondere primarer biliarer Lcberzirrhose)
- bei Krebs der Brust oder der Gebarmutter (auch
nach Behandlung),
bei Fettstoffwechselslorungen.
- bei Enzymstdrungen. wie Dubin-Johnson- und
Rotor-Syndrom sowie Sichelzellenanamie
- wenn wahrend einer fruheren Schwangcrschaft
Gelbsucbt. anhaftender Juckreiz. Blaschenausschlag (Herpes gestationis)
g^stationis) oder Mmelohrschv/erhongkeit (Otosklcrosc)
(Otosklcrosc) aufgetreten
sind,
12 Wochen vor gep’anten Operaticnen und bei
langcrer Bettruhc (z. 3. nach Unfallen).
• Noristerat solite nicht oder nur nach sorgfaitiger
Nutzen-R.s.ko-Abwagung angewendet werden

J

I

• Von ciner erneuten Injektion ist abzuseben
wenn wihrend dcr Anwendung auftreten
- erstmalig migraneartige oder haufiger unqewchnt starkc Kopfschmerzen. akute Sehstbrungen, ersle Arzeichen von Venenenlzundungen
mil B'utpfropfb.ldung (2. B. ungewohnte
Schmerzen odcr Schwellungen in den Bcincn)
stechendo Schmerzen betm Atmen oder’
Husten unklarcr Ursachc. Schmerz- und Engeqefuhl rm Drustraum (In alien diesen Fallen
besteht erh<hto Thrcmhocogcfuhr),
starkerer Blutdruckanslieg.
fruhere Depressionen.
~ krankhafto Veranderungen der Lebcrfunktion
und dcr Horm'onspicgel.
Dassolbe gilt fur den Fall, da3 es wegen dcr gleich^it.gen Anwendung anderer Medikamonte (siehe
.Wechselwirkungen mit anderen Mitteln") zu einer
Schwangcrschaft gekommen sein konnte Uber
den Schwangerschaflsverdacht ist mit dem Arzt zu
sprechen.
Zur Beachtung:
Im Zusammenhang mit der ancrogcnen Restwirkung vonjstyrmjrivatcn smd m fruheren Jahren
ais dicse Substa.^en rn sehr hoher Dosierung zur’
Schwangerschaftserhaltung angewendet wurden.
auch nach Gate norethisteronhaltiger Praparate
emzelne Faile von Vcrmannlichung der iiuOercn

Geschlechtsmeikmalti weibUher NnUSPbcrc.
beschneben worden. Boi den w.-nigm Schwa
gerschaften. fu denen e s bishcr u ahrend des
. klmgens dcr Noristerat-Wi/kung gekrm-n.- i
wurde ein solchcr Etfekt jedoch meh! t ect. • >
Nebenwitkungen
<
Die havfigslen Nebenwirkungen sind Scrim •
Oder Durchbruchblutungen und auch au-h <
bende Blutungen (Amenorrhden) Nach Absft.'i
des Praparates kann der Wiodere ntritt d s :r '
maBigen Eisprungs stark verzogo-l son und um'.
Umstar den mehr als ein halbcs Jarir betru*Vercinzelt werden Kop'schnv-rzen. her^- 5..,
Schwindelgefuhl, Oepress.onen, Akne. vorub- ■;
hende Ubelkeit. allorgische Reakuonen und st.
Here Gewichtszunahme beobar.htr-t
Nut bci idIiy dnhaiiencjfn e.'uiungcka ic es a
bracht sein, fur 10 Tage zusal/iich em Gesta'
Ostrogcn-Praparat zu geben. z B t<,chch 1 k ■ i- ••
Prosiston*. wobei etwa 1-4 Tad- '’ach E nr.-r • •
der letzten Tablette e no Entzugsblutuog ems Wenn die Anwendung wegen Ausblc.bens von B j
tungen abgebrochcn warden ist (siehe .r?
rungsanleitung'), sind wetter* diagn-jstische ri'j'nahmen zur Klarung der Ursachcn notwer : Liegt koine Schwangcrschaft vor und hair d"Amenorrhb weiter an, ist besonders bei jung ■
Frauen cine Spczialbehaiicilung erforderheh.
Bei dcr Anwendung von GcM-.g- nen wurde t •
emigen Patientinnen eine Vcrminderung der G'
cosetoleranz festgesteilt. Daher soltten Frauen,
die zum Diabetes (mellitus) neigen (Pradiabebkermnen). bei Anwendung von Noristerat sorcfait '
beobachtet werden.

■■

J

b1

*

A

1I

Ia
4

1
J
5
i

't
y. j

I

nachdem heutigen Kenntmssiand kann mcht ausgeschlosscn werden. dafl die Gabe hormonaler
Emptangn-.sverhutungsmiUel rmt einem erhohten
RiSwo venoser und arterieiier thromboembolischef Krankheiten verbunden ist.
Warnhinwets;
5ei Rauchennnen. die hormonhaltige Arzneimitiei
:ur Schwangerschaftsvcrhutung anwenden. be-teni en erhohtes Risiko. an zum Tetl schwerwiet-.-nden Folgen von Gelaiiveranderungen (z. B
Herzinfarkt.$cntagantali) zu erkranken Das Risiko
r.rfnmt m«t zunuhmendem Alter und steigendeni
Zigarettenkonsum zu Frauen, die alter ais 30 Jahre
smd, souen deshaib nicht rauchen, wcnn sic hormonnatitge Arzneirruttel zur Verhutung emer
Ger-w^ngerscnaft anwenden V.'enn aul das Raucnen n*ch! verzichtet v.ird. sollen andere Verhutungsmethooen angewendet werden. besonders
bci
aktoren

to d«esen Fallen ist der Rai des behandelnden Arz
ret erfizuftolen
Wechselwirkungen mil anderen Mitteln

Der Arztist uber die regblmaBige Einnahme anderer Med-kamente zu unterrichten. weil verschiecene Svbstanzen z 8. Barbiturate. Rifampicin,
vnpcrUen. uno Arzneirr .ttel gegen Epilepsie (wie
bejiacton. Carbamarepin. Pnenytom. Pnmidon) c>e Wirkung von Noristerat beemlrachtigen
kormen.
DosierungsarJeilung •

D»e erste ln;efctian wird mnerhaib der ersien funf
'age eines Zyklus vorgencmmen. Die nachsten

drci Spritzen ^nd unabhangig vom Zyklusvcrlau!
m Abstanden von jeweiis 8 Wochen zu verabreichcn
Danach ist alle 12 Wochen (84 Tage) eine weitere
Injektion erforderlich Anderenfalls besteht von
aer 13 Wocne an kem ausreichender Schutz mehr
vor emer Schwangeschaft.
Bei besonderen Umstanden (z. B. Reisen, Feterluge) laBt sich der Abstand zwischen den Spritzen
um emu Woche verkurzen.
3

8

8

i

I
I

12

12
Wocti.jn

aul 8 Wochen verkurzten Injektionsmtervailen
nahm die Sicherhcii deuthch zu

Arzneimittel!
Fur Kinder unzuganglich aufbewahren!

Besondere Hinweise

Eigenschatten

Die Wirkung von Noristerat beruht in erster Linie
aul einer sich uber die gesamie Dauer aer Anwendung erstreckenden Veranderung des Schleims
• im Gebarmutterhals. so dao dei mannhche Samen
nicht weit genug vordringen kann. Hormonuntersucnungen hahen weiterhin gezeigt. dd»J mnerhaib
der ersien 5-7 Wochen nach dei Injektion die
Eire.Jung durch den hohen Plar.maspiegel an Norethisieron unterdruck t wird Daruber hmnus ist die

5

3 -

Pilaster zu versehen. damit d.e Losung mcht zuruckfheBen kann.

Schlc-imh?'.1’ fipr r'.--!? ■c-v ftr-

i

1 Ampuiie Noristerat
Die jeweiis nacnste Injektion soil nur dann gegeben werden. wenn es mnerhaib der letzten 10 Wo­
bben zu emer menstruationsahnlichen Blutung
gekommcn is! Sons! muB Noristerat abgesetzt
und erne Schwangcrschaft ausgeschlossen wer­
den

Art der Anwendung
Clige Lwsur.gen v.ie Noristerat smd ausschlieBlich
ir.trhmujk jiar zu mjizicren; msbesondere ist erne
Injektion m Hlul'uf.tBe zu vernieiden Es empfiehlt
s.ch, die Liroprilzstclle anschliefJend mi! emem

ii

AuBerst selten sind nach Langzeitanwendung von
Hormonen. zu denen auch der im Noristerat er.thaltene Wirkstoff gehdrt. Veranderungen an Oer
Leber beobachtet worden. oie das Absetzen ces
Praparates erforderlich machen konnen Daher .st
der Arzt zu infcm.ieren. wenn ungewormte Oberbauchbeschwerden auftreten. die mcht vor. setost
bald vorubergehen.

Packungen
SpriUampullo zu 1 ml

DM 26.69 n at

i.yl,

einer Schz/d.igerschufl mcht ausreichend vorbereitet
Der Empfangnisschutz beginnl bei vorschriltsgemaBer Anwendung urn Tag der ersten Injektion.
Wahrend der klinischen Versuche wurde Noristerat im allgememen m I2wbchigen Aostanden injiziert Die empfangnisverhutende Wirkung war
dabei nicht so zuvcrlassig wic bei der bekannten
.Pilie*. Die Zahl der zu erwarter.den Schwangerschaften. wenn z. B 100 Frauen Noristerat 1 Jahr
lang crhallen, lag zwischen 0 und 3.6. Die Mehrzahl
der beobacht«ten Schwangerschaften net in die
Zeil n«xh den ersien beiden Injektionen Mil tortschrtitender Ar.wcndungsdauer und bei zu Begmn

SCHER.. .3
796631

Code-Nr 497

Starve C3 Ir33

$

i

.£>•

THE DRUG CATALOGUE (of DENMARK), 19P5

(LAEGEMIDDELKATALOGET, 1985)
A TRANSLATION OF SOME EXTRACTS.
PAGE 156.
CONTRACEPTIVE, GESTAGEN, PARENTERAL

Indication: Hormonal contraception specially where it is judged
that the woman cannot understand or remember to take tablets

daily.
Contraindications: Previously a history of hepatitis and reduced
liver functions were contraindications, but newer research indicate
that medroxyprogesterone has a positive action on the liver
function possibly through an immuno suppressive mechanism.
efiAggts; Serious: Anaphylactic reaction sometimes with the
injection. Other side effects: Bleeding disturbances, menstrual
irregularities, breakthrough bleeding, spotting, amenorrhoea,
are very common. Besides these, headache, pain in the extremities,
nausea, acne, oedema, loss of hair, vertigo, depression and
reduced sexuality (loss of libido).
Preparations

Depo-Provera UPJOHN, Medroxyprogesterone
Nori sterat SCHERING, Norethisterone Enanthate

PAGE 706-7.

Noristerat

SCHERING

Norethisterone Enanthate

Indication:

Same as above.

Amning (Breast feeding): Milk/plasma concentration is below 0.5.
Can give changes in the contents of mothers milk, reduced milk
flow and gynaecomastia for the child. Side effects depend on
the dose.

Contraindications:
tho others.
Side effects:

History of thromboembolism. See page 156 for

See page 156.

BEWARE: The treatment ought to be stopped at the first xiguxiaf
complaint of migraine headache and or often heavy headache,
yisucjl disturbances*, signs of thrombophlebitis, jaundice, raised
blood pressure, or pregnancy.

^5 ?
gestagent hormon til de forste tabjetter, sAledes at cervixslimen pAvirkes i hele perioden ligesom ved brug af »mimpiller*. Derved har man opnAet, at de flerfasiske pneparater har de tre angxv»~^—----- > —
Uonsprmparaterne. Kombinationsprmparaterne og de
“^er.rXXr vbkerP^el8rvSeBlbnem ~

-----

lynestrenol eller noretisteron, og dosis er mindre end den,
som benyttes i de fleste kombmationsprmparater.
Farmakokinetik. Gestageneme optages hurtigt fra

—

«J.

Farmakokinetik. Se gynaekologiske midler med gesta-

gen og estrogen side 161
loner, iiormontu
-------- - —.
raterne synes at give faerre blodnmgsforstyrrelser end
lavdosistabletter af kombinationstypen med de samme

SXeT"
forste dogn ved udskillelse io"n^ption,
1 urm og faeces. speeielt i tilHormonal kontraception, specielt
to^lp’r^p^ater ikke tiles eller awepteres.
tr^^SinHikaGoner Uregelmsessige blodnn
1
^a„aiintr med minipiller, se neden-

hyppigt
Rivirkninger. Uterinblodningsforstyrrelser sea
i
Kmitraindikationer. Nyere undersegelscr tyder pA, at
(5-20%) i de forste behandlingsmAneder, menl de synes at
risikoen for tromboemboliske komplikationer forages vedr aftage ved fortsat anvundelse. Det drejcr Bl£ om »endring
.
samtidig tebaksrygning og alder over 35 Ar. Kombina-■
af cykluslaengde,* pletbledning, gennembrodsblodnmg og
'
tionspraiparater bor abnindeligvis ikke gives til kvmder,I amenori Udebliver menstruationen, ber man sikre mg, at
”
\ som ryger meget - isier i 40-Ars aldcren. Se endvidere
kvinden ikke er gravid, inden fortsat behandhng med ge­
^J Xyna^ologiske midler med gestagen og estrogen side 161
stagen gives. Der kan desuuen ses kyalme, opkastning,
HBivirkningcr. De bivirkningcr, man har lagttaget, er
svimmelhed, hovedpine, libidoforandnnger og allc^^e
eet de samme som ved anvendelse af kombinationsreaktioner, men disse bivirkningcr er sjreldnere end ved
Jg^Lnweparateme. Kvinden udsflettes dog for gestagenpAvirkkombinations- og flerfuBeCkombinationslpriBparator.
Qiagen i kortere tid ad gangen, og pAvirkningen af ute', Yinfllimhinden er mere wfysiologisk*. Tromboeensikoen,
Pneparater
. som mence at vmro knyttet til estrogenkomponenten, er
Exlutena® organon, Lynestrenol
C/ ' den samme som ved anvendelse af kombinationspneparaGesta Plan (dak), Noretisteron
V
,
terne. Se endvidere gynaekologiske midler med gestagen
Microluton® schering, Levonorgestrel
og astrogen side 161
,
Microval® wyeth, Levonorgestrel
»iwsExr. Interaktioner. Se gynaekologiske midler med gestagen
Mini-Pe® byntex, Noretisteron
og astrogen side 161

Kontraceptiva, gestagener, parenterale

‘

Kontraceptiva af to-fasetypen, udelukkende med ostrogent hormon 1 forste fase

Den restagene effekt viser sig ved dels at pAvirke cervixslimen dels at pAvirke uterinslimhinden og hsemme ovu-

.\ .

Pn ■sparater
Fysioquens* organon, Komb.
Ovanone® ergo, Komb.

Fannakokinetik. Efter dyb intragluteeal injektion angi­
ves gestagenet i den anbefalede dosis at bhve absorberet

Kontraceptiva
.
af to-fasetypen med tilssetning af en
ringe maingde gestagent hormon 1 forste

“.ksoner at kvindon ikke kan foratA eller huske at tagc

^^S^'^tracepUon. ismr hvor man

Rontraindikahoner. Tidligere regnede man hepatitis og
kronisk nedsat Icverfunktion for kontraind.kation men
nyere undersegelscr tyder pA, at medroxyprogesteron
tvsertimod har en gavnlig effekt pA leverfunktionen for­
mentlig gennem en immunosuppressiv mekamsme.
Bivirknfnger. Alvorlige: Anafylaktiske reak^°"eF er

Praeparater
Binordiol* wyeth, Komb.
Sequilarum® schering, Komb.

Kontraceptiva af tre-fasetypen. med
stigende indhold af gestagent hormon og
vaneret lavt indhold af ostrogent hormon
((

i tilslutning til injektion. Andre bivirkningcr:
ningsforstyrrelser med vekslende mtervaller,
brudsblodning, pletbledning og menostasipenoder er hyppige. Desuden ses hovedpine. smerter . underekstremiteterne, kvalme, acne, ankeledem, hAraffald, mammelhed,

Praeparater
Fironetta® schering, Komb.
Trinordiol® wyeth, Komb.
Triquilar® schering, Komb.

depression og libidoforandringer.

Kontraceptiva, gestagener, »mlnlplller«
Princippet i denne metode er, at den konstante
koMtante gestagen^tagenpAvirkning af cervixslimen bindrer spermatozoemes gennemtrmngning. Det tilstrmbcs at give en sA bile
lille gestagendosis, at ovulalionen ikke pAvirkes. Derimod er der en vis
luteolytisk effekt og formentlig en 1 ‘
.
”2
endometriet og tubamotiliteten. Tubletteme tages hver
dag. Dor holdes aluA ikke pause under menstruationen.
Metoden er i praksis mindre sikker end andre former for
hormonal kontraception. Usikkerheden angives hl omkring 1-4 graviditeter pr. 100 kvindcAr. GAr der mere end
ca. 24 timer mellem indtagelsen af to tabletter, er meteden usikker og bor suppleres med en anden kontraceptiv
metode i de folgende 14 dage.
»Minipillcrne« indeholder gestageneme: levonorgestrel,

Praeparater
.
Depo-Provera* Upjohn, Medroxyprogesteronacetat
Noristerat* schering, Noretisteronenantat

^tuTp^i^k^ Androgener

156

rx

2 ^<2
(tide.

dngligt.T*
ilOgangp
binyremc
nioner* hv
Testoaten
estere af
steron, c!
bevaret c
»f de art ’
fekt. Disr
tid er Dw­
eller testHgt 8prT V.
aluUc
fekten i
Join kun
Farmak'
ter peror
res dels i
Peroral t
400 mg i
tabietfor
tet» men
Teatoe tc
torier, hv
vena cav
doeer pA
TestoeteralL Det
ter delvi
lisering
ca. 120 1
Artific***
steron c
gives pe
Bortset
stere int
Btoetero
dage. Aj
handele
steron,
prsepar
kombir
en hurt
gives of
i 1 mftn'
virknin
Testoatforsele
rende e
clitoris
ning fr
doaer, a
hoa kvi
Afetobrd.vjk a

G03B

Androgener er betegnelsen for steroidhormoner, som bar
viriliserende virkning. 1 puberteten bevrrkor de yooksta^
celeration og udvikiing af sekundmre konskarakterer bos
mmnd. De bar ogsA betydning for spermatogenesen og
sty re r funktionen af epididymis, prostata og vesiculae scminales. Det mest potente af de naturbge (genume) am
drogencr er testosteron. som isier produceres 1 testes, t
voksne mind produceres normalt ca. 7 mg testestero

og kan
lerne. I
poraer.
hvor d
end de
hverv*.
roider
Effekt
hxeinr.
andixx
begge
gonad
som rr
Teslo

C er

Ifd,

w.
■ i i iimnnn imi 'n iB<»,nnn naisirfinnrr~ -iriwin" im i im i

DEI5

/
ftgiintraartikulser anvendelse). 1 ml indeholder 40 mg
^nethylprednisoloni acetas i aqua ad iniectabilia. Tilsat
feacrogolum 4000, natrii chloridum og konserveringsmidAel: myristyl^y-picolinium chloride.
Farmakokinetik. Injektionsprseparatet bar depotvirkning. Virkningen indtrseder efter 4-24 timer og varer indtil 2-6 uger afhsengig af lidelsens art. Se endvidere glukokortikoider side 174
og glukokortikoidprseparater til injektion i led side 177
Indikationer. Se henholdsvis glukokortikoider side 174
og glukokortikoider tilaystemisk behandling side 226
SAfremt parenteral behandling findes indiceret: Visse alyorlige allergiske sygdomme (asthma bronchiale og svsere
tilfelde af rhinitis allergies) og alvorlige inflammatoriske
bindevsevssygdomme Qupus erythematosus disseminatus,
sjseldnere reumatoid arthritis).
Til lokalbehandling i led, seneskeder og bursae, isaer ved
arthritis rheumatoides. Se endvidere glukokortikoidprseparater til injektion i led side 177
Doseringsforslag. Individ uel og afhsengig af sygdommens art, jvf. omtalen i glukokortikoider side 175
Bemcerk: MA ikke indgives i.v.
Lokal behandling af led. 4-80 mg (0J-2 ml) efter applikaV jonsstedetfi sterreK* og lidelsens svserhedsgrad. Se endviderc glukokortikoidprseparater til injektion i led side 177
Benujcrk: Efter anvendelsen kasseres evt. overekydende
indhold i hsetteglasset.
Amning. Der forcligger ingen meddelelser vedr. udskillelse i modermselk. Ber ikke givee til diegivende.
Kontraindikationer. Anvendelse til born eller gravide
ber kun ske pA tvingende indikation. Se endvidere gluko­
kortikoider side 176
og glukol ortikoidpraeparater til injektion i led side 177
Bivirkninger. Se glukokortikoider side 176
og glukokortikoidpneparater til injektion i led side 177
Interaktioner. Se glukokortikoider side 176
UdlvB
Pakninger og priser
O inj.vaiske 40 mg/ml,vandig susp,
1 htgl. a 1 ml kr. 63,90 25 htgl. a 1 ml kr. 1198,35
1 htgl. a 2 ml kr. 100,65 25 htgl. a 2 ml kr. 1899,50
1 engangsspr. a 2 ml kr. 100,65
1 htgl. a 5 ml kr. 224,15

Depo-Provera® upjohn,
Medroxyprogesteronacetat

(

gosd
Parenteralt kontraceptivum til kontinuerlig anvendelse.
Omtalt i afsnittet side 156.
Dispenseres i form af
injcktionsvceskc. 1 ml indeholder 50 mg medroxyprogesteroni acetas i aqua ad iniectabilia. Tilsat natrii chloridum,
macrogolum 4000, Polysorbatum 80 og konserveringsmid­
ler: methyl is parahydroxybenzoas og propylis parahydr­
oxybenzoas.
Farmakokinetik. Efter dyb intraglutseal injektion ab­
sorberes medroxyprogesteronacetat over en periode pA 3
mAneder. Metaboliseree i leveren ved hydroxylering. Udskilles hovedsageligt med galden, en mindre del med urinen som sulfater og glukuronider. Eliminationen er bifasisk med en biologisk halvtid i plasma pA ca. 30 timer i
slutfasen.
Indikationer. Hormonal kontraception med rent gesta­
gen, isser i tilfselde hvor man skenner, at kvinden ikke
kan forstA eller huske at indtage en tablet dagligt.
Doseringsforslag. 150 mg (3 ml) dybt i.m. i glutsealregionen hver 3. mAned. For at udelukke graviditet, nAr den 1.
injektion gives, anbefales det, at den gives inden for de
ferste 5 dage efter, at en normal mcnstruationsperiode er
begyndt eller i perioden efter on fedsel.

Amning. Mselk/plasma-koncentrationaratio er < 0,5.
Der er protraheret effekt Kan give vaginalbledning og
mammavsekst hoe det ammede barn. Modermaelkens
eammenwetning kan sendree og nwelkemwngden nedssettes, hvorfor amning mA frarAdee.
Kontraindikationer. Tidligere tromboemboliake komplikationer. Se endvidere kontraceptiva, geetagener, par­
enterale aide 156
(
Bivirkninger. Se kontraceptiva, geetagener, parenterale
aide 156
Bemark: Behandlingen bar eeponerea ved farategangaforekomst af migraeneagtig hovedpine eller hyppig forekomst af ussedvanlig kraftig hovedpine, akutte aynaforstyrrelaer, tegn pA tromboflebitis eller tromboemboliake
forekomster, planlagt operation, immobilisation, ikterus
(kolestase), kraftig blodtry ksstigning og indtrAdt avangerskab.
UdlvB
Pakninger og priser
inj.vfeske 50 mg/ml,vandig ausp, 1 htgl. a 3 ml kr. 87,40

Deprakine orion, Valproat

N03A

Antiepileptik um.
Omtalt i afsnittet side 254.
Dispenseree i form af
enterotabletUr a 100 mg, 300 mg eller 500 mg natrii valproas,
tabletter a 300 mg natrii valproas,
mikstur 60 mg/mt 1 ml indeholder 60 mg natrii valproas i
aqua purificata. Tilsat smagskorrigenser. hindbasr-csaens, kirsebser-essens, saccharinnatrium og aorbitolum,
konserveringsmidler: mcthylis parahydroxybenzoas og
propylis parahydroxybenzoas samt farve: Erythrosin E
127,
mikstur 200 mg/ml. 1 ml indeholder 200 mg natrii val­
proas i aqua purificata,
suppoaitorier a 100 mg eller 300 mg natrii valproas.
Farmakokinetik. Absorberes hurtigt og nseeten fuldstsendigt (85-100%) fra mave-tarmkanalen samt fra rektalslimhinden. Maksimal plasmakoncentration indtnoder efter 1-4 timer, efter indtagelse af enterotabletter efter ca. 5 timer. Ca. 90% bindes til plasmaproteiner. Se
endvidere valproat side 253
Indikationer. Fortrinsvis til metabolisk epilepsi (primser
generaliseret epilepsi) som f.eks. pyknoleptisk petit mal,
juvenil myoklon epilepsi evt. med generaliserede krampeanfald og fotosensitiv epilepsi. Kan ogsA have effekt ved
sekundmr generaliseret epilepsi (bl.a. myoklon-astatisk
epilepsi) samt ved partielle anfald.
Doseringsforslag. reroralt og rektalt. Voksne. Behand­
lingen kan startes med fuld dosis 20-50 mg pr. kg legemsvsegt dgl., evt. fordclt pA 2 doser. Skolebom. Initialt. 300
mg dgl. Vedligeholdelscsdosis. 2040 mg pr. kg legemavsegt i dognet fordelt pA 1-2 doser. Sm&bsm. 20 mg pr. kg
legemsvaegt i degnet fordelt pA 3-4 doser.
Bemrrrk: Tabletteme bor indtages umiddelbart efter et
mAl lid. Enterotabletter skal sluges hole, mA ikke tygges
eller deles.
Leverfunktion (alkalisk fosfatase, laktatdehydrogenaae
fl PH), serum-bilirubin, aspartataminotransferase (ASAT))
og trombocyttal skal kontrolleres for og efter 14 dages og 1
mAneds behandling. Derefter hver 3. mAned i det ferste
Ar. Det er vigtigt at instruere patient eller pArerende om
initialsymptomeme ved den toksiske hepatitis.
Man ber tilstraebe behandling med sA lille en degndosis
som muligt.
Amning. Mmlk/plasma-koncentrationsratio er ca. 0,1.
Der er ikke beskrcvet bivirkninger hos det ammede bam.
Kontraindikationer. Ix-werlidelsc. Sc endvidere val476

&

^rl
Norflex* riker, Orfenadin

I

1
'

s
r

*

M03B

Antiparkinsonmiddel med antikolinerg virkning.
Omtalt i afsnittet side 256, 323.
Dispenseres i form af
injektionsveeske. 1 ml indeholder 30 mgorphenadim citras
i aqua ad iniectabilia. Tilsat natrii chloridum, natrii hydroxidum og antioxidant: natrii pyrosulfis,
tabletter a 100 mg (mrk. NX - riker) orphenadmi citras.
Indeholder laktoee.
Farmakokinetik. Absorberes fra mave-tarmkanalen.
50% udskilles renalt. Ca. 70% gAr over i blodbanen. Meta­
boliseres hovedsageligt i leveren. Biologisk halvtid for enkeltdosis 17 timer, efter Isengere tid 3040 timer. Steady
state opnAs ved indgiftsintervaller pA ca. 12 timer.
Indikationer. Paralysis agitans, parkinsonisme. Svser
dystoni eller parkinsonisme fremkaldt af neuroleptika.
Se endvidere antiparkinsonmidler, antikolinerge side 255
Doseringsforslag. Parenteralt ved medikamentelt induceret parkinsonisme. 40-120 mg (1,3-4 ml) dgl.
Peroralt. 100 mg (1 tabl.) 2 gange dgl.
Amning. Forholder sig formentlig som bipenden, for
hvilket stof felgende gselder: Udskilles i modermselk.
Mselk/plasma-koncentrationsratio er ukendt Hjertearytmier er beskrevet hos det ammede barn. Mselkenuengden
nedsaettes.
Kontraindikationer. So antiparkinsonmidler, antikolinergo side 255
Bivirkningcr. Sc antiparkinsonmidler, antikolinerge si­
de 255
Forgiftning. Se antiparkinsonmidler, antikolinerge si­
de 255
Interaktioner. Se antiparkinsonmidler, antikolinerge si­
de 255
Ik Iv B
Pakninger og priser
O inj.vseske 30 mg/ml, 3 amp. a 2 ml kr. 55,90
O tabl. a 100 mg, 50 stk. kr. 76,70

D

n.

Kl-

10

,5.
ce-

Norlsterat® schering,
Noretisteronenantat
Parenteralt kontraceptivum til kontinuerlig anvendelse.
Omtalt i afsnittet side 156.
Dispenseres i form af
.
injektionnuoeske. 1 ml indeholder 200 mg norethisteroni
enantas i ricini oleum. Tilsat benzyli benzoas.
Farmakokinetik. Efter dyb intraglutseal injektion ab­
sorberes noretisteronenantat over en periods pA 3 mAneIndikationer. Hormonal kontraccption med rent gesta­
gen, jsier i tilfmlde, hvor man skenner, at kvinden ikke
kan foretA eller husko at indtage en tablet dagligt
Doseringsforslag. 200 mg (1 ml) dybt i.m. i glutaealregionen. For at udelukke graviditet, nAr den ferste injektion
gives, anbefales det, at den gives inden for de ferete 5 dage
efter, at en normal menstruationsperiode er begyndt eller
i perioden efter en fedsel. De nseste 3 injektioner
med 8 ugers interval, derefter gives 1 injektion hver 12.
HgA-

ng
in-

er.
>0
Sl­

t

NormacoP schering, Komb.

~ r

Amning. Mselk/plasma-koncentrationsratio er < U,o.
Gestagcner kan give sendringer i modennselkens sa^
menssetning, nedsat mmlkemcengde og gymekomasti hoe
det ammede barn. Bivirkningerne er dosisafhtcngige.
Kontraindikationer. Tidligere tromboemboliske komplikationer. Se endvidere kontraceptiva, gestagener, parentcrale side 156
.
Bivirkningcr. Se kontraceptiva, gestagener, parenteral
side 156
f
Bemcerk: Behandlingen bor seponeres ved forstegangsi

A06A

Sammenaat afToringsregulerende middel.
Omtalt i afsnittet side 61
Dispenaeres i form af
granulat. 1 ml indeholder 430 mg bassorin, 75 mg frangulae cortex og 300 mg saccharum. Indeholder laktoee. Tilsat farve: Sukkerkuler E 150.
Farmakokinetik. Virkning indtrseder efter 8-10 timer.
Indikationer. Obstipation. Se endvidere laksantia, sammensatte side 61
Doaeringsforalag. 5-10 ml morgen og alien efter dlltideroe. Tygges ikke, men skylles ned med vand.
A mning. Udskilles i modermselk Kan give diard hos det
ammede barn.
Kontraindikationar. Se laksantia, sammensatte side 61
og laksantia med primner virkning pA tarmmotorikken si­
de 61
Bivirkningcr. Se laksantia, sammensatte side 61
og laksantia med primaer virkning pA tarmmotorikken si­
de 61
UdlvH
Pakninger og priser
granulat, 250 g kr. 52,45 1000 g kr. 169,30

Normlson® wyeth, Temazepam

o-

»-

rekomst af migneneagtig hovedpine eller hyppig forekomst af ussedvanlig kraftig hovedpine, akutte synsforgtyrrelser, tegn pA tromboflebitis eller tromboemboliske
forekomster, ikterus (kolestaae), kraftig blodtryksstigning og indtrAdt svangerakab.
UdlvB
Pakninger og priser
inj.vseske 200 mg/ml, olieopL, 1 amp. a 1 ml kr. 68,80

N05C

ling|
tolen
tome
dere
For?
de 26
Intc:
rolep
Udlv
Pak
kaps
kapt-

Nor
Din-J
On>_
Dwp
injek
(som
kape.
Indel
farve
mg),<
Blue
zin E
Norp
disop
171
Fare
mace
lig al
make
ningz
disop
Indi!
systo
flimr

Hypnotikum og anxiolytikum af benzodiazepingruppen.
Omtalt i afsnittet side 268.
Dispenseres i form af
kapsler a 10 mg eller 20 mg temazepamum.
Farmakokinetik. Temazepam fin des i oplest form i kapeleme. Det absorberes nsesten fuldstsendigt fra mavetarmkanalen og maksimal plasmakoncentration nAs efter
ca. 1 time. Hypnotisk virkning indtrseder i lebet af time
og varer ca. 7 timer. Metaboliseres i levercn hovedsageligt
til inaktivt glukuronid. En ringe del metaboliseres til den
aktive metabolit oxazepam, som ligeledes inaktiveres ved
kobling til glukuronsyre. Ca. 80% af en indgiven dosis
udskilles med urinen hovedsageligt som glukuronid. Eliminationen er tofaset: en fordelingsfase med en biologisk
halvtid pA ca. 1 time og en langsommere eliminationsfaso
med en biologisk halvtid i plasma
ca. 8 timer, noget
kengere hos mid re.
Indikationer. Sevnloshed. Se endvidere hypnotika og sedativa side 265
Doseringsforslag. 10-30 mg for sovetid. JEldre og sva^'elige. 10 mg.
Amning. Der foreligger ingen meddelelser vedr. udskillelse i modermselk. Bor dog ikke gives til diegivende de
forste 4 uger efter fodslen og kun med forsigtighed i resten
af ammeperioden.
Kontraindikationer. Depressive tilstande. Gives med
forsigtighed til gravide. Se endvidere anxiolytika, benzodiazepinderivater side 262

mgp.
time.
Infus
mulij
pr. k.
Total
1 *<'ror
mg h
letter
hand
trol. ?
hori a
Depo
deleft
Amn
lelse
ning
kan i
Kon<
dell*

Be/ncerk: Forsigtighed tilrAdes ved bilkorsel og maskinbe-

Biv»r

tjening.
Bivirkninger. Paradokse rcaktioner (ekacitation) kan
formentlig opstA, isser hos wldre. Hovedpine, svimmelhed
°g kvalme kan forekomme, men er i region dosisrelatervt.
Allergiske rcaktioner i form af urticaria er set. Behand-

For,
Udh
Pak>
Oin,

D<Mk

mg p
over
lobet
opstZ1
i.v. u ■

The DRUG DICTIONARY (of FRANCE), 19 85

48

( VIDAL t 1985)

A TRANSLATION OF SOME EXTRACTS
PAGE 963.

NORISTERAT
JNorethi sterone (enanthate)
INDICATIONS :

Long acting contraceptive to be used when it is not possible to.
use other contraceptive methods.
CONTRAINDICATIONS:

-- confirmed < r suspected pregnancy because of the reported poss­
ibility of sexual ambiguity of the foetus (of borh sexes).
— for lactating women because a small quantity of plasma
Norethisterone and/or one of its metabolites may go into
the milk.
Serious hepatic insufficiency; Dubin-Johnson syndrome/ Rotor
syndrome/in previous pregnancy a history of jaundice/ herpes
or severe itching.
— Hepatitis and recent history of hepatitis.
-- history of thrombo-phlebitis .
-- Arterial or venous thrombo embolic disease because of risks
which cannot be totally rejected.
— Breast cancer and endometrial cancer.
-- Undiagnosed Meno-metrorragies.
-- polycystic ovarian dystrophies/ estrogen dependent diverse
benign breast diseases.

SPECIAL CARE (TO BE AWARE OF):
-- possibility of pregnancy must be eliminated before the first
injection or before a re-injection in case of amenorrhcea
during the treatment.
-- there is need to be prudent in case of history of infarction
myocardial or cerebral/ diabetes/ arterial hypertension.
— thes return of fertility may be delayed for several months
after the theoretical activity of the drug.
— the. administration of the drug must be stopped in case of
increase of blood pressure/ change in hepatic tests/ change
in glycemia/ sudden obesity/ sudden migraines/ occular troubles/*
depression and chloasma.
PRECAUTIONS:
An initial clinical check up must be done and during the treatment
there is need for periodical check up with breast examinationt
uterus examination and vaginal smears.
INTERACTION WITH MEDICINES:
Simultaneous intake of Rifampicin# barbiturates/ some anti convulsantS/ phenylbutazone/ compromises the efficacy and
tolerance of the treatment by enzymatic induction and acceleration
of hepatic degradation.

UNDESIRABLE EFFECTS:
— Disparition o£ the menstrual cycle/ replaced by metrorragies
of variable Intensity or by amenorrhoea.
-- ponderal increase.
-- possibility of acne/ chloasma/ seberrhoaa/ increase in loss

IS

'

■

A

4?
of hair.
— aggravation of insufficient venous circulation in legs.
— gastro-intestinal troubles.
— possibility of cholestatic jaundice and itching.
— changes in breast.
— changes in libido.
— in some predisposed subjects# aggravation of depressive state.

<

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16 da- s un (M‘-u

M * 5U
t<A >

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f• ' 8
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au moprobamate

gnmme d* 1
'
•tercuha,
altopiUgh*. rt tfAj.t. v,.m.un

pemt. S<-c c*o< A 40 % . Co»ect.

- FOURNIER FRERES
Ph^m^a
' 9??51 ^FNNEVULIEAS

'*0'

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^ORGAGIL

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mart ••*• WA lOrvi
V

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FORME •' PRESENTATION
■■''■4 ' ‘'iram,7» .'7/Rn .< ,'io
COMPOSITION ;
P 100^
I
Gomnsu d« MuicuhA..............
Si. Q
■
AtUpulgre (s,f»cnUa n-aiu'minmm
O' t»*
m.iynu.srum)... .
I* g
.M6p;ci,?.mate ...
■
^9

H7l pr armaceu’.ques . T6! . {1) 79063-03

nZ.? k’?; b,^'Um”A «•

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Une ru.ru,,0 j, „.t £0,t„(,nl s , 0!? 3rnnof(>

nORCURON

SORT DU MEDICAMENT :
La gomme d© stutcuua
■X'’^;1!,;1"apu!(''", na
el sonl AhmriAos p,lr

Voir :

COMPLEMENT AIRE

■■

i
i

P .€

rc ei
tr>

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t

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■'

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(saumon cla:r)

ta»c

•LES .
if- lam.-cara^

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r»om,»^ iribi^ue. ••■naraifl o«

CONTRE-INDICATIONS •
Affectrons s>on,,a; h„,e

;aOk:»»

-■ >wfMT :
^^.nistralion oral© d i mg de noreth.sterone
,
j ^ures
*
• 0^' vo »? ora*© est b>nnas-aue avec une cnase
’*
00 »a demi-vie est g environ 3 heures et une
p___
ou la demi-vie psi ae ; omre de fi r.eures
.»
par IO lOie 01 oxcruie da is les urines jusou a

PRECAUTIONS :

bo-ssons .'ricooi'sees
pendant le traiien.en! r-j tr;f.;...,. ,.P i.
GfeConseillbfe
~ L iees a la tprese
----------r,ce
- oe gorr.me de siercuha
prudence on
on cas
<
de ;r.ugacd on par aWat.cn de U
coi.oue
•—par arerabcn de U moin.-rie
- Er. «s de d.ab«,«. I9n„
a,jn appon fle , j g 0(.

en progesterone

■ 'ni/cs FOjRr;|Ea H '
.le
Te

92231 '?D-c3-7^
D’-armaceuiq^^ •

INTERACTIONS medicamenteuses

adjutant ou ccmDiementaire de la chirur.
>
ai oes autres tranemen:s en cas de-cancer
•*« a« 1 •^domeir-.»

nemer.t ne oouvan! e.re excite i kP/,s SI m •Ji? laau.re n.ed.ear.um 'a d.s.ance ae
d'“'ni•'■'• tfAir - .■ .•;
| EFFET INDESIRA9LP • j x
I sensai.cn de baiionn^er.t abdomna?"' " 'M

.MfaC/tiOM

ou svsoecree en ra.son Oe la 0oSS,b,l,,e
M»«uPf.e ces ice (us des 2 se<es

»-

8n:\::Xe c£,t,^^
,vo<’,,s2
absorbed apresie r/eu,
™ *!. A 2.U,,?fe*s a

•*”-» r»nr-4-<>pr.leLiboues
. — r**^< 0 •« tonciion heoatioue

enf.?-

c-eu: t»H«s
Meme ie granule sec cans •a'tn’ 0,3 ‘nier,,t en ca5
ccns’fpat.or.
! verre d eau
S !a Ooucne 61 3vaief ^ns macner ^ec un

-**»
I* rason des risaues thrombo-em^
^o.'iaues e!
* •" ** ^uvem eve tota.emen: ecaf'es
— •w.-n.M.at.on en cas de surv-nue
«•'-• aue oene oe la v.s.on C’bicp.e
• • ••* ae ta it-i.ne

JT'oze.p.ne e, SOft)|to(

->N :

5r ite ae 24

‘

0 *

‘^’•l<vPrr»f.c.,QUo^

—< - .—Munh-s

1 p-vf-y.-J. ht-aa-

»•• e

CZL'i
• < tu»

•'

j Coui du tra loment jcurnaher ; 2.06 a 4.63 F.

j tableau
TABLEAU c.
IAMM
n .««•>«»
I a m « 3?.-> nta
^f.^2
(-g/e) ..
PRIX 3R 30 p Z A J’n
M,s sur 10 fna'ChA en 1931
PRIX ; 38.30
-r 3
SHD
r
rF *
H ' (PP'” de 375 g)
Aomb See Soc. a 70 % - Collect

''fneu. ou tnrombot-Ques ;

4m. Scents a mfarctiluS n»yocar<lioue ou c©re•’ de d abete

Laboratoires NORGAN
-1. rue de Mwnd - ,-S003 pARIS _ Til. : O) iz:.hi_;o

**kES;

•’• ’*jes a-T --ernee rsa-ynemenfs
tntercurrents
,----------------------------

A

-

w-

---------- -—•..

-

- - a^g men ration oe la pi'os.te
v"■,'i rp .'.'Oor.fM k'

- ~~^v.na^nr£ 'e,,'euc*e

membros mfeneurs

noristerat

1 -on e-et o«
’■' r t-

norethisterone (enanthate)

chu.es:a:ique e: de
Dfunt
.
■•'^T'a-res
*'**"»• :• hb.do
* oT’’*?
^gravat.cn d un eta: dement.

r

ev un a-~s^»»

FORME e! PRESENTATION •
so/uze .■;■ c:.1hle
Bcile Oe ,
COMPOSITION :
Nc^tnistemne (DC!) enanthate
£tco.^f benioxu 0© t^nryie. nuU©

jw» »i POSOLOGIE :

<?4A^rrT?r‘n'®s pa' j°ur
f c^.'.m©s paf JOur
( SORT DU MEDICAMENT •
?*
Cues 4 une a-roc-.e
1 e- enforcer
la dose

*

- *.

- C”

IPvrnaher ; 2.93 $ 7 34 F

1

.
1 * •’ S’’p.*9)
p \^rW'S Sur ,e rnarcbe en 1&59
■ S
p c
’
a
<'^CCrPr'mes)
* r>.
K
|
^^-Coi.ect

i *

8 Cr

••

es!

progress”emint.

ma**rc^«na.«eiqws

‘ i PRCPSiETES :
I

* ^.auon ..1U

4 l’‘'nHa"'. ...............-................. .

Ce3e.26
‘•'f—'.SE’- Tot (1)7,6-44-30

I
,iu

P A 'r.D.
200 mg

♦ an/

'^eMY-LONGUET

f ,v-l

i- OGiE :

arf ,

xi".’Xn°: x't?

poui s'opper les
> jours pour
1

«

.6.©,:

' ' ... ...... .

MODE D’EMPLOI et POSOLOGIE

4, •> *a- ■»*»• Q •i:?.TP'n*»nt

j-.i'atp

oe ™

'

uani ies j premiers mots n.- crOs^n^* -■

1

1 ■

. •—^r»-*

^marche pn 1R€fT>E So< r

’,n

-

' esl“

d« tvo** norsierotoe
.-v* •» * *?,*f sur ,a giairo cervical© aboufcssent a

. -. /' MS esd ie .t^
• 4

- ? o-

,...;

INDICATIONS :
Tranemum Symp,oma!,qu8 Oo, „lopathiec

p boite
J.20 g

■

0 75 a 1.51 F.

>

'
j

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^erb^r.

r»n«ioly|iqua

- ^—sparent:,! ne 9eufc

p comp
20 mg

a °ts..4,-l.on Oes

• ■! ''.no

Boite de 60

a 3 ..

0

r.t

1 4 •,
/1^ p msenrent ne ia
nv/queuw dtgest.vo Adson.* u.?.
j e* vv •• itini-s
Gon.rr.e t7H sre-cu/.a »nwc»lage

NORFORS'

«■ c ,e

sort:© par Ifj tractus
pnr ,<s !f5c,us sasm-^
•’' Gti 10 a *2 I'iMin li rst 6lir-,.:re a .. ,
'°us
1,6
tc-.

• >■ %
.. ..
; PAc..;iF-rs.

i

1 -

ms • ‘

T

CONTRE.INDIC Al IONS

<
*

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'xO.,-v6s

,'tfs
'tfS toxtes
/2.</e5

p^r ie \',>yistfe

f3 Same

■-? ■' ■—....

-

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s..t:„ ...^

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■

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MISE EN GARDE :
- La r>oss>b*hte d ure gros- esse dmi ^ue Alim»r.6e-f»w»»ulaj>remigre
rnjocnon. ou avant u»»h rHinjection en car. d amunorrheu pendant
le traiterrienl
-------------------- - r
- La prudence s'impose en cas d’anli'.cerfents d'lnfarctus myncard»que ou cdrdbrai de diatele. d hyperuKt»,io<i antrielle
- le reiour de ia ferfilite peul etre ni”ore pitisu'.tts mo:*, aprfes la hn
tn^onque de l activiie du produit
- intenompre t admints'.rat-on tiu prodint ph c js tp augmentation
anormale de la tr’nsjon vrpr.rtlie nud hrri'.nn ne'. It-SlS hepatiques. modificabon de irt •, rc“’T../.- Mavefi.p i tmp ncosue. survenue de migraines trout... s n< tna.ies elai o* piess.l, chloasma.
PRECAUTIONS :
Eflectuer un bnan cun.que 'nma e? one surve'iiance period-que en
cours de traitement. avec e*amen qes sems e: de Tulerus Irotns
vaginal
INTERACTIONS MEDlC AM: NTE'jSES
La pose simuttanee de ufa -pirme l-arbiiunques .ertams ant.convuls.vants (nya.rniomes). pnenyibutazone. compromet I'elfrcaciie el
la tolerance du trademem par induction enzymatique el acceleration
de la degradation hepatique
EFFETS INDESIRABLES :
- Disparinon du cvcie menslruet. remplace par des moircrragies
d abonoance variable ou par une amenorrhte.
- Augmentation ponderate
- Possitilne de
acne, chioasma. seborrhet, auamentahon de la
pilcsite
Aggravation d une msuUsance vemeuse des membres inf^neurs
- Troubles gastro-mtestmaux
- PossiDihte d iC’.ere cro'es:auque et de prunt.
- Modifications rr.ammaires
- Modification* de ia libido
- Chez certains sujets piedisposes. aggravation dun etat dooressit.

L

I

964

Oini. p de Holm . rtni4<.«»dt?nls d'tchwp gm.id.aun •d>o|>athigue
< r>i»nw; ur.Ki-1>Uo*> f.ij Qm pn.t.l q>AV'diquM sAvrte
H»t|M|nu hi
••dHi'ts mcuntt. d hupabte
AniM'.A-li-nts |.‘HOint>o phuM.ihquus
- Maladm'. lhrnmi>(> umbo qih”. atiiMiuiiijs ou vetnoiises. on rmson
riH<. tisQnws qiH rw« fMMiv«*nl ehe loi;«l«rnvnt nrntMs
- Cancer (lu SWti u! do I er».lomplrc
M<>r>c-tnA!rnitagH.-s non rimgnnst<QtiAes
- Dyslioph.es ovanenrxes pnlykyjutques. flections mamma.res
bemg'MtS d«verses esfrogeno-oeperwianies.

MODE D’EMPLOI et POSOLOGIE :
L’mjection sera effectuee par voie I M. pro'onde avec
une sermgtie
en verro
La premise mjechon don etre etlectuve en c
vyvi= VCIH,e
d'K.iul du cycia (entre le
• el le 5* jour) Les quatre prem-eies u■actions se.’ont orabcuees a
un intervene de a semames. les-d.f-ct.ons su.vantes a un mtervalle
de 12 se/names
.

TABLEAU A
A M M 323 86/ 6 (’982) - PC 40 - Mis sur le march** en '’083
PRIX : 29.80 + SH.P - Remt Sec Soc a 70 %

j

t
SCHERING
Z I oe Rojca x-Est
Rue de Tourers - BP 69 - 52390 LVS-LEZ-LANNOY
Tel
(20) 75-97-20

r
1

* NORLUTENS.

5

I
> f
i

TABLEAU A.
A.M M 307 349 4 (1961) - Mis sur ,e m •-• PRIX ; 10,00 F + S.H P. (20 com:,:. •
Remb. S6c. Soc. £ 70 % - Collect
Laboratoires GRCMY<0‘.
12, p'ace de la O*-'-'se
92090 PARIS LA DEr 9\S£ -

* NORMACOLSPS
(sans bou-Ca-ne,
gomme de storcubi

FORME cl PRESENTATIONS :
Grat>ul& enrnb& _■ Boltes oe 375 g e» 1 -g
COMPOSITION:

p luO g

Gomme da sterciiha............
fit
Exciptent saccnarote bic.nDonate a: — larirte tMencno. carbonwe de ea'Ctvm
v- r» • a--

SORT OU MEDICAMENT :
La gomme de stercuha n ost pes aiscr: e*

PROPRIuTES : La gomme de
de pfoprieies h/cirophilet eie*c.. ,
•
augmentant le volume oea sei.i?;
Delai d aetton . apres queiques jc^s 7.t .-a -s

CONTRE-INDICATICNS : Afr>c‘.'

p comp

I

5 mq

I

p boile
100 mg
go'nme a'at»aue stearate a*

SORT DU MEDICAMENT :
Le pic senque apres administration orale d i
mg de nor^thisterone
est obter.u entre 1 e‘. 2 heures
La cmefique du proddit par vo-e ora:? esl biphas que a zee une pnase
rap.de de distribuiion ou la dem.-v.e est d envircm 3 heures e: une
phase d ihmmat.on terne ou ia demr-vie est de I'ordre d« 8 heures
Le Nortuten est metaooi.se par le lo.e et .excrete dans les urines
ju*qua80%
PROPRIETES :
ProgestaM de synmese oe type no^steroide.
L efiet anbgonadouope et I e'’e: sur l« gla.re cerv./aie aboutissenf p
un eftel contraceptif
Compense I'msuu sanre kt K'oges:erone
Action anti-estrogene

a

MODE D’EMPLOI et POSOLOGIE ;
- Troubles lies a une tnsuH.sarx* «n ^iu^admimstratlor* Cyci.que . 1 ou 2 con .?• cycle.
- Hemorrag.es fonctiormelles : 2 a < co.■
par cycle, a rdpeier ftventue.n mem
vants.
- Endomeuiose : traitement contmu 1 a 4 rpar jour
Cout du traitement journaber : O.SO « 2 ?Z ~

PRECAUTION : Prudence en cat? Tr: - motneite coltqufc.

Boite de 20

COMPOSITION ;
No<ethisterone (001)...
E’C piant ae -bn ce nz lact'-M. i*«c
nvKjrteaium. gcT.r.e laaue

EFFETS INDESIRABLES :
— Modifications des regies, amermirn*?** «
— Acn4. chloasma, seborrhoe.
- Prise de po>ds
- Aggravation d une msulr.sance vetneuse c- Troubles gastro-miesimaux.
” Posr.ibilite d ictute cnoiesianque el Ju pr - Modifications mammaires
- Modifications de la libido
- Chez certams sujets predisposes

INDICATION : Traitement symrz' '»

nor^thisterone

FORME el PRESENTATION :
Cornprimes, sec.t! les (Llanes)

PRECAUTIONS :
- En (.as d hArrmrtag<<*s h,«i»h»“s Hl»
.
vdnfiA le diagnostic
- En raison des risques tiiromuo umi
-w<.
ne freiivenl Al'e lotaierr.iml oc.«rt<-s
mturrupl-on do I Mdir.wi.’.tratmn »»n tas r.
■ de troubles ocul.nres leS qu.* t>«' _
lAsmns vasculauvs du u i..!h «.
- d’ac cidHnls fhiomt>r>-i»ml'Cii<q....s
.
- de cAphaiees irnporianies .
- prudence en cas d anUke 'e"ts 0 »r»
Cdr^bral. d'hyperiens on et de d.ar.ett

INDICATIONS :
Troubi.-s lii'-s a une Hwy'-wK e n-’ proges.iurv,..
CPU* ol svi.vs en p.s.iKle d<urrioulrtritns mer.struv lus. •>,'..■imt: e pic•'./•••Ltruel
me )
- Hemorrag.es lonchonnitliex et .-nef»f»'rAy»fe? de*
- Eodometrm*^

n?-.-. '.munt
n./nrljs*
.n.i .")Cv

COSTAL f.o CATIONS :
- Gfjss.?$se tc .i’iue o.j SG.p.-c.v? en rmson ue la pc-.ss.L.btA
tegnalt-e d
j«te so» eit*
I«h-.:s nes 2 s.-*es
- Femmes en penoo*. d a « te i-cnt
- Ar.ter.edvntt thrumio .>t ■.•tn qj«.s
■ Allerai or:*
ce ta ' mcb..n h:-;..i|lqve

EFFtT INDESIRABLE : S^ntat-Gri

--

;...

MODE D EMPLOl ut POsOLOGlE • :. u
deux ou trois puncinaux repas
et avaler sans» .richer avac ..n .< -•. : ...".
Cout du iraitemant ;oumaher : 0 70 . ■ ■ z ~

-

VISA 311-16552 (1955) - M s sur
PRIX : 26.30 F (LoTte de 375 a) - 65.".C F
Remb. S6c Soc i 40 % - Cwl ect

Laboratoires N'C-G21. rue de Madrid ~ 7500& FAP.,f; - "j

* NORMACOL A LA SO
gomme de st^rcob., r/. ;...

FOAME el PRESENTATIONS :
Gran-jie enrobl Solies re 37£ g p. ' • •:

COMPOSITION:

•?. i

•“if iivrn- de Herri:h<T
• ’ <;
; flourda'.'ie p:jlv^»'‘,ne
£tcp-«nt
L»>*rix>‘>>*!v Je I
er*.v;p f
r
■
SORT DU MED'Ca rvtr. tlT :
La gou.-ne de s'ferc.jka r. es: p.:■•. . :
I **s antnraqwino'^S Ut u.
••
cfron pml Ab'em/.n
- ,
PROPRIETCS • GsM. m de
, .
mAca-.iqiie.
ce dmp.’.eh <
niunthiit 'v •o'w- e dvs i.e1 cs
Rr-r Jrt ne la*./ ! • • n.r.. ,

.

I

■7 '#J:"

4-i

American Journal of Obstetrics and Gynecology

«

i omulfd hi 1920

volume 142

mimlwr 6

part 2

March 15, 19K2

1
■?

CO-CHAIRMEN’S
WELCOME

s
■a

A perspective on progestogens in oral contraceptives
WH.LIAM N. SI’Ei.LACY

■3

I
■i

i®

5
.1
a
ir I?

I
2‘il

,9

Oral cos i rac.f p i i \'es arc now rcc<»gni/cd as the

;in<l prrgnaiKy raicN began in increase. Ai one cx-

most dice live means ol picvctitiiig pregnane s. The*
(lings utilized today arc* signifuantly different Irom

ucmc.a progestogen piejxiralion wiihout any rsirngeii
was introduced into die market plat c. but because <d

those originally entered into the market in die carb

poor cycle tcmirol ami an increased pregnancy tale, it

IVtiOs. and thee will probabh change again in the' third
decade’ ol ihcii use.
I IinIoi ie ally. steroid eont i aception was developed in
th< Lu I'J.’dls and introduced into clinical use- as a
high
combination estrogen and progestogen

nevei gained widespread use.
As we eiiler the third decade of oral contrace ptive
use in the HWOs. it is dear that some vascular cd Tec is <»l

<nal contraceptives |x*rsist despite die low estrogen
content of the current prcxlucts. It is now evident thai

|iu»<Iii< t m the* early HKiOs. Doling that liist decade,
'•ic onginal investigations lot used on the Ix nclit ol

the progestogens have* their own lyjKs <»l svstemic cl
Tee ls, and the international s\ inposiuni. dcse libcd in

P'cgnanc) prevention and the risk of abnormal cyc le
hkeding. Soon alter their widespread introduction into

Mil)scc|uciil pages ol this Jot knai . details a number ol

< iuieal medicine, it became apparent (hat those sle-

’’•ids had some adverse systemic cllecis accompanying
'licit use. ()HC ()| l|R. n)()S| significant of these was the
l,l(l< '< d lic(|ucncyol venous thromlx>sis and throm^hiuIxiIk disease. With data from several epideiniol“K’t studies, it became clear that the estrogen comjx)n<nt ol these drugs was associated with the thrombosis
l'"’I>lcin. I he scientific community then began a “tun1,11 'ision approach to mexlifying the’ steroid con'’•'^‘Ptivcs during the 1970s. In that second de•“k. .i scries ol products was developed that con-

11,1 d Nut.dler and smaller amounts ol estrogen until
0»v (
'Hem 30 to 50 pg oral contraceptives were deBclow those levels of estrogen, the hy|x>‘’’••I.IIIIK
piluitary suppression became less cffcctis’e.

studies concerning systemic elTccts ol the progestogens. Included in this list ate the elevation ol blocul

pressure, the alteration in set tun lipids with a pat tic ti
lar ellecl on decreasing the high-density lipoprotein^,
and (he ability to modify carbohydrate metabolism,

with the resultant elevations of blood glucose and

plasma insulin. The concern about all of these systemic
changes is that they may accelerate atherogrnesis and
result in clinical problems for the usci

As these new data emerge, the scientific community
will now Ix-gin to look al both steroid coin)x>ncnts used
in the oral contraceptives and will most piobahh modily the progestogen component in suhsc<|ucm prep­
arations to lowered doses of weaker ste roids. This
new lotus in steroid coni racepl ion will be the ImiicIimark lor future oral contraception.

717
t

I

I

?

/

i ^7W

"LA

*

' \

,

/

V ,^4

PAPERS
$3

Relationships between chemical structure and
biological properties of progestogens
at
■

IIEXR1 ROZENBAUM, M.D.
Paris. Praacc

P^e^ogeHs are classed In (hree ways: by chore,cal £,rucIure. by blo(

icE|

"

=C”

I’kouf.s i ogi.ss are usually classified in three ways—

a:
hs

according to chemical structure, biological properties,
anti alfmity lor hormonal receptors. However, it seems
ddh< ult to draw parallels among these classifications.
• s-.inple. most of the 19-norsteroids are androgeun. but some that Ixrlong to the hydroxyprogestcr-

°'iv group also have androgenic properties. Some pro-

gestogens with strong biological properties have a very
afhiuty fot hormonal receptors. Is it possible to
(‘A"' S°,nc ‘“"‘htsions about the biological properties

0 •' given ptogestogen from its chemical structure?
be answer is not easy.

Ihr substituent h, C-/7 jxisiiion seems lo be less iinpor-

luni. since an acetyl grouping or a ^-hydroxy group in
die presence of an a-mcthyl or ethinyl induces a binding aHinity to the progestin receptor.
An unsaturated grouping, such as cthinvl, increases
the progestational potency of the product.’2 If we add
an acetyl grouping to the molecule, the binding affinity
decreases, but the progestational |>otcncy increases,

probably because of a delayed catabolism. For example,
norethindrone acetate is considered more potent than

noreihindronc. The rr/nox^l of C-19 tnrihyt enhances
bmding to the progesterone receptor.12 but this modifi­
cation leads to some affinity for the testosterone recep­

Progestational activity

lai I*1 ,,,otfcsl;a’onal activity of a progestogen is re^Hosome functional groups on the steroid nucleus.
structure is a common feature for the
Red
C
‘i hgand to the progestin receptor:
Kroun,,|,g 'hC doub,c bo,,d or reducing the 3-keto
P decreases the molecule s binding affinity.'-'2

tor. I his is not the case for norethynodrel. probable
Ijecause of the presence of a A5 double bond instead of

a 44. Introduction of double bonds in A9 or in 49 and
411 enhances binding to the progesterone receptor'2;
houexet. this modification leads to a more marked
binding to the testosterone receptor, such as norgesuicnone. a potent progestogen with some androgenic

activity..-/ lOa-methyl (rrouf) instead of a 10/3 enhances
/

/hr Cna.r dE/udr r! dr Trailrmr,,/ dr la
•' aofmusr a t'Holdlal Antoinr Brclrrr, Pari,.

,le',ri Ko^nbaum. M.D . Auti„ Che!
Faculte dr Mrdrcinr dr Pans, 15, Bur
l^ru, 1-75008 Pans. Fra,ter.

piogcstational activit) of the compound. l)\<liogesicr-

one. in spue of a decreased binding activitx to the pro­
gesterone receptor, is a more |X)tcnt progestogen than
progesterone. A mrlhyl frrouf, or a halogen grouft intro­
duced at l»oMlion C-6 leads to an increased progesta-

? <-,378/82/O6O719^06500 60/0©
I9K2 The C. V Mosby Co.

719

.

' ■ <linnc 142
\ untlxT fi. Pari 2

fl
■ JIN

Chemical structur© and bioiogfcal properties of progestopens

androgen, and glucoconicoid. X-ray crystallography7

has revealed the flexibility of this steroid, which seems
to possess a certain degree of overlap with conforma­

tions of testosterone and progesterone.
■

723

some metabolic effects.-4* These effects may be due to

the androgenic and/or the glucocorticoid-like activity”

of this compound and may result from the Ga-melhy!

group of this steroid.

■V’’

Metabolic effects and chemical structure

\ gicat deal of attention has lx*en Icx uscd recently

on the metabolic effects induc ed by progestogens. Main

areas of investigation follow.

Another question arises about these drugs. Some
progestogens act as pnxlrug. In other words, the liver
wil’ have to convert them into anotiier prcxluct. Is this

additional liver work desirable/ Is it not more advisable
to use the efficient progestogen directive

Hepatic dysfunction. High dosages of some proges­

>

togens (norcthindrone or lyncslrenol) may increase

Comment

serum transaminase levels'6 or the bfomc>suIfophtha­

It is difficult to draw any firm conclusion alxjut the

lein (BSP) elimination rate™; however, megcstrol acc-

i.iic-. even at 20 or 30 mg/day. fails to produce any

:lf•><lili<ation.*‘, By a parenteral route, medrox jnoges-

1

i. M.iic acetate increases the BSP elimination rate.’’4

■M/.{

<I1
s

Hypertension. Norcthindrone acetate al 30 mg/day

"‘•I

inc leases set urn renin substrate and renin activity.10- "

Ihdi ogestcroneat 30 mg/dayor megcstrol acetate al 15

mg/day docs not produce these effects.10 Mcdroxypro-

gestcronc acetate- inchit cs hypei te nsion in 2T5? of cases.4
I he-

Royal College of General

Pi actitioners’ study

showed a correlation between frecpiency of hyperten'•

•‘"<1 P’ogcstogen activity of oral contraccplives.x‘

Lipids.

19-Norsteroids decrease the high-density

lipoptotc in < holcstcrol * and triglyceride levels.19- 2"

I m <1 iii c oinbination with estrogens, norgestrel inhibits

the triglyceride increase prcxluccd b\ estrogens, while

■i

mcgcsirol acetate enhances the estrogen effects?7

Carbohydrate metabolism. A decreased glucose tol-

S jff •

rance- and an increased serum insulin have lx*eh re-

sx’itc-d with some lO-norsteroids^ 40or with medroxy-

"■>< 'terone acetate? The metabolic effects produced

l"'»gc*stogen are dose-dependent and arc observed
’t'atnlv with 19-norsteroids or with medroxyprogeslcr-

“"i ■'< etale. I he 1 7a-cihinyl group seems to lx* rcs|xm"tble loi sonic metabolic effects of both progestogen and

chemical structure and biological properties of proges­

togens. One is tempted to state that androgenic ac tivit\
and adverse metalxilic effects arc linked. We must re­
mem lx-1. however, that a lew years ago some inves­

tigators thought that the inhibilon ac tivity of proges­
togens resulted from either an in vivo conversion to

estrogen or an androgenic effect at the hypothalamohypophyseal level. We know now that lx>th 19-norsie-

roids and 17a-aceloxyprogcsterone derivatives c an in­
hibit the luteinizing hormone icsjxmsc to luteini/ing
hormone-relcasing hormone.7 In other words, some
progestogens do not need any androgenic or cstio-

genic activity to inhibit ovulation. We must rcmcmlx i
that a slight modification of the steroid molecule can

lead to great differences in the steroid s metabolic ef­
fects. 1'iom a chemical |X)im of view, there* arc very lew
differences between norethynodrel. a steroid with es­
trogenic effects, and norcthindrone. a steroid with an­

drogenic activity, and Ixtwccn lyncslrenol. a highly |x>tenl inhibitory progestogen with androgenic activity,

and allylestrenol. a steroid devoid of any inhibitory oi
androgenic activity.
In essence, one must consider each progestogen
separately. Io know the propeities of a given proges­

togen we must use* chemical classification, hormonal

vMtogcn. Medroxyprogesterone acetate, however. dcx*s
l"” b-nc such a side chain and is still able to induce

:i
?;ra
‘•sH

. ’1

I

bd
' L/i

.K

ii I
%-----

not least) the clinical findings in women.

REFERENCES

■J C

JO

receptor studies, animal biological tests, and (last but

'

,K...... .
K . Ja.,ne. <).. Vink,,. R.. C1 a|.: Progeucrone’Hiding proteins, m vitro binding and biological activity of
diHcrent steroidal ligands. Ada Endmrinol. 78:57-1
19/5.
l-'biie. E.. Ecrland. L.. Ugace. L.. et al.: High inhibitory

•'divity of R 5020. a pure progestin, at the hypothalamic
•Hk nohypophysial level on gonadotropin secretion Eei"I Steril. 28:1 101. 1977.
•-''ne. I).
(rtilab, 1 ., Arai. K..rt al.: The metalxilic fate

oralh administered 31 i-noiethynodiel and 3H-noreth"kIione in humans. Biochem. Pharmacol. 12:905, 1903.
* ""•m. <• : Dc|M»-mcdroxyprogcMcrone acetate as a c<»n'•."c-puve agent: Its eflect on weight and blocxl pressure
Am J. Ohsift. Gvni.goi.. 114:97. 1972.

5. lamgcojx, C.: Anchogcn and estrogen conversion ratios
in aging women. Mauiritas 2:13. I9H0.
b. Mazaheri. A.. Eotlierby. K.. and Chapman. J.. Metabolism
of lyncsUcnol to norclhisicrone by liver homoL’cnate I
Endocrinol. 47:221. 1970.
7. Mornon. J. P.. Iklettrc. J.. lx*picard. G.. et al.: Interac­
tions of hormonal steroids. Progestogens. |. Steroid Bioclicrn. 8:51. 1977.
K. Mukherjea. M.. et al.: Mfcct of medroxyptogrsieroncat rtaie contraception on human scrum rn/vmvs I nt I
l et til. 26:35. 1981.
'
J
9. Nash. IL: Depo Prove t a. A review, (amtiaieption 12:377
1975.
10. Oclkcrs. W.. Schonrshofer. M .and Bhimel. A.: Eflrrtso!
progesterone and four synthetic piogcstogens on sodium

WORLD HEALTH ORGANIZATION
i

PDT/D1784.3
ORIGINAL: ENGLISH

ORGANISATION MONDIALE DE LA SANTE
•G

DRUG INFORMATION - JULY-SEPTEMBER 19R^F

t;-

J

CONTENTS

I

GENERAL POLICY TOPICS

1.
(

II

Harmonization of advertising and labelling requirements

1.

Injectable Contraceptives (II)

2.

Beta-adrenoreceptor antagonists and retroperitoneal fibrosis .... 12

7

III

RECENTLY-APPROVED PHARMACEUTICAL PRODUCTS

IV

OTHER RECENT REGULATORY DECISIONS

i.^ue

formal

3

REPORTS ON INDIVIDUAL DRUGS

(

The

ge

1.
2.
. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27 .

Anabolic steroids..............
Aminophenazone ................
Amiodarone
Aspartame......................
Buprenorphine
Carbadox ......................
Combination products ...........
Dapsone and pyrimethamine
Epontol
Feprazone
Glyceryl trinitrate
Hydroxyquinoline
Indalpine......................
Isotretinoin
Ketoconazole
Latamoxef
Methyldopa
Methyltestosterone and testosterone
Metoclopramide
Mianserin
Naproxen
Nitref azole
■ . . .
Paracetamol
Pentazocine
Phenacetin
Piperazine
Piroxicam......................

of

document

this

publication,

It

quoted

agreement

of

the

World

Authors alone

<are

responsible

in signed articles.

or

. 29
. 29
. 29
• 29
- 29
. 30
. 30
30
30
30
30
30
31
31
31
31
31
31
32
32
32
32
32
32
32
33
33

doci not constitute

Ce

document

not be reviewed,

II

ne doit faire

should

abstracts d.

16

translated
Health

without

the

rdsumd

Organization,

for views expressed

ni

I'autorisation

;

Santd.

Les

ne

constilue

d'aucune

de

pas

une

publication.

I'objet d'aucun compte rendu ou

citation

ou

I'Organisation

opinions

exprimles

signds n'engagent que leurj auteurs.

traduction

sans

mondiale

de

dans

articles

les

la

r-S

PDT/DI/S^-^
page 7

II

REPORTS ON INDIVIDUAL DRUGS

in
either
resulting
information on decisions
section provides background
This
the
For
States
.
in
Member
of specific products
wi thdrawal or restriction in the use
review of
this information is difficult a short
countries
where
access
to
benefit of
relevant published literature is provided.

1.

INJECTABLE CONTRACEPTIVES (II)

progestogenic contraceptives,
of the injectable
:
The efficacy and short term safety
(NET-EN), were
enantate
norethisterone
and
(DMPA)
depot medroxyprogesterone acetate!
case
with other
is
the
bulletin.
However, as
t
discussed in the previous issue of this
that will ultimately
safety
in
the
longer
term
steroid contraceptives, it is their

determine their future use.
DMPA has been registered for long tens contr.cept.on when
Within the past two years
or unacceptable, in Sweden and the UK, while both DMPA and
other Mnethods are inappropriate
In
this purpose in the Federal Republic of Cerroany.
■
lfl
ve
been
accepted
for
this purpose in the teueia
NET-EN have
scientific experts, has now
a Public Board of Inquiry, composed of invlte^
contrast,
» evidence does not provide a
the US Food and Drug Administration that the available
advised t
marketing in the USA (1).
nt basis for determining that DMPA is safe for general
sufficient basis for
restatement of a position
In essence, the report of the Public Board of Inquiry is a
that all contraceptive
requirement
It derives from a formal
previously adopted by the FDA.
rodents,
dogs
and
monkeys
(2) and that any
dogs
drugs must be tested for care inogenicity in as constituting evidence of lack of safety,
be
regarded
positive findings must, de facto,
contest the
the validity of applying these
Other national drug
regulatory authorities
guidelines to steroid hormones.

(

considerations at issue, and to
It is thus timely to provide a brief account of the
in countries where injectable
pidemiological
data
generated
review these in the light of e
contraceptives are currently in use.
Exnerimental careinogenicity__da£a

Rats

(

•13

i the rat.
NET-EN,
KET-EN, however, which is mainly
in
DMPA is not demonstrably carcinogenic
animals and in women, is predominantly
estrogenic in
l
progestogenic i n other laboratory
it enhances hypophysial prolactin sec ret ion.
Predictably,
in
this
species,
rats.
Given that
of hypophysial and mammary tumours.
This, in turn, favours the development
have been
are a consequence of oestrogenic activity, and that they
t h e s e t union r f.
of the
major
portion
ly following massive dosage over a
demonstrated i n clear excess only
to the
relevance
been
argued
that
they
are
unlikely
to
have
has
life s pan, it
Less
of benign and malignant
use of
of NET-EN
NET-EN (3).
(3).
Less predictably,
predictably, the
the yield
;
cont raceptive
also
increased
among
rats
receiving
NET-EN
and another study, i n
hepatic tumours was also increased among rats
is
now
in
hand.
which norethindrone is used as a positive control,

1J compounds in rodents
the vagary of testing the carcinogenicity of steroid
In any event,
commissioned by the United
;’1V been demonstrated in a series of studies coramis;
has previously been
The fortuitous use of animals from moie
Kingdom Committee on Safety of Medicines (4).
strain-dependent variations
posed
the
existence
of important
than one breeding colony ex
in response.

Beagle dogs

and malignant breast tumours,
Dose-relat ed i ncreases in the incidence of benign have been described in beagle
and
adenocarcinomas,
tumours
inc lading mixed mammary
of 1-25 times the contraceptive
bitches exposed for up to 7 years to the equivalent
this
dose
of
NET-EN)
(5-7).
dose of DMPA (or 1-40 times

J

if-

5" 7

PDT/D
page

PDT/DI/bH.3
page 8

haems
Ac e t v
admin
haemo
serum
been

Whether or not the beagle model is appropriate for carcinogenicity screening ,
All progestogen
progestogeus has been a subject of debate for 10 years (8).
including progesterone, have been claimed to produce these lesions provided that thare administered over a period of several years by an appropriate route at high enou,
have not been induced in rats or monkey
dosage (6,9,10).
Corresponding mallignancies
„
This has aroused speculation that the basic subcellular mechanisms determini:
biological responses to progestogens are distinctive in the beagle bitch (10).

32. t:

* » atypic;
Critics sceptical of the relevance of the experimental findings point to the
hormonal mechanis;
pattern of estrous activity in the dog, and to the unr<epresentative
,
controlling these changes (11-13).
The beagle differs profoundly from women in i:
sensitivity to specific progestogens and estrogens (14) and in its metabolic a
target-organ responses to these compounds (15).
A number of substances that ha
potent progestogenic effects in women display predominantly es trogenic activity :
beagles (15).
Among the more apparent discrepancies in response• is the capacity (
progestogens (unopposed by estrogens) to produce endometrial C}ystic hyperplasia
toxicological
tests
are
oftbeagles
to
the
extent
that
animals
used
in
hysterectomised to obviate pyometra.
Other metabolic disturbances that develop amo
these animals are expressed by anestrus, obesity, anaemia, increased production •
growth hormone, acromegaly, impaired carbohydrate metabolism, multiple endberinopath

The I
not b
di seas
block)

/ (See I

(f 33. Tr
The Ur
more t
ant ide
infonr
i mined i

£See P

glomerulopathy and thromboses (5-7).

•

The view of the United Kingdom Committee on Safety of Medicines, which is shared
other drug regulatory authorities within Europe, is that the mammary changes in t
beagle cannot be regarded as indicative of a significant hazard to women, and that t
use of this model for long-term testing of contraceptive steroids should not
regarded as a mandatory requirement for registration purposes (16).

The F(
inform
va1 pro
admin i
di scon
c onvu1

The FDA Public Board of Inquiry, however, docs not make concession to this view.
1
not contesting the thesis that the potential to induce malignant mammary lesions in t
beagle is shared by all progestogenic substances,, its report concludes that the
lesions cannot be disregarded as possible indicators of risk.
It points to a num er
similarities in the epidemiological and biological characteristics of malignant mammi
neoplasias in the dog and the human including their age specific incidence (17), the
relationship to ovarian hormones (18) and their possible common derivation from duct
epithelium (19).
Too little is known,
it argues, of the mechanisms by whi
progestogens produce these lesions to justify rejection of the evidence.

See I’D-

Rhesus rnonkevs

34. VA

Both nodular mammary lesions (20) and endometrial tumours (20,21) have been identify
in female rhesus monkeys injected regularly for periods of up to 10 years with DMPA
dose .
NET-EN nt up to 50 times the normal contraceptive dose.

(

changes in the ductal epitheli urn - va riou«
The manirna ry nodules and hyperplasticprecancerous lesions
les ions and care inoma-i n-s)
benign
nodular
hyperplasia,
described as
the mid-dc
(22) - were demonstrated exclusively in several monkeys that received
cone 1 u<J
the
UK
Licencing
Authority
has
to
DMPA.
An
expert
advisory
panel
(xlO) of
rend
a
prop,manive
done-related
effect
that «pre J r. fl d i f fercnccfi and tlx* absence of
Boa rd
(22).
However,
the
EDA
Public
use
lesions
irrelevant
to
contraceptive
these
felt that changes resembling a prvcancerous human lesion could not
Inqui ry
discounted , particularly in light of the apparent resistance of monkey s to agents th
induce ma 1ignanciea in breast tissue of other species (1).

Anyone
invi ted
The rape
Switzer

Final autopsy ol the high-dosed monkeys revealed that two (of 12) animals in the DK
study and one (of 12) in the NET-EN study had developed poorly differentia'
adenocarcinomas, generally considered to be of endometrial origin (21), although th
precise cellular origin is disputed (1,21).
There is broad agreement that these lesions are likely to be drug-related, particul*
since spontaneous endometrial tumours in the Rhesus monkey are excessively rare I
Notu lhelcsfi, their relevance to women has been questioned because they occurred only
the atrophic endometrium of high-dosed animals (21).
In women, carcinomatous chan
rarely develop in an atrophic endometrium, but they have been described (23).

PDT/DI/84.3
page 9

ihe FDA Public Board ot Inquiry stresses, howver, that insufficient animals were used
lesio
u,11 K reas°nobl® confidence the possibility that the experimentally-induced
io ke,
i induced at lower dosage.
It also cites evidence that the Rhesus
orocroo7 b
relatively unresponsive to progestegens.
Finally, while conceding that
ehdometrium" i^
"Hnically in the treatment of hormone-dependent cancers If the
endometrium, it considers that there is no basis for excluding the possibility that,

diffemrCsages^ffk'08811"

parad°xical effects °n the neoplastic process at

Human Epidemiological Data
Fundamental disparities in the assessment of
toxicological evidence among national
regulatory authorities are exceptional. Attitudes are preconditioned to
some extent in the
USA by an earlier FDA conclusion, fformulated when
an application to register DMPA as a
contraceptive was disallowed in 1978,, that a fli
lignificant patient population in need of the
drug is lacking in the United States.’
Caution may also be engendered by awareness that the
carcinogenic potential of prenatal exposure to d
diethyl
iethy1st
stilbestrol
iIbestro1 and of postmenopausal
estrogen replacement therapy was first identified in patient populations.

Ip any event, the practical consequence of the
recommendations adopted by the FDA
Public Board of Inquiry - on the assumption that
they will be upheld - is that
progestogenic injectable contraceptives cannot be introduced in
the USA until such time aa
direct evidence is generated elsewhere
Chat their long-term use carries no significant
carcinogenic hazard.
f
'
Epidemiological
proof of their safety, collected in accordance with
recommended guidelines (24),, would take many years to
assemble.
A prospective evaluation
now in jprogress within New Zealand,
for instance, will not
completed until 1990; even
then, the women most recently recruited into the study will behave
been followed
for only
five years.

Much of the earlier published information on the occurrence
of hormone-dependent cancer
in women who have used cither DMPA or NET-EN is uncontrolled, <
and it relates largely to the
consequences of relative short periods of use and follow-up (25-37).
None of these data
definitively excludes a significant drug-related risk, and two
» apparently positive findings
have attrzicted particular attention;

Cervical screening ol
of more
more than
than 1000
1UUU
women enrolled in a clinical study of DMI’A
1000 women
undertaken in the USA
provided
an
incidence
2-3 times
USA provided an incidence of careinoma-in-situ
greater
an expected (26,35).
It
It is
is likely,
likely, however,
however, that known risk factors for carcinoma of
the cervix were strongly represented within the group (37).
Moreover, half the
with positive cytology had first received DMPA less than 8 months earlier, in women
which
case the change s may well have antedated exposure (38).

((

Three deaths from breast cancer were reported from Canada
among 583 mentally retarded
women who had received long-term treatment with DMPA
ith DMPA (33).
This is some 25 times
greater than the expected incidence in a
comparab1e age-cohort in the general
population (22).
However, other risk factors are evident within this group; not only
were many of the women nulliparous, they had
also received prolonged ttreatment
rca tment with
psychoactive drugs and ant i c onvulsants.
3no.se early data are now placed in more secure
perspective by preliminary data obtained
from Kenya, Mexico and Thailand within the
context of a multinational, hospital-based case
control study conducted under
the
auspices
of
unde
the World Health Organization,
The study is
designed to
to assess
assess the
the influence
influence of
of DMPA
DMPA and other steroid contraceptives
on risks of
neoplasaa, including breast:
breast and cervical cancer (39),
and this interim analysis i s based on
a total of some
some 250
250 cases
cases of
of cancer
cancer of
of the breast, 450 cases i
of invasive cervical cancer,
and a larger number
The
number of
of controls.
controls.
The findings relating to
cancer of the breast a re
consistently ---reassuring: overall the frequency of the disease wa s
lower among women who had
used DMPA (relative risk
0.7;
isk 0.7; 95X con f i denee interval 0.4-1.2),
and thi
this reduction \ju s
greatest among women exposed f or mo re t h a n 36 months
and thou c aged over 30 years nt t he
time of first exposure.
In contrast, the Ircqucncy
frequency of
of invasive
invasive cervical cancer
was slightly increased among
women who had received DMPA.
Overall, thia increase i
DMPA.
was not significant and no clear trend
Of ln
i /Jei‘fln£ riGk witb duration of use was
use
Nonetheless, the highest irelative
risk (2.20;»* 1.15-4.21) was recorded among a i ; evident.
among
sinn 11 group of women exposed for more
• than 5

page

10

pdt/d:

page

haems
Accty
adnii r.
haemc
se run
been

32.

Pie

not
di se
bloc
(Sc<

<

33.

Pie
moi
ant
in!
irm

years. a similar estimated
among' lonr-r*™ " estlmated increase in i ’ ‘
risk for invaSive cervical rusers
of c
WO ConaborativeUS
"SudOf
cancer has been report,
Study (1.53/
steroid contraceptives,
prospective studies
(40)
. both within the sa,
and within three
other recently-report,
Cervical
cancer is common,
of cancer in
women (44).
Even in some developing rcountries it is the _
WldelF used will give
a small increase in riskTc"
Sequent fo,
rise to -bstantial numbers of add ti"??!?^
associ8ted With
with a drug that j
15 liable to be ~
numbers
of
delayed when
cases. F 0"0/^- <iia8nOSi
cytological scr_
normal Hmenstrual
'”enStrUal patCern i» disr^ted'
reening is itpracticabre™
i
disrupted and when
association with
However
Pren,ature to conclude that
-a injectable “
c- "t^ceptives^arbeen'establish
it would be dproin the epidemiologic
been established,
that
conclude
aI data
-- as yet assembled that it is no
oral contraceptives.
no indicati
that injectables
are
ess safe than
than combine
It still
remains possible that c
"
excess of cervical
r_. .
confounding factors are
cancer reported in these
readily adapted
responsible for the
. -J and <
various studies.
spparen
to examine
u’°rk is a iready in extended
Fortunately,
the WHO study i,
the
risk
of
cervical
hand to include {
in fee t ions
--1
cancer
in
greater depth
possible risk factors for serological tests for
herpes and j
study, and to
PaP i11oma viru:
analyse separately data c cervical r
neoplasia
in
subsequent
ond on the various
°n the various histological t
phases of th
-J types and dosages of
marketed steroid ctypes of cervical c—estrogens and
cancer,
contraceptive
progestogen
• ‘Tod the results will be’
products.
*S ^frently contained
High priority
- .. v. J 11
is being
-- -a communicated at the
accorded
to
these
’ earliest
studiei
opportunity.
e f e re n c e s

1 . Report
of the Public
1984.

(S

.

Berliner

VR.

contraceptive

3A

US Food
product s.

it

v;
3i

d
C

S

(

and

Inquiry on Depo-Prove ra,
US Food and Drug Admini
st rat ion,

Ibrug

Administration

ActaLEndocrinologlc

Requirements

ffOr
VK

'oxicity

testing

of

--- 1974; _75 (supplement
Neumann F von
185): 240-265.
Hcrnswordt-Wallrabe R>
Steinbeck
Elger W, Graf KJ
H.
Special
problems
Hasan SH, Webring M, f\l
cont racept ives.
toxicity
Niahino Y,
-£l£JLn d oc r i n o 1
of
long-acting
• 2^ (supplement 185):315-354?
?.
o'epot
4 . Coinnii 11
ee on
Safety
of Medici nes.
London, HMSO,
Care inogenic i ty
1972.
tes ts
of ora 1
cont racept £ves.
5. Long-to rm
Depo-Provera
S t udy
in
dogs.
be ve 1 oprnent
Final
Corporat ion 1976.'
report.
International
Research
and
6. Ung-tenn
Depo-Prove ra study in dog
Final report.
Dawaon Corporation 1982.
/. Long-term
t
...
toxicity
st udy
of
SH 8.0393
rp-ternationn]
(
(Norothind
rone
•• 1 Research and
Deve1opment
enanthate)
in
female
Corporation
dogs.
-..a 1983.
8. R‘o rkshop
on anima] rt e .*; t i ng v
’■••qu i regents 1 OI1 • ‘•a: io-;.-.]
I n.1 I i f.ufes3 of Health,
n,,w generation steroida1
• April 27-29, 1 983.
contr.Tcepi i vrs
9 e Fran I
Kiy"n KT, Murchison Tf
,
bitch
‘•J*
Mninmary tumors and oerum
'with
medroxyprop,,;.
L'.J.jJ.1 i I1^-^L£t<-Z2_LLt^
V Hud cif-I.
roH340-346f St f’; on(.•
hormones in the
1979.
32;
acetate or
3.

p

Board of

progesterone

JO. Hligge

■IH.
e t_y r in.i rv

1 1 • Sh

Frogestogm
■s
and mami!-j rv
e £££ ] 9 3 0 ; 28.199-202e

t UirKitj7 s

in

the

beagle

for

bite h.

four

years.

M2£rl£ch_JJj

rt

■ oo 1

i c. a 1

12. Owen ].N, hrigK.;
MH.
re 1 e v.i nc e to
human
j£.- 309-379.

J

a n i ma 1 s .

Cont raceprive
steroid
enreinogenicity.

ttoxicology
—
d i cal
——
_J

in the beagle
bitch and
Rose a r c h a n d £pinion !; its.
19 76;
X

-.t-—- ——

(p 0

PDT/DI/84.3
page 11
13. El Etreby MFA,, Graf KJ, Beier S, Eiger W
Gunzel P, Neumann F.
Suitability of the
beagle dog -as <a test model for the tumori»<?nic
potential
of
contraceptive
steroids; a
short review. Contraception 1979; 20:237-746.

14. Graf KJ, El Etreby MFA, Richter KD, GiinzeJ p
of different progestogens in the beagle bit^h.

Neumann F.
The progestogenic potencies
Contraception 1975; 12:529-540.

15. Graf KJ*, El Etreby MFA.
Endocrinology of '^production in the female beagle dog and its
significance
in
r
——
mammary
gland
tumourtjgenesis.
Endocrinelogica
Acta
Endocrinologica
1979;
90
(supplement 222):l-34.

16. Coinrui t tee on Safety of Medicines, United Ki^gd
om. Open coumunication to WHO, 1979.
17. Schneider R.
Comparison of age,
cancer. Cancer 1970; 26:419-426.

sex and

18. Owen LN.
A comparative study of
Cell f-athology 1979; 2:257-275.

canine *nd human breast

cancer.

19. Fisher ER, Gregorio RM,
Cancer 1975; 36:1-85.

et

of

Fisher

B

a 1.

20. Long-term Depo-Provera Study in Monkeys.

incidence rates

The

pathology

Finn)

Report.

Investigative

invasive

breast

International

Development Corporation, 1979.

I

in human and canine breast

and

cancer.

Research

and

21. Report of a WHO Consultation to review hit(
fological data from monkey studies relating
to progestogens and uterine malignancies, G«rneva°
, February 28, 1983.

I

22. Report of the Panel of Persons appoint*-/’ by the Licensing Authority to hear the
application by Upjohn Ltd for a Product Licence to market the drug Depo-Provera as a
long-tenn contraceptive.
UK Department of
Health and Social Security, The Government
Bookshop, 1984.

n

t

23. Bokhara JV.
15:10-17.

Two pathogenic types of endomt-.* riai carcinoma.

Gynecologic Oncology 1983;

24. Guidelines for documentation of epidemioloj/j
’• c studies.
Epidemiology Work Group of the
Interagency
Regulatory
Liaison
Group.
>American
Journal
of
Epidemiology
1981;
114:609-613.

(

25. Schwa 1 lie PC.
Experience with Depo-Prover* a s an injectable contraceptive .
Reproductive Medicine 1974; 13:113-117.

26. Schwallie PC,

Mohherg NR.
Medroxyprogesterone
Advances in Planned Parenthood 1977; 12:36-43.

Acetate;

An

injectable

Journal of

contracept ive.

27. Rail HJ, van Nickerk WA, Engelbracht BH
ai.
p
Comparative contraceptive experience
with three-month and six-month medroxypr6Keaterone
-- • acetate regimens.
Journal of
Reproductive Medicine 1977; 18:55-60.

28. Zanartu J, Onetto E, Medina E, Dabances
A.
'
Mammary
gland nodules
cont inuous exposure to progestogens.
Contraption 1973;2:203-212.

29. Pena-Delgado J, Aleman-Hcrra M, Baez-Reyet a
Long-term use
acetate in contraception.
Sem.mario Medico Mexico 1981; 98:331.

of

in

women

under

medroxyprogesterone

30. McDaniel EB, Pardthiasong T.
Incidence of
breast nodules in women ireceiving
i L. o multiple
doses of medroxyprogesterone acetate. Jou£2£l of Biosocial Sciences 1973; 2:^3-88.
31 . Greenspan AR, Hatcher RA,
Moore M et al.
,ne association of depot-medroxyprogesterone
acetate *and breast cancer. Contraception 19^0; 21:563-569.

32. Liang AP, Greenspan AR, l.ayde PM et al.
,r'
^i»k of brenot, uterine corpus, and ovarian
cancer in women receiving medroxyprogesterone
.J injection.
Journal of the American
Medical Association 1983; 249; 2909-2919. ’

1

?!
*tS

fef'
H

i

1T:

I 11
; 1i
|

II

I

II

;|| a

SPECIAL PROGRAMME
OF~~’
RESEARCH, DEVELOPMENT
AND RESEARCH TRAINING
IN
’——
HUMAN REPRODUCTION

?

If
T
■f

jm
fe.

ii-

U:

FW

it
Fife:
I®
IBs

i
:•

?■

fewv
iw'

>■’

t

I#

■

'■

i

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K

II

IW.
Il-O
''
fc

FOURTEENTH
ANNUAL REPORT
1985

I

Mi

JI

uttu .
'.^<

'tefe!:

1

" '* '

■

I? .■??. ■'

X- •■

WORLD HEALTH ORGANIZATION

F
R

a

d

<■

K'
&

'0

Kvi

■i j'■■■...

^>N'

i/'L

»■.

.

.

.

L

..

.

- n. . .a.

•

i.

■

«■

!
FOURTEENTH ANNUAL REPORT

<

then has approached suitable industrial
partners
to
share
the
product
development costs. During the past 14
years more than 60 drugs and devices
have been made available to the
Programme for testing in clinical and
preclinical studies from more than 30
companies in some 20 countries. More
than 30 formal agreements have been
concluded or are under negotiation with
25 companies in such countries as
Australia,
the Federal
Republic
of
Germany, Finland, France, Japan, Mexico,
Netherlands, Switzerland, the UK, and the
USA.

Furthermore, the Programme has
developed good working relations with
the pharmaceutical industry in a variety of
ways. Where products are marketed, but
comparative
data
are
unavailable,
industry has provided compounds and
devices for comparative trials, most often
free of charge. Where products are not
yet marketed, the Programme has carried
out a variety of clinical studies, thus
significantly contributing to the early
registration of the products. Finally, in
certain instances the Programme itself
has been responsible for initial research
and development of a new method, and

Achievements in research and development
i

undertaken
by
a
collaborating
programme, the National Institutes of
Health (NIH), to possess long-acting
properties. Three of the four new
compounds developed are covered by
patents issued by the US Patent Office.
Clinical trials indicate that at least two will
provide contraceptive efficacy for three
to four months in doses seven to ten
times less than that employed in the
available injectable preparations, depotmedroxyprogesterone acetate (DMPA)
and norethisterone enantate (NET-EN).

These achievements are presented
according to the Task Forces responsible
for research and development activities.

New

and

improved

methods

of

fertility regulation

Long-acting systemic methods

I

t

Approximately five million women
world-wide
are
currently
using
long-acting injectable and implantable
steroidal contraceptives, and
it
is
believed that many more women would
use such methods if they were further
improved. Accordingly, and because of a
lack of adequate developmental efforts
by the pharmaceutical industry, the
Programme synthesized more than 200
new progestogen derivatives, many of
which were shown in animal testing

I

Following extensive pharmacokinetic
studies and a Phase II clinical trial, two
types
of
new
monthly
injectable
contraceptives containing both estrogens
and progestogens are being evaluated.
Both provide
significantly improved
bleeding patterns compared to those
induced
by
progestogen-only
formulations and large-scale clinical
l

2

<■

achievements of the special programme since 1972

'< 1987.
testing will be completed by early
The Programme is the only agency which
is engaged in the development of
once-a^month injectable formulations.

■

■H

1970s,
many
Through
the
—were investigated
biodegradable systems
by the Programme, but none came to
fruition. One of
c. these, the Alzamer
dev -e. entered a Phase I clinical trial.
Although it achieved zero order release
characteristics, it gave rise to local
new
approaches
to
irritation,
so
implants,
such
as
biodegradable
polylactide fibres, are being explored. In
NIH,
clinical
collaboration
with
assessment of a new single implant
(Capronor®) has
contraceptive device
been Warded out. The implant releases
levonorgestrel (LNG) for about 12-18
months. Its main advantage is that it is
retrievable during its active lifetime, after
which it biodegrades in a few
few years'
years

higher amounts (30pg/24h) at least for
three months; and a third which releases
the natural hormone, progesterone, at a
rate of about i0mg/24h. The last
mentioned device, which is intended for
postpartum use, is being developed
jointly with the International Committee of
Contraceptive Research (ICCR).
Since bleeding irregularities constitute
by far the most important reason
for
discontinuation
of
steroida
contraceptives, the Programme has
focused the attention of the international
scientific community on the incomplete y
comprehended
association between
endometrial
bleeding
and steroida

contraception by organizing a symposium
number of
on this subject and initiating a ~*
international research projects The book
Endometrial Bleeding and Steroidal
1979,
Contraception,
published
in
remains the most authoritative review of

the state of art in this area.

time.

1

I

t

W
1

T>' •

Pt? ■

rjr^ ' •

ite
'B-W?'

Oral contraceptives

A vaginal delivery system has been
developed, which provides constant
blood levels of LNG by releasing
2Opg/24h of the drug during a period of
Its
main
at
least three
months,
self-administration
advantages are easy
’seifa-removal and fertility regulation
and l
minimal steroid load, the lowest of
with a
all existing steroidal contraceptives,
There is also noj need to remove the rings
at any time <during their active lifetime.
Prototype equipment has been designed
large-scale
for
and
constructed
manufacturing of the devices, and a
was
Application
Product
Licence
submitted in June 1985.

■

Bl

The number of oral contraceptive
(0C) users world-wide exceeds 5
million. Almost all family planning
programmes include at least one OC
preparation among the fertility regulating
methods offered. Even though the use of
OCs is increasing primarily in developing
countries, most of the informat.on on
adverse and beneficial effects has been
countries.
obtained
developed
in
of
the
Therefore,
objectives
the
the
Programme
emphasized
have
following:
assessing
the
medical
risks
following: assessing
and benefits of currently available OCs
^J, multinational studies in
multicentred,
different ethnic groups, especially m
developing countries;
co'—o<;' the effect
e1fecl o'
lactation;
and
interactions
various OCs on
------------ in
between OC use and diseases common
developing countries, such as malaria.

More recently
recently developed vaginal
devices which will shortly undergo^clinical
assessment, include one which also
releases 20pg/24h of LNG at least for six*
months; another which
v------- releases slightly

schistosomiasis and filariasis

F
BS

R'W

I[ 1'
If
,

w
If’

3

i'

It
.'i

ffc-T .'<■ Si >-M,
iMrar iiiiii i'iT" f
•

—
■ ';.. - f

■

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FOURTEENTH ANNUAL REPORT

for impartial advice, which may require
international comparative trials. Examples
of such studies conducted by the
Programme are the comparison of inert
IUDs with those releasing copper or
progesterone, the comparative trials of
long-acting or monthly injectables, and
various methods for the termination of
early gestation.

methods and a dual analyte system for
measuring urinary steroid glucuronides.
The Programme also carried out the
first impartial international assessment of
the cervical mucus (ovulation) method of
NFP in a large-scale five-country study. A
high method-effectiveness,
but low
use-effectiveness was found.

Safety and efficacy of long-acting agents

Safety and efficacy of current
methods of fertility regulation

More than 7000 subjects participated
in a number of pharmacokinetic studies
and
large-scale
multicentred
trials
involving different doses or regimens of
DMPA
and
NET-EN;
several
in
collaboration with the Indian Council of
Medical Research (ICMR). The results
indicate that the currently used dose (150
mg) of DMPA might be reduced to 100
mg and that the optimal frequency of
administration for NET-EN is every two
rather than three months.

Modern
methods
of
fertility
regulation, such as OCs and IUDs, have
been available for some 25-30 years, and
the common metabolic changes and
short-term adverse and beneficial medical
effects of these methods have been
addressed
in
a
large
number of
publications. The great majority of
published studies, however, have been
conducted in developed countries and
corresponding
information
from
developing countries is scanty. Since
people from developing countries may
differ markedly with respect to genetic,
environmental, nutritional and other risk
factors for disease, and since risk-benefit
ratios are also very different, it is of
questionable
validity
to
extrapolate
conclusions about contraceptive safety
from developed to developing countries.
Moreover, developing countries may
dramatically differ from each other with
respect to risk factors for diseases.
Hence, there are compelling arguments to
obtain comparative data for every
important method, from a variety of
developing and developed countries.

Because of concern that there might
be an increased risk of breast cancer in
DMPA users based on the development
of mammary carcinomas in beagle
bitches treated with approximately 25
times the human dose of DMPA, the
Programme
initiated,
in
1979,
a
multicentre
collaborative
study
to
examine the relationships between the
use of DMPA and of oral contraceptives
and the risk of cancer of the breast,
cervix, endometrium, ovary and liver.
Preliminary results of this still ongoing
study indicate a relative risk of 1.03, and
thus provide no evidence that the use of
DMPA increases the risk of breasl
cancer. The relative risk for invasive
cervical cancer was 1.2, and of ovarian,
endometrial and liver cancers 0.7, 0.3
and 1.0 respectively. None of these
estimates are statistically different from

In
addition,
several competitive
products may sometimes be offered with
different claims and prices to developing
country governments; in such situations,
governments frequently approach WHO

1.0.

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ACHIEVEMENTS OF THE SPECIAL PROGRAMME SINCE 1972

users compared to users of intrauterine
devices. A seven-centre study, with more
than 1000 subjects, of two OCs
containing ethinyl estradiol (EE) in
combination with norethisterone (NET)
and levonorgestrel (LNG), respectively,
indicate
an
approximately
similar
decrease in HDL-cholesterol and an
increase in triglyceride levels, which
appeared to be more marked with the
NET-containing preparation.

Another multinational case-control
study examined the relationship between
injectable contraceptives (DMPA and
NET-EN)
and
the
risk
of
pelvic
inflammatory disease (PID). The odds
ratio of acute PID associated with current
injectable contraceptive use was 0.5,
suggesting that injectable progestogens
may actually protect women from acute
PID. Studies are approaching completion
on the return of fertility after long-term
use of injectable contraceptives and on
the long-term development of children
exposed
to
medroxyprogesterone
acetate (MPA) in utero, or to DMPA via
breast milk.

c

Neoplasia and oral contraceptive use
is among the most important yet difficult
topics to study, because of changing
contraceptive preparations, the relative
rarity of cancer in the general population,
and the long latent periods in the
development of the disease. The great
majority of data obtained in developed
countries has shown no overall effect of
OCs on the risk of breast cancer and
strongly suggests a protective effect on
endometrial and ovarian cancer. Finally, in
all studies of cervical cancer, the difficulty
of adequately controlling for confounding
variables such as sexual activity has
posed
and
still
poses
substantial
problems of interpretation.

Safety of oral contraceptives
In the 1960s, OC use was found, in
developed countries, to be associated
with an increased risk of hypertension,
venous thromboembolism, stroke and
myocardial infarction, and the risk was
linked to the dose of estrogen. In the
early 1980s, it was also found that
progestogen is a risk factor, leading to
extensive studies on the effects of
various progestogens on lipid and
lipoprotein metabolism.

Since information from developing
countries is extremely scanty, in 1979
the Programme initiated a 13-centre
collaborative study in 1 1 countries. The
study's purpose was to evaluate the
effect of steroid contraceptive use on the
risk of cancer of the breast, cervix,
endometrium, ovary and liver. Studies of
this type are of special interest, since OCs
may well provide real medical benefits,
such as a protective effect against certain
types of cancer, particularly those of
ovarian and endometrial origin.

Little information was available,
however, about the risk associated with
OCs in developing countries. Therefore,
the Programme initiated several studies in
mid- and late-1970s; many of these are
approaching
completion.
Preliminary
results suggest an increased risk of
pulmonary embolism with OC use in two
developing countries participating in the
study; however, the small number of
subjects will limit the conclusions that can
be drawn from the study. Preliminary data
from a four-centre study on four OC
preparations suggest a general tendency
toward increased coagulation among OC

Preliminary analyses on OCs and
invasive cervical cancer have been
published by the Programme; a relative

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Hl SI AHCH AND DLVfcLOPMENI

Current activities
A list of current projects undertaken by the Task Force is provided in Table 1.

Li

Table 1 : Studies on long-acting agents for fertility regulation

Study

t

Compounds

Centres

No. of Start
subjects

End

INJECTABLE CONTRACEPTIVE PREPARATIONS TWO TO SIX MONTHLY

/M//’ t t\l) Wl-lW
Use effectiveness and
side effects of different
dc^ages of DMPA

DMPA 150mg
or 100mg/90 days

Alexandria
BangkokfSir)
Karachi
Kingston
Ljubljana
Manila
Szeged

1200

1982

1985

I fleets of DMPA and NET-EN
on lipid and lipoprotein
metabolism

NET-EN 200mg/60 days
DMPA 150mg/90 days

Bangkok (Chula)
Havana
Mexico City

120
per
centre

1986

1988

Effects of long term use
of DMPA on lipid metabolism

DMPA over
4 years of use

Bangkok (Chula)
Christchurch
Mexico City
Nairobi

20
per
centre

1986

1986

1976

1986

i

A7 II THO TO-SIX-MON'THI. Y INJTX TAHTES
Quality control, physico­
chemical studies and
(oimiilalion of jiiogeslogen

Various

Ashton-under-Lyne
London

Minnesota

e:.tei ■.

c

A ph.itmacokinelic study of
nt»w long acting
progestogen esters

HRP 001/002, 6 25,
12.5 and 25mg

Iondon

20
per
centre

1985

1986

Mexico

A i'1' fimacokinetic study of
nrv.' long acting progestogen

HRP 003,
10 or 20mg

Bangkok
London
Mexico

20
per
centre

1986

1986

A pli.iiin.irokindic study of
.i n<-w long acting progest
< i<|cn
oxime

HRP 011, 20
or 40rng

Bangkok
I ondon
Stockholm

20
per
centre

1986

1986

I'li.i- <■ I :.ludy i»l a new
Ioikj .K.imtj proyustogcn
estri

to be selected from
HRP 001. HRP 002,
HRP 003 and HRP 011

Bangkok (Chula)

10
per
centre

1986

198 7

25

■' tn-

S'

■

Beijing

Rome
Singapore
Szeged

^7
FOURTEENTH ANNUAL REPORT

Study

Compounds

Centres

No. of Start
subjects

End

I

3:
i.
-

2. INJECTABLE CONTRACEPTIVE PREPARATIONS-ONCE-A-MONTH

Phase III clinical trial
of HRP 102 and Cycloprovera

HRP 102 (NET-EN 50mg
+ estradiol valerate
5mg) Cycloprovera
(DMPA 25mg +
estradiol cypionate
5mg)

Alexandria
Bangkok (Sir)
Birmingham
Havana
Jakarta
Karachi
Leningrad
Manila
Mexican network
(5 centres)
Santiago de Cuba
Szeged
+ 3 centres
supported by FHI
(Guatemala City
Rome, Valdivia)

200
per
centre

1984

Pharmacokinetic studies
of HRP 102 and
Cyt.lopr ovi.-ra

DMPA 12.5mg +
estradiol cypionate
5mg. NET-EN 25mg +
estradiol valerate,
5mg

Bangkok (Chula)
Mexico City
Stockholm

20
per
centre

1984

1986

I'h.iso II clinical trial of
C.ycloprovera and 1/2 Cyclo
provera

Cycloprovora (DMPA,
25mg 4 estradiol
cypionate 5mg) and
1/2 Cycloprovera
(DMPA, 12.5mg
+ estradiol cypionate
5mg)

Alexandria
Jakarta
Mexico/Durango

100
pur
centre

1986

1987

Phase II clinical trial of
HHP102 and HRP 103

HRP 102 (NET-EN 50mg
+ estradiol valerate
5 mg) and HRP 103
(NET-EN 25mg +
estradiol
valerale 5mg)

Alexandria
Bangkok (Chula)
London
Mexico/Durango

100
per
centre

1986

1987

Pharmacokinetics of
certain estriol esters

4 estriol esters

Berlin (West)
Stockholm

56

1986

1986

Polycaprolactone
implant releasing
levonorgestrel al
either 20pg or
30-50pg/day

Bangkok (Chula)
Bombay
Jakarta
London
Los Angeles
Rome

20
per
centre

1986

1987

1987

<
■ }

3. IMPLANTS
A comparative Phase II
.study of two bioorodible
delivery systems for levo­
norgestrel of different
length (Capronor)

26

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RESEARCH AND DEVELOPMENT
>

Study

4. VAGINAL RINGS
One-year Phase III _
clinical trial of 3
months WHO vaginal
ring

Centres

20pg/24h
levonorgestrel

Bangkok
Beijing
Bombay
Cali
Chandigarh
Geneva
Havana
Juiz de Fora
Karachi
Leningrad
Ljbuljana
London
Lusaka
Manchester
New Delhi
Shanghai
(2 centres)
Stockholm
Szeged
Tunis
Wuhan

987

Beijing
Chandigarh
Havana
Juiz de Fora
Leningrad
Ljubljana
Lusaka
New Delhi
Paris
Salvador
Santiago
Shanghai
Singapore
Szeged
Tunis
Wuhan

50
per
centre

2O»ig/24h
levonorgestrel

t.

I

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1

c

Start

End

subjects

€
Two-year Phase III
clinical trial of the
3 months WHO vaginal ring

No. of

Compounds

1982 1985

n

I
1985 1988

£

20pg/24h
levonorgestrel

Beijing
Juiz de Fora

90

1983 1985

Mc.'unrual blood loss

20jig/24h and
40pg/24h
levonorgestrel

Stockholm

48

1985

1986

Pharmacokinetic/pharmacodynamic study of a WHO
ring releasing
levonorgestrel
in combination with
estradiol releasing
patches

20pg/24h
levonorgestrel

Santiago

20

1985

1987

Follicular growth and
development with low dose
progestogen therapy

T

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FOURTEENTH ANNUAL REPORT

f

Centres

Compounds

Study

No. of Start
subjects

End

re)

ha
ov
br
di­
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5. POST PARTUM CONTRACEPTION

$

I

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Pharmacokinetic/pharmaco- •
dynamic study of a proges­
terone releasing vaginal
ring

5mg and 10mg/24h
progesterone

Stockholm

The use of progesterone
releasing vaginal rings
post partum (in conjunction
with ICCR)

5mg and 10mg/24h
progesterone,
TCu380A/IUD

Assuit
Khon Kaen
Lusaka
(+ Campinas, Santo
Domingo, Santiago
supported by the
Population Council)

225
per
centre

The use of LH-RH agonists
as post partum contra­
ceptives

Buserelin
Nafarelin

Torreon
Edinburgh

40

1986

1987

1

1986

pe­
al'

1988

m

1985

m
di
di
ap
W

1987

rif

9<

EFFECTS OF PROGESTOGENS ON ENDOMETRIAL BLEEDING

Basel
Stockholm

I ndometrial changes and
inteimenstrual bleeding

I
I

90

1981

1988

Therapeutic effectiveness
of ethinylestradiol and
estrone sulphate on pro
longed bleeding in women
using DMPA for contraccption

DMPA 150rng/12 weeks
0.05mg ethinyl­
estradiol, 2.5mg
estrone sulphate

Alexandria
Bangkok (Sir)
Karachi
Manila
Rome

100
per
centre

1986

1987

( Heels of progestogens
on structure and function
of the endometrium

Vaginal rings
releasing 20pg/24h
levonorgestrel

Basel
Dublin
Leuven
London

120

1985

1987

Kiov
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I. Injectable contraceptive

4

preparations two-to-six monthly

c

began in July 1982 to test the hypothesis

that a dose of 150mg of DMPA is more
than adequate to give a full three months
contraceptive effect in most women. It is

DMPA and NET-EN

comparing IbOmg with lOOmg of DMPA
Use ellecliveness

and

side effects

and is being undertaken in seven centres,
Alexandria, Bangkok (Siraraj), Karachi,
Kingston, Ljubljana, Manila and Szeged.
Recruitment ended in December 1984,
with a total of 1187 subjects, i.e., 99%

of

different dosages of DMPA
This study, represents the last Phase
III clinical trial to be undertaken by the
7 ask
Force
on
the
injectable
contraceptives, DMPA or NET-EN. It

of the target of 1200 subjects. Follow-up
was by the end of December 1985.

28

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RESEARCH AND DEVELOPMENT

There have been two pregnancies
reported in the lOOmg group whilst none
have been in the 150mg group. The
overall discontinuation rate is similar in
both
groups.
There
are
more
discontinuations, however, for heavy
bleeding in the lOOmg group (3.8% vs
1.1%) and more for amenorrhea in the
150mg group (10.5% vs 6.1%). This
pattern was found in most centres,
although as observed in all other
multi-centred clinical trials there are
marked inter-centre differences in overall
discontinuation rates. In this study
disruf)tion of regular bleeding patterns
appears to be a greater problem in
‘Western and Moslem countries giving
rise to higher discontinuations, whilst
good counselling
in
Bangkok
and
Kingston could account for the low
overall discontinuation rates observed in
those centres. Final analysis should be
completed and a draft paper available by
June 1986.

o

I fleets of DMPA and NL7 LN on lipid and
lipoprotein metabolism

Although there is no evidence to link
these two long-acting contraceptives
with cardiovascular disease, the effects
of steroidal contraception on lipid and
lipoprotein metabolism, and particularly
on HDL cholesterol, has become an issue
of concern during recent years. There are
still no prospective studies to date which
have adequately addressed the effects of
DMPA or NET-EN on these parameters.
7 hus two studies have been designed,
one comparing the effects of DMPA and
NET-EN over a 12-month study period
and the other measuring various indices
of lipid and lipoprotein metabolism in
subjects who have received DMPA for a
continuous period of at least five years.

o

Problems had been experienced in
comparability of assay results among
centres participating in these studies.
This was compounded by difficulties in
maintaining ultracentrifuges in good
working order. Thus a reassessment was
made of both the state of knowledge in
the field and the most appropriate
methodology currently
available
to
undertake these studies. A group of
assays has been selected and the
methods fully standardized. It is expected
that the methods will have been validated
in each of the participating centres and
the clinical trials started early in 1986.

J.
I .

fl !

I i

Long-term sequelae

I

The Report of the Task Force on
Safety and Efficacy of Fertility Regulating
Methods presents progress in studies
previously reported by this Task Force on
the possible association of DMPA and
cancer; the effects of DMPA on progeny
exposed to the drug 'in utero' or via
breast milk; and the return of fertility
following
use
of
injectable
contraceptives.

I:

New two-to-six monthly injectables
The U.S. Patent Office has granted a
patent
for
various
esters
of
levonorgestrel
and
norethisterone
emanating from the Chemical Synthesis
Programme undertaken by the Task
Force. Three of the levonorgestrel esters
are being studied further and are coded
HRP001, HRP002 and HRP003 as well as
one
levonorgestrel
ester
oxime
HRP011.
Two of these esters, HRP001 and
HRP002, were first tested in a preliminary
pharmacokinetic
/
pharmacodynamic

29

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r.

I
jcational background?

y ; _r
fccc

Ac-

-

Public Soard
Depo Provera

Chicago and then did a mod ical internship at Cock County

currently er.p

Hoover. where

Hcspita

Srinch

't

2,

continued in

tne dtstrioution

tr e

cancer.

risk of breast cancer associated witn the use of menopaus al

are

estrogens.

Acting

A

a member of any professional societies?
also

cwt

prtgra-

i
i
1

i

3ra

r e •■'o i t - r r e n t _ ■
tn a

ad' i-r

a member of the Amer loan

at p r e s c n t

A.
t

of ray tnecis was the

there wa o.

A.

1

doctoral program and obtained

was tnere a thesis requirement for your doctorate?

once med ?

A.

in epidemiology m

in epidertiolegy from Harvard in 19*^6.

nor an

disease

master's degree

cm which 1 obtained
•tgy?

nt a-

I entered the

Harvard Sonocl of Public Health, Departr.ent of Epidemiology,

ne

A.

Following that,

a-.se in

miclogy

A•

1

of Medicine in 1968 fro- Loyola University in

cf

:.o.

K«

Environmental Z~'-

t

obtained my degree

courses receiving a SA degree in *9t4

?.CS£aT NILAS ~C

C.

and crewed leal

ion of liberal

and took a

Docket No. 'SS-2•24

re;

versi ty o f Nctre Dav.e

at t.". e

- trendec

‘ 2s

rs .

a

an

A.

Depart-ent

invited memcersnip?

mat

Yes .

become a member.
members of

“mated ry
; ve rs

r as tn cted nurncer

« e.

pe o p . e t n a t

be

an indiv -.dual

me society.

There

long to

13

a

oci ety

up. ctner peep -e are nominated by mergers
1 11 a t e

me oasis

tne

of epidemiology.
of t h a t

■1

vulnerable site in hur.ar.s.

I

indicate the potential
neopl as ia;

=*cassays are -s^’l

“■

i particular substa-.ce

-s-ally end up

with a ccmbinati

■

X !!

|

studies and case- —ntrol
evaluations of those cancers about which
you are particularly
suspicious, either because of the biology or the results of

estroce.n use is associated

animal bioassays.

also.

Certainly, 1 t.nink, because
of the circumstance and the
animal bioassays,

Shi? between hormonally-reloted
.7:.- •<.

extensively studied.

- the biology

cancers and D.yPA needs to be

3ut it’s not neeessaril-.’ t

these are tne only sites

be associated with some

•difference in risk of neeolasla.

Q.

Hccver, many people. including toe

Tomeany, have said.

imolicitly or exoli

Cepe Prcvera has beer, used f
ever a -ii

and that

would have

j

Since ’ 9 7 1 ,.we have
come to realize
e s t e r o1 causes cancer in
exnosed offspring, that
■"er.ooa jsa 1 estrccens cause endometrial
cancer, that
segue.-. -al oral
contraceptives cause endometrial
cancer, that
c e r t > i cent racept ive
preparations cause neoplastic
growths
in tne liver, and some evolving
evidence that long-term
ST i

nteroreting the most likely site i

..mat's why in these circumstances you

a

.lions of wcrer.-years

t e re i s

estrogen evidence in 1971, and you
could put «ooub as nuch reliance in the validity of
assuming
a lack of carcinogenicity fron current DMPA data
as you could
put - n tne similar
statement a bo u t estrogens in 197:.

doesn’t relying on that ^v idence
as sort of an ad
•“■oc study suffer from the
very preclems that you've discussed
all
tnese apidemiclocical studies, for example.
terms of losing patients?

A.

assess long-term health
-ata derived from investigations

side effects is notoriously ocor.

like to replv
mencoausa1 ^strocens.

1iteratorv animals.

ar. ana 1 o

Estrogers rave been cor.-

since the

8

of

•■•■hat react

du vou have to that

?xccse i

i t h excess risk of breast
cancer
The evidence to date with
respect to D.m?a is net even

Vp to

s because of •-1 :

-“starces,

:*: ■ io-- - _

no appropriate comparison groups', a

3".’lys IS .

Often,

ic

no aopre-

me

account relevant confounding
"'••en ii mere

:s

no system

t r. e attempts that are done

■- m i 111 c r. c

ex'.

There is essential!y

to assess long-term health effects,

:s

study,

that

t -e

pm

be either not
•* 3 :

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Collovcd-UD for a lone er.ouch period of t.-e, it

:p;‘-

identify a problem.

i1

There is just
I declar? und:r penalty of perjury that the foregoina is

f 'i criticisms of the human evidence to date, due to its lack of

1' ■ 4

true and correct.

quantityr its lack of quality, and
inherent biases in
and the
the inherent

Executed on

!

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1 13Ck °f fUk frcn '-°Pu:a—c-s which ha-.-e failed to

p

[\ ^-O* exce£s

under the methods emoloyed.
Rcoart .Solan Hoover,-M.D., ^ci.b'.

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VHAl LIB* * F’ V

INJECTABLES AND IMPLANTS

5 A

8 < cc > r J

I'opia.ilion IntonH.itton Program, The Johns Hopkins University, TTThi'irtrw Ttr jm7 (.•2-1 Nonh Broadway. Baltimore, Maryland 2l?Ur>. USA

Long-Acting Progestins—Promise and Prospects
[Biters' Summary

In the continuing search lor better methods

o- i,-mi!, planet' g, Icmg-acting progc’slms otter both promise

i
I

and

eiiis. Progestins, which are synthetic hormones that

act like ihe natural female hormone progesterone, can be* adnanis’crcd m at least live? different ways to prevent pregnancy

(

•

la'bu contraceptives,

o

hormone releasing IUDs,

o

Now lhailand. where about

Zealand.

and New

12 percent of .ill c ontraceplors

use DMPA, is purchasing supplies independc’iitly, reduc mg

the nc-c-d lor donations. Monthly mjec tables made up ol a pro

< - ,i montli oral pills.

c

mated 2.3 million women are using DMPA. Use is most widesprc'ad in Jamaica, Thailand, Sri Lanka,

mostly DMPA, to developing countries annually in 1978 81

a 'ma! uni', ., .md

o

I

weeks for the lirst six months and then every 4 2 weeks. An esti-

cies supplied half a million to two million doses of mjec tables,

mis pl.p cd under the skin,

:

ministration using 200 mg at either B-weck intervals or every B

About 275,000 women use* NET EN. International donor ar;un-

jut < •'.ici’d'-'i pffiods of time. They male possible:

o

less often in a 6-month dose. NET EN is recommended lor ad­

gestin and an estrogen arc used in Moxie o and C nma.
I

Diftco nl pn i.i?' .tins are dlcr live lor dilleirnl periods ol lime,
Pun-, iihi d.ui-, oral
’plises
il << (intr.k
(inlr.k rcpli
’u". are clfcrtivc Io: only

la airs

I he eltecliveness ol sonic progestins can be

p:(il. f ■. . .I I(\ m< oiporatinj: them in an injee t.ible solution or a
(.iii- i •' .il rjaitu.tlly releases the hormone, 1 bus they c an be

i

Both DMPA and Nil

EN arc highly «tl<*c live, with annual

pregnane y rales ol less than one per I(X) users. I hey have lew

side elfec Is apart from mcnslru.il disturbances
using DMPA g.iin weight

Some women

usually !rom one to five kg. Most

women do not become tortile lor lour or live months a'tcr

ria-i n .< Sa <'Of month Io live years or more.

disc onlinuing use, but there is no evidenc e that lerlilily is pci
( )l <11.11

l< < In .
®

I

I

.r

l< n'.e- : II r Icslcd, .it Ic.lSl ihlCC ll.lVC pl ived highly cl

mancnlly impairc’d. Injec tables have none onlr.ic ejrtivc licn<-

< ■e.'. .a lnij; i ontrac eplivcs

Ills.

I liesc are:

>\\piois sterone acetate in its depot lorin (DMI’A;

tllCii

I pfohn c ompany trade name, Depo-Provera),
o

neo thmdionc enanthate (NT!

LN; Schering AG trade*

< reused supply of breast milk. DMPA, like oral (.ontrac eplivcs.
rediK es the risk ol pelvic inflammatory disease1 (PID). Also.
OMPA may reduce the symptoms of sic kh’-c ell disease, a go

netic disorder most common in parts of Africa and in peopk

:i.h:.f. ’ »<a ■iei.il). and
o

*

Some lactating wonicn taking DMPA may have an m

of Atric an anc estry.
u)|c< l.tble prcp.w.ili'/ns; Ihr third is used in

in .t tv. • I

*■

\.HU ar. i .'i ’ if
■

CONTI NIS

I

n ■. .int.i'.'e of long-acting progestins is that they elimi-

I! ..1

;ieed lor spec itii ac tion al the time ol c oitus, sm h .is

C, Ilf I

,i i p.irfmii or lor daily a< lion, sue h .r. I.iking i pill. \l

■ ■ me

nicnsti

A major disadsaiil igc ol

Usage

Inject.idles
K-24

- pioye-.iins now in use* is ib.it they disrupt the normal

LHecliveness

i ci le

Side Effects.................................................................

. . !' 2(>

..................................

. . K-2‘J

< ausing irregular bleeding. Lic k of menstrual

I here is no evi-

Effects on Reproduction

deni c II.at tnese menstrual changes pose a risk to hc-allh. In

The Question of Cancer

I,:. (

Continuation and Acceptability

pi-ii.>ds

It

or

•<

oe i asionally, heavier bleeding,.

to ihe eUi-nl that they reduc e menstrual blood loss, they
fcd'.H <

i

»

i.i!

:!if\ arc reversible

. N I' ♦

Background

tin- risk of anemia.

Ihe major question still un-

i s a. licth'-r long-term human use ol c crlain jHogeslms

<

!< < teases the risk ol various cane ers

Injectable Contraccptives
I ao in|e< table contrac cptives are w-idcJy available
.mil Nl 1 I N

ti.c.

DMPA

( )ne <a both have been used in about 1(H) c oun

IJMPA is usually given in a T-moiilh dose of I 50 mg, and

. K-31

. .

Once-.i-Monlh Injectables

. K-3r>
. . K-36

Progestin Releasing Intrauterine* Devices.

. . K-37

Implants..........................................................................

. . K-3B

Vagina! Rings...................................................

.

New Researchon Long-Acting Methods .

. . K -12

K-41

.............................................

. K-4-1

Bibliography.................................................................

. . K-47

Program Challenges

—

-------

i.■ ■■

------------- --- - .

■mi’1"

*i<ijfates
Tabic 5. Mammary Nodules in Beagles Treated with Df/iPA

body ever time, so (hat the animals are- e ventually ex­

and in Controls, IRDC and Dawson Studies

posed to far more than 50 times the ec|u-valenl human

dose.

IKIX Study

In the recent hearings before the US FDA Public Board of In­

DM PA Dose

Controls

lx

25x

quiry on DMPA (see p. K-20), a pathologist sugge sted that the

No. examined

16

No. with nodules
No. with malignancies

9a
0

4
3
0

16
12

rare type of cancer, adenocarcinoma of the endocervix (the

monkey tumors were not endometrial cancers, but instead a

2b

Dawson Study

inner wall of the cervix), which had spread to the endome­

trium (120). Subsequently, a group of pathologists convened
by WHO reviewed uterine tissue slides from the three mon­

keys with cancer and from other monkeys. They c oncluded

DM PA Dose
Controls

lx

lOx

25x

that the three tumors were probably endometrial in origin and
unlikely to be endocervical (646). Also, in contrast to earlier

No. examined

20
2
0

No. with nodules
No. with malignancies

(Ontrols

20
1 1
7

20
15
10

20
12
9

Progesterone Dose
~25x7
lx<‘

opinions (568), they decided that all three tumors were of the
same cell type (646). The tumor cells resembled endometrial
plaque cells but not enough is known to be certain whether or

not the tumors developed from the endometrial plaque ((>46).

Human Studies Show No Risks
No examined
No. with nodules

No. with malignancies

20
0
0

20

13
0

20
4
2

‘'\(xluii-s tranMent in 7 of 9 animals
"• .f ‘n<M-I.I-. with metastases to other organs
given in amounts equivalent to Ox) or 25 times the normal
*
. I . .I . .
I
t
4
. .iii.H r. ,il ph.iM' levi-l of f.rogi Mffonr

su.iK,- !Koi s|U<h Ir.inkelal (IbO). Upjohn (S27). Dawson study-C.ulson
■Mb. I • • -k <•! al (h40 Upjohn (527)

Three types of evidence suggest that progestin injec tables do
not cause cancer in women:
® the results ot epidemiologic and clinical studies to date,
♦ the fact (hat progestins arc used therapeutic .illy with

some Success to treat certain cancers,
• the findings of studies on oral contraceptives, which

show no additional risk of breast cancer and suggest a
protective effect against endometrial and ovarian c ancer.

No epidemiologic study has yet demonstrated lh.it injcctables
weir luund m three DMPA healed monkeys. The nodules
were app.iiently tot al nodular hyperplasia, an abnormal but

are linked with any type of cancer. Most of the studi<?s, all of
’Which have been on DMPA; have involved short term users,

benign giowlh of normal tissue. No tumors were found in

however, and so would not be able to detect risks for long­

monkv\ s ret eu mg 50 times the equivalent human dose* (527).

term users, if such risks exist (216).

Information on NIT [N is not yet available
Preliminary results from the most powerful study to dale show
Endometrial Cancer in Monkeys

I nd< >iu< h1.11 , .UK
kr\

1

re.

vvas disc overed in

ol 12 autopsied mon-

mg ><) times the equix.dent human dose of DMPA

-'’’d as of early |9B i in an ongoing study, one* of 24 re-

t <-i\ itv.; >i) times the equivalent human dose of Nt T LN (568).
None I .is been found in controls in these studies. Several cases

of < i ■ :om< trial tamer have been reported in other monkeys
nof exposed t() progestins (527). but the incidence of the dis

<

no risk of cervie al or breast cancer with DMPA use. Wl K ) is

conduc ting a case-c ontrol study at II i enters in rune toun

tries. I he study is investigating c urrent or past use ol oral < on

Iraceptives and injet tables .imong women with < .mr er t>l the
reprodui live organs, breast, liver, or gall bladder and am.-ng

women without cancer.

Preliminary analyses < out rrning

DMPA have been < onducted on data from (he thn e partic ip.it
ingccnlers in Thailand, where DMPA has been userl tor almo t

20 years. By early 1983 (he WHO study had collr. led more

1% iirikmmn.

than 5()() cases of cervical cant er and t ornp.ired them with
\s w.i.i (he breast tumors in beagles, the* relevance ol these
nndm... to women has been questmned:

© In the monkeys, the endometrial cancer occurred in

• in altopha , or atrophied

endometrium (527, 646). In

waix-n endometrial t ancer is often linked to hyperplasia

(abnormally rapid growth ol normal cells) induced by rs-

In 'I'.eii '-I 1. 1.4b2) I )MPA and other progestins suppress
'•ndumetrial growth and prevent hyperplasia in women

> iibi. 344).
Some pathologists contend that the endometrial cancers

m monkeys are ol a different cell type from endometrial
i am ers in women (527, 529, 5(>8).
( >(<<• pathologist hypothesizes that the tumors in DMPA
u« .Hed monkeys origin,iird Inanan epithelial plaque that

■ 0

forms in response toprogesiin or progesterone- (529). This
•hin lure doc's not occur in women (4, 462).
o

With hormones, large- dose's such as those given to the*
monkeys th.it developed endometrial cancer may cause

qualitatively dillerenl effec Is from low doses (4, 523). I urihetmore, because monkeys cannot rnc*(abolize these*

,1 ‘O* MJLY1 lf >£1 j<l_ IY

[s

more than 1.800 < ontrols. Preliminary analysis deb t led n<> itlationship between DMPA use and eitht r invasive or in sitti

(noninvasive) cervical cancer. By early 1983 the study had a

90 percent chance of detecting, a risk as low .is I n times
greater lor users than nonusers (647).
The WHO study also has collected more th.tn 100 t .im s oi

breaM cancer in I hatland and compared them with more than
1,800 controls. The preliminary results indicate m? increased

risk of breast cancer with DMPA use and may suggest a slight
protective effect. By early 1983 the study had a 90 percent

chance of detec ting a relative risk as low as 2.5 (G47)
7 he numbers of < uses of other i an< ers, including imkIoiih ln.il
cancer, collected by WHO have been too small lu .m.ily/r

WHO notes, however, that:
flu* p.iucity of c asrs of cancer of the uterus, ovary and he­
patobiliary organs (liver and gall bludderj with a hi.iory of

DMPA use, in a ( ountry where DMPA use is o-ason JJ/ wuji
spread, is rcassu/mg. The data do suggest lh.il no sul..i.mii.d
public health problem due to DMPA exists, al le.ist r. )t.(iding
these i ant ers. (<>47)

K 33

I
(

c

TERATOUX-Y 27:215-222 < 1983)

Embryotoxicity of Norlestrin. a Combined Synthetic
Oral Contraceptive, in Rhesus Macaques

(Macaca mulatta)
s. PRAHALADA ANO A.G. HENDRICKX
California Pnmale Research Center, University of California, Davis,
California 95616

ABSTRACT
Thirty timed-mated pregnant rhesus monkeys received Norlestrin (Norethindrone acetate, 2.5 mg, and ethinyl estradiol 0.05 mg per
tablet Parke-Davis) orally at four different dose levels. The dose levels were 5,
10 25 and 50 mg/day/monkey and the doses were administered during early
(days 21-35), late (days 33-46), and throughout (days 21-46) organogenesis
except for the 50-mg-dose-group animals, which were treated only during eai y
organogenesis (days 21-35). All except the animals in the 50 mg-dose gioup
were allowed to go to term (165 days gestation). Pregnancy for the animals in
the 50 mg-dose group was terminated by cesarean section on day 50 of gestation jmd the fetuses were fixed, serially sectioned, and examined histologically
No teratogenicity was observed. However, the prenatal mortality rate (38.5%)
was higher for the Norleslrin-treated animals than in the control colony (-!/<■).
Eight animals aborted between days 40 and 78 of gestation and ™
cases resulted in stillbirths at 139 and 165 days of gestation. There was a
higher incidence of abortion (44.4%) in the 25-mg-dose group. Norlestrin treat­
ment during early organogenesis also resulted in a higher abortion rate (37.5%)
compared to treatment during late organogenesis (22.2% abortions). No mo.
phological abnormalities were found in infants observed at birth or in juvem
inonktys which died of natural causes or in those that were sacrificed over a
period of two years. No histopathology was observed in the 50-day-oid fetuses
examined by serial section. Examination of endogenous maternal serum estro­
gen and progesterone levels in Norleslrin-treated monkeys (25 mg/day, days
21-35) suggested that placental steroidogenesis was not affected; however, the
lower levels of estrogen in maternal serum suggested that the ovarian steroido
genesis was affected. Although the precise pathogenesis of this
bryolethality is not known, several observations in this study suggest a d.rect
generalized embryotoxic effect. Thus, this study for the first time has demon
Strated that, while Norlestrin may be embryolethal at 100 times the huma
contraceptive dose equivalent (25 mg/day) in the rhesus monkey, nevertheless

♦

I

it does not affect the offspring which survive the exposure.

Synthetic
Synthetic sex hormones have wide use in
human medicine. Women are given sex hor­
mones lt> test for pregnancy or lor an obstet­
ric reason. Hormones are most commonly
given as oral contraceptives, especially in re­
cent years. The most widely used pral contra­
ceptive continues to'he a combined daily dose
of a synthetic progestin plus an estrogen.
Althqugh oral contraceptives are highly ellicient in preventing pregnancy, accidental ex­
posures during early pregnancy arc possible.

i
(

Such exposures have occurred and have been
the subject of extensive reviews >n recent
years (I.alil Ambani et al., 77; Briggs and
Briggs. ’79; Schardein, '80; Wilson and Brent,
81)
Multiple congenital malformations, al­
though controversial, have been associated
with exposure to sex steroid hormone preparReceived February 5. 19H2; accepted Auguat 17. 1982

I9H3 ALAN R USS. INC

s

■

<z

216

s. PKAHALADA and a.g hendwckx

cifically to examine for the presence of those
ations during the early weeks of gestation
malformations reported in the human.
(Nora and Nora, ’75, 78; Nora et a
78,
Lorber et al„ 79). Significant among the re­
MATERIALS AND METHODS
ported malformations are those of the genital
Thirty adult female rhesus monkeys fMo17act (Wilkins et al., ’58; Wilkms 60; Jacobcaca mulatta) were housed individually in
son, ’62), neural tube (Gal et al., 67 Gal,
aluminum or steel cages and ipal"ta."1’e<i
’72) limb reduction defects (Janerich et a .,
accordance with standards t!Sta^'sh^
’74)’ and cardiovascular abnormalities (Levy
Federal Animal Welfare Act and by the Insti­
et al ’73; Nora and Nora, ’73,b, ’76a,b; Nora
tute for Laboratory Animal
et al.’, ’76). Moderate growth retardation and
(ILAR). The monkeys were on a iz-nou
mild to severe mental retardation have also
lighting schedule, temperatures average
been observed by Lorber et al. ( 79). In con­
22°C year round (76-80°F, 45% hurnidi y .
trast to these data, no relationship of hor­
water was provided ad libitum, and Purina
mone use to developmental malformations
monkey chow (15% protein) was fed twice
was evident in several other studies (Laur­
^Menstruation was detected by visual ex­
ence et al, 71. Mulvihill et al, 74; Nishi­
mura et al, 74; Yasuda and Miller, 75,
amination of the external genitaha All
Ferencz et al.,’79).
males were mated on alternate or on con­
Most experimental studies on synthetic es­
secutive davs between days 11 and 15 of then
trogen and progestins have been done using
menstrual cycles (the first day ofj observed
mice, rats, and rabbits. Less common is the
menstrua) bleeding was considered as day
use of guinea pigs, dogs, and monkeys as
of the cycle). The females were exposed to
experimental animals. Synthetic steroidal
proven fertile males for 0.5-2 hours per day
estrogen administered alone as Mestranol or
according to a standard protocol for tin ed
ethinyl estradiol did not result in teratogen­
mating A successful mating was indicated
icity 'm dogs (Kennelly. ’69), rats 'Saunders
by the presence of spermatozoa in a vagina
and Elton, ’67), or rabbits (Saunders and Elsmear. The middle day of the breeding period
when it
it
ton, '67; Chang. 74). Synthetic progestins
is considered day 0 of pregnancy when
alone appear to be teratogenic m mice auhnstone and Franklin, 64; Takano et al,
^Detection of pregnancy prior to day 25 was
Gidley et al, 70), rats (Neumann et al, /4 ,
accomplished using hemagglutination mln
rabbits (Takano et al, '66, Andrew and1 btm
bition test for monkey chorionic gonudot.<>
pies ’77), and rhesus monkeys (Wharton an
pin in urine between days 18 and 23 o
Scott ’64). The embryotoxicity of several
□resumed pregnancy (Hodgen et a ., Ml
combined hormone preparations has been
Pregnancy was confirmed by manual palpa,
studied in laboratory rodents and Iago
tion^of the uterus per rectum after day 30 of
morphs. The combined synthetic estrogen
gestation (Wilson et al., 70).
and progestins are not teratogenic in mice
Norlestrin, a synthetic steroidal conti acc
(Takano et al, '66), rats (Saunders and Llton,
tivelnorethindrone acetate, 2.5 nig,^nd cl I■67; Saunders, '67; Edgren and Clancy, 68,
inyl estradiol, 0.05 mg per tablet. 1 a>k
or rabbits (Saunders and Elton, 67, Chang,
Davis) was administered orally to piegna
■74) however, embryoletbality was an incon­
rhesus monkeys. There were ten groups o
sistent feature, obtained only when doses of
three animals each. The period <> treatment
a nontherapeutic level were adnnmsteretL
and dose levels are shown in lahit 1.
Although experimental studies in labora­
The dose groups were 5, 10, 2o, ant .>
k
tory rodents and lagomorphs are consistent
The dose is expressed only as a total o no
in response to synthetic sex hormones dm ing
ethindrone acetate content, for the sake o
pregnancy, such studies are very scanty in a
convenience. The dosage expressed as nig
species phylogenetieally closer to man, such
day/monkey corresponds to 20, 40,
,
as nonhuman primates. The embryotoxidty
200 times the human dose equivalent based
of combined synthetic hormone prepai ations
on the body weight. There were three periods
in monkeys has not been reported in the 1 Of treatment. They ^-re. (1) varly orga> <■
erature. The present study was unde taken
genic period (days 21-35 of gestat ion). 2 lat
to test the embryotoxicity of Norlestnn, a
organogenic period (days 33-4(, ol ges a ion
combined synthetic oral contraceptive, in
and (3) the entire organogenic peuod (days
rhesus monkeys (Macaca mulatta), and spe

I

I

I

I
i

ii

>

s PKAHALADA AND A G-HI NDRICKX
Which most accidenUl exposure to synthetic

220

buXw ^X^al’epTdXological studies
Review of se
£..correlation between
has not shown a definitepregnancy
hormone administra
d
b ,go) Syn

.rE«»
le^-d t—es wa^unrelaU^U,

and maHormtal’0nLimstration in humans
thetic progestin adn’i "Xion of the female
has resulted in mascu
wilkins ’60; and

mental malldrn
the remaining
physical exami .
of Bge
eight Juvende monkLis
abf thal could
^Vrela0^d to Nnorlestrin exposure during or-

ganogencsis1 •Hi; NoXt ah, ’76;

discussion

This study has shown ^at^^trrn^ot

.(25 mg/day)did not rest It. >. ny Ur

77t

C<in'^-Gal0S^imb redaction defects

h

cific malformations ha
with hormpne exposure,

y

.e n()l been
investigalors

-u(er<>
lal ^^^^"Emhryotoxic
, ,110W aP Sl'I" X" studies1 n()on
teratogenic uKx • •
the specific com >in.
acetate and ctr >

C>p

• f nOrethinclrone
(the compOreported
.... .

trogens in i-u.i. am. ini(.(. (Takan<) et al., ’66;
embryotoxic cfic
rats (Edgren
.
Abbat.ello and hsuddc.
and Clancy,
>
Saunders and

,;:n.

1

E U,n’ 7 | uX)ns were primarily einbryomone combmati .
significant
lethal and du no
exposed fetuses,
teratogenic eflc teratogenic in mice
Norethindrone a, m ( - .64) rat (Neumann

,j0hr’74> X Gurus and Grant, ’64), and

TSgf -

combined ayn^al

known Several observa

xs.,

^Vi^'examZion of an aborted fetus and
piaXaXaledanimUilytKemb^osmal

for its gestational age w>tl a v

P

(„

*•
C J(W iton and Scott, ’64). 'I he tera­
those oi noimai b
cases. I his
monkey (Wil. rtor
manifested as mastogenicity was I
yfciuse<. Sludies by
cuhmzation of
pregnant rhesus
Wharton and Scott (6■>
P> ii,;)|.elhind,.une
.......................
monkeys de"u;'’i’
of stillbirths, virilcauses mcieasec
..ndervotorcbidisin
‘“''‘’T’VXes Xw "administered 25 mg
in male fetu^s, in y
week
norethindrone dmb
and contin.
^""r'hout change untfi delivery. However, l'eWH:l'of sUroid synthesis (Tullner and
ued without cha h
h<)rm()nc was adminin the present stiKly. n
period-the pe
istered ‘'[‘'^... “g^'.nitalia difierenUat.es in
,-md wlu n
,hTlle treatment was eon........ .. .....

XX JS "days !»-«> of gestation) in

T

1
I

NORLESTRIN EMBRYOTOXICITY IN RHESUS MONKEYS

221
during the period of Norlestrin treatment or
first time in a nonhuman primate species
soon after, but the placenta was expelled be­
that norethindrone acetate and ethinyl estra­
tween days 40 and 78 of gestation, with or
diol in combination administered during
without the embryo.
early pregnancy do not result in malforma­
Next, it is hypothesized that embryonic
tions; however, it does appear to exhibit a
de.ath without apparent malformation in
dose-dependent embryolethality.
Norlestrin-treated cases might be due to se­
vere imbalance in maternal endogenous sex
ACKNOWLEDGMENTS
hormones. The hormone profiles show that
This work was supported by NIH grant
‘Tig. 3) during the course of Norlestrin
RR00169.
• idministration the maternal plasma proges­
terone was the same as control values. The
LITERATURE CITED
pattern of circulating estrogen and proges­
Abbatidlo, E.. and C.L. Scudder (1970) The cfTfct <>f
terone values in control animals reported
norethynodrel with mcstrunol treatment of
.
of K
pregnant
<
i
here closely resemble those reported by At­
mice on the isolation-induced aggression ofr their
male
offspring. Int. J. Fertil., /5.182-189.
kinson et al. (’75), although the estrogen levAndrew. El) . and R.E. Staples (1977) Prenatal toxicity
i S
Norlestrin-treated animals were
of medroxyprogesterone acetate in rabbits, rats and
’< t (Eig. 2l. The lower levels did not result
mice Teratology. /5( 1)25-32.
Atkinson. L E . J. Hotchkiss. G R Fritz. A H. Surve J D
'• aortion immediately except in one ani­
Neill, and E. Knobil (1975) Circulating levels of ste­
mal (monkey 01. Fjg. 4d), where both estro­
roids and chorionic gonadotropin during pregnancy in
gen and progesterone dropped to less than
the rhesus monkey, with special attention to the res
control basal values resulting in abortion/
cue of the corpus luteum in early pregnancy. Biol
Reprod.. 12.335-345.
resorptiop on day 35 of gestation. Estrogen
M H., and M. Briggs (1979) Sex hormone expo­
levels, however, returned to normal by the
sure during pregnancy and malformations. Adv. Ste
tenth day posttreatment in two of three ani­
roid Biochem. Pharmacol.. 7.-51-89.
mals, suggesting that the lower level of estro­
Chang. M.C. (1974) Effect of medroxyprogesterone ace
gen seen during and for a few days post­
tate and estrogen on the development of the early
rabbit embryos Contraception. /O(4):4O5-4OS)
treatment was drug related.
Curtis.
E.M., and R.P Grant (1964) Masculinization of
It has been shown that ovariectomy on day
female pups by progestogens. J A M A.. /V4 395-398
23 of pregnancy was followed by a fall in
Edgren. R A., and D.P. Clancy (1968) The effects of nor­
•serum estrogen concentrations to near zero
gestrel. ethinyl estradiol, and their combination (ovral)
on the young of female rats treated during preunanev
and remained very low until day 40 of gestaInt. J Fertil.. /3.(3):209-214
tion, while progesterone levels were not ap­
Ferenc/. C.. G M. Matanoski. P I) Wilson. J Rubin C A
preciably affected (Atkinson et al., ’75).
Neill, and R. Gutbrrlet (1979) Maternal hormone ther
Despite the absence of ovaries, the second
apy and congenital heart disease. Teratology. 11) 26
(Abstract).
gestational rise in estrogen levels (day 40 of
Gal. I.. B Kirnmn. and J Stern (1967) Hormonal preg
pregnancy.) was observed. Based on the ob­
^IS^i
Un<1 Congen*U‘1 ’’’“Iformations Nature,
servations in ovariectomized monkeys, it can
be extrapolated that lowered estrogen levels
Gal, I. (1972) Risks and iMmefits of the use of hormonal
during the period of Norlestrin treatment
pregnancy test tablets. Nature. 240.241 242
Gidley. J.T. H.D. Christensen. I H. Hall. K.H Palmer
wer
>t detrimental to pregnancy mainteand M.E. Wall (1970) Teratogenic and other effects
nam and that Norlestrin probably acted as
pnxiuced in mice by norethynodrel and its 3 hydroxy
a negative feedback for gonadotropin release
metabolites. Teratology, 3(4):339 344.
Hemoncn. O P.. I) Slone. R R. Monson. E B. Hook, and
which in turn resulted in a decrease in estro­
S Shapiro (1977) Cardiovascular birth defects and an
gen synthesis from the maternal ovaries. In
tenatal exposure to female sex hormones. N Engl J
addition, the normal progesterone levels dur­
Med . 2.96(2) 67-70.
ing the period of Norlestrin treatment sug­
Hendrickx. A G.. and Binkerd. P.E. (1980) Fetal deaths
in nonhuman primates In. Human Embryonic and
gest that placental synthesis of progesterone
Fetal Death. I.H. Porter and E.B. Hook, eds. Academic
was not affected.
Press. New York, pp. 45-69.
Finally, examination of 50 day fetuses and
Hodgen, G.D., G.T Ross, C.K. Turner, D.L Barber, and
placenta exposed to 50 mg Norlestrin/day/
AMO Conner (1974) Pregnancy diagnosis by a hem
agglutination inhibition test for urinary macaque cho
monkey during early organogenesis (days 21 rmnic gonadotropin (mCG) J. Clin Endixrmol Melab
3.)) revealed no abnormalities. These obser­
38 927-930.
vations reduce the doubts that possible malHutchkiss, J . L E Atkinson, and E. Knobil (1971) Time
lormat ion's m an aborted fetus might have
course ncrum estrogen and luteinizing hormone (I.H)
l»een masked by autolysis.
concentrations during the menstrual cycle of the rhe­
sus monkey Endixrinology, 8.9.-177- 183
In summary, this study has shown for the
l

Jacobson, B.D < 1962) Hazards of norethindrone therapy

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third edition

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editors

1AY I. GOLD, M.O., F.A.C.P.
Chnk.l P'oleW <>'

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JOHN B.

M.D.
f Ob t t c and Gynecology, College of Medicine

M.SI Soo.,

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with 59 contributors

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77u. editors and publrshe-r have exerted every effort to ensure that dru.
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Fsesssae
t.s a new or infrequently employed drug,.

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MeJwal Depart.nent, Harper & Row l uWishers, Inc., ^,>0

Avenue. Hagerstown, Maryland 21 740
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Library of Congress Cataloging i.i Publication Data
(rokl, Jay J
Gynecologic endocrinology.
Includes bibliographies and index.
1 Endocrine gynecology. I. Josimov.ch John B
193L
joint author 11. Title. 1DNLM. 1. En3ocrine diseases. 2. Endocrine
o1°K>3. Cen.tal diseases. Female. W1 5O> <- ■ \
BC159.GB4
1980
618.1
<9-2~J5I

ISBN 0 (Xi-140954-.5

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526

Abnormalities of Sexual Development or Fundion

hopes of preventing spontaneous abortion,
norethindrone was administered daily to 82
women during most of the first 12 weeks of
pregnancy. Despite similar dosages and lengths
of administration, only 15 of 82 female off­
spring were masculinized. Genes might control
maternal metabolism, placental transfer, or
fetal metalxjlism of a potential teratogen.
Hormones That Produce Female
Pseudohermaphroditism.
Testosterone. Testosterone enanthate and tes­
tosterone propionate masculinize the female
external genitalia in rats, rabbits monkeys, and
humans. 6u Methyltestosterone and androstenediol masculinize human fetuses. These ob­
servations continue to be germane because pa­
tients with endometriosis are occasionally
treated with methyltestosterone.

(
Progesterone and 17(i-Hydroxvprogesterone.
Progesterone and its 17a-nydroxy analogs are
weak androgens. If administered during preg­
nancy, neither progesterone nor 17a-hydroxyprogesterone virilizes female fetuses of rabbits,
mice, or rats. In humans female pseudoher­
maphroditism has occasionally lx*en associated
with maternal progesterone administration;
however, a causal relationship remains un­
proved. 17a-Hydroxyprogestcrone is likewise
probably not teratogenic, although the associa­
tion of fetal masculinization and maternal in­
gestion has ix-en reported.
Mcrlroxyprogesterone. Medroxyprogesterone
(Piovera)
(tia-mclhyl-17o-hydroxy progester­
one), unlike progesterone, can lx* absoilx-d
oially. In humans Burstein and Wasserman18
administered medroxyprogesterone to 172
women prior to the 12th w'eek of pregnancy
(TOlli week of embryogenesis) in hopes of pre­
venting spontaneous abortion. Only 1 of 82 fe­
male offspring had clitoral hypertrophy, and
none had labioscrotal fusion.
Norethindrone. A synthetic progestin derived
lioin 19-nortestosterone, norethindrone is more
potent per milligram than progesterone and
can Ik- absorbed orally. Animal studies had in­
dicated that norethindrone was less androgenic
th.m testosterone; therefore the flrug seemed a
suitable candidate to increase progestin levels.
Unfortunately administration of norethindrone

to pregnant patients was frequently associated
with masculinization of female external genita­
lia. °-J " 2b' |n fac(t norethindrone and ethis­

terone account for most cases of teratogenic fe
male pseudohermaphroditism.
Masculinization usually occurred only if high
doses of norethindrone were administvied prior
to 12 weeks of gestation. Labioscrotal fusion
occurred only if the drug was administered
prior to 12 weeks./0 If norethindrone was ad­
ministered after 12 weeks, clitoral hypertrophy
sometimes occurred, but labioscrotal fusion
never did. If norethindrone was administered
prior to 12 weeks and then discontinued, the
clitoris was relatively small at birth, irrespec­
tive of whether labioscrotal fusion was present.
In other forms of male or female pseudoher­
maphroditism the extent of clitoral enlarge­
ment, urethral displacement, and labioscrotal
fusion are proportional to one another; thus
discordance among the three suggests terato­
genic female pseudohermaphroditism.

Ethisterone. 17a-Ethinyl-testosterone (ethis­
terone) is a potent oral progestin. Like noreth­
indrone, ethisterone was originally admin­
istered in hopes of preventing spontaneous
abortion. lake norethindrone, it masculinzized
the female offspring of mothers who ing<‘sted
the drug during the appropriate gestational
stage.

NorethyiKxlryl. Norethynodryl is structurally
similar to norethindrone, but despite earlier
suggestions to the contrary it docs not appear
to be a potent teratogen, ruchmann-Duplessis
and Mercier-Parot 1failed to produce female
pseudohermaphroditism among offspring of
pregnant rats to whom the combination
norethynodryl and mestranol (Knovid) was
administered.
Diinethistcrone. This is chemicalL similar to
ethisterone. Because of this similarity, one
might also expect dimetlusterone to produce
female pseudohermaphroditism if given to a
susceptible fetus in an appropriate dose at an
appropriate embryonic stage. However, no
data are available in humans.

Norgestrel. 'This is a 19-nor-testosterone deriv­
ative. In addition to Ix-ing progestational, nor­
gestrel is antiestrogenic; uterine growth is
greater in mice treated with estradiol alone

i

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24 / Disorders of Sex Chromosomes and Sexual Differentiation

than in mice treated with both norgestrel and
estradiol.40 Norgestrel masculinizes rat fe­
tuses,40 but few* data are available in humans.

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Other Compounds. Ethynodiol diacetate is a
19-nor-testosterone derivative that does not
masculinize rat fetuses;40 no human data are
available. Megestrol acetate and chlormadinone acetate are acetoxyprogesterone deriva­
tives
structurally
related
to
medroxy­
progesterone. Based upon their chemical
similarities to medroxyprogesterone and pro­
gesterone, megestrol acetate and chlormadinone acetate probably would not cause
masculinization in humans.
Practical Advice Concerning Administration
of Progestins During Pregnancy

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.Based upon the above data the following clini­
cal suggestions can be offered. 1) II administra­
tion ol a progestin is indicated during preg­
nancy.
progesterone
oi
17o hydro.xyprogcslcioiie arc the preferable agents. If an oral
medication must be used, medroxyprogesterone
is prelcrable to compounds containing ethis­
terone, methyllestosterone, norethindrone, or
norcthmdrone acetate. Nonetheless these com­
pounds may im lease the risk of Ictal cardio\ ascul.u anomalies follow mg hormone adminisliation?4’ 2) Because even limited exposure to
<ci lain hormones might masculinize female fe­
tuses or cause anomalies, one should diagnose
piegnam ics on the basis ol assays lor chorionic
gonadotiopin or its /? subunit, rather than as­
sessing whether or not uterine bleeding follows
admuustration of a progestin. 3) A patient who
in successive cycles experiences no withdrawal
bleeding following cessation of oral contracep­
tives should not continue to take the drug un­
less pregnane} is excluded. However, most oral
conliaccptives contain only small amounts of
piogcstins, and hence the risk of fetal viriliza­
tion is probably low.

527

adenocarcinomas metastatic to the ovary (Kru­
kenberg tumor). Verhoeven et al203 reviewed 15
reported cases in which virilizing tumors were
associated with pregnancy. Among the oil
spring were 18 females whose external gem la ha
were described. Nine had clitoral or labia! !i\
pertrophy, but only one16 had labioscrot.d
fusion.

Aminoglutethimide
Arninoglutethimide was incriminated as a cause
for female pseudohermaphroditism by Ilf}' et
al*1 and Le Maire et al.1 2 The drug inhibits 3
/Tol-dehydrogenase and possibly other biosyn­
thetic enzymes; thus its teratogenicity might l>e
expected. In the two reports cited above,
wou.cn who ingested the drug throughout their
pregnancies were delivered ol females with ch­
loral hypertrophy, labioscrotal fusion, and a
persistent urogenital sinus; mullerian deriva­
tives and ovaries were normal. On the other
hand, others have detected no abnormalities in
ollsprmg born to mothers who received amino
glutethimide. Originally used as an anticonvulsive ding, aminoglutethimide has been re­
moved from the commercial market because it
interferes with the synthesis of thyio.xine and
cortisol.

OTHER FORMS OE FEMAll

PSEUDOHERMAPHRODIHSM

Genital abnormalities may also result bom
maldevclopmcnt ol the genital (ubciclc, cloa
cal membrane, urogenital membrane, or the
entire hind end of the embryo (sirenomelia). In
some ol these malformations the external geni­
talia may Ik* so abnormal that the sex ol rearing
is in doubt; thus the designation female pseu­
dohermaphroditism is appropriate. These rate
disorders, discussed elsewhere,11 include ex
strophy of the bladder, exstrophy of the clo.u a,
and sirenomelia.

Virilizing Tumors in Pregnant Patients
Andi ogen-secreting tumors in a pregnant
woman can masculinize female fetuses, al­
though jiatients with preexisting androgen-se< icting tumors rarely become pregnant. Fetal
masculiniz.ition has been reported in pregnan­
cies associated with arrhenoblastoma, Leyilig
cell (umoi, hiteoma of pregnane} , and certain

MALE PSEUDOHERMAPHRODITISM
Male pseudohrrmaphrodites are individuals
with a Y chromosome whose external genitalia
fail to develop .is expected lor normal males.
Some authors apply the trim only to tl l( )S< ■

whose external genitalia are ambiguous < “nough

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Drugs in
Pregnaw ane
Lactation

S REFERENCE GUIDE TO
FETAL MIEONATAL RISK
.

1

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1

Gerald G. Brlggsxrharm;
Clinical Pharmacist. Women s Hospital
Memorial Hospital of Long Beach, California
Assistant Clinical Professor of Phormacy
University of California. San Francisco
Clinical Instructor in Pharmacy
University of Southern California. Los Angeles

Thomas W. Bodendorfer. ptiarm.o.
Detroit. Michigan
Formerly Clinical Pharmacist
Memorial Hotfrital of Long Beach. California
Aaaitlanl Clinical Profeaaor of Pharmacy
Univaralty of California. San Francisco
Clinical instructor In Pharmacy
University of Southern California. Los Angeles

Boger K. Freeman, imo.
Medical Director. Women s Hospital
Memorial Hospital of Long Beach. California
Professor ol Obstetrics and Gynecology
University ol California. Irvine

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Sumner J. Yaffe,M.o.
Director. Center for Research for Mothers and Children
National Institute of ChHd Health and Human Development
National Institutes of Health
Bethesda. Maryland

WILLIAMS & WILKINS
Baltimoro/London

jjfe

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•■■•71'*7

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Copyright €>, 1983
William* & Wilkin*
428 East Preston Street
Baltimore. MD 21202, U.S.A.

lib**

AU rights reserved. This book is protected by copyright. No part of this book may be
reproduced in any form or by any means, including photocopying, or utilized by any
information storage and retrieval system without written permission from the copy­
right owner.

I

Made in the United States of America

i

Library of Congrcau Cataloging in Publication Data

[
!<

Main entry under title:

□ruga in pregnancy and lactation.

'I
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Includes index.
1. Fetus, Effect of drugs on the. 2. Milk, Human—Contamination. I. Briggs. Gerald
G. [DNLM: 1. Catalogs. Drug—United States. 2. Lactation—Drug effects—Catalogs.
3. Pregnancy—Drug effects—Catalogs. 4. Fetus—Drug effects—Catalogs. 5. Infant
Newborn—Drug effects. 6. Drug therapy—In pregnancy. QV 772 D795]
RGO27.6.D79D79 1983
618.3'2071
82-13392
ISBN 0-683-01057-3

Composed and printed at the
Waverly Preaa, Inc.
Mt. Royal and Guilford Avea.
Baltimore, MD 21202, U.S.A.

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Instructions

nursing infant. In many studies of drugs in breast milk, infants were not allowed
to breast-feed. Readers should pay close attention to this distinction (i.e.,
excretion into milk vs effects on the nursing infant) when using a Summary
Those who require more details than are presented should refer to the specific
references listed at the end of the monograph.

Risk Factors

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Risk Factors (A. B. C, D. X) have been assigned to all drugs, based on the
level of risk the drug poses to the fetus. They are designed to help the reader
quickly classify a drug for use during pregnancy. They do not refer to breast
feeding risk. Because they tend to oversimplify a complex topic, they should
always be used in conjunction with the Fetal Risk Summary. The definitions
used for the Factors are the same as those put forth by the Food and Drug
Administration (Federal Register 1 980;44:37434-67). Since most drugs have
not yet been given a letter rating by their manufacturers, the Risk Factor
assignments were usually made by the authors. If the manufacturer rated its
product in its professional literature, the Risk Factor on the monograph will be
shown with a subscript M (e.g.. CM). There were no instances in which the
manufacturer and the authors differed in their assignment of a risk factor but
the possibility for this exists. Some Risk Factors have an asterisk (e.g.,
sulfonamides, morphine, etc). These are drugs that present different risks to
the fetus depending on when or for how long they are used. In these cases, a
second Risk Factor will be found with a short explanation at the end of the
Fetal Risk Summary. We hope this will increase the usefulness of these
ratings. The definitions used for the Risk Factors are presented below.
Category A:

Controlled studies in women fail to demonstrate a risk to the
fetus in the first trimester (and there is no evidence of a risk in
later trimesters), and the possibility of fetal harm appears
remote.

Category B:

Either animal-reproduction studies have not demonstrated a
fetal risk but there are no controlled studies in pregnant women
or animal-reproduction studies have shown an adverse effect
(other than a decrease in fertility) that was not confirmed in
controlled studies in women in the first trimester (and there is
no evidence of a risk in later trimesters).

Category C:

Either studies in animals have revealed adverse effects on the
fetus (teratogenic or embryocidal or other) and there are no
controlled studies in woman or studies in women and animals
are not available. Drugs should be given only if the potential
benefit justifies the potential risk to the fetus.

Category D:

There is positive evidence of human fetal risk, but the benefits
from use in pregnant women may be acceptable despite the
risk (e.g.. if the drug is needed in a life-threatening situation or
for a serious disease for which safer drugs cannot be used or
are ineffective).

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Instructions

Category X:

w'O? l not allowed
e xtinction (i.e..
ng a Summary.
to the specific

i

Studies in animals or human beings have demonstrated fetal
abnormalities or there is evidence of fetal risk based on human
experience or both, and the risk of the use of the drug in
pregnant women clearly outweighs any possible benefit. The
drug is contraindicated in women who are or may become
pregnant.

»■

based on the
‘•ip the reader
■< fer to breast
. , they should
i-.e definitions
»od and Drug
st drugs have
Risk Factor
?r rated its
uraph will be
I .1 which the
risk factor but
asterisk (e.g.,
derent risks to
these cases, a
the end of the
nc»ss of these
oelow.

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• ‘ a risk to the
ice of a risk in
h um appears

• ■monstrated a
• ujnant women
adverse effect
confirmed in
:d there is

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there are no
n and animals
f the potential
ut the benefits
Je despite the
mg situation or
, tot be used or

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82
Ni I roglycof m-Norolhmdr one

24G/n

2. Helnonon OP. Slone D. Shapiro S. Birth Detects and Drugs in Pregnancy Littleton Publishing
Sciences Gioup, 1977.371-3

Name:

11

"li I

NITROPRUSSIDE
Risk Factor: D

Class: Antihypertensive

^03

is'

Fetal Risk Summary

No reports linking the use of nitroprusside with congenital defects have been
located. Nitroprusside has been used in 7 pregnant patients to produce
deliberate hypotension during aneurysm surgery or to treat severe hyperten­
sion (1-3). Transient fetal bradycardia was the only adverse effect noted (1).
Nitroprusside crosses the placenta and produces fetal cyanide concentrations
higher than maternal levels in animals (4). This effect has not been studied in
humans. Avoidance of prolonged maternal use and monitoring serum cyanide
and/or thiocyanate levels in newborns exposed near term are recommended.
Breast Feeding Summary

No data available.
Reference*
1

2

3
4

Donchin Y. Amirav B. Snhnr A. Yarkoni S Sodium nitroprusside lor aneurysm surgery in
pregnancy Br J Anaesth 1 976.50.849-51
Pauli J. Clinical report of the use ol sodium nitroprusside in severe pre-eclampsia Anosth
Intensive Care 1975,3 72
Rigg D. McDonogh A Use of sodium nitroprusside lor deliberate hypotension during preg­
nancy Br J Anaesth 1981;53:985-7.
Lewis PE. Cefalo RC. Naulty JS. Rodkey RL Placental transfer and fetal toxicity ol sodium
nitroprosslde Gynecol Invest 1977;8 46.

Name:

NORETHINDRONE
Risk Factor: D

Class: Progestogenlc Hormone

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Fetal Risk Summary
Norethindrone is a progestogen derived from 19-nortestostorono. It is used In
oral contraceptives and as hormonal pregnancy tests (no longer available in
the United States). Masculinization of the female fetus has been associated
with norethindrone (1-3). Jacobson observed an 18% incidence of masculin­
ization of the female infants born to mothers given norethindrone (2). A more
conservative estimate for the incidence of masculinization due to synthetic
progestogens has been reported as 0.3% (4). The Collaborative Perinatal

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n/249

Norethmdrone

'^'vgriancy Liltlofon Publishing

A1

Risk Factor: D
'4

■ nital defects have been
it patients to produce
1 treat severe hyperten= Averse effect noted (1).
cyanide concentrations
is not been studied in
■ -iitorrng serum cyanide
'f,rm are recommended.

Breast Feeding Summary

1
.'Jo for aneurysm surgery in
|

i <<• <• himpsia Anesth

hyj>(.tension during prog-

Project monitored 866 mother-child pairs with 1st trimester exposure to
progestational agents (including 132 with exposure to norethmdrone) (5).
Evidence of an increased risk of malformation was found for norethindrone
An increase in the expected frequency of cardiovascular defects and hypo­
spadias was observed for progestational agents as a group (6). Dillion ob­
served 2 infants with malformations exposed to norethmdrone (7). The con­
genital defects included spina bifida and hydrocephalus. Both estrogens and
progestogens have been associated with the occurrence of congenital heart
defects but because of overlap, the data is not sufficient to adequately
separate their effects (8).

Norethmdrone exhibits a dose-dependent suppression of lactation (9). Lower
infant weight gain, decreased milk production and decreased composition of
nitrogen and protein content of human milk have been associated with norethindrone and estrogenic agents (10-13). The magnitude of these changes is
low. However, the changes in milk production and composition may be of
nutritional importance in malnourished mothers. If breast feeding is desired,
the lowest dose of oral contraceptives should be chosen. Monitoring of infant
weight gain and the possible need for nutritional supplementation should be
considered.
Roforenc«A
1

J

X.

Hagler S. Schultz A. Hankin H. Kunstadter AN

Fetal elfecis ol steroid therapy during

pregnancy. Am J Dis Child 1 963.106 586-90

2

Jacobson DO

Hazards of norethindrone therapy during pregnancy

Am J Obslut Gynecol

1962;84:962-8

3

Wilson JG.

Brent RL

Are

female sex hormones leratogenic? Am J Obslct Gynecol

1981;141:567-80
*

md fi-!... toxicity of sodium

4

Bo'-giovanni AM. McFadden AJ Steroids during pregnancy and possible fetal consequences
Ferlll Sleril 1960.1 1:181-4

5

I leinonen OP. Slone D. Shapiro S Birth Dufvcts and Drug;, m Pregnancy I itllclon Publishing

6

Ibid. 394.

Sciences Group. 1977 389.391
7

Dillon S Congenital malformations and hormones in pregnancy fir Mod J 1976.2 1 4 46

H

Heinonen OP. Slone D. Monson RR. Hook EB. Shapiro S Cardiovascular birth detects and

9

Guiloff E. Ibarra Polo A. Zanartu J. Toscanini C. Mischler TW. Gomez-Rogers C

antenatal exposure to female sex hormones. N Engl J Med 1977;296:67-70

Risk Factor: 0

Effect of

contraception on lactation Am J Obstel Gynecol 1974.1 18 42-5

io

Karim M. Amman R. El-Mahgoubh S. El-Ganzoury 0. Fikri F. Abdou I Injected progestogen

and lactation Br Med J 1 971; 1:200-3
11

< sterone. It is used in
' > longer available in
‘.as been associated
•( idence of masculin■hmdrone (2). A more
’ on due to synthetic
■ 'ffaborative Perinatal

w

12

Kora SJ. Effect of oral contraceptives on lactation Fertil Steril 1969.20 4 19-23
Miller GH. Hughes LR. Lactation and genital involution elfecis of a new low dose oral

contraceptive on breast-feeding mothers and their infants Obstel Gynci ol 1970.35 44

13

Lonnerdal B. Forsum E. Hambraeus I

50

Eflect ol oral contraceptives on composition and

volume ol breast milk. Am J Clin Nutr 1980.33 Bib 24

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1 Pregnancy: A Clinical Review
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Vr Bi B

A review ol the extensive literature on the subject indicates

that s< x hormones have been associated with a wide variety of adverse clinical
(ondtlions lollowing us.tge during pregnanes. About 230 cases ol female pseudolu'i maphrodil isni have been re|>oited following use ol hormones with androgenic
poh-nev . but m.r.< iihm/al ion obsei ved with estrogens in a few females mil)

i e|)i eseiit
(

■

only

adi cn.il st nnulated

pseudohermaphrodit ism.

1'eminizat ion

of

‘ .males, mostlv b\ piogeslogens in some 15 cases, is unproven al present.

4

1

Keah.ing the limitations ol the published studies when all present data are

A

i mnsal'i ed. I hei e seems no just ificat ion lor undue concern over the induct ion ol
iiongemlal imij-.eiiii.il maltol mat ions through hormone use in pregnancy. The

availabh' data on the associat ion to cardiac, limb, and ('NS delect s. and to several

1

inalloi mati\<• syndromes, are not convincing: the effects ajjpear to be remarkably
nonspecific, the studies are contradicted by a large number of negative reports,
and an increased incidence ol defects with increased usage has not materialized.

3

'M:

A po . -iblc exception are the ('NS malformations asstx ialed with the use of the
atil il<a I ilit \ agent clomiphene. and careful surveillance is warranted at present.

\\ IhIo a i e.r-i »i ial dr ml <-| pi <*( al ion liom this review would be that hormones

|m • • nt no map>i I ei atogeiiK* hazaid. elimmal ion ol hormonal expo-ane w believer

3

po • ibh doling pi c/'.ii.iiH \ is suggested
■f

inliodthlmn ol sex hormones as
.igcnl ■ I hoi c has been concern <>\ or
. ..silth liarmtul cl lei t s on I he off sp, ing ol
v. h.o u- « the agents during pregnancy
4 . cetH'ii'
e!H cl li >'
I undci st andahle. because hot
1 .. ai,■ m ide -plead u- c w ol Id u ide as oral
C. . ui\t
and have lotmd additional
stluiipv loi ( hi cal ened abort ion and
1 ■
',' • 111X1)11ich nev . as ant mcoplasl ic treat
. m al picgiiancv t c^f ■>. and loi ol her in
■ ,i- well \s a ding gioup. they lank
a
'
tin I S in imagt . ahead ol antibiotics
X ’.inijUth/ci
Then loo. the lei v or created
'f decade by t he association ol vaginal

v--

. jn \ oung wonu'n exposed in utero to es
5inaii\ v eat s previously has accelerated
■$. • concern o\i‘r their safetv.

The Inst adverse effects ol hormone admin­
istration during pregnancx dale back to the
early 1950's, where androgens and synthetic
progest ins given I herapeut ically were reported
to induce pseudohermaphiodil ism in female
oflspiing. More recently, feminization ol male
offspring and a variety of other defects have
been reported. There also arc indications that '
progestogen estrogen mixtures may induce;
limb reduction defects. ( aidiovascular anoma |
lies, multiple malh i mat i ve syndromes, and
central nerx ous s\ stem abnormalities At least '
one specific hormonal agent, the antilertility
drug clomiphene may also be frankly terato­
genic. In mid-1977 in fact, the U.S. Food and

7

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1

252

J.L. SCHARDEI N

Drug
promulgate] a rule*
t>rug Administration promulgated
requiring patient warning in labeling of pro­
gestational agents, stating that there is an in­
creased risk of birth defects in children whose
mothers have taken these drugs during the
first 4 months of pregnancy, in addition, pro­
gestin use was not recommended to prevent
habitual abortion or to treat threatened abor­
tion, because of the evidence of potential harm.

i
so

G.«?tfTndlCaL1On L° Lheir, USe as a dia£nostic

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test tor pregnancy was also given. The ruling
applied to a large number of specific progestogens and their salts and esters, as well as to the
19-nortestosterone derivatives, the C-21-sub­
stituted progestins. 17-hydroxyprogesterone.
and surprisingly, to progesterone itself, in
December 1978. final implementation of the
requirements was made*.
We shall examine the evidence on all these
points in this review, utilizing all available
data. I he data will be examined both in those
cases where the agents were discontinued prior
to conception, and where they wen* used dur­
ing early pregnancy through either intended
therapy, inadvertent use in unsuspected preg­
nancy. or in pregnancy testing.

I

Jwharu
Mel hyltcstosterom

Mfl Imthlr io|

B*KyIi

.‘“si

C,.-.
wim uuuim C.w -__
Progestagens. As with androgens,

pseudohermaphniiuirm is Xo induced
-spring
— ------whose
«
•
. . __*
l
mothers
were treated
withers

tain synthetic progestogens in pregnA^’^i
Progestogens may be converted into andTf 1
gens in mother and fetus (Wilkins, ’60). Soa< 1
with chemical modifications to the stucturf M
\
the 17-position as shown below, have weak i» T
herent androgenicity (Venning. '65) and dos<s ryl ‘Bo.u-,.
■Clu- .
of 200 mg/day are associated with severem**.
OMWm
culinization. '1’he drugs w'ere given in
[ff* *ClU-n I
1950s and 60s in instances of habitual
•Cites |
threatened abortion.

S lC,lr- '

Oil

.

_

—C.CM

Norvi hindrone

l.lnisl vr<H>i'

fX'ITJt.SI.XIJAIJ l Y

*W-

OH

|

Of the progestins reported, ethisterone and | h'Ethist..,
Masculinization
norethindrone are the most active, accounting I
approximately | Hv
In 1953, Zander and Muller reported the first for fully three-fourths of the- -«-r
r
’
■
’
’
____
„
F
v
.,
v
Mwuinunvm.
CUs<vs
masculinization
reported
to
dal*
case of a child masculinized by the administration of a hormone to the mother during preg- ^^’de 2). While not lessening the importance I
i_ .uof this observation, this number represents
i
nancy. In
this.. case, the woman was treated
with an androgen, methandriol. Later. Wilkins fewer than the number of nearly 600 cases said 1
| Norvt I.:
and his colleagues (58) published on a number to be involved by Cahen (’66).
Although the lesion is usually attributed U> I
of cases of masculization due to progestins
I
taken by women during pregnapey. The de­ synthetic progestins, natural progestin (e.g-. I
fects occur with both classes of hormone in fe­ progesterone) appears to be responsible for al I
male offspring and are due Indirect androgenic least 10 cases of masculinization, while other »
action. Androgens apparently simulate the ac­ reported cases, like those with norethynodrel B
|
tion of the fetal testicular secretion on the uro­ may be chance occurrence (Venning. '61).
1 he actual incidence of female pseudoher- K Norvt h •
genital sinus and the external genitalia, but do
not appreciably effect differentiation of the maphrodit ism following administration of pro- F. Prop-*-'
genital ducts or the gonad (Grumbach and Du­ gestogens is not high. I n one series of 650 preg |
charme. 60). 1 he effect in man is comparable nancii‘s during treatnamt with several progesHydrox
to that obtained experimentally in animals tins, only 0,.‘)% of the result ing females were af- rfected
(Bongiovanni
and
McPadden.
’
60).
Ina
I
(Greene et al.. ’39; Keveszet al.. '60; Suchowsky
Metho
group of 174 pregnancies in which inedrox)- I
and Junkmann. ‘61).
Other'
progesterone was gi\-en. the frequency of the |
Androgens. There has been a total of about anomaly was ().6' < (Burslein and Wasserman. I
35 cases of fetal masculinization reported to
64). .Jacobson ( 62) recorded a higher frequency I
date, as shown in 'I’a)»le |. Androgens have a of )8.3% among 82 infants of mothers given I
•Ch■(ir.o
chemical structure as shown below. The norethindrone; he believes this agent enhances I
•Chh.
hormones in these cases were taken in the the potential for virilization. Ishizuka et al I
‘Inelu
1950s and 60s as antitumor therapy or for (62) reported a risk of about 2.2% among 888 I
•Citv
other indications including alopecia, nausea pregnancies in which progestogens were used- L
’Cite
and vomiting, weakness, hypotension, and
Tino
'E«l.rul l(<-KiN|'r. N<. HI. ^2 37643-.ITtHM. Julv 22. IW77
•Imh.
pruritis.
■H>A Drug Hull.. A.-16 37. Ifc-c. IW7M-Jan. I4J79

•Tit^
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Drug

ft 'voidd appear that sex
relal;
hormones hl * '
.Th,
)«*<-n associated with a wide variety of advert
<hmcal situations following use
‘
‘
either behn
Ltosent us,
j oneepdonor during pregnancy.
hen. swns little doubt that'given to pnf
.
feu
inh t '\<),npn; hormonal preparations havifij f «UCed by ,
‘Pfxar to !
iren •tn
potency, namely andn>
g S and certain progestogens. can mascu'i*
^eS. Siru,
< iii..r
tl> the extent of at lex«i
®rogenic |>.
™ "''"'Wnent. with or wjthout Ubar
. fhe role.
ne.es attesi"".
pthp’ TWe are^
Spring I

Neither u;,s th, re a

"I .irx1''who'ind Uk'"’"41 l!‘e*,lls,’ring

I

'ives for on., t "f".'

Oral "'"'raeep-

fording

' «i

{oat pre ...
«
Briere\
..
meth li ' ? n<”‘‘lhindrone, methundriol, and
7, < H
r‘n"rOn" ‘,ssl,<i"'e.l with the vaM J filing

""-horI,1..„..s.T|,.'; i I .
( ;U1I
””,,Hn<r wasnons.gnifi-

A number o| O( |h.f . ■ I..tn .h( . ,
in almost .| i/Dl')
i

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'n<ii.< tu.n

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•"igi-rtitii/ rnatforniationf

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( I'l'.i hi.kIih.,;

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drome o| .:
theeniitx
doubt fnl v.
Prove (
*s a tei.uo;

(I

IM.umlf, ;1|„| K| (
1

c°nvin< in;Pr«d syndr.
nlion o| ,1
hlon<- u-.e

As poiniet!

•*l SMIfl (
A.

aerved in .
Plasia (Api
As for
hormones
^ue con.< r
sidered. II
Conunon .1
^•fects am:

a,sSe.SS (he
p,

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llniii>iifii ,.( .,j

rep,,.-.

,,f of
insu|
t «™|j i ’
m.iiei
7
"l’<'">lh..t„sl IPiii,,e
weeks
gestation,
week i'h'o
’"I.U ll"' ‘''k'lith gestational I ^sterone (
•iltfihui i <S<> !n c‘,s<‘s have resulted has beto | inhibit ing
hereby no
,,",,,,,“(H“,h’’ hut that (here are different

. .. ■'“"“o-.xsxiii.fxsr1

I

[

i K,-,J treat n

.. ■':::“exix

)&’■

v'i r,‘<<’,‘<ivd ">ses. in that order

respectiv 7

""

'.•I.

1M

rvniark.ibh
widi- vane
'night li.o,
h‘cts in iesp
age over (h<
ah'zed (Ano:
Animal 1 ■'
interpret al
respect io 1
Particular h
script ion-,
genic rfle.
agents.
Ambani <
examining
pregnam i<

••On-.
•»C>

i

* $$ * *
F’.

93
HOHMOXES /\N1) MAI.EOHMATtO.XS

I

(i

265

■ susceptibilitv rates among individuals, proboral contraceptives prior to conception, or
3bly relating to metabolism of the hormone
cither
intentionally or inadvertantly in earlv
have
taken I he resultant risk would appear Io In*on
pregnancy, that the weight of the evidence
Iwrse ■• the order of less than 1*. among hormones in
suggested that the rates of occurrence of conbvi ore ■ present use.
genital malformations were not increased from
4 Ihe few cases (eight) of masculinization incontraceptives treatment prior to pregnanev.
j/fuccd bv estrogen (mainly diet h\Istilbestrol)
W hilc there also did not appear to lie in an in­
(ippeio 1° be paradoxical, and mav represent
crease in malformations following treatment
.Ilicll
J ?:<h adrenal stimulated pseudolnr rnajihro
with hormones doru^ pregnancy, difficulty in
• ulin
1 tiiles. since hormones of t his class have no an
docummitmg
conclusively such a relationship
it h ast J ^iig'.-nic pi opert ies
haired them from taking a more definitive
labio. j The role of hormones in feminizal ion of male
stand. As so well staled by these aut hors: "'Fhe
in nted |dfspring has not been proven al present.
P'ohlem of conclusively proving a small in
11 ;kinj'
Ucerdmg Io Apold e( al C7(i). n is piobable
‘’‘•imc of rare abnormalities is very formid­
• nt s to
n.il progestins (and ot her hormones?) mav in
able.
• i. with
^frre with the fusion of (he urethral fold.
Ixpidemiologic studies reporting relation
"L and
za<bngt lo hv jiospadias About |:> cases havi*
ship- of increased general malformation rates
'• \ asl
>vn i» ported, cspeciallv following progesloand hormone use are contradicted by an
1 "kRt
an
Hralini-nl. I he postulate has been made
equally large number of negative studies
I would 4 h.it maternal progcslogens might impair lesHowever, it should be enqihasized that many
i .it ion
< .xidoiic production in the fetal testes by
ol
the above cited studies, both positive and
: .‘i ional 2 ."hthilmg J,? hydioxy.stci oid dehv di’ogenase.
negative, suffer from design imperfections,
(
’ >;itnhv mimicking the genital anomalies ob
which mar (heir validity. As pointed out by
II lerent t uvrd m congenital virilizing adrenal hv per
Kullander and Kallen C76). Keith and Berger
dasia (Aarskog. 7p. '^,it
( 771. I layden and I’einstein C79), Janerich et al
i A> for specific malloim.itions induced l>\
( 79) ami others, I he ndative lerato/,'enic
,riix’iies. I here seems no just ilication for un
liabihtics ol the various agents were not differ
J-je concern, when all present data are con
cntial ed in many st udies. and details of dosage
, . 'M> ^.
JiTed. 1 he available
dal n <>n ( he t wo most
z.....
........... '•••!
and timing of administration were not consid­
j. ninon associations made, to cai diov ascular
ered in a number of others. Lack of proper con­
j .f.'ds and limb reduction anomalies, are not
trols. methodological differences, and biases
l.r>
| jnvincing. and the C\S delects and the sev•r»r>
related to exposure recall, pre-exposure sus­
t Jsyndrome t\p, s also offei little substanti
ceptibility to bear children with birth defects
J.J..II ol dii<«ct association to maternal hor».h
and reasons for exposure, and inadequacy of
22
J..nr use during piegnancv II is |o(i ear lv lo
sm veillanre lo detect defects are other delici! „.>s the relationship ol the KI KSSKS syn
i-ncies commonly noted in the studies. Even
| - ini' ot dcle< is to hormone exposure since
variation in use <>f clinical terminology arid
1 yenlily is so recently described, but it seems
704
chemical nomenclature create problems in
< jbllul whether such multiple features will
mterpretat ion
•. i\ c to he i el at cd to a single et ioj< >gic fact < >r.
1 U
Realizing lull well t he limitations of the pub­
1 .pointed out editorially (Anon . 7 la), if there
lished literature. I must agree at this time with
s .atri.ilogeiiu of Ice! of iiormoncs. I he effect is
I he conclusion set forth recently by Rothman
I Tatkablv nonspecific, since there is such a
and Louik I 76) that "a reasonable interpret a
ill)
.♦ > v.niciv of delects iepoif<-<l. And one
“o'1 '’f the dal.t would be that oral contra
4 -I.l have I< Al
xp. cled an epidemic o| birth <le
7b
replives present no maim teratogenic hazard.
<» tI In*
Ik- great
;• ■ • increase
'
; /- hi
in response tI o
in pill us
Or. as sl.ited editorially in another wav. ’the
y_- •At r the.|)a?
1 lie. pa> I1 decade, w Inch has not nialeri
evidence linking hormone ingestion w’ilh mal'>4
j, :ul (Anon . Mb)
formal ions is ext remelv tenuous" (Anon.. '7 la).
3»i
j Animal experimentation has not aided in the
2.2.‘>2
I here remain persistent pleas of warning
: .yrpiclulion o| th.- Imdmgs in humam with
and faulion In summarizing his several
.‘’•07
r|w-cl lo hormone (or prtigeslogen estmg'e.u
studies (cited by ( he/., 76). .Janerich, and real
.J..'.l.n I.' ) medication ()ri|v :.,p(,(adh de
izing hilly the studies are inconclusive and
179
J..-ip(i''D' have appeared recording a teralo
subject to criticism ol design, still believes the
M.s
j..; rlfect from administration of these
results to be strongly suggestive of a causal
7s
association between hormone exposure and
2G
]
el al I / ,) concluded from a re\ ievs
anomalies,
with risk estimates about twofold
j i.iiiiin'/’. lhe induction of inalfor mat ions in
1H1
the normal (depending exactly on when there
4. .guuncies following disconi inuancc of use of
was exposure to the hormone)* The Nora s and

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Baler. S.. B. Say. T. I’rrnar. and A. I lit soninez. 119731 B,rt>

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their assnrial.es f7K) also urge caution in
hormone use. estimating that there is a prob­
able two- to fourfold increase in malforma­
tions, particularly congenital heart defects,
among users of progest ogen'est rogen drugs
during pregnancy. Citing a 1973 estimate that
there is potential exposure to progestogens
and estrogens during embryogenesis in
300,000 pregnancies each year in the United
States alone, these workers make the plea toi
elimination of hormonal exposure whenever
possible, but at the very least, in cases of
threatened abortion and as pregnancy tests.
Most of her scientists who have considered t his
question concur, and there is support in some
quarters for retraining from hormonal post
coital contraceptive methods as well. The
current labeling practices of hormonal agents
should go a long way in satisfying these objec­
tions.
The final unanswered question deals with
(he teratogenic potential of the antiferlility
agent clomiphem*. The IK cases reported to
dale of CNS malformations suggest that I here
may be an associat ion between drug usage and
niailoMnalion. and cardul surveillance is wari.mled in an altenqit loclatily the relationship.

1

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r

f '*i

K

,1.1,. SCHARDEIN

' ■

i1

h;

r
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w*. progesw
16-26.
fc’hvn. J., and H
foducteurs de
Cook. H.H . C

defects <hh! oral eunlrucepttxv> l.uncet. 2.109S.

Banks. A I.. It N Rut herford. and VV /X. Coburn 119J>5.

nancx- and progeny after um* of progestin like subs
for contraception Obstet. (''.xnecol, 26.-760-762.
Barrett. ( .. and C Hakim (19731 Anencephak. ovu’a
stimulation, sublet I ility . and illegitimacy

Batts. .1

X

II H

Ora) conlrace

luincet.Z

Am J. Ohsic
Cope. E., ant! E

Valdes Daprna. J W-

Bunnell. M

.^’JF

J.

17/. hy
Gynaecol. Hr
Crvmbie. DI.
*ilh

and VV R Green (1972) A cum- of cy clopia Am. J Ubs
G vnecol . I /2 <.57 Gbl
Bet num. B IP'? •) (‘ongemtal abnormalities associated With

•ndK.W (>
Hr. Med. .1 .

maternal < l"mipli'-ne ingt'st ion. I ..meet. »’ H < S.
Biah. X . H lx-xenthal. M
Xltaras. and X'. Ben-Adert-

David. T.J . "f

(1978) Aneiuephaly ant! clonuphene-intlucisl pn-gn»nn

oral honnom
Davis. M.E . »>

-183 -IM-1.
,s.nblatl!9WT»*
Birntierg.C II, I. .1 Brandinan, anti B Gn
o| rlliiiixl eslratli"! m piegn.mcv Am J
Acta Obstet Gyurx-ol Scand .

<;

h.noI . U7 I 151

H53
Bam. ami

borrnunes on
!•»<< S<m I
Dws knuinn, VS

,

I K

Gault! (I9l.ti)
pseudo hermaphrodite preM-nting * ith bilateral crypto

Bissel. VV 11 . AD

Puttinger tl

bestrol dur u

chidism. Br Med. J . / 279 280
Black. J A . and J I K. Bentley 11959 Effect on the oew»

Obstel. (Ar
Dillon. S ir.»

of rintliogi-ns given during pregnancy. I.anccl. I >•
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1 ain<‘-i

Ghnistx-'

TRANSFER OF CO^RACEFTBT STEROIDS IN MILK OF WOMEN
VSi:
ONG-ACTING GESTAGENS

12
2
Kukulkam , K. Fotherby“, K. Shrimankcr ,
2
2
M. Mangalam and K. Towobola

S. Koetsawang’, P.

’Family Planning Research Unit, Department of Obstetrics and Gynaecology,

Siriraj Hospital, Bangkok 7, Thailand
9

Department of Steroid Biochemistry, Royal Postgraduate Medical School,
Ducane Road, London W12, England

ABSTRACT
Levels of norcthistcrone and medroxyprogesterone acetate were
measured in scrum and milk of women receiving the injectable contracep­
tive formulations Norigcst and DepoProvera, respectively, throughout
complete injection intervals. In 5 of 10 women receiving Norigcst, scrum
norcthistcrone levels were indctectable by 8 weeks after injection and
only 2 women had detectable levels of norcthistcrone in milk at this time.
In contrast, 8 of 10 women receiving DepoProvera had detectable levels of
medroxyprogesterone acetate in both serun and milk 12 weeks after injec­
tion. The ratio of the milk:serum concentrations of norethisterone varied
from 0.12 to 0.92 (mean 0.34) and for medroxyprogesterone acetate from
0.12 to 2.60 (mean 0.88), It is unlikely that these differences between
the two formulations are due entirely to differences between the binding
of norcthistcrone and medroxyprogesterone acetate to serum proteins. The
area indcr the curve of serum steroid concentrations plotted against time
was only 50? higher for women injected with DepoProvera than for those
injected with Norigcst but the area under the curve for milk values was
400 times higher. Assuming the infant ingests 600 ml milk daily, the
daily intake of steroids in the first week after injection would be
0.5 to 2.4 Mg for norcthistcrone and 1 to 13 ug for medroxyprogesterone
acetate. By 8 weeks after injcctior,the amount of norcthistcrone
ingested would be small but that of medroxyprogesterone acetate would
still be significant.
Submitted for publication February 5, 1982
Accepted for publication March 10, 1982

Address for reprints:Dr. K. Fotherby, Royal Postgraduate Medical
School, Ducane Road, London, W12, England.

in
APRIL 1982 VOL. 25 NO. 4

321

1

Table m.
MuatUn (Y

5CSPt) and A
for the
regression line
steroid concentrations (pg/ml) b’’ Fle“l'i5 the locaritb
f) of the milk
against cute (X weeks) a
eff<‘gCSt ?r DepoProvera
DcPoProvera to two
r
injection of
groups of voren (n - correlation
efficient)

Women receiving
Norigest

Subject

1
2

B

A

3.4875

0.2325

3.5266

0.1603

3

3.8708

4

2.7447

0.1622

5

3.6866

0.3330

0.2661

6

3.5314

0.1944

7

3.1352

O.1999

G

3.4629

0.1396

9

3.0969

0.1092

10

3.8862

0.3748

Mean

3.4429

0.2172

0.3587

0.0854

SD

CONTRACEPTION

- At) ohe1?

R

B

A

R

0.94

3.5106

0.0260

0.63

O.98

0.93
0.99
0.98

0.99
0.99

0.95
0.99

3.7469
3.3973

3.5268
3.9518
3.4136

3.6514

3.8062
4.2190
3.5407
3.6818

0.2634

0.1127
0.0492
0.0910

0.1548

0.1102
0.1497

0.1509
0.1637
0.1157

•0.90
O.83

0.54
O.85
O.83
O.69

0.90

0.93

Trans!
af NET and MPA to the infant as as
by
the area under the curve (AUC, ng/ml/day"^ssessed
T)

and milk steroid C O n O o r^ T" r*

36.24

4.91

0.14

31.81

26.30

2

0.83

30.89

9.05

0.29

22.55

20.20

0.90

3

30.04

9.21

0.31

21.85

16.27

4

0.74

5.38

2.04

0.38

31.71

24.82

0.75

5

7.46

4.56

0.61

71.47

30.12

6

0.42

14.77

5.53

0.37

22.12

9.88

0.4:;

7

12.15

2.26

0.19

23.00

14.04

8

0.61

36.91

7.71

0.21

25.33

25.03

9

0.99

22.64

3.86

O.17

52.72

50.29

0.95

19.82

6.19

0.31

26.15

14.65

0.56

Scrum­
milk
ratio

21.63

5.53

0.30

30.87

23.16

O.72

10.99

2.54

0.13

17.49

10.90

0. 19

samples; from women i
injected with Norigest and DepoProvera were
0.34 * 0.19 and 0.88 t

- - O.56, respectively.

conoentrations plott^d'ag^s^ ti^e0^'
f°r th' C’
serin and milk
-Phasiso the narked dif^/X^ t’h™
17
and again
two injectable formulations
Although the AUC
only 50^ higher than
for milk was 400$: higher
th. serm-milk ratios
based upon AUC ^easurenents were similar to tho^'oH^'
—-.wd above.

) of servtn

1

Mean
O.O462

. •

AUC for women
injected with
DcpoPr.overa
Serum
Milk

O.89

SD

1

piunea against time

Serum­
milk
ratio

10

0.1124

y am «

AIC for women
injected with
Norigest
Serina*Milk

Subject

Women receiving
DepoProvera

0.93

Table IV.

DISCUSSION

The values obtained for serum ievelsofnorethisterone
and
medroxyprogesterone t.;-.'..
acetate
in lactating
Thaiwomen--- - in
--------• W
—• this study
W VMM
------t
similar
to
those
reported
previously
(5
_
-------M. 6
«

are
-» lactation
7) for non-lactating
Caueaulmi and Thai ____
_
J- that
Caucasion
women, suggesting
v— j vas not influencing
f O rm 111 3^4
jootable
’
---- 7 formulations.
-xvuo. Also for both
rhe logarithms of the serua HET
slniUr to those reported pr.Ho^lV
0, 7)
7). ^Xe^'
n, soae^" thTuptake
of Norigest fro. the injection site is ko^o b^rtp’id ’and ser» 2^
of NET become ^deteeUbU Ty'sit
occurred in 5 of the 10 women studied in ?he r"
‘ ; this
.
present
investigation.
This
evidence, together with the fact that ovulation
is known
r
i to re-occur
w t
8 weeks in about 32% of women injected with Norigest
(8)
) and the

326
APRIL 1982 VOL. 25 NO. 4

APRIL 1982 VOL. 25 NO. 4
1

lUMR/XCLriKz-

cli^S'trlLrT^^ges^C^ hashed0?? ^h'^

mulations of 6estLe4' £ sntte
S /T u°men Usin£
videly used
laXtLTvo’on sJee the^do

PCri°d

those of NlCT.
..era six-month period this value would be about
three-fold if the injection interval for Norigest Ls reduced to 8 weeks.
The exposure of the infant therefore to the gestagen is significantly
less with Norigest than with DepoProvera. However the effect, if any,
of the two steroids in the infant would depend not only on the amount*
transferred in the milk but also on their rate and type of metabolism in
the infant. Both these aspects of metabolism differ for the two steroids
in human adults *(17) and it is likely that they would do also in the
infant. Moreover in the human adult and in experimental animals, the
potency and spectrin of biological activity of the two steroids varies
considerably. These factors need to be taken into account in assessing
any possible adverse effect in the infant.

for-e

the quality or the quantity of milk secreted kaPPCar t0 affCCt Cithcr
w rllk was reported (10) to var-vfJ f
Thc concent^tion of MPA
after injection of DepoProvera with a^decli
onc wcek
vithin 4 weeks. Hthougl, d o vSues^detectable values
reported in the present st^dv ^ub^tfk ?
sijrilir
those

still present at 4 weeks (from 740 r c m^C°nSc”<trati°ns
w®re
second study (ill
wbtw lu /J
5’S0°
°ur study.
Tn a
studied throughout nest of an Tn jection^eri^ tT'’ I>'poPr0''era vcre
in milk were vithin the range foiind in the pTsent st^yenThtiOnS °f
to be no previous renort'- nf
n
t
p esent study. There appear

9:10 for HP* and I.?. 10 for NFTrfi.'

J?”

..er™

J^5ing by our r«ults (about

*■

Uid in the same subject atTiffereTT'“ thcTra,tio both between subjects
the difference i^ the Ltiol for m
be'n
that
binding of the steroids in blood (II, 12)
iffl i^kTodV'?'”10'5 \th'
^ilablTf*' 'r' T Ubmin (13)
PtesunaTy aS C
t0
asTi SbfT
? ^ilk• t!ET is k™'71 to bindthe serum >PA is
J to SNUG as well
j.y not more
to SHBG and therefore unavailable for transfer
the large difference in thc milk:serum ratio unlikely to account for
for the two steroids and

;.“:s Kt
IT TTT ^•ffercnce in the amounts of the two steroids transf'l T
h' UIfantuiS ^'iioited by the difference between the values
for the area under thc milk concentration-time curves (Table TV)
Tttl m f rs^T bl00d Tter “•’'“ion
Norigek^to^So The
occur

Ardh? H f w \7 d?yS S° that
sorae of the vonen this peak in serin
by the tireTh f ■ T” T
“ the Present “udy would have passed
wlrk 6 TTs L illT STP
taken- Hovever>
opon previous
thin 0= IT
y w £?U5' “ Crr°r “ thc ^“lations of less
uTd (?*-n T h SM’e problbly applies to KPA. Thc dose of DepoProvera
111-er cor e) aFPears to be lover than that of Norigest (200 mg) but thc
ver corresponds to 145 mg norethisterone so that the two doses used
thl
"iuivalent- Usins a 12-week injection interval for
the two formulations, thc amounts of KPA transferred are about four-fold

“

Assuming the volume of milk ingested by the infant is 600 ml per
day, one week after injection this would correspond to a daily intake by
the infant of from 0.5 to 2.4 ug NET and from 1 to 13 ng MPA. By 8 recks
after injection the amount of NET ingested would be very small, less than
0.2 yg, whereas for >?A the quantities would still be significant (from
Twelve weeks after injection the amounts of MPA
being transferred could still be up to 1 |ig/day.. However,
L______, in addition to
considering the maximum amounts that the infant may be ingesting', the
continuous exposure of the infant to the contraceptive steroid ...^
may be as
important as the maxii.nun amount ingested on a particular occasion, Usin*;
the mean values for the concentration of MPA in milk during weeks 11
.. and
12 after injection of DepoProvera, the amounts transferred to the inf.int
would be not less than 0.3 |ig/day, so that if the infant relies on its
pother’s milk- as its sole source of food supply during the first 6 Months
it would receive at least this amount of MFA every day »uid on most days
considerably wore, ir one assumes an injection interval of C weeks for
Korigest, the s.v-ie .u-ount or more of norcthistcrone would be ingested by
the infant on only about 5(£ of the days during the six-month period.

In the absence of knowledge concerning the amounts of the two steroids
necessary to produce any effect in the infant, it is not possible from ■oiir
work to assess what the risk to the developing infant would be but at
least tills study does provide values based upon a sufficiently largo
number of samples to give some idea of individual variation and to know
with some accuracy how much steroid the infant is receiving. Based upon
the amounts of the contraceptive steroid transferred to the infant,
Nori’est would appear to be preferred to DepoProvera but this ignores the
many other factors nentioned above which have to be taken into considera- .
tion. A recent review (18) suggests that the amounts of steroid ingested
with the milk are inlikely to have any significant adverse effect on the
developing infant.

ACKNOWLEDGE* ENT
Tliis work was supported by a grant from the Special Programme of
Research in Hman Reproduction of the World Health Organisation.

4
328

APRIL 1982 VOL. 25 NO. 4

APRIL 1982 VOL. 25 NO. 4

329

-

■

f
ON IRACEP liUS

COM U ACEPTlON

REFERENCES

1.

2.

Kesseru-Koos, E., Hurtado-Kco, H., Larranaga-Legufa,
A. and Scharff, H-J.:
Fertility control with norethisterone enanthate, a long-acting parenteral
progestogen.
Acta Eur .Fertil
“crtil
4:203-221 (1 973).

LEVELS OF COMTRACEPTTr'E STEROIDS IN BREAST MILK

AND PLAS^tA OF LACTATDJG WQ<EN

Zanartu, J., Dabancens, A., Bravo, R.R., Pupkin, M. ,
Rosenberg, D.,■ Mendez,
---------- ' G- and Guerrero, R. :
.Morpho­

B. N. Saxena, M. D.

logical study of the human ovary and mammarv gland
under the long-term, effect of progestational aqents.
Acta Eur Fertil
4:187-201 (1973).

3.

Weiner, E. and Johansson, E.D.B.:
Plasma levels of
norethindrone after IM injection of
_ 200
_.J mg norethindrone enanthate.
Contraception
11: 419-425 ( 1975) .

4.

Howard, G., Warren, P..J. and Fotherby,
'
K.: Plasma
levels of norethisterone in
--- receiving norethisl.i iwomen
terone oenanthate intramuscularly.. Contraception
12:45-52 (1975).

5.

Franchimont, P., Cession, G., Ayalon, D. , Mutsers, A.
and Legros, J.J.: fSuppressive action of norethisterone
enanthate and acetate
la on gonadotrooin levels. Obstet
Gynecol. 36:93-100 (1970).

6.

Warren, R.J. and Fotherby, K.:
Radioimmunoassay of
synthetic progestogens, norethisterone and noraes -rel
J Endocrinol 62:605-618 (1974)

7.

Saxena, B.N., Shrimanker, K. and Fotherby, K. :
Radio­
immunoassay of serum norethistcrone oenanthate levels
in women after intramuscular administration.
J Steroid
Biochem, In press (1977).

!•

to
■»

* .-4:

3.

Khosla, T., and Lowe, C.R.: Indices of obesity derived
from body weight and height. Br J Prev Soc Med 21:
122-128 (1967).

9.

World Health Organization Expanded Programme of Research,
Development, and Research Training in Human Reproduc­
tion.
Multinational comparative clinical evaluation
of two long-acting injectable contraceptive steroids:
norethisteronc oenanthate and medroxyprogesterone
acetate.
1. Use-effectiveness.
Contraception 15:
513-533 (1977).

K. Shrlmajiker, Ph.D.
J. G. Grudzlnskas, M. R. C. P.

•

Department of Steroid Biochemistry
Royal Postgraduate Medical School
London W12
Joint Academic Unit of Obstetrics,
Gynaecology and Reproductive Physiology
St. Bartholomews Hospital Medical College
and the London Hospital Medical College
London, ECI

ABSTRACT

Hormonal contraceptives have been used in breast feeding women
by many clinicians. However, secretion of these drugs in the breast
r.ilk has not been adequately investigated. In the present study,
radioimmunoassay methods were used for estimating the contraceptive
drug levels in breast milk and plasma samples. In 7 lactating women,
after the injection of 15>0 mg medroxyprogesterone acetate • MPA
(Depo-Provera), MPA levels in breast milk were similar to plasma?
the ratio being almost 1 : 1 throughout the study period (up to 8?
days). In a group of women using oral pills (2 women took a
combination pill containing 150 pg d-norgestrel (d-Ng) and 3® ^ig
ethinylestradiol, another 5 women took progestogen-only pills contain!
350
norethisterone (NET)), the levels of d-Ng and ^ET in breast
milk were about l/lO-oh or less than those found in plasma.

Accepted for publication October 11, 1977

I

i

CONTRACEPTION

CONTRACEPTION 5

DISCUSSICK

This study e.-ployirg the radioimmunoassay methods confirms the
indirect evidence previously reported oy La'< as et ai. (3), about
the presence of synthetic contraceptive steroids in the breast milk.

Tne ratio of i-BA in plasma to mllx (1 : 1) re.r.alr.ed constant
throughout the study period, up to 8? days in the subJect-Cp (Table I).
In contrast to MA, the concentration of both ICET and d-h'g in the
pill users was about 1/lCth or less in the breast milk. It is not
clear as to whether this difference in breast milk concentrations
of these progestational steroids is due tc their structural or
metabolic differences (l.e. 17-hydroxj'prcgesterone versus
19-nortestosterone derivative), or whether it is due to their different
routes of administration. The data from d-Kg users suggest that
the drug does not appear to accumulate in milk.

-4

J

S'

fcl

Isolated reports have described significant skeletal changes (6)
and‘'the occurrence of gynaecomastia (?) in breast fed Infants of won-en
taking synthetic contraceptive steroids, however, most studies (2)
have failed to demonstrate any deleterious effects of steroidal drugs
In suckling Infants. It is important to point out that the duration
of Infant follow-up has been short in these reported studies. Thus,
the Information regarding the effect of contraceptive drugs in the
development and future reproductive functions of these infants is
lacking.

BEFEREMCES

1.

Potter, R.G., Masnlck, G.S. and Gendell, M.
Post-amenorrheic versus postpartum strategies of contraception.
Demography 10 (1); 99-112, February 1973.

2.

Population Reports - Series J. Number 4, July 1975.
Breast feeding - Aid to Infant Health and Fertility Control",
Department of i’.edical and Public Affairs, Tr.e George Washington
University .’’.edical Center, 2001 S. Street, M.W. Washington DC 20009.
Daumas, K.P., .’alkani, P.K., Bhatnagar, S. and Lauras, V.
Radioactivity in the breast milk of lactating wocer. after cral
administration of >i-norethynodrel.
Am. J. Obst. Gyn. 98: 411-413, 1967.

4.

Slirimanker, K., Saxena, B.N. and Fotherby, K.
A radioimmunoassay for serum medroxyprogesterone acetate.
J. Steroid Blocher, "in press" 19'f7.

5.

Warren, R.J. and Fotherby, K.
Radlolnmunoassay of no 10th. 1 sterone or norgestrel.
J. Endocr. 62: 605-618, 1974.

6. Breibert, S., Bongiovanni, AJ-i. and Eberle in, W.R.
Progestins and skeletal maturation.
New England J. .
’•’ed.. 268: 255-256, 1963.

7.
In Bursary, the preliminary data fror. our study has demonstrated
the presence cf some of the contraceptive steroidal driAgs in the breast
rcilk. Further studies are necessary to deterr.ine the various metabo­
lites and biological activities of the contraceptive drugs In the
breast milk as well as metabolism of these drugs in suckling infants.
Such studies are a pre-requlslte before one can routinely recommend
the use of hormonal drugs for post-parturn contraception.
AC KNCXLE DGEJZ STS

We are Indebted to Dr K. Fotherby for the use of laboratory
facilities to carry out this study. Wc are also grateful for the help
ful suggestions of Professor T. Chard and assistance (in recruiting th
study subjects) of Dr D.G. Evans, Dr Y.S. Gordon, Dr C. r ox, Hrs D.
Knight and the Consultant Obstetricians and Gynaecologists of the St.
Bartholomews hospital and the British Hospitals for ’-‘others and Babies
Woolwich, U.K. JGG is supported by a WHO Fellowship Research Grant.

Curtis, E.H.
Oral contraceptive feminization of a normal male infant:
Report of a case.
Cbstet. Gynec. 23: 295-29-3, 1964.

CONTRACEPTiON
CONTRACEPTION
1.

2.

3.

I

4.

tl

REFERENCES
^'idhol’n, 0. » Kaivola,
The use of cconjugated '• and Timonen, s,
Ann. Chir. Gynaecol. oestrogen in oral’ contracepti on.
Fenn. 63: 150-185,
1974.
As tedt, B., Svanberg, L.
Jeppsson, s•, Liedholm,
Rannevik, G.
P. and
The natural
of combined oestrogenic hormone oestradiol as a new
oral contraceptives.
componen t
Br. Med. J. !: 269, 1977.
Greenblatt, D-J- and Koch-Weser J
Ora 1
n°CotUabPtIVeS and ^^ensi^.
Boston (^^ho’-ative Drug Surveillance A report from the
Obstet. Gynecol?
Program.
' ----412-417, 1974.
Low, 3* and Oparil,
S.
Oral
contraceptive pill hypertension.
J. Reprod.
f-f. Med. 15 • 201-208, 1975,

, 5.

Beckerhoff, r.,
Vetter, W., Armbrus ter,
and Siegenthaleer, W.
Luetscher, J.a.
Plasma aldosterone d
during oral
Lancet 1: 1218-1219,
contraceptive therapy.
, 1973.

6.

Saunders, D.M., Hunter J r
eu
The effect of oestr.L , ’C; ’ Shutt. O.A.
and O'Neill, B.J.
factors and lipid and ° valerat:e therapy
women.
P
3nd oestro?en levels in on coagulation
oophorectomised
Accepted for publication
Aust. N.Z.
Obstet. Gynaecol. 1978.

IN WOfEN RECEP,TNG THE

K. Fothcrby1, Geraldine Howard2, K. Shrinanker1,

M. Elder2 and P.G.T. Bye^3
^oyal Postgraduate Medical

School, Ducane Road, London W12 CHS;

9

“Department of Obstetrics

London W6 and

and Gynaecology, Charing Cross Hospital,

3’Schering
(
Chemicals Ltd.,

Burgess Hill, Sussex, Jkigland

.ABSTRACT

mtr^s
^:ctinonwof
:?
receiving a single
uitramuscuiar
injection
the
ten twomen
to 200
CrtM
0CTlanthate.
of
the
ten
——— appealed
—
days
of
injection
days
Hot.of Ejection and a
further
four within
days.
]Fol
by
ovulation
occurred90
i^
subiec^^hii^/™^
17 nOt foUov^
A*.. .*1
%
*five
---- ——•
V'
occurred
in
five
subjects
and in a further subject wilhU 90 dayswithin 6o‘
th'
evidence of follicular or lut^i
°ne S1*bject shwed n°

Accepted for publication October 17, 1978

d

ntraception
CONTRACEPTION
60 days after injection
this subject had five episodes of varinal
bleeding.

Ihrcc subjects (8) and in one out of four subjects (9). In the present
-tudy two of the ton women seemed to have ovulated within 00 days of
{ricction and a further four within 90 days. However follicular activity,
-rnbably not followed*by ovulation, occurred in five subjects within 60
44’'vs
and in
in aa further
further one subject within 90 days of injection.
ys and

Pharmacokinetics of norcthisterone
restaT1'0 WaS 3 Vide variation in the rate a* • • • at’r'which
the administered
gestagen was metabolised, the tine required fo
t
the plasma
levels
—
(lJItiUSterOneutO becorae undetectable'(< 100 pA/nl)
;- —-J of
varying from 73
When the logarithms <
. — —^.1 sTdSt'lin
individual SUbjeCb W?re
plotted against tine, an approximately
the period from 30 to 90 days
The slone
WaS obtaJJled for
The slope of this
rate at which norethisterone Cas^etabolis^d
T line Udicatfor the slope the more ranid h • e™bollsed> the greater the value
the 10 subjects studied (Table T the T' °r netabolisnl- Fw 7 of
within the range of 13-18 XW^P’tS r-—--•'
S1°PC feU
remaining
three
subjects
appeared to metabolise norethiste-------slope varying from 3.7 - 7,9 no■e^one more slowly, the value for the
. There was no correlation between
the rate of metabolism of norethisterone
as indicated by the value
(r’I
T m all
Tcases).
P°ndral index> b'ifibi or weight of the subjects of
.'(R
< ’o
0.^,0

-<’*• 'W'

I

DISCUSSION

STL

she "d thT-90 hayS' Using thiS dose’ Kirton’andecLett^O(6)bC1J’E
showed that in three subjects the tine taken for the return 6f
th^^10"/? den°™!ratCo by a plasma Pr°Sesterone level
greater
atT»Jeh^ T
238
245 dayS respectively after injection
were stillTtect^hTT ?nOUntS of raedrc”QT’rogesterone acetate
ere still detectable in plasma. These results indicated that the
L^iod’Lrt1^ relCa1Sed fron’ the injection site over a prolonged
period and that nomal ovarian function would not return for a^

7

£Xep±
is -b^^^

'So
•'?

interval- Sinilar

In this study we have used a lower limit of 5 ng/ml for the
concentration of progesterone in plasma indicative of a functioning corpus
hrteum. Adoption of a lower limit, e.g. 3 ng/ml would have made no
.difference to the number of ovulations considered to have occurred within
/'0 days of injection. It is known however that in wmen taking daily low
Poses of gestagens orally, morphologically and histologically normal
corpora lutea may be produced but their capacity for synthesis of
progesterone is diminished both in vitro and in vivo (10, 11). Thus the
'inding of a low concentration of progesterone in blood may give a
'dsely low impression of the incidence of ovulation.

|

Whether the exogenous gestagen would be adequate to prepare the
•rterus for implantation should ovulation and fertilisation take place is
•nknown. There were however two patients in our much larger clinical
<f*ries who became pregnant seven and eleven weeks respectively after an
injection of 200 mg norethisterone oenanthate. In both cases the
gestational age was confirmed by ultrasonic B scan measurements of the
'octal crown-rump length. It is reasonable to assume that in these
ritients the corpora lutea were functioning but we have no data as to
the circulating levels of norethisterone at that time.
This study has only considered women having one injection of
■orethisterone oenanthate. There is evidence of a decrease in the rate
of metabolism of norcthisterone with subsequent injections and there may
h? accumulation of the steroid after more than seven injections (12).
Thus it is possible that there may be a consequent delay in the return
ovulation in women receiving multiple injections.

The ability to determine when women receiving injections of
rorethisterone oenanthate will first ovulate would be an advantage in
choosing the optimal injection interval. The ponderal index of the
subjects in this study was calculated since it was thought that the
degree of obesity might affect the rate of absorption of gestagen from
the depot site and its subsequent metabolism. However there was no
relationship between the ponderal index and the rate of -decline of
plasma norethisterone levels or the return of follicular or luteal activity
tnd, as found previously (12) it was of little value in predicting the
rite of metabolism of norcthisterone oenanthate.
These results suggest that inhibition of ovulation is the principal
of action of intramuscular norethisterone oenanthatc but that 90
days after the injection} ovulation has returned, in half of the subjects
, -rd is likely to return soon in most of the others. The prompt return of
I ovulation necessitates an injection interval that is relatively short.

CONTRACEPTION

!2if)
demonstration of an early abortifacient effect of norethisterone
(XtT) IN THE PRIMATE (BABOON)

Lee R. Beck and Valerie Z. Pope

£

■

Department of Obstetrics and Gynecology, Uni
University of Alabama
University Station, Birminghaim, Alabama 35294 in Birmingnarn,

I

S-

ABSTRACT

I

a
• u-

continuous controlled

SB'S2'”-—
-

l; accePJea explanation that low-dose synthetic progestins exert their
. aceptjve effect by mhjbiting sperm transport and/or preventing implantation.

Submitted for publication September 9, 1981
Accepted for publication December 8, 1981

i

O

INTRODUCTION

Small particles made of biodegradable polymers in the form of microspheres have
been effectively used as injectable controlled-release systems for contraceptive
steroids (1). Biodegradable microspheres made of the polymer, d,l-polylactic acid,
which release norethisterone (NET) continuously for six or three months follow-ing
a single injection in primates have been described (2, 3). The serum levels of NET
following treatment with microcapsules are dose dependent. Lower doses have no
discernible effect on ovarian function whereas higher doses maintain systemic
levels of NET in a range sufficient to inhibit ovulation for up to six months. The
purpose of the present communication is to report the results of a study to
evaluate the effects on fertility of a non-ovulatory inhibiting dose of the longacting NET microcapsule system. The rationale for this study was based on the
expectation that low systemic levels of NET acting at the level of the cervix,
uterus and/or fallopian tubes (i.e.,"minipill effect") will prevent pregnancy in
primates without disrupting the normal menstrual cycle.

Ten milliliters of peripheral venous blood was rejectee and centrifugec ano tne
serum was stored at min
5°C until hormone cor
rations were determined by
*;adioimmunoas-say. For me NET radioimmunoassay, anquots of G.5 mi of serum
diluted with 2.5 ml of distilled ^0 were triple extracted with 6 ml of diethy lether.
The pooled extract, dried under nitrogen and resuspended in absolute alcohol,was
assayed using rabbit antibody against NET (kindly provided by Schering AG, Berlin,
West Germany). The sensitivity of the assay is approximately 10 pg/mi. Control
baboon serurn samples produced a NET blank in the assay which varies between 100
and 200 pg/ml. Accordingly, 200 pg/ml represents the working lower limit of
sensitivity of the NET assay. Total estrogen anc orogesteror e were assayed by
radioimmunoassay procedures previously described ’.2).
The radioimmunoassay for bCG is an heterologous double antibody precipitation
technique, utilizing rabbit anti-ovine beta LH 'serum H-26, courtesy Gary Hodgen,
NIH) as the first antibody and cow anti-rabbit IgG as the precipitating antibody.
Urinary bCG previously standardized against human chtr.unic gonadotropin is used
as standard, and the sensitivity of the assa> is approximately 2 mlL. Interassay
variation of 30 assays was 8.9%, and within assay variation for 10 samples assayed
at four dilutions each was 7+/- 2%. Serum samples obtained irom baboons around
the time of ovulation do not yield measurable levels of crossreacting gonadotropin.

MATERIALS AND METHODS
RESULTS

The physical-chemical properties of the injectable NET microsphere system used
for this study have been previously described (3). Microspheres made of d,lpolylactic acid which contain 20% by weight NET and range in diameter from 100
to 125 pm provide continuous release of NET for 3 months following a single
intramuscular injection, in a. previous study, using baboons, we showed that normal
menstrual cyclicity, endogenous ovarian steroid production and ovulation are
inhibited for 3 months following treatment with microcapsule doses containing 25
to 100 mg of NET. Doses of the identical formulation containing less than 5 mg of
NET had no discernible effect on either ovarian function or menstrual cyclicity U).
In order to evaluate the effects of treatment on fertility using a non-ovulatory
inhibiting dose of NET microcapsules, a group of normal, healthy female baboons
were treated by intramuscular injection with a dose of microspheres containing
2.5 mg of NET.
For tlie fertility studies six baboons were treated by intramuscular injection with
NET microspheres suspended in 1.5 ml of physiological saline on day 22 of the
menstrual cycle. The treated females were housed with fertile males during the
period of maximum sex skin turgescence, which corresponds to the fertile period.
Fernales were bred during each of 3 consecutive menstrual cycles following
treatment or until they became pregnant. Following deturgescence the baboons
were physically restrained once weekly and blood samples were obtained until the
first day of menstruation for the determination of serum NET levels and for the
diagnosis of pregnancy which was based on the determination of chorionic
gonadotropin hormone levels and serum progesterone. A group of 5 non-treated
baboons were used as controls for this study.

The five control baboons all became pregnant during the first two cycles, and the
resulting pregnancies progressed normally to term. A total of 23 matings in the 6
baboons treated by intramuscular injection with the NET microcapsules resulted m
nine pregnancies as evidenced by missed menstrual periods, the occurrence of
chorionic gonadotropin hormone in the serum and the maintenance of serum
progesterone levels greater than 3 ng/ml. Weekly serum samples were obtained to
verify the temporal increase in chorionic gonadotropin hormone which is
characteristic of normal pregnancy in the baboons. The 39% conception rate in the
treated baboons is lower than normal for our colony. However, because of the
small sample size, this cannot be construed to mean that treatment prevents
conception. Surprisingly, 6 of the 9 pregnancies in the treatment group ended *
abruptly due to spontaneous abortion between the 27th and 35th day of pregnancy,
reducing the actual fertility rate to 13%. None of the control pregnancies ended in
spontaneous abortion nor have we observed spontaneous abortion to occur in
control baboons in any previous fertility studies.
Figure 1 shows the normal serum profile of chorionic gonadotropin and
progesterone in a representative control baboon during the late luteal phase of the
menstrual cycle of conception. Figures 2 and 3 show the serum levels of chorionic
gonadotropin hormone and progesterone in the 6 baboons who aborted their
pregnancies during treatment with NET. In five baboons vaginal bleeding was
followed by a rapid decrease in serurn progesterone levels. No external bleeding
was observed in the 6th baboon, but progestin levels in this baboon fell to 1 ng/ml
on day 27 of pregnancy and an ovulatory perinea! cycle was initiated five days
later. Pregnancies in the 3 remaining baboons wno conceived during treatment
progressed normally to term and serum levels of bCG and progesterone exhibttec
patterns similar to those observed in control p-egnant baooens.

i

e
LU

98

J.ANU ARY 1982 VOL. 25 NO. 1

JANUARY 1982 VOL. 25 NO. 1

90

-J-b.

50

However, the level
Although the NET RI.^
serum samples produce

samples could oe
high enougn

- ---- •••- Accorctngb
NET levels sePum
in theNET 'alue?PrT
signtftcant.

▲

E

o
c
LU
2T
O

doses. On the basis of these exnerimePrPP
NET in baboons that receive a 2 5 rre
and the duration of release will Hp Tnn

a
A

5

□

o
■a

cr

cn

LU
O

f

or
a.

1.0 -D

eg

0031 to the differences between the
pre<?ict that the serum levels of
W1H ^ry between 200 and 300 pg/ml,

X ^T VebL‘0°

'he 2

dose does not generate serum i
is
e
significance, the qualitative demonstration of NFT’ th S
be ° quantitative
from the baboons treated with this dose when ET ' > ' SerUm samP‘es obtained
dose-response exper.ments, p v des the bash forTt
“gh' °f the earller
the fertility experiments received JX,
‘or estimating that the baboons in
from past experience and the experience PTL^LLlL^n^aVs^' L 1"°*
NET in excess of one ng/ml are necessarv m
' thaI serum levels of
daily dose of approximately 0.1 mg NET
Acclrdm T'^’h Th'S requ‘res a total
fertility study is approximately 1/3 If th/A; Accord‘r,8|>'’ the dose used in this
ovulation.
oxunately MJ of the mmimum daily dose necessary to inhibit

▲
A

LU
b—

o

A

&

▲

io

■

■

blank uas not

in previous experiments, however, we tested hiRhe/6^'' '‘■
f‘^.':on!ldencemicrocapsule formulation (*,) In these
, /r
d
he ,denl‘^J
treatment with 50 25 and15 ™ nf m>Perirnents,the serum NET levels following
permit quantitative anaTvsis The\ , Croencapsulatec NET were high enough t!
profiles and daUy Lum leveis w^rePTUCea Para“el
NET

□

□
A

A
discussion

a

□

0.5 F
O

i

<«•
tmgs
effects even though ovulation mL7 no b“tt d
Thrill P,tent
progestogens have more than one mechanism If IL Th,s Provldes evidence that
mechanisms of action include inhibition of cn 1 contracepnve action. Alternative
(9), reduction in the m JcvcTe .
r P!
m,8ra,10n tProugb cervical mucus
alterations in the endometrium (1 ) IVinteTf 80nadotroP‘nsand LH (10).
There is also evidence to XaLs ttLLL}terfere"ce Wlth 8a™fe transport (12).
low doses interferes wnh ovS bLvnTht!nuous administrat‘oo of progestogens in
(H, 13). This latter otaervatiLpro!^
rnetabolism of progesterone

□

ad

H

when administered continuously? have early Ibor’lTfa?""8 'Tl
progesterone is necessary for .the maintenar.ee of early p/eglLIy.beCaU5e

0.1 L
0

10

20

il.1 Lift
! 't

a

30

40

days POST-DETURGESCENCE

50

Figure 3

NET. Lute symbols represent values from same animal.

102

JANUARY 1982 VOL. 25 NO. 1

e^LrX‘tifL?entSeffdeycStUPPL
that lo* serum levels of NET exert an
early abortifacient effect in
cycle of conception.
ThlVreltmem ViThVL1"1!conIinuou*‘y during the
The treatment, at the dose‘level
conception by blocking sperm transport and/or °Se.level Iesfed> did not prevent
the generally accepted sperm
mechanLm
of aetton
L"0" *hiCh ‘S COnIrary ,o
transport
and/orofTo?
implantation
mechanism of action of low-dose rcase, L
pregnancy
was
diagnosed
by
the
occurrence
se5t°S
reA?n.fy. *as 'Mnosed by the occurrence oT
of ^°
chorionic
” eni- ln each
hormone and elevated serum progesterone levels hL
chor'on‘C gonadotropin
serum
levels.misLd
Had aLL mOnit,ored hormone
levels, these pregnancies
couldprogesterone
hive been easily
could have been easily missed, and the
menstrual cycle would be falsely interpreted to TnL ’rh
? resulting irregular
the treatment acts to
prevent fertility prior to implantation
The to mean
Z ...that . Ihe
'minipill" and long-acting
subdermal
implants cause irregular menstrual cycles and have'hithe^
b'een
--w.) thought to exert

JANUARY 1982 VOL. 25 NO. 1

103

<0

*

CONTRACEPTION
' 7.
the level of the
endometrium

’c-t.nno EM. <
..m-at experience with implant contraception. Contraceotxn
i:-... 1978.

-^iario C.
Long-acting systemic contraceptives.
:HO
:c 5,..,
Sympos.u—. on
323-^6?S
Fer:-h:> ReSuJation- Copenhagen, Bogtryk^enet Forum?!?

--------- ----- PP

SWWWsi
X=
rP
consideration when testing synthetic long-acting progestins.

sSLethe
—
taken
into

9.

Roiand M.
Prevention of sperm
sperm migration
migration in:
into the uterine cavity oy a
microdose progestogen. Fertil Steril 21:211, 197G.

1G.

Saunders DM. Marcus SL, Saxena BB, Beling CG and Connell EB. Effect of
dai?. administration of 0.5 mg of chlormadinone acetate on plasma levels of
follicle stimulating hormone, luteinizing hormone
and progesterone during the
menstrual cycle. Ft rtil Steril 22:332, 197 1.

il.

Moghissi KS anc Marks C. Effects of microdose
norgestrel on endogenous
gonadotropic and steroid hormones, cervical mucus
properties, vaginal
cytology ano endometrium. Fertil Steril 22:^24, 1971.

12.

Hucson R, Pharriss BB, Tillson S and Reno F
F
Prechnical evaluation of
intrauterine progesterone as a contraceptive agent. Ill
Embryology and
toxicology. Contraception 17:489, 1978.

13.

Taymor ML 1 and
l
0 Levesque
Leve^ue LA.
LAof serum follicle stimulating hormone
luteinizing hormone and plasma
-- - 6 Hormone
progestin during microdose chlormadinone
treatment. Fertil Steril 22:1, 1971.
’

ACKNOWLEDGEMENT
Rei^Ut^n^NorthVe
undgran\fOr
ch on Fertility
supported by the Program
for Applied Resear
Research
PARFR 83N(214), contract AIDlescb3608
SUbCOntract PARRH-98, subcontract

references

1.

2.

Beck LR, Cowsar
Injectable Particulate (
Systems. In:
I
on Research Frontiers
Regulation. PARFR. Series
Series on Fertility Regulation. Zatuchni GI y
PP 213-229, Harper and Row,

swiss,

Auing^jeS XHcrSu^Cont5:" ™

iI
nxo’,

r cePtJv^ System.

Am J Obstet and

3.

Beck LR, Pope VZ, Cowsar F~ ’
Tr^^-Xlinth^lnjectX^Co^
TR’
(Baboon). 3ConUpDe1Contraceptive
CS;X"%71^ Microsphere

Ev^^tion of a New
Primat«

u.

Beck LR ano Cowsar DR.
Biodegradable microsphere
contraceptive system.
Acta Eur Fert, 11:139-150, 1980.

5.

?’„a”1re2'Wa?au'ou 3’ Cortez V, Giner ?

Gynecol Vol. 135, 419-426, 1979,

I

F1°WerS CE’Jr' N- Long-

J. Aznar R, Casazola J and Rudel H.
Low doses of' progestogens as an approach
--n to fertility control. Fertil Steril
17:49, 1966.

6.

101

Misheli DR, Jr, ,Moore t>E.
Roy S, Brenner PF, Page ma.
Clinical
performances and endocrine
profiles
containing a combination of estradiol and with contraceptive vaginal rings
d-Norgestrel. Am J Obstet Gynecol
1 30:55, 1978.

JANUARY 1982 VOL. 25 NO. 1

Vi

JANUARY 1982 VOL. 25 NO. 1

105

-■n

CONTRACEITION

ECTOPIC PREGNANCIES DURING USE OF LOW-DOSE
PROGESTOGENS FOR ORAL CONTRACEPTION
P. Liukko, R. Erkkola and
L. Laakso
Department of Obstetrics and C
University Central Hospital Gynaecology
Sf
-f Turku
Turku, Finland
Department of Obstetrics and C
Gynaecology
Central Hospital
- -- - of Vaasa
Vaasa, Finland

ABSTRACT

Ectopic• pregnancies
4
in t'"Y® Flnnlsh hospitals
In the years 1973°- were
1976 . studied
"“total^f
Of these, 30 (12.6 ») occurred In □L” C?SeS was fou"d •
Ptogestogens for oral contraction then’s??
progestogens sold In the area!
le! fi5ures for
--« xn cne areas served by the
’
•
h
Droa
S
\°
f
ectopic
pregnancy
w^fouV^T64 fOr eaCh ProaeBI.°L!Ct°P.1C._?
re5nancy
J5e riSk factor
- — 9 women years
norethisterone 0.3 mg,
rag^Lynestrenol 0.5 mg
ectopic pregnancy
IP
^.oi) .han other progestogens.

'“5;

m -j;.

Accepted for publication September
29, 1977

I
*1
J

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l.i'i 1UA

is

COSTRACEi'TIOA

. rl.x

.s
LS

it is
strenol
= . .-crar. years. ...ese -.9
, (p < O.O1, Poisson 1s
- - -arr -es /lsS/ = re'toPlc- pregnancy than other
'r120t1.cn.
c e s t - 7 e n i c prepar ations.
in woman using
xree ovarian pregnancies occurred
“o.5 mg for contraception.

dose progestogens
^T7.udy, Patrents on Lp-^^aP
raOofSaneectopl<= pregin
Vaasa
'
3e;
"aUns^or tbls^lfferenc^are^he^
for this
the less common
cc^on use of
at ion Is t ak.« =
uhenthe
thepopul
population
o’-cgestogcns in^■presu-tably
Tu»
,,.k\v t
ve higher rate of p
—
dose

J
.1

.7 §

C°nSrinaTXinVer:nty
si^lflcant difference, vhen^
’7 S'”
rate

^..“eoVloTrn^th groups -ere similar.
In
■■ ‘
t materials published i^the ^cpulat.on
’terms of use
Ac - r.mg to ^-^Vlnderin
terms
trel 0.01 mg it
m -I), the ?ear^ Index
1is 00.9.
Siin For
For d-norge
d-norgestr
flgure3
Repc rt
lynestrenol 0.5 .g
e o.3 mg 1.4. If
f or 4.3 and ^r note this teron^
onsidered
as
are c
.as
’ * 3 could have
of
pregnancies
crudely
used
,
a
n
nU
mber
c_
r
.
are
lynestrenol- users , 146 preg• or. en VC3rS'Jthe^‘pregnancies for
for ].
36 pregnancies for
expected
:
been
one out of
d-norgestrel users and
uiixcalculation,
nancies for d
Based on, this
and d-norgestrel would oe
norethisterone use.s.
lynestrenol
■ 4 -or-nne the ratio
ten pregnancies on J noretnisterone
ratio would be one
for
i.-ectopic, whereas

out of four.

----- ! carried by difrisk of ectopic Pre97^2y
x:. = r. comparing the one
has first to
‘erent minipills,
preparations.
‘rates for different
a mgner frequency of C-w—-* ectopic
•_o tr.ere are, i" ^actthe
'
pregnancy :
- -C mnlpllls than t
belong,
Zf.Jns must also be sought.
all the
t^e
ovarian
tubes
both
norsteroldSM toJ^movement of
(4)
.
^rtt^ly^ouantltatlvely
and quan
SergsD^ and others
ectopic pregnancy
In her c- —
progestogens
•
study
. . . -J . •
» r
indicates that ...e
Our
still •

!

"ftis theory is supported by several studies which confirm
that lynestrenol 0.5 mg efficiently suppresses the hypothalamic-pituitary-ovarian axis, inhibits ovulation and at
.
decreases the active function of the corpus luteum
•jMh (5-9) . The fact that the three ovarian pregnancies occurred
■
oc lynestrenol also supports this theory.

In

^Sn-users and non-users ^are ^conpared,

I

r Our study also shows, however, that lynestrenol C.5 mg
L carries a significantly lower risk of ectopic pregnancy
|. than the other progestogens studied. The lower pregnancy
| rate with lynestrenol suggests that the progestational
I properties of lynestrenol in a dose of 0.5 mg are more
I potent than those of the other progestogens in the doses
L reported.

5

3

'i

■>

¥hen low-dose progestogens were introduced, they were
reconvnended above all for adolescent girls in whom disturbtace of the ovulatory mechanism could not be tolerated
during hormonal contraception. The increased risk of
Ktopic pregnancy now associated with the mini-pill is,
however, an unpleasant prospect for young nulliparous
ween.
la ectopic pregnancy is an unhappy experience for any
patient; it can be fatal, and at the best of times causes
lorbldlty. Treatment for ectopic pregnancy considerably
reduces the chance of having more children. It is common­
ly estimated that the possibility of conception after an
•ctopic pregnancy is reduced to about 50 %, and still lower
lllgures have been presented (10). Indications for the mini>111 may have to be reassessed in the light of the inci­
dence of ectopic pregnancy.

41

te superiority of lynestrenol over other progestogens is
obvious, and switching patients to this drug advisable.
.Lynestrenol does, however, also carry a small risk of
pctopic pregnancy, and it is therefore preferable to
[recommend combined hormone contraceptives if their side
Idfects are acceptable. It is clear that there will clways
special cases where combined preparations are contra■-^SSlftdlcated. and where low-dose progestogen contraception
p needed. This applies to hypertensive, diabetic, and
^«se patients, to women with a history of thromboembolic
Lsease, and to women who for other reasons may be unable
louse combined preparations.

I
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(

Ide effect of female sex
hormones on fetal
development and Infant
health
Report of a
‘•WHO Scientific Group

oC

Technical Report Series
657
I

j
World Health Organization, Geneva

1981

I

F

r

10^

I
six

WHO SCIENTIFIC GROUP ON THE FHECI OF F EM Al E
hormones OX eetai df.veioi-mesi sm> ixfxxi iuxiih
( /( 'il l d, 111 ~ 1

I

THE EFFECT OF FEMAEE SEX
HORMONES ON FETAL DEVELOPMENT
AND INFANT HEALTH

i

i
i

Members

Dr L. Albcrman, Pediatric Research I nil. Guv Ho'. .J,. I ondon. E.ngi.-.rd
Dr H W Berendes. Epidemiology and Biomeirv Re □ rch Program. Na'ion..; Instnute of Child Health and Human Development. Bethesda. MD. ISA A'nnr-

Dr Ge Qin-sheng. Department of Obstetrics and G.naccologv. CapitU Hospital.
- > (\ 'ice-Cha:rm..-: i
Chinese Academy ol Medical Sciences. Beijing). ■Cn:na
School of Hygiene
Dr R. H. Gray. Department of Medical Demography.. London
L.

and Tropical Medicine. London. England
Dr S. Harlap, Department of Medical Ecology. Hebrew University. Hadassah Medi­
cal School, Jerusalem. Israel (Rapporteur)
Dr O. P. Heinonen. Department of Community Health. University ol Kuopio.
Kuopio, Finland
Dr I. S. Marton. Postgraduate Medical School. Department ot Obstetrics and Gynae­
cology. Budapest. Hungary
Dr P. Nylander. Department of Obstetrics and Gynaecology. University of Ibadan.
Ibadan. Nigeria

Secretarial

Dr M. A. Belsey, Medical Officer. Special Programme of Research. Development
and Research Training in Human Reproduction. WHO. Geneva. Switzerland
Suitzerland
(Secretary)
Dr C. L. Berry. Department of Pathology. London Ho>pital Medical College. London.
England (Temporary Adviser)
Dr M. Briggs, Deakin University, Victoria, Australia
HO Consultant )
Dr D.T. Janerich. Cancer Control Bureau. State of New York. Department of
Health. Office of Public Health. Albany, New York. USA r Femporary Adviser)
Dr A. M. Kuliev. Laboratory of Human Cytogenetics. Institute of Medical Genetics,
USSR Academy of Medical Sciences, Moscow. USSR (W HO Consultant)

\ WHO Sc;enti!ic Group on the Effect of Female Sex Hormones
on Fetal Dexelopment and Infant Health met in Geneva from 10 to
14 December 1979. The meeting was opened by Mrs C Standley.
Special Programme of Research. Development and Research Train­
ing in Human Reproduction, on behalf of the Director-General.

1. INTRODUCTION

Female sex hormones1 have now been used for nearly forty years
for a variety of purposes, including the treatment of threatened
abortion, habitual abortion, premature labour, infertility, and dysmenorrhoea. They have also been used as abortifacients. as agents in
pregnancy tests, and. most widely, as contraceptives. Well over 30
naturally occurring and synthetically derived sex hormone formu­
lations have been used, and with the exception of their use in contra­
ception and in the treatment of dysmenorrhoea and infertility, their
application is often based on little or no sound scientific evidence of
their efficacy. The widespread use of these preparations around the
time of pregnancy’, whether just before, during, or just after, has for
many years raised questions about their effects on fetal development
and infant health.
While there is no evidence of any frequently occurring adverse ef­
fect on the fetus, a number of rare adverse effects have been reported.
These effects, however, cannot be ascribed to the general category of
sex hormones but can only be attributed to specific hormones used in
the treatment of particular conditions. Furthermore, rhe risk-benefit
ratio for steroidal contraceptives may differ considerably from that of
the use of sex hormones in pregnancy tests and in the treatment of
1 In this report the term sex hormone" is used to describe unv *jNt.jr.ce. natural
or synthetic, having biological properties similar to estradiol, te'to'tcror.c. or proges­
terone. "Hormonal c- ntraception" is taken to mean contraception
tr.jimcnt with
sex hormones (as defined).

4

5

I

!10

(.

threatened abortion and
tility. The risk-benefit ratio and the
problem of rare advert
in the pub!;, .it large .an be be-t
judged b\ coiwideiing:
■-he frequence o* :>e ot ^ex horm(2) the reason" for their
and (3) the cftic.icx ot the treatment
Until the dexelopmen: o: hormonal contraceptives, the medicinal
use of female sex hormorc-. though widespread, was mainly confined
to women who had acccs-' to sophisticated medical facilities in the
developed countries. The advent of hormonal contraception and the
initiation of national family planning services and their incorporation
into primary health care have made female sex hormones the most
widely used simile tvpc uf drug in the history of medicine. It is esti­
mated that between 50 and 65 million women are currently using oral
hormonal contraceptives (/1. and that 1.5 to 2.0 million women are
using long-acting injectable hormonal contraceptives. At least 50% of
all oral contraceptive users and nearly all the users of injectable con­
traceptive hormones are women in developing countries.
The use of hormonal contraceptives involves a potential risk for
the progeny of the user: a fetus may be exposed to the influence of
exogenous sex hormones when conception occurs soon after discon­
tinuation of the contraceptive, when the use of hormones is started
early in pregnancy, and when conception occurs as a result of contra­
ceptive failure. In so far as hormonal contraceptives are used for
spacine births, the proportion of women becoming pregnant within
two months of discontinuing may range from 15% to 35% (WHO,
unpublished data). In addition, even with failure rates for oral hor­
monal contraceptives as low as 0.3% per year, as many as 160 000
fetuses a year might be exposed to the effects of them.
Breast-feeding infants may be affected by female sex hormones
when the use of hormonal contraceptives is initiated soon after delisery. Health and family planning clinics urge the adoption of contra­
ceptive measures at this time tor a number of reasons. First, women
have a high level of motivation to accept contraception just after
they have borne a child. Secondly, the side-effects of the contracep­
tives are much better tolerated then, thus improving the chances of
their continued use. Thirdly, there is an increased contact of the
woman with health and family planning services. Finally, while lacta­
tion does provide contraception over a varying period of time depend­
ing on the frequency and intensity of breast-feeding and the health
and nutritional status of the mother, it cannot be considered a reliable
means of contraception. It o estimated that 0.9% to 11.0% women
using no other mean- ■ : contraception -vcome pregnant while still

i:!C\tiing H.-. .
'.he hrsi postpartum ovulation) (2). Hence. man\
women icm:jo .md are provided with additional contraceptive meas­
ures. including hormonal contraceptives. Such postpartum use of
hormonal comniccptivcs max have adverse effects on breast-fed in­
fants through modification of the quantity or quality of breast milk or
through the entry of hormones or their metabolites into the infant via
breast milk. It is believed that exposure in the first few months of life
is likely to be more critical than later exposure. In some settings such
exposure may be occurring among as many as 9% of all infants.
The use of sex hormones in other circumstances varies widely be­
tween countries and at different times. Progesterone and similarly
acting synthetic agents arc still widely prescribed in the treatment of
habitual or threatened abortion, although their use has been discon­
tinued in many countries for lack of evidence of efficacy. In some
countries as many as 30% to 40% of fetuses are exposed to hormones
in these circumstances. Similarly, pregnancy tests based on withdrawal
bleeding following the administration of sex hormones are still used
in some countries, though they have been superseded by more reliable
methods.
Many health authorities have recognized that exposure of fetuses
or newborn infants to female sex hormones may result in a major
public health problem. Birth defects are the most obvious develop­
mental disorders of concern in the offspring, but it is not sufficient
to limit an inquiry into the effects of hormones on fetal health to birth
defects only. Other measures of the health of the offspring are at least
as important. These include measures of pathology such as late fetal,
neonatal, and infant death rates, as well as a consideration of sponta­
neous abortion rates and chromosomal abnormalities in aborted pro­
ducts of conception. The list of items to be considered must also in­
clude measures of other characteristics such as birth weight, sex ratio,
monozygotic and dizygotic twinning rates, infertility rates, and behav­
ioural abnormalities. Changes in these characteristics may be indirect
indicators of beneficial or adverse effects from steroidal contraceptive
use. These characteristics and possible susceptibility of the infants
to the modifying effects of sex hormones may vary in different popu­
lations.
To provide a scientifically sound basis for health policies, a careful
evaluation is required of existing research into the specific types and
uses of sex hormones in relation to their potential risks to fetal devel­
opment or infant health. Several types of exposure and indications for
druc use have been studied in an aggregate manner in the scientific
•7

i

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n\
I

I National Health Authority (FRGj

^Berlin 1 July 1983

Press and information section?

reaction on the letter of 10 June 1983

Measures taken by the National Health Authorities on the drugs ’Depo-

Clivinor’ and Noristerat’.

Dear. Ms Merkel,
After a thourough debate about the benifits and risks of the so called
’three months injection’ the National Health Authorities have ordered

c

j rather substantial limitation on the use of these drugs.

The details

can be found in the enclosed press release.
^According to the press release of the (FRG) Health Authorities their use
can only be justified in rare cases;

the products are clearly second

: rate* No reinvestigation on whether or not the drugs_§jH;iLLd^e-iill(/^ed
has been ordered, because, for a limited number of patients, the benefits

of the drugs outweigh the risks.

Sincere]y,

—-•v-T.-.

■,7A^ryyw;.^.i x ... iyyR

''* ' • ; f

I;’

Presse- und Informationsstelle
Bundesgesundheiuam:
Fcstantcnrift:
Fostfach ^3 00 13
D-1000 eerbn 33
Fernschreibor: O1S4O16
Telefax: (030) 6303 2741

/

r

“i
BuftOsgesundheitsarry. Posriach 330013. D-1000 Berlin 33

Frau
Beate Merkel
Luisenstr.

Wir bitten, alle Zuschrif.
ten an das 9GA nicht an
Eiruelpersonen zu nchter;.

19

4800 Bielefeld
L

J

ihre Zeichen und Nachricht vom

Gesch.-Z.: 8itiet>« Antwon angeDen

10.6.83

Pr

Telefon. (030)

Berlin

8308 2776

01.07.83

MaEnahmen des BGA gegeniiber den Arzneimitteln "Depo-Clinovir n
und "Noristerat”
Sehr geehrte Frau Merkel,

das Bundesgesundheitsamt hat nach grUndlicher Erdrterung von
Nutzen und Risiken der sog. "Dreimonatsspritze n cine erhebliche
Einschr&nkung der Anwendung dieser Arzneimittel angeerdnet.
Die Einzelheicen kdnnen Sie der beigefugten Pressemitteilungentnehmen.
Nach dem Bescheid des Bundesgesundheitsamtes ist die Anwendung
nurnochin ganz bestimmten Fallen zu vertreten; die PrSparate
__slnd eindeutig Mittel 2. Wahl.’• Ein Widerruf der Zulaseung wurrde
nicht angeordnet, da der Nutzen der Arzneimittel fill' einen
begrenzten Patientenkreis die Risiken dberwiegt.

o

Mit freundlichen GrilBen
Im Auftrag

(

Hcr.nl rrr

r

Anlage

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e.tuLM*anu
burxUkgot .orti

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v'mi ir>'4«*t>*o*ng r
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113
Press release by the National Health Authorities of the Federal Republic
i

of Germany,

dated 4 July 1983*

The National Health Authorities limit the use of contraceptive
(the three months injection)

injections

The National Health Authorities in Berlin have severely limited
the use of Depot-injections as of 30 June 1983.

It concerns the drugs 'Noristerat' of the Schering Company, in Berlin and
’Depo-Clinovir' from the Upjohn Ltd in Heppenheim.

The products

have untill now been used as contaceptive and marketed without any
significant limitations.

The risks of these drugs exceede those of other contraceptives.
The drugs can, according to the National Health Authorities1
(

decision,

only be used by women with normal menstrual cycles

who can not use other contraceptive methods or the pill.

The

drugs can only be used when the possibility of pregnancy is totally

excluded, in order to guarantee that deformations of the unborn
are avoided.

Moreover, according to the decision of the Authorities,

the drugs may not be used during lactation or when suffering from

certain illnesses, because that would lead to unjustifyable
health risks.

The side effects, for example irregular menstruation,

and headaches, must be specified in the instructions for usage
accompanying the drug.

In its investigation of the latest scientific insights on the
(

benefits and risks of the drugs the NHA heard national and international

experts, among whom a representative of the WHO, on 24 March 1983
during a public hearing.
The suspicion, discussed during a special session, that the drugs
may cause cancer has not been established, according to the NHA,
despite

thorough investigation.

The suspicion that the active ingredient of 'Noristerat’ Norethisteronrnantat
causes cancer is founded on a case of cancer of the uterus which occured

in research on monkeys, which has not yet been concluded.

Many cancer­

specialist feel that this suspicion would not holf true for humans.

High doses of the active substance have not demonstrated cancer in another

i. k L

X

/

-2-

press release

ilH

test on 16 monkeys, which lasted for ten years.

The suspicion that the active substance of ’Depo-Clinovir’
medroxyprogesteronacetat causes cancer is based on two cases of

cancer of the uterus in monkeys and a number of cases of breast

.cancer in tests on dogs.

The national and international experts, however,

do not consider the observed cases of cancer in monkeys

an affirmation of the suspicion that it would cause cancer in
humans.

The cases observed in dogs do not allow any conclusions

(

on the applicability to humans on whether or not cancer is stimulated

given our current knowledge, because the animals have an especially
sensitive reaction to the substance.

The active substance is being

used in the treatment of breast cancer andcancer of the uterus
in humans.
Recently ^^fiave been public

demands, to forbid the drugs;

because

the are being used in the Third World under irresponsible conditions.

Such situations can not be grounds for the NHA to take measures
against the drugs within the territory of the FRG, because the risks

caused by usage in remote areas
manner by different measures.

can be diminished in a responsible
The NHA has informed the offices of

the WHO and other nations of the meausres taken.

1

yiWNR.IB

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MW, I,,.■HUI. I i

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4

i

hcrausgcber: rcfcrat prcssc * offenilichkchsarbck — bundcsgesundheitsamt — thiclallec 88-92 _

presserechdich verantwonlich: klaus jurgen hcnning

3

06/1983

bga-pressedienst

L

1 Berlin 33 — id. 83O8-2775/2776/2777

______

4.

ii5
Juli

1983

L

n

Bundesgesundheitsamt
schrSnkt
Anwendung
von. .Injektionsprapa- !
raten zur Schwangerschaftsverhdtung ("Dreimonatsspritze")I ein .
i

Das Bundesgesundheitsamt in Berlin hat mit Bescheid vom 30. Juni
1983 die Anwendung von Depot-Injektionspraparaten zur Schwangerschaftsverhutung weitgehend eingeschrankt.
Betroffen sind das Arzneimittel "Noristerat11 der Fa. Schering
AG, Berlin, und das Arzneimittel "Depo-Clinovir" der Fa. Upjohn
GmbH, Heppenheim. Die Praparate waren bisher in der Bundesrepublik Deutschland ohne wesentliche Einschrankung zur Schwangerschaftsverhutung bestimmt und in den Verkehr gebracht worden.

J

('l J

F”*
|
’
,
»

J)1e Risi ken dieser
____ Arzneimittel sind grdBer als_die anderer»
Pr5paraVe" zur~ Schwa ngerschaf ts ver hilt ung. Die Arzneimi ttel dUr- I
Ten 3 a her nach '’clCT' Ent’S che i dung des B undesgesundheitsamtes nur i
bei Frauen, die einen normalen Zyklusverlauf haben und andere L_
Methcden der Kontrazeption nicht vertragen Oder Antibaby-Pillen
nicht einnehmen konnen, eingesetzt werden. AuBerdem muB vor F*”
der Anwendung der Arzneimittel eine Schwangerschaft strikt aus- !
geschlossen werden, um MiBbildungen beim Ungeborenen mit Sicher- !
heit zu vermeiden. Weiterhin durfen die Arzneimittel nach dem *—
Bescheid des Amtes in der Stillzeit und bei Vorliegen bestimmter n.™
Krankheiten nicht angewendet werden, da sonst unvertretbare ‘
Gesundheitsrisiken drohen. Die Nebenwirkungen, z.B. Regelstorun- •
gen und Kopfschmerzen, milssen in der Gebrauchsinformation der
Arzneimittel im einzelnen angegeben werden.

Zur
Ermittlung
des
neuesten wissenschaftlichen
Erkenntnis- ■
standes uber Nutzen und Risiken der Arzneimittel hatte das i
Bundesgesundheitsamt
in offentlichen Anhorungen am 23und L-,-..
24. Marz 1983 in- und auslSndische Gutachter,
Gutachter, darunter auch
Vertreter der Weltgesundheitsorganisation (WHO), gehort.
’i

t

*

1

M

Der bei der Senders i tzung diskutierte Verdacht, daB die Arz- i
neimittel Krebs verursachen, hat sich nach Auffassung des Bundes- i-gesundhei tsamtes bisher trotz eingehender Untersuchungen nicht
best&tigt.
<
i
Der Krebsverdacht filr den Wirkstoff von .’’Noristerat”. Morethi- I*
steronenantat ,
beruhte auf einem Fall von Gebarmutrerkrcbs.
der in noch nicht abgeschlossenen Affenversuchen aufgetreten —
war. Nach Ansicht zahlreicher Krebsspezialiston ist cin Ver- ;
dacht ftlr den Mehschen nicht gegeben. Hohe Mengen des Wirk- 4

■ -

•

i 1^.. '4

//6
stoffs isben in einem anderen, zehn Jahre dauernden
an sechz*hn Affen nachweislich keinen Krebs verursacht.
/

Versuch

Der KreUverdacht fUr den Wirkstoff von ”Depo-Clinovirn,
Medroxypr^gesteronacetat, beruhte auf zwei Fallen von Gebarmutterkr^s bei Affen und vereinzelten Fallen von Brustkrebs
bei - VertJichen an Hunden. Die bei den Affen beobachteten Faile
begrilnd^i nach Ansicht inin- und
und auslandischer Experten einen
Verdacht als Krebsursache beim Menschen ebenfalls nicht. Die
bei der, Hunden beobachteten Faile lassen den SchluB auf eine
krebsf cr-.ernde Wirkung bei Menschen nach gegenwartigem Erkenntnisstan< nicht zu, weil die Tiere auf den Stoff in spezifischer '^ise besonders empfindlich reagieren.
Der Wirkstoff
beim Menschen zur Behandlung von Gebarmutterund Brutxrebs therapeutisch eingesetzt.
In jiing^^r Zeit ist in der Of fentlichkei t die Forderung
I ben worsen, die Arzneimi ttel zu verbieten; sie wiirden ;inerhoder
, Dritten
unter unvertretbaren Bedingungen angewendet.
• Derarti;i UmstSnde kbnnen Jedoch das Bundesgesundheitsamt nicht
zu MaBr^rnnen gegen Arzneimittel fUr den Bereich den Bundesrepubli k >utschland veranlassen, wenn die F.isiken, die bei der
Anwendur.; (jer Mittel im Inland entstehen, durch andere
Mafinahmen
vertretbares MaB begrenzt werden kbnnen. Das
! Bundesg^—ndheitsamt\ hat die Dienststellen der WHO und andere
I Staaten on den getroffenen MaBnahmen unterrichtet.
ende

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29

28

6.8 Administration of DMPA and NET-EN and follow-up

The initial injection of both DMPA and NET-EN should
be given during the first 5 days of the menstrual
period. ThlT timing of the initial injection is very
important, to avoid administering the contraceptive
hormone during an early, still undiagnosed pregnancy.
Failure to observe this rule may result in the exposure
of the unborn fetus to the progestogen.
The woman should be re-examined for the development
of any problems, and to receive the next injection, every
3 months if using DMPA, and every 8-12 weeks if using
NET-EN (depending on the dosage schedule being followed).

For the
The technique of injection is important,
microcry
stall
ine
formulation
(DMPA),
it
is
essential
(in
microcrystalline
(DMPA),
order to ensure that the correct dose is administered)
that the vial should be well shaken before aspirating the
suspension into the syringe. NET-EN is formulated in a
viscous oily solution which needs special care when
aspirating it into the syringe, and during injection in
order to ensure that all the material is ejected from the
syringe and that no leakage occurs around the needle, If
the vial should have been stored in low temperature, it
is advisable to warm it before giving the injection, The
preparation should be given by deep intramuscular
injection, preferably into the gluteal muscles, although
in many cases the upper arm may be more convenient. The
injection site should not be massaged.

6.9 Treat went of bleeding problems
A majority of women who receive either DMPA or NET-e-N
will experience a change in the pattern of their usual
menstrual cycle. Adequate counselling on the anticipated
side-effects (including bleeding problems), when the
contraceptive is begun is essential for minimizing
unnecessary concern on the part of the woman receiving
the contraceptive. A worn .n who has been informed o^ the

possible side-effects and their probable health
importance will be less alarmed, and will be better able
to judge when she should consult her physician or health
worker. The importance of side-effects should not be
minimized, however, and she should be instructed to
consult her physician or health worker if she experiences
prolonged or heavy bleeding.
Each woman who does return with prolonged or heavy
bleeding should be evaluated for anaemia.
If she is
found to have iron-deficiency anaemia, she should receive
appropriate iron therapy, such as ferrous sulfate.

Many clinicians administer estrogen preparations as
treatment for bleeding disorders associated with
injectable progestogen contraceptives. However, no
comparative study has demonstrated the effectiveness of
this approach to treatment, nor has any other approach
been studied and shown to be effective either. The World
Health Organization currently takes the following
approach to the treatment
" —t of bleeding disorders in its
clinical trials o f both DMPA and NET-EN, recognizing,
however, that its effectiveness has not been adequately
demonstrated.
If the bleeding is heavy or prolonged, the following
regimen is recommended:
(a) The woman should -first be evaluated for possible
causes of the bleeding (other than the steroid) and also
tested for anaemia.
Ferrous sulfate should be given, if

indicated.
(b) A woman experiencing moderate and prolonged
- or heavy - bleeding due! to the steroid should be given
3 times daily for 3 days.
25 pg of estradiol, one tablet
t

(c) If this therapy is ineffective, or if the woman
initially presents with very heavy bleeding, she should
be given 5 mg of estradiol cypionate in ar. oily
suspension intramuscularly; and this dose should be

r

,’‘-

f
•I
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30

repeated once if the bleeding does not stop within 24
hours. Additional medical advice may be indicated at
this stage.
(d)t I£t.aft:er
■
hfvinS received 10 mg of estradiol
cypionate intramuscularly,, the bleeding
e continues, the f
woman should be referred for possible dilatation
and
curettage.

I

’ I;
7.

COUNSELLING

Each woman, preferably with her partner, should be
informed of the various contraceptive methods available
and the risks and benefits of each method should be
clearly explained.
The final choice of method should be
hers, unless absolute contraindications exist.
If her
choice is an injectable hormone - either DM?A or NET-EN then the nature and type of the common side-effects
should be explained, with an emphasis on their transient
nature. She should be assured that she is welcome to
return to the clinic at any time to discuss problems and
any coubts that may arise.
It is a recommended practice
to niaKe the woman aware of the possible side-effects of
D.. A or NET-EN, rather than to let her believe it to be
free ot any problems. Discontinuation because of
side-effects is less common among well-informed women.

’■’S:

w
l

■

In normal practice, the woman should receive her
flrr lnJ!c‘ion d'J-lnS the first 5 days of menstruation,
as described above. This rule helps to ensure that
she
IS not pregnant when receiving the injection and
maximizes the contraceptive efficacy during the first
month. Subsequent injections should be administered
every 12 weeks (+ 5 days) for DMPA. In the case of
NET EN, the injections should be given every 8 weeks
(+ > days) for the initial 3 injection intervals, and
then every 8-12 weeks.
Irregular bleeding (including prolonged bleeding,
spotting and ammenorrh' ea) is the common cause for
i

*

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i

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35
.reas.-teeLing their infants, either ::n:raceotiv. caaiso oe use: immediately rostoartum.
H'wever
who are breast-feeding their infants, it is not
advisable to use NET-EN, because there is little
information on its effects during lactation.
DMPA does not appear to have any deleterious effect
on either the <quantity or the composition of breast milk,
and some studies have demonstrated
—.... — _.„__.. an increase in tne
amount of breast milk produced and n the duration of
breast-feeding. The breast-feeding infant receives less
than O.S1? of the maternal dose of DM? A ..nd probably
absorbs only a portion of that dose,
Infants whose
mothers received DMPA while breast-feedi
^-ing appear to
develop normally, both physically and mentally,
at least
till the age of 13 years.

®Conception after discontinuation of inject ions

I

Following discontinuation of DMPA, most women
experience a delay in the return of ovulation,
the length
of delay varying considerably among individual
women.
Thus, women who attempt to become p-_
pregnant after
discontinuing DMPA will probably have~
J a delay of at least
several months before conceiving. The average time
between the last injection and conception is about 9
months, including the 3 months of intended contraception;
more than 904 of women become pregnant within 2 years of
discontinuing DMPA.
No information is available on conception following
discontinuation of NET-EN.

8.4 Use among young adolescents

The consequences
c—
for sexual development of
interrupting- pituitary
j activity in the first few years of
adolescence are not fully understood and concern has
occasionally been expressed about the administration of
hormonal contraceptives to young eirls.
However, if
sexually active adolescents are not able to use other

-ethods, an injectable hormonal method may be prescribed,
s^nce the social, medical and psychological consequences
ot unwanted pregnancy and abortion outweigh any
pnysiological reservations that currently exist. Until
further knowledge is gained, it is advised that (if
possible) hormonal contraceptives should be avoided
within the first 2 years of the menarche. In such cases,
advice on other methods must be given.
-•5 Use among women over the age of 40

Although the adverse cardiovascular effects
associated with the use of combined oral contraceptives
have not been demonstrated for the injectable
progestogens, there are other potential problems
associated with the use of DMPA and NET-EN by women older
than 40. In particular, the irregular menstrual periods
(including amenorrhoea) that occur among most women
receiving either DMPA or NET-EN may be mistaken for
premenopausal signs, and the injections may unwisely be
discontinued.
In these women, it is difficult to
determine the onset of menopause and the concurrent
cessation of the need for contraception, because of the
irregular bleeding patterns caused by the drug.

Women who have had their desired number of children
should be advised to consider sterilization. If doubt
exists regarding the status of their menopause, hormonal
methods can be replaced by other methods of contraception
that do not interfere with ovulation.

9.

PROGRAMME IMPLICATIONS

Injectable hormonal contraceptives should be included
among the family planning methods available at the clinic
or other health facility offering an integrated family
planning service. Their simple delivery makes them
suitable for administration by trained auxiliary health
workers who (with appropriate training) can carry out the
counselling, selection and follow-up. For this purpose

<3

36

it is advantageous to prepare suitable checklists since
these will ensure that the procedures are carried out
efficiently and safely (with no important points being
overlooked) and will facilitate the decision whether a
medical opinion is necessary (see section 9.2 below).

Before a decision is ta^en to use a nonclinical,
for the distribution
* T, 7. ”
. system
--------- - of injectable
contraceptives, the following should be considered:

(1)

••1

I

(2)

(3)

1

The decision must be taken by the programme
authorities and accepted at everv level of
operation. This sometimes necessitates a
revision of the regulations governing health
professionals, or legislative changes.

The distribution system must be under the
supervision of the national family planning
programme.
The proper training of all the personnel
involved must be guaranteed, and this training
should be supervised by the national family
planning programme.

(4)

Supplies and proper channels for distribution
are needed and should be in operation.

(5)

The necessary drugs and facilities for the
management of bleeding problems should be
available (see section 6.9).

■

(6)

Such a system requires the support of medical
fac i 1 it ies to cope with the special clinical
problems.

9.1 Training of personnel

1

The training given to personnel who will be
responsible for providing injectable contraceptives in
any family planning system must ensure that the
participant s;

37

understand the concepts and rationale of family
planning;
are c apable of describing the different
contraceptive methods available and their risks
and bene fits;
identify the cases that present a
contraindication to the use of the injectable
contraceptives or «.
special problems that require
medical intervention and/or
--- supervision;

know how to instruct the women effectively on
the expected side-effects and
on the need to
return for follow-up;
recognize the complications and make the
necessary referrals;

maintain basic records for management of
patients and programme evaluation.

The duratiion of this kind of training will
be
determined by the level of
'
-- basic
--- c 1...
knowledge
and experience
of the trainees and by the capacityr cf
of the clinical
facilities where they are to be taught.
9.2 Checklists

Checklists have been developed for auxiliaries
primarily for the screening of women who can be given
injectable contraceptives without being examined by the
physician; they can also be utilized in follow-up
visits. Once established, the same checklist should be
used by all categories of personnel, who should be
trained in its use.
An acceptable checklist must permit the detection of
all those with contraindications to the injectable
contraceptive or with problems that require medical
intervention or supervision. An example of a checklist
xor nonphysicians is given in Annex 1.

38

39
REFERENCES

••

10.

CONCLUSIONS

Injectable contraceptives provide a highly effective
and acceptable means of fertility regulation with certain
advantages for women in both developed and developing
countries.
As far as the short-term use of long—acting
progestogens is concerned, the main disadvantage for most
women is the disturbance of the menstrual pattern, but
the principal concern is with their long-term safety.
Although there is no long-term experience with NET-EN,
that with DMPA so far gives little cause for concern
except for the as yet unresolved question of carcinogenic
risk, a question common to all steroidal contraceptives.
^c.ln^<,enc€ of many diseases varies markedly throughout
’tWe' iiorld and the risks from steroidal contraceptives are
likely to be different for different populations.
The
risks attached to the use of injectable preparations in
ahy country must therefore be carefully evaluated and
weighed against the benefits they confer.

I

Bulletin of the World Health Organization (1982) 60
(in press).

International Planned Parenthood Federation (1980)
IPPF International Medical Advisory Panel meeting October 1980. IPPF Med. Bull., 14, No 6.
3.

Federal Register, (1978) 43: 28555-28556.

Perez-Palac ios, G., et al. (1981) On the mechanism of
action of progestins. Acta endocrinol., 97: 320-328.
5.

Fotherby, K. (1981) Factors affecting the duration of
action of the injectable contraceptive norethisterone
enantate. Contracept. Detiv. Syst
Svst..
., 2: 249-257.

6.

Sang, G.W. et al. (1981) Pharmacokinetics of
norethisterone enantate in humans. Contraception,
24; 15-27.
-------- c----

7.

Kirton, K.T. & Cornette, J.C. (1974) Return of
ovulatory cyclicity following an intramuscular
injection of medroxyprogesterone acetate.
Contraception, 10: 39-45.

8.

Ortiz, A. et al. (1977) Serum MPA concentrations and
ovarian function following intramuscular injection of
Depo-Provera. J. clin. Endocrinol. Metab., 44: 32-38.

9.

Fotherby, K., Koetsawang, S. & Mathrubutham, M.,
(1980) A pharmacokinetic study of different doses of
Depo-Provera. Contraception, 22; 527-536.

10. Fotherby, K., et al. (1980) A preliminary
pharmacokinetic and pharmacodynamic evaluation of
depot-medroxyprogesterone acetate and norethisterone
enantate. Fertil. Steril., 34: 131-139.

N

/A 3

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I

SECOND EDITION

HAZARDS OF
MEDICATION
A Manual on
Drug Interactions, Contraindications, and Adverse Reactions
with Other Prescribing and Drug Information
ilifors < lies.
Anct I of
uC Of
»te of
|cjllh
nsic

on.
da;
rug
rvsdl-

rch
3):

ERIC W. MARTIN, PhD
Medical Editor

Clinical Research Editor

Arthur Ruskin, MD

Frances O. Kelsey, MD, PhD

Drug Reaction Editor

Medicolegal Editors

Edward Napke, MD

Donald J. Farage, LLD
Don Harper Mills, MD, JD

Patient Response Editor

Pharmaceutical Editor

Stewart F. Alexander, MD

I

<

Robert W. Elkas, PhD
■

Associate Editor

Ruth D. Martin, DSc

or
tr-

)
<>f
1

J. B. Lippincott Company

■

Philadelphia and Toronto

5
!

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/a 3
-

-

•-■

I

Copyright © 1978 by Eric W. Martin and Ruth D. Marlin

copyright © 1971 by Eric W. Martin and Ruth D. Mart.n
1SBN-O-397-5O389-X

Library of Congress Catalog Card No. 78-14265
Printed in the United States of America

1 3 5 7 8 6 4 2

non of brief excerpts I
Dhotoprint. microfilm, or any
mhe'r mean"'wHhout wntten permission from the copyright

owners.
4

(

i:

fe

Library of Congress Cataloging in Publication Data

1

Martin. Eric Wentworth.
Hazards of medication.

Bibliography: p.
I. Ruskin. Arthur. II
RM302.M36 1978b
ISBN 0 397-50389-X

615.1,

78-14265

J

Welfare is intended or should be inferred.

/
/

^1558^
)*
A0'

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•• fi

—->U4-----

i

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c

potentially hazardous drug reactions and interactions pinpointed by his drug profile, (3)
dispense accurately a high quality product,
and (4) verify that the patient receives and
responds to the prescribed medication in (he
desired manner. This entails proper educalion of the patient and follow-up.
Every one of these objectives must be attained if patients are to receive optimum and
rational drug therapy.
A basic premise
is use of the proper dosage in the specific patienl being treated. The skill of the prescribing physician in selecting medications and his
knowledge of their physiological actions and
inherent side effects as well as required varialions in dosage are the keystones of each
clinical problem (see page 107). For example,
digitalis and its glycosides are some of the
nn'ist effective drugs in worldwide use. Yet
the problems of underdosage, overdosage, in­
toxication, and acute major rhythm distur­
bances are seen every day in increasing com­
plexity. 19
Rational drug therapy avoids undesirable
situations by starting only with rational ideas
for new drug products, and then implement­
ing these ideas with sound scientific research
and development, good manufacturing praclices, proper distribution techniques, cornpetent prescribing, dispensing and administralion, and finally suitable monitoring of the
patient. livery one of these links in the chain
of events in the drug delivery system has an
important bearing on the competence and ef­
fectiveness of medical care whenever drug
therapy is an integral part of that care. Accoidingly, regulatory agencies such as FDA
closely monitor all medications and are con­
stantly on the
t alert to prevent irrational drug
therapies, especially those that presentl serious hazards to the patient.
But in the final analysis, the patient must
depend on the therapeutic knowledge of his
own physician and on his own ability to com­
ply with the therapeutic regimen prescribed.
Thus thorough knowledge of the patient and
individualized attention throughout therapy
can increase the probability that the patient
will follow instructions and receive maxi­
mum benefit with minimum hazard.

OFFICIAL DRUG HAZARDS
Since the 1962 Amendments to the Federal
hood. Drug, and Cosmetic Act were enacted,

Official Drug Hazards

3

FDA has become much more stringent with
regard to claims allowed and precautionary
information presented in package inserts.*
The Agency now requires that warnings of
hazardous situations be clearly staled. These
precautionary statements are usually re­
tained in each subsequent revision of the inserts. However, some warnings are dropped
whenever additional information demonstrates that the hazards are not as serious as
they were originally believed to be.
FDA often requires warnings to be added
in revisions of some inserts. Thus in 1977, the
Agency published new labeling for eslrogens24 25 that emphasizes (I) the risk of endomelrial cancer in estrogen users is up to 14
limes greater than in nonusers, (2) the risk of
limb reduction abnormalities- in fetuses ex• . (|1C
posed to estrogens is nearly five limes
spontaneous rale, (3) gallbladder disease is
increased two- to threefold in postmeno­
pausal estrogen users, and (4) other adverse
effects—thromboembolic disease, hepatic ad­
enoma, elevated blood pressure, worsened
glucose tolerance, and severe hypercalce­
mia—may occur. A patient package insert
must now be supplied wilh every prescription
•
‘
62
for estrogenic drug
products,
Typical official drug hazards have been
documented5 and they are grouped in pack­
age inserts under specific headings: Contrain­
dications, Warnings, Precautions, and Adverse
Reactions. These vary widely wilh the type of
medication.11
The value of package inserts as accurate,
authoritative, and dependable sources of
medical information for the physician has
long been questioned. This is because they
have often been poorly written, and are mcomplete, inappropriately documented, illogically compiled, and inconsistent. Inserts
for the same drug product vary in content
from one manufacturer to another. Also, un­
less the physician requests them from a phar­
macy or the manufacturer, or purchases
original packages of drug products, he may
never see the latest inserts. Moreover, most
•The original Federal Pure Ftxxi and Drug Aci <>l
l‘AX) was concerned wilh aduheratum and miibranding.
Not until after the sulfanilamide tragedy (page 26) ol
1938 was safety of drugs made a requirement in the re­
vised Act of that year. And nut until the thalidomide
tragedy (page 27) was the Act made strict enough to
include efficacy and many other requirements through
enactment of the Amendments of 1962.

i
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i

(

i

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/^6

x
i

.1

Pitfalls of Medication

4

occur when prescribed medications are used

3 believe that the government
practitioners

COmllanapemsTpSic ulcer, barbiturates in
f

(page 82).

Jjd/

n a lhor.

b

the package inserts.

Contraindications

Warnings
be particularly
Whenever
potent
drugs canceriain
vviiv
r
•
v
under certain circuny
^ai^c warnings arc included in the labelstanc^4 * ££ gencrany pertaini to ex„ .. those
.hose' ansm|
arising from
treme
nazarua . .
. vc $
af
acute hypersenti.Uyi^^^'
Idriged use, effect, on he fetu j n
a
ations in patient response. Fig. >
typical example.

“ ‘"“'“a”

Warning

drug niarKcicu

j

which is
is sold
sotu by
u}

unique
S ST“a“JIclass
""i‘exists
|UC labeling
'“and
“"fis

rnpany. These reltpn bv experts un-

(/
der contract to I DA-

heeded or death may occur.
administration^

Contraindication

»“« “f

P,„.,n

known hypersensitivity to the drug-

/•<X-

Q ■

."s=-==SS

HHS-==-v
mtdes must not be used
(,ll’er

^eOfeac|lons are more apt

Xctrm md.v.dua.s with a history o. sensi.lv-

in^nlS concerned

,,Y’° T^WerwZocumemed reports o.
There have beenulin hyper­
individuals with a history
sensitivity who have
with
persensitivity reactions w■
ponicilcephalosporins. Be'ore the py
jng
l,n. caretui inquiry shou d
previous hypersens.t.vity reacHons
P

, hns. cephalosporins, and ottwr^aherge^^^

allergic reaction occu .
d w,th the
discontinued and the pane
antlhistausual agents, e g .
Senous anaphylacmines.andco^osero^
toid reactions are noi c
emergency

‘‘’"tTS Editions found tn

"nd with mtcracuons that may

"“•Xo"
corticosteroids.

'.7^ --

X'Xn

cvcry package ol eecry- p
P
lh(. manufaclurer
c,al regulaiory d.xu' ent
Xch must appmve
under the close scrutiny
nrofnotjonal brochures us
every word. 1“rc bu, £re designed to be author,ra’uvVp^Xg guides w.th tegal m.pbe.t.ons.

a penicillin tablet.

_____

_____ —-------

298

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I

Adverse Drug Reactions

of the ADRs reported in the literature are
really suspected, not proved. As the adjective
implies these are working, often tentative di­
agnoses. Obviously, faulty statistics can
therefore readily be drawn from the litera­
ture.
Another very serious complication is use of
the term “drug." It is commonly applied to
either a drug product or an active ingredient.
But the literature attributes all ADRs that
occur with a product to the “active ingredi­
ent" only. Thus, until the data published in
the literature are presented in terms of both
active and inactive ingredients as well as the
product name this situation will always be a
major complication in the epidemiology of
adverse drug experiences.*
When such complications as unreliable
ADR diagnosis and inconsistency of ADR
terminology are added to placebo effect, in­
adequate ADR reporting, and poor commu­
nication- no one should be surprised that ad­
verse drug reactions and interactions are
confusing and poorly understood by many
practitioners. More emphasis on proper use
of medications in the medical curricula is
sorely needed.
In this era of chemotherapy physicians
should prescribe drugs with at least the same
care and criteria they use in recommending
elective, necessary, or emergency surgery for
a patient. They should carefully consider the
benefits and hazards of taking the drug(s)
and whether in the patient’s particular situ­
ation it is advisable to have “chemical sur­
gery." Only then will the problem of adverse
drug reactions fall into proper focus. 324-5
324 5
Definition of Drug Reaction

A drug reaction may be perceived through
signs and symptoms or through abnormal
clinical laboratory test results, and it may
manifest itself as a disease or syndrome.
When a drug is administered to a human
being, two types of drug actions may or may
not occur: (1) desired drug actions which are
• Hidden agents (in foods, beverages, and drugs) that
cause reactions have been described and lists of products
containing specific drugs that produce allergic reactions
arc available from such sources as The Allergy Founda­
tion of Lancaster County, Lancaster. PA 17604.
FDA’s eflorts in this area have been inadequate in the
opinion of allergists.

the preventive, diagnostic, prognostic, or
therapeutic effects primarily sought, or (2)
undesirable drug reactions which are the ef­
fects not primarily sought. Of course, neither
would result from no action which may be
most desirable.
No drug is so precisely specific for recep­
tors and properly potent in its effects that it is
effective in exactly the desired manner in
each patient to whom it is given. No drug is
absolutely free of some capacity to produce
unsought reactions in a certain percentage of
patients. These unsought reactions may be
harmful or harmless. They may even b<
beneficial The harmful effects (serious ad­
verse reactions), however, are the ones that
cause concern—anxiety for the patient s wel­
fare, and apprehension lest the prescriber be
involved in litigation.
Optimum medication of humans requires
every physician to balance therapeutic effec­
tiveness against possible undesirable reac­
tions. Thus, the judgment of the physician is
continually needed as he evaluates his pa
tient on the one hand and the drug actions
and reactions on the other. The most critical
decision that he may be called upon to make
is whether a given “reaction" is actual!)
caused by the medication or by something
else.
In attempting to cope with semantic prob
lems arising from the term “adverse drug re
actions," the Food and Drug Administralior
coined the term adverse drug experiences foi
all adverse reactions associated with any giv­
en drug therapy, i.e., those occurring during
or subsequent to the administration of the
given medication. Thus, all reactions that <k
cur in a patient while he is receiving a drug
or within a certain period of time after he ha;
stopped taking the drug, are grouped undv
this heading, whether they are adverse expen
ences definitely caused by a drug or advers*
experiences not definitely caused by a drug,
Mere association of an adverse eflect with <
drug does not establish a cause and effect rc
lationship. It does not automatically justif .
reat
classification of the effect as an adverse rea<
lion induced by the drug.

Classification of Drug Reactions
Only when adverse experiences are deh
nitely shown to be caused by a drug can the-

4

Adverse Drug Reactions

stic, or
. or (2)
the efi neither
?may be

jr recepMhat it is
inner in
i drug is
produce
ntage of
may be
?ven be
ous ads that
.n s wel|Tiber be
uircs
it ellvcle reacMcian is
his pa’ actions
< critical
^o make
dually
tthing

.prob­
it L’ re­
union
for
y
. ‘'ring
the
it ocdrug.
( e has
.nd er
periverse
th a
t re­
ctify
eacI
1

klihc\

i

correctly be called drug reactions. Otherwise,
they are simply adverse experiences which
may be coincidental with drug therapy but
not necessarily caused by it. Even if a reac­
tion js definitely shown to be a drug reaction,
it should not necessarily be called a serious
drug reaction. This term should be reserved
only for those reactions which are definitely
harmful to the patient, possibly1 life threaten­
ing (Table 9-1)j otherwise they should be
called minor drug reactions (Table 9-2). Ev­
ery drug reaction, serious or minor, can be
classified as a (1) side effect, (2) extension ef­
fect, or (3) drug interaction effect. It may be
localized or systemic.
A side effect is different pharmacodynamically from that effect primarily sought. Dif­
ferent pharmacologic mechanisms may be in­
volved or different organs may be affected by
the same pharmacologic mechanism. For ex­
ample, an antibiotic may produce diarrhea as
a secondary effect, although its primary effect
is antimicrobial. The diarrhea is usually the
result of a direct local irritation of the mu­
cosa. Additional side effects such as nausea
and vomiting may also be produced concur­
rently by the irritation. Another example is
that of an anticholinergic agent administered
to relieve the pain of peptic ulcer or spastic
conditions of the gastrointestinal tract by
means of its parasympatholytic activity. Oth­
er secondary autonomic effects such as blur­
ring of vision, dryness of mouth, dumping
Table 9-1

Table 9-2

Acidosis
Anorexia
Chromatopsia
Cramps
Diarrhea, mild
Dizziness
Drowsiness
Euphoria
Fatigue
Fever, low grade
Glossitis
Headache

Examples of Minor Drug
Reactions1
Hiccup
Nausea
Paresthesias, mild
Pharingitis
Proctitis
Pruritus ani
Skin rash, mild
Stomatitis
Vaginitis
Vertigo
Vomiting
Weakness

•Some of these reactions may become serious adverse
drug reactions if they are sufficiently intensified A patient
may be incapacitated by a very severe acidosis, emesis,
headache, etc.

syndrome, and ataxia often cannot be
avoided. Immunologic reactions (hypersensi­
tivity) and idiosyncrasy may also be the
cause of side effects of varying degrees of se­
verity. Classification of such effects has been
published by an allergist.”2
Side effects usually occur when a drug has
more than one pharmacologic action. It then
may influence more than one body system,
perhaps have multiple neurologic or muscu­
lar activities. Thus dextroamphetamine, used
primarily as an antihyperkinetic or anorexigenic to control appetite because of its CNS
stimulant properties, may cause the following

Examples of Major Adverse Drug Reactions

Addiction (physical or psychological dependence)
Allergic reactions (hypersensitivity}
Anaphylactic shock
Atrophy of any organ or tissue
Blood dyscrasias (agranulocytosis, aplastic
anemia, bone marrow depression,
thrombocytopenia, etc.)
Blood pressure changes (severe)
Blood sugar changes (severe)
Cancer (neoplastic disease)
Cardiopathy (arrhythmias, decompensation, etc.)
Coma
Convulsions
Death
Encephalopathy (severe CNS involvement)
Exacerbation (peptic ulcer. Infections, etc:)
Hearing impairment (deafness, etc.)
Hemorrhage (severe)
Impairment of psychomotor activity
lodism. bromism. etc.
Kidney dysfunction

299

Libido reduction (severe)
Libido enhancement (severe)
Liver dysfunction
Mental depression (severe)
Mutation
Ocular damage (blindness, etc.)
Pancreatitis
Paralysis
Peripheral vascular collapse
Photosensitivity (severe)
Psychoses
Resistant organisms
Respiratory depression
Skin reactions, severe (see Table 9-10)
Superinfections
Teratism
Thyroid depression

Tolerance
Ulceration
Withdrawal symptoms (severe)

tlkA
f

J...

316

'’M'' '

Adverse Drug Reactions

KI

Table 9-8
Drugs Which
Can Induce

I
Blood Dyacraglas (Continued)

Agranulo­
Drug

b
I

:.Z’

!
I

Sulfacytine (Rencquid)
Sulfadiazine
Sulfamethizole
Sulfamethoxazole (Gantanol)
Sulfisoxazole (Gantrisin)
Sulfoxone
Tetracycline
Thiacetazone (Seroden, etc.)
Thiazolsulfone (Promizole)
Thiocyanates
Thioguanine
Thioridazine (Mellaril)
Thiouracil
Tolbutamide (Ormase)
Triamterene (Dyrenium)
Tnmethadione (Tridione)
Tnpelennamine
(Pyribenzamine)
Vincristine
Vitamin K water-soluble
analogues

cytosis
(Leukopenia)

?

Aplastic
Anemia
------j

Hemolytic
Anemia

?

?

Megalo­
blastic
Anemia

Pancyto-

Thrombo­

penia

cytopema

?

explained on the basis of bone marrow toxic­
ity resulting from inherited sensitivities to
aplastic anemia,
drugs and from the actions of environmental
Aplastic anemia (aregenerative anemia
chemicals
such as benzene, carbon tetrachlo­
bone marrow failure, hypoplastic anemia.’
KT?' re .rooL0T ancmia)- first named by ride, hair dyes, insecticides (DDT, lindane)
and“ trichlororhch in 1888, is the most serious of the plant, sprays,
a , solvents,■ TNT. —
"‘vudrug-mduced blood dyscrasias. The mortality elh>Te- Oth(:r biologic agents include.* <conrate may reach 80-100% if the causative
causative o
“,ons (e.g., the
. cond
wwuuiuuns
tne Fanconi
banconi :syn­
agent is not identified and withdrawn rapran- drome
drome)> and ionizing irradiation. It is
idly, and appropriate therapy initiated.
’
^>^ne|Ij|rneS assoc,atcd with tumors of the thyIn pure aplastic anemia, there is complete
absence of all types of hematopoiesis in the
Hemolytic anemia is discussed in Chapter
in connection with hypersensitivity and
aTmTb
C'l tyPeS °f ap'aS,ic anema maY
affec the production of only one or two of pharmacogenetic influences. Table 9-8 lists
the elements of the blood, and result in var- many medications that have been implicated
1OUS combinations of anemia, leukopenia, in
ln this
lh,s an
dys<
andd the other blood dyscrasias
and thrombocytopenia. The clinical sympC
—Cancer,
~
Carcinogenicity.
the second leadtoms of aplastic anemia may appear rapidly, in£ cause of death by disease
-------- . is undoubtedly
1 arncularly with antmeoplastics and ionking 'the
k-------most complex health problem urgently
irradiation. But with most chemicals the onrequiring solution. The International Cancer
set is ins.d.ous and delayed, often not maniongresses and other groups repeatedly re-------- —Jge conIn the past, many cases of aplastic anemia cernmg the 200 or more malignant diseases
have been designated idiopathic (chloram­ which physicuns must identify and attempt
phenicol in 50% of all cases). As the mecha­ to treat. Yet, m spite of good communication,
nisms of adverse drug reactions become bet­ progress is painfully slow. Manv malianant
ter understood, the condition may often be neoplasnc disease entities are not’eass to pin­
point and for practically all of them no cures

i

£

SWSSS’,h'M S'1 ' ~aass

I

I

k

i
I

■ f
ew- -.

.-a

/
Adverse Drug Reactions

317

Table 9-9 Typical Carcinogenic Agents •*
are available, only palliatives.* The major
difficulty lies in the fact that they are almost
Hair dyes
certainly composite processes—biochemical Aflatoxins
(phenylenediamines)
oAminoazotoluene
and immunological as well as viral. This 2-Aminofluorene
Herbicides
makes the development of prognostic indica­ Androgens
Implants (metal, plastic)
Maleic hydrazide (liver
tors as well as identification very difficult. Antineoplastics
tumors, mice)
(alkylating)
But metabolic studies of in vitro cultures of
3-Methylcholanth rene
Antivitamins
malignant cells, identification of cancer-pro­ Asbestos
Naphthylamines
ducing viruses, synthesis of DNA, and other Benzene
Nitrites
Nitrofurans
techniques are improving insight. Also, with Biphenylamines
Nitrosamines
more accurate characterization of the pro­ 3.4-Benzopyrene
N-Nitrosodialkylamines
Busulfan
teins involved, classification of neoplasms is Carbon tetrachloride
Norethindrone c
becoming more precise. The cancerous disor­ Chloroform
mestranol?
Oral contraceptives?
ders are now frequently designated by means Corticosteroids
Pesticides*
of the protein products of neoplastic cells, •Cyclamates
Pronethalol (Alderlin)
disorders of immunoglobulin synthesis (al­ Cytotoxic antineoplastics
Radiation
4-Dimethylamino- .
pha. gamma, and mu chain diseases), or oth­
Thioacetamide
azobenzene
Tobacco smoke
er specific biochemical terminology.2
Dimethylbenzanthracene
TRIS (flame retardant)
So many chemicals and other agents (dis­ Dioxane
Trypan blue
Epinephrine
ease. faulty nutrition, genetic influences, im­
Viruses
Estrogens
munologic deficits, implants, parasites, radi­ Food Additives (some)
Vitamins (deficiency or
excess)
ation, tobacco, trauma, viruses, etc.) appear Freons (liver tumors,
to induce cancer or predispose patients to the • mice)*
disease that it is difficult to define the caus­ Griseofulvin (liver
ative agent. While much human cancer is in­ v.iumors, mice)
duced by chemicals, certain microorganisms • For example, when Freons used as propellants are com­
are undoubtedly involved. Polyoma virus is a bined with piperonyl butoxide. a pyrethrin pesticide syner­
known potent oral tumorigenic agent.137 gist.’*4
Breast cancer, Burkitt’s lymphoma, cervical
cancer, leukemia, postnasal cancer and sar­
Aflatoxins, produced by Aspergillus Jlavus,
coma are all strongly suspected of being a pathogenic mold that may be present in
caused by viruses. These and other carcino­ certain nuts, cereals, and other items used as
gens are found in the air, food, water, or the food, are potent carcinogens. In 1960, poul­
try’ feed containing contaminated peanut
environmental substances contacting man.
In the environments of large metropolitan meal induced the mysterious turkey X dis­
areas, some known carcinogens like 3,4-ben- ease that killed more than 50% of the British
zopyrene are ubiquitous. So also are indus­ turkeys. The nitrosamines also are potent
trial pollutants, pesticides, solvents, and var­ carcinogens in a wide range of organs of var­
ious vapors and suspended particulate ious species. These may be formed during
substances that have been implicated as car­ cooking when ingested nitritesf react chemi­
cinogens. In these congested areas, such a cally with secondary amines present in the
vast array of potential carcinogens is present food.52 Those who contact certain chemicals
that it is exceedingly difficult to decide defi­ in laboratories or in industrial chemical
nitely that any given drug or other chemical plants may be particularly vulnerable.51 Ben­
is the carcinogenic culprit in a specific pa­ zidine, used to detect occult blood, and other
aromatic amines have been implicated in
tient. Table 9-9 lists some typical agents.
cancer of the urinary bladder and of the pan­

I
*

I

t

> 1

*JL,

i
(•>

i
1

•Complete remissions have been achieved at the Na­
tional Cancer Institute in six types of fast growing can­
cers: acute leukemia, Burkitt’s lymphoma, certain childh<xxl solid tumors, choriocarcinoma, Hodgkin’s disease,
and testicular tumors.

f During 1971 the FDA look steps io lower the pres­
ent limit of 100 ppm permitted in UkhIs Io perhaps a
tenth of that concentration because of its carcinogenic
potential.

331

Adverse Drug Reactions
Table 9-20

,132,233

Drugs That May Induce Liver Disease*_______

Drug

.*n)

3'von)

'f
ized by
blood

,h

The

include
patient.

resenv
nducing

a moraundice

.c.tetion
non on
lutalhiof glu­

es.

See

i

<* of
.on.

*: Ta-

< A d,idv the
thern*he ex• renal
failure,
and lisdiaracia. may
r there:ts with
cause,
mnisier
poien.1 funccloselv

Cholestatic
Jaundice

Hemolytic
Jaundice

Hepatocellular
Jaundice

Mixed
Jaundice

Acetaminophen (Tylenol)
Acetanilid
Acetohexamide (Dymelor)
Actinomycin
’
Amitriptyline (Elavil, etc.)
Amphetamine
Arsenicals
Arsphenamine
ASA
Beta-phenylisopropylhydrazine (Catron)
Carbamazepine (Tegretol)
Carbamazine
Carbarsone
Carbutamide
Chlorambucil (Leukeran)
Chloramphenicol (Chloromycetin)
Chlordiazepoxide (Librium)
Chloroform
Chlorothiazide (Diuril)
Chlorpromazine (Thorazine)
Chlorpropamide (Diabinese)
Chlorprothixene (Taractan)
Chlortetracycline (Aureomycin)
Cinchophen
Colchicine
Diazepam (Valium)
Diethylstilbestrol
Dinitrophenol
Ectylurea
Erythromycin estolate (llosone)
Ethacrynic acid (Edecrin)
Ethionamide (Trecator)
Ethyl carbamate
Gold salts
Glucosulfone sodium (Promin)
Griseofulvin
Halothane
Indomethacin
Imipramine
lopanoic acid
Iproniazid (Marsilid)
Isocarboxide (Marplan)
Isoniazid
MAO inhibitors
Mepazine (Pacatai)
Mepharsen
Meprobamate
6-Mercaptopurine (Purmethol)
Metahexamide
Methandrostenolone (Dianabol)
Methimazole (Tapazole)
Methotrexate
Methoxyflurane
Methyldopa (Aldomet)
Methylestrenolone (Normethandrone)
Methyltestosterone
Mitomycin
Neoarsphenamine

^hesTTe^to^x-c.t.esTave^l beenTeported in the literature ” ~ « * « * * * “ « w
life 313-3,•

“Potentially fatal complications Read labeling carefully.’”

b

b

b

" ’* *° ““ * * ,<xx’“

"2

•r —

/3^

J

332

Adverse Drug Reactions
...

Table 9-20

«

<

w
• V

,

•

•

■

.

•

Drugs That May Induce Liver Disease (Continued)

Drug

Cholestatic f

_______________

- Jadndice /

Nicotinic acid
Norethandrolone (Nilevar)
Norethindrone (Norlutin)
Norethisterone (Norethindrone)
Norethynodrel (Enovid)
Novobiocin
Oxyphenbutazone (Tandearil)
Oxytetracycline
Paracetamol
Para-aminobenzyl caffeine
Para-aminosalicylic acid (PAS)
Penicillin
Perphenazine (Trilafon)
Phenacemide (Phenurone)
Phenacetin
Phenazopyridine
Phenelzine (Nardil)
Phenantom (Mesantoin)
Phenindione (Danilone)
Pheniprazine (Cavodil)
Phenobarbital
Phenothiazine
Phenoxypropazine
Phenylbutazone (Butazohdin)
Phenylhydrazine
Phenytoin (Dilantin)
Polythiazide (Renese)
Primaquine
Probenecid (Benemid)
Prochlorperazine (Compazine)
Promazine (Sparine)
Propoxyphene (Darvon)
Propylthiouracil
Pyrazinamide (Aldmamide)
Ouinacrine (Atrobrine)
Quinethazone (Aquamox. Hydromox)
Quinine

Hemolytic
Jaundice

Hepatocellular
Jaundice

Mixed
Jaundice

J;

Rifampin

Sulfadiazine

1!

Streptomycin
Sulfanilamide
Sulfonamides
Sulfones
Sulfonylureas
Tannic acid
Tetracycline (Achromycin, Tetracyn. etc.)
Thiouracil
Tolbutamide
Tranylcypromine (Parnate)
Triacetyloleandomycin (Cyclamycin, TAO)
Trichloroethylene
Tnmethadione (Tridione)
Urethane
Zoxazolamine (Flexin)

'■

(

‘K

c
Vol. 64, No. 4, pp. 481 -6IS

1986

F

I
!
9|

58
I
7 >1

BULLETIN

OF THE WORLD HFACTH ORGANIZATION
Ift DEjlJORGANI^AriON MONDIALE DE LA XANTE

I

■3

it

i■ ®sgS J.fK’SM«>4"
Update — Le point

WHO Working Group

Extra-ocular chlamydial infection

481

II

G. M. H. Waites

Regulation de la fecondit6 masculine: progres reccnts

493

o-' I
tjj I

I
WHO Scientific activities — Activifes scientifiques OMS

j

r

l,ic\cnlitm af maternal mortality — Evaluation of the streptozyme lest for itreptocxncul antibodiei —
Aniimalanal dtuy rnk
...............................................................................

503

enhun tie hi mortuhit* maieinellc — Lvaiuation du test a la streptozyme pour la recherehe des anticorps
strcptococi iqucs — Risque htf a un antipaludique
....................................

50?

Continued on outside back cover
Suite paye -I de la couverture

y
I
t1

1

control

of cancer of the

A VVHO MEErrNc*

° U°'‘4
1^16

cervix Mteri*

Cancer of th»
-^Zdc ^th°^^

1

’ Ca^cer in
■’ ^omen
.......... :ed
'ce Points
a^d specific
ntOrt^ity if i, is

w ear/y

too,

ra,d‘o<^rapv,
-• cancer.
•
....... ..

favor

r/^ reZZ"""^ ‘n

thf
■JnIn.s c enting
-Lr \vhen

pro^Z?rasf''C f■'enon

Once in ht
J^quency Of Sc/
groups jj
60 years.

r
, been
epithelial

fZee'^ ^fdTe-0^ °^' Z
/:
^Zfery
-■
-'"z^
Z hrre yars fOr
^/■fyZfOi,ablf^

Ep’DEM/OLOGY

AND etiology
lc second

(-•nib bean

••^’o^nfriesf/) .

/,ca’ China

jnx ’

irc an^ mX in Ihi,c world. the

Wo^n; howc,
,n voung
°bscrved Wi
\ 'h'n a coXViuT"'"^ - S°r'ed
CDuniry. For‘
S'x 10 «ven
fte»<ons
RePUb|ic
’ncidcncc
NonhAmenca
•norih-east
U,in Amc.c.
scen in lndi.-“"
'
^'ope
con)pafed io

wo'"ena 7C;rn' incr«« ha?X7nCCr in

°nnual

n“mber Of

No Of
ne** ca,es

’5 700
4< 000

USSR

I

■ PProxirnaie|,

- estiniatcd p-:!n"ual ine,dc„cc
.'cyor countries
-■
'^on/
lhrC(
by

• ’^cfs of f/lc

for^%ofni;^7a,,f

•tths m v
J.CV,CW “ b-ued

Geneva ?7 ’S'"
?' •o
,o ’c™
Cane"
"'

4701

from
were

Afnco

4 7 200

China

31 300

Ind-t

36 Soo

J®Pan

’31 500

As,a

:?'nCn i;’ ‘ .u.n

w ere due

Thu r^.

6,6 6,7

, Ias«
'Umo^

7’ 600

p«,„

9 700

... .

'O cancer

rc^n on
4

‘ °f ,hc rJa'"c.pa(1(I

?O 300

1 200

-1,1
W,U be found

new cases of

’05 joo
f»n

7ottl

* °ata troi■m I975

607-^

—

354 300

tso 400

ad^Pted ffom'

Pa'^et al. (/)

i

A WHO MEETING

608

Recent figures from 28 developed countries (2)
indicate that cervical cancer mortality declined by
approximately 3O°7o between 1960 and 1980; early
diagnosis through screening has been a major factor
in this decline. The quality of information available
for analysing morbidity and mortality of cancer of
the cervix is very uneven and largely depends on the
level of development of the health system in the
country.
The development of squamous cervical cancel is
strongly linked with human sexual behaviour. Recent
studies have provided some evidence for vencreally
transmitted etiological agents, such as human
papillomaviruses (3). Consideration has also been
given to the possibility of other etiological factors
such as smoking, hormones (including contra­
ceptives), and nutrition (vitamins); these factors may
also interact with papillomavirus infections.

Sexual behaviour. Epidemiological studies have
pointed to the overriding importance of sexual
experience with multiple partners and early onset of
sexual activity in the etiology of cervical cancer. The
risk of cervical cancer is increased more than 10-fold
for women with six or more sexual partners or when
sexual activity is begun before the age of 15. Male
sexual promiscuity also appears to increase the risk of
cervical cancer in the female partner and might be as
important in this respect as female sexual behaviour.
Other variables related to sexual behaviour —such as
age at marriage, number of children, history of
divorce — do not independently influence cervical
cancer risk.

Viral factors. Most of the experimental work
attempting to relate cervical carcinogenesis to) a
transmissible agent has been devoted to viral
v..
research. Although alphaherpesviruses 1 and 2
(herpes simplex viruses) have been suspected since
1968 to play a role in the etiology of cervical cancer,
recent studies do not support this notion. Evidence is
accumulating for a role of specific types of human
papillomaviruses (HPV 16 and 18) in cervical, penile
and vulvar cancer etiology. The DNA of these viruses
is found in the majority of these tumours as well as in
their precursor lesions and induction of dysplaslic
precursor lesions has been achieved in heterografted
human cervical tissue (4). Papillomaviruses have
been found to interact with chemical and physical
carcinogens (initiators) in animal as well as in human
systems.
Circumcision and genital hygiene. Evidence does
not support the hypothesis that the partners of
circumcised men have a lower risk for cervical cancer.
Care must be taken to determine circumcision status
by physical examination as opposed to only
questionnaires or interviews because the results

obtained from the latter may be misleading. There is
also no scientific evidence for a relationship between
genital hygiene and cervical cancer risk. However,
most of the studies to date have been conducted in
countries where the standards of personal hygiene are
relatively high.

Contraceptive methods. Barrier methods, such as
the diaphragm and condom, offer a degree of
protection against cervical cancer that cannot be
explained by confounding variables; even after
adjustment for these, cervical cancer risk for
diaphragm users is about one quarter of that in users
of other methods. Studies on the use of oral
contraceptives and cervical cancer indicate that
certain groups of long-term users (four years or
longer) may have a relative risk of 1.5 to 2.5 for the
disease.
Epidemiological studies
Cigarette smoking.
• cigarette
•
’ ’ is; a risk factor
strong|y suggest that
smoking
for cervical cancer even after the confounding factors
related to sexual behaviour have been taken into
account. Tobacco-related substances, such as
nicotine, have been found in the cervical fluid of
smokers and could act as co-carcinogens to viral
________ _________
infections.
However, the absence of a dose-response
relationship in some studies leaves room for doubt
about the causal nature of the association.

Nutritional deficiencies. Some investigations sug­
gest that localized deficiency of folic acid may be
associated with a higher risk for mild and moderate
dysplasia, and that there may be an increased risk for
women with low beta-carotene and retinol con­
sumption. However, there are no indications at
present that compensation for nutritional deficier. ies
will decrease (he risk for cervical cancer.

PRIMARY PREVENTION

Prospects for the primary prevention of cervical
cancer arc good because epidemiological and
experimental data have linked carcinoma of the
cervix to defined risk factors. In particular, there is a
reasonable chance that vaccines can be developed for
immunoprevention since in animal models spon­
taneous regression of papillomas appears to be
mediated by cellular immune functions. However,
the exact role of papillomaviruses in cervical cancer
pathogenesis has yet to be established. The clarifi­
cation of this relation and the development of suit­
able vaccines for immunoprevention, and possibly
even therapy, should be pursued with high priority..
The development of squamous cervical cancer is
strongly linked with early onset of sexual activity and
multiple sexual partners; sexual behaviour of the

--- ------- ----------- —
•j'.’ i?.

...... ...

in

■■~rar ; r'. -r

I

!

<
rec*, i
I he

CONTROL OF C.ANl

'CEROFTHECJEJjVfx UTERI

behaviour, and® delayi °s

I

609

‘his wouldlls*ggesI,Cad^'i‘^<:cn ™P|ica‘<“f- While
h

lesions Qf^rutedn^ceX

sexually active life
■
^Ornmcncement of a
expected in campaigns ^chan11^65 W°Uld bc
habits. Nevertheless inform r‘ £C thCSC ^Te-style
Programmes on the’ role of sexCarbdehedUCai,On
cervical cancer and the use of b*Xr ?
*0Ur ,n

D«»criptiv8
clMjification

P^inv.9)ve

CervK^I lntraepith.|ial
Neeriasi. (ClN) riassd,cation

Mild dysplasia
ClN grade I

Moderate dysplasia

CIN grade I!

Severe dyspiesia

ig- At the
smoking may be emphaskedgn,riCanCe °f SIOppin8

ClN grade in

Carcinoma in situ (ClSj

ClN grade III

PATHOLOGY and natural history

I

history Of cervical
carcinoma
Knowledge c
concerning the natural r
"ras “dysplasia"
■!
■’ 'nS'Cad of lhc ,wo
history of
squamous cell
carcinoma is important
classification has bee^
This
designing a control
—t when
Table 2 gives an
ad°P‘ed by many workers,
cenix is a j
histological ctofi ™3
Tsio" ofdescriptive
-. u,scasc. )t begins with
preneopias.ic ,changes which may
lesinne
sifjcation of preinvasive cervical
develop over a period of 10
CIN-das'slficafiond'Thy " m0 35 nimpared wi‘h ‘he
CCrViCaJ Canccr- The years or more into
classifications are e^' i36'
'ha! the lwo
rnain objective of
onsetCofCanCCf COn:ro1 Pfogratnmes is
difference
is
that
tl/'cb
compa
"b
,
c. The only
lri„
.
— •■5 ,o Prevent the
onset of mvas^c carcinoma
intraepithelial neon!
■ c asSiflc;"lon °f cervical
diagnb,,s and
tr^XoH^^Xr;^ d—•
didgnbsis
and treatment
carcinoma in sito 'T?'nc,udcs ^'“'dysplasia and
invasive
stages,
when a 100%T
d ln8 "s p'finvasive
j*
----...
*
»-- - > -••».•« e _
makesnodiffeX "in rerm3'0?0''’
C'N’"1' T'"S
I'hstopathologically
listopathologically. prcinvasT™"
'S P0S,S,'blc/j>,
develop usually throuuh srv "i
cc'vlta' lesions
caused co„
confusion
management,
but has
(usion wh
whe() compari|)1
. rfIul(j
(mild-moderate(mild-moderate-severe) wfiidH
°f dysplas.;t
Classificafion of Tom
l"'|.crna'i‘’l,il1 Hi’lologicnl
and finally l0 invasion M
'O "'“'’"mu m
needed- in parficu!
CCr'iCi" ca'cinoma is
'ently agree with the concern h’* pal,lolo«l5l« curof mi^oinvasive taXmr,,d
C°nCCpl
and carcinoma in s.tu „Ty eo "n5""" d>'sph‘s|a

cfeXmi?n,0UrS?- 7>- A SCCOnd and
in‘raepSrC^'r^ 'T ?f

P'ogre^^e6-rr3 Of

squamous carcinoma and thaX h P'os'ess in'0
may on rare occasions di t i '"odc""e dysplasia
disease.
"S d‘"rc"v 'csult in invasive

deYAeiopOsU1:throurRhal,y 3"
'Phhelial changes, nXTofd

Ph3S"

Of

cancer
",,ra-

Kress to invasion. Some stiuf
nccc5sar’,y Pro30-35% of preinvasivelesions rr'
C Sh°Wn lhal
1 he milder forms (mild and
S spontancously.
■”e highest reXsJon ra
sX i,''<,ySP,aSia)

Possible to determine a
progress and which will „of

n°l 31 prcsc”‘
Wu'Clh ,CSIOns

mtraepithelial neoplasia si ouM
S”Cd,rUn’ of
Pmenuany malignant and
Lid Ld"S,dCred as
managed appropriately.
d U’crcfofc he

Classification of cervica/ neoplasia

There is
cytologica!
fvconimcnded by th.
the series on

guidelines for the da« r
*'''f "’o'' detailed
‘he classrf,catton of tumours into
subgroups, and review recent knowledge on
morphology as n relates to prognosis.

tARLY DETECTION

The

rationale

for

early

detection

(secondary

p'S^^r°T^
disc3s‘d^
»T the disease
S^f ,n a higher cure rate than

-ec anrdi~xnx:xn"d
cervical neoplasia If the detection
d ^c,,on of preinvasive
Preinvasive
disease has virtually I itor'3 X lrC',lcd' P'cmvasive
Rical nrnrATi
a,,y a 100 '° cure rate with simple surinvasivc
Cases diagnosed in an advanced
35% Cv o
nVC‘yCar
’han
cancer contmHr SCrccn,n« Programmes for cervical
’han 30 years (5)7°
Opcral,on now for more

It

?

'1

/c

A WHO MEETING

*

i
'■

Evidence for overall effectiveness

expected to have two major"^’^"u«
the mcidence of the fully developed symptomatic
ehmcal lesion and it should reduce mortality ? °m the
disease. Thus, evaluation of the impact 0 screenme
programmes relies largely on the study of rates "f

differs g“hi^ a’”*; t"*"

S^a',r'ndS0W-"-“
Well-organized screening
programmes
have been
shown r
to *be effective in reducing
morbidhv
°and
J morbidity and
mortality
mortanty from the dir
disease, in the Nordic countries
following the introduction of screening in the n H

a., -s

1^5 8 (P). |n Canada, the incidence of cervical
^n4CCfpopped from
to 6.9 and mortality frOm
crrA ° 3-3 PCf 00 000 womcn during a 20-ycar
screening programme in British Columbia.
ahh
Un,,cd K‘n«dom, it seems likely that(
although screening appears to have had little effect
largely because of inefficient use of resou ces thr.
™r,ah,y
-OUH have increased further in the
es^blKhe?CrCCn,n8(y0}- Twoarc« of Scotland with
esubhshed screening programmes have experienced a
X and oCverfCrCi,SC
in W°m"
”

i

I

11 is the unscreened women who (end to be at
highest risk (about 10-fold higher) and most of the
mortainy from the disease occurs among them In
conclusion, the available evidence suppons that at
mortar, f'60'’’’ reducIion of boIh morbidity and
monainy from canccr of the cervix may be achieved
through wcll-organized screening programmes

I

Extern o/otigoirtg screening programmes

siJcheedt.\lCn„' '°r nhiCh scrccn,"S Programmes have
eded or failed to decrease mortality from
extern'0^0'“' "T “ lar*Cly rcncc,<:d in 'hc
screening 4?
SC °f 'hC
* risk by
screening. There is a marked difference in the extent
of screening worldwide. In many developing
cxistent'o’ YKninS f°r CCrVi<a, Cancer “ non
cx.stent or, at most, sporadic, whereas in some other
areas the screening is extensive. Successful screening
programmes m developed countries, e.g., in the

i
■I -

J

screened at regular intervals.
Screening programmes in :several countries were
reviewed to determine the extent of coverage
currently being provided:
— In China, screening was started in 1957 in Beiiinc
and subsequently extended to Tianjin. Shanghai and
other pans of the country. Annual, biannual and
tnannual screenings were established as a routine in a
number of districts. More than 16 million women
nave been screened in the past 15 years.
— In India, facilities for cytology arc at present
rcsinctcd to the larger urban centres which also have
Scrw^n u°r canccr d,agnosis and treatment,
of short tr
WSCnlia,ly in«»ution-based and
has been
dura‘,0n> and only limited information

SSF

~

be provided to only 25Vo of the
year 2000.
^fnnnn!hdiOnCSia’u CanCCr ,rcatrnenl facilities and
cytopathology laboratories arc available in only a few
hospnals, mostly attached to a university. Screening
»s performed mainly within the infrastructure of
Recent dZ^show th:!
years of a^ ahhoXnlyof"ClX’vTcal'^^cc?
patients were in that age group,
-In Brazil. 75% of cases of the uterine cervix are
d'aSn°5cd wjth invasive disease. Current pro­
grammes for detection and treatment are only able to
cover 2% of the female population at risk
hh^5hilC’ SlCrccnin« is Performed in 16 cytology
'a^ra ones throughout the country, which have an
overall capacity of 500 000 smears annually. Women

child b r//rCrU,tCd m°S,ly ,hrOUSh malcma) and

DrestnhfC| bh/fann Y plannin8 Programmes. With the
present laboratory capacity all women between 35
nd 60 years of age (approximately two million) could
be screened at five-year intervals.
i7i|1iamf|Jn?ar!faamCy,?J0Sy screcninS P'OS™nimc was
labm n
’^ Cytology is performed in 72
laboratories throughout the country. With a target
population of 3 250 000 women between 20 and 65
ove „ f
'hC pr"cm ,abo«'ory capacity of
screed
can be
screened every three years.
4o\n7r0rUPa”,''mil'Cd ,h"'> °vcral1’ “PProximatcly

''on,cn developed countries and
less than 5 /. of women in developing countries have
the < ^i"
Ci‘5' °"CC in '"C
ri«
I"
the developing countries, the limited screening
than 35
r" fOCUS °n y°"nf:Cr
>h“'
than 35 years of age.

:.v.l I

S

•!

i

i

■'

t
v

CONTROL OF CANCEK OF THE CERVIX UTERI

611

Approaches to screening

grammes is mandatory for the
success of screening
activities in many areas.

appropna.dy"plannedTnd tak?^"”"' mUSI
must be
following aspects
, r •'nl° ac<:oun' ,hc

Jmpedimenls to screening
One of the key questions to ask of a country’s
peening programme is “who is responsible^’
the ansVto^thT^^ SCrCCnin8 P^^mes.'
me answer to this question is clear, although the
pecific organization mechanism varies from country

planning and evaluation)- (d)

:rrux,ry dcpcnding °n ih'

In most developing countries, cancer control
programmes are inadequate and screening activities
do not appear to effectively reach the most Vulnerable
populations. In many countries cervical cancer
.

done at the primary health care level and w thin £
existing health care facilities- (dx ’ I
he
oJganSon oTdug'osls

.nd.vidual should be .dented as Wn

es^n"^

X the"^' COOrdlna,'"S. ™on»oring and evalu

o^ePrograPs^^^islsS^r"'
~^d^eZin heal,h ‘”'~IUre

s-ni'rX^^^^'^Xor'f'3

comprehensive cancer health Lr

i

rern
f°/7hC or«an‘zat'on of laboratories the
recordmg of data, and the follow-up of abnormal
Findings are i^adequate. Current training of cytopathologists and
—J »cytotechnologists in some
some areas
areas is
is
poor, and (here is
i
f’andyd‘za,'2n in cwrnculum
eduvery

rn°re

I
I

I

services0 by"'or C0S"y '° dtvc,op
biology
sentces by unhztng an established infrastructure
(MCH/Fp7’nro"al and Chi'd hcall,’/fan>ily planning
MCH/FI ) programme, rather than developing a
separate vert,cal screening programme. However i
ery important to keep in mind that cervical cancer
election
programmes
have
different
objectives.and
TheMCH/FP
a^ 0nrnon
Pf~‘«
programmesCOSI
is |8encfrd,lv (>n -hunger women for
whom the ccost-bencf.t ratio of screening .s poor.
rurthcr, the responsibilities
.................. monitoring screening
coverage and coordmaung
case follow-up and
treatment arc rcqucntly not accepted by the
MCH/I'p rprogrammes.
—
Ootim-il coordination
•
'•'Piimat
between cervical
■w“‘ Cdnccr Section and MCH/FP pro------- -- • • •

I M I

'ha'

Sives
unneXry

T""C. “ CVid'"CC °f

ih., i k
cscrecmng of the same group which
>1 creby becomes a very low-risk group- screening
,nc?udaem'n" S’’°^d 'hcrCror‘' direc‘ ‘h- Xu",’0K
mclude women who have never been screened before
rXeXoftl
°nCS a' hiEheS1 ri'L frequent
e l-nse t
U'Or”Cn a P°P“h>lion. a. the
« h resu ,
P'Tr'K"' °f ll"s««"«l women.
II result in a very low cost-benefit ratio for the
I "e w!;,“PKT"‘'
"IC'C;,SC l,,c ^'>efit of
' . , 1“’ •"e hetng scteeited, and will not reduce
morbidity or mortality from cervical cancer
in most developing countries, even those with
jn’m’proHde^r0^''10"015- “'“"‘"S aoivitics cannot provide adequate coverage of the population at

I. 1
i j

!

612

A Who MEETING

h
!° ,rn,tCd rcsourccsmany developed
and developing countries, screening activities, where
they exist, are performed within different health care
facilities with little planning and coordination of the

programme. This lack of organization and assign­
ment of responsibility is the main impediment for the
success of screening programmes.

Collecting smears in the community

where obtaining endoccrvical samples is not feasible
the minimum recommended procedure is a scrape
taken from the squamo-columnar junction as
described above.
Smears should be fixed immediately by either
commercial spray-fixatives or by immersion in 95%
alcohol. The method of air-drying of smears, which
are subsequently rehydrated in a 50% glycerine-water
solution before being stained, has been successfully
used for several years by at least one large-scale

Collcctmg of specimens for cytological screening
screening programme, with considerable savings in
shou d be decentralized to facilitate access to the
the cost of fixative alone, and deserves consideration
population at risk. Primary health care facilities
for routine use.
(such as maternal and child health and family
Slides must be properly labelled and attached to the
planning clinics, venereal disease clinics, hospital
appropriate requisition forms. The delivery of
outpatient dimes, etc.) may be used for this purpose
specimens to the laboratory should be scheduled on a
coHS’denng that the cost of the additional workload
weekly basis at the most, to be sure that the cytology
should be mmimal if the clinical examination proreports return to the clinic not later than three weeks
cedure is organized to include the taking of smears as
after the smears were taken. Delays of over one
a routine. The qualified person responsible for the
month will interfere with appropriate follow-up and
OkCrfi oIpcrat,on of the primary health care facility
will eventually result in discredit to the programme.
should also be responsible for the follow-up of cases
To achieve adequate follow-up. each clinic should
with abnormal cytology at this level.
have a simple alphabetic card file to help identify
It is not necessary that smears should be obtained
women who have been screened previously and to
only by gynaecologists; other medical personnel such
locate patients with abnormal reports who require
as nurses (nurse-midwives, public health nurses
referral for final diagnosis and treatment.
medical social workers, etc.) and even technicians’
specially trained for this purpose, may take satis­
Screening intervals and the identification
factory smears. Although it may not matter who lakes
of high-risk groups
the smears —gynaecologist or nurse —it is very im­
Data from screening programmes in eight
portant that the practitioner responsible for this task
—mvowu ai
iu
should also be responsible for communicating
and
countries in Europe and North
America have been
^-!tining
cytology
report •V
to waaw
the woman
and her
U^d lo estimate the risk of invasive disease associated
wx ------- -- --doctor and for ensuring
f_"_
with different screening strategies (12). The results
.
- adequate
.
- follow-up
and
indicate that for women aged 35-64 years the
management of patients with abnormal cytology
reports.
reduction in incidence from screening every two years
is as great as that from annual screening, and that the
reduction in incidence from screening every three
Preparing smears
years is nearly as great (Table 3). While less frequent
Adequate specimens can only be obtained after
visualizing the cervix through a vaginal speculum
without a lubricant. Smears obtained from the
vaginal pool and specimens obtained by patients
should not be used owing to the high false-negative
rates expected from these techniques.
The most reliable sample is a combination of an
endocemcal aspiration (or cells obtained with a non­
absorbent corton-tipped applicator from the
endocervix) and a circumferential scrape of the
transformation zone around the squamo-columnar
junction. Both samples may be put on a single slide,
without affecting the sensitivity of the test. The use of
single slide specimens is an important point to
consider when planning cost-effective screening
activities, as two slides
......j per patient will practically
double the overall
cost of the programme. In cases

Table 3. Reduction in the
cumulative rate of invasive
cervical cancer <•■•-•
over the age range 35-64 years, with
different frequencies
of
— ^f screening*
Frequency of
screening

Percentage reduction m
the cumulative rate*

No. of
tests

1 year

93.3

2 years

93.3

15

3 years

91.4

10

5 years

03.9

10 years

,64 2

30

?

6
3

* Adapted from reference 12.
* Assuming screerung occurs at age 35. and that a previous
screening had been performed

J

W!FW

J

i

i

i

•■•.if

e
CON''<OLO'C^—ct.et.xp,^

screening offCI <
years gives a M^SXa.on\7n"r^ninM CVCry 10
assume tc;„
,Ola' (<«)%) coverage of lIbeSCeS'‘n'a'«
Screening all
J "omen every l0 year JJu popu,af‘On.

I

more than jscreening 50% o/the » ’ ach,evc much
years.
"onten every fjVe

'

f“'^XgaICar

-~.S ?Und in "te protection
Allowing two or mor nC8a"vc £-“-.

-- ™car ^n in .hat

'hrai ‘h^.s considerable
1"' - - ,n- Th,s suggests
v-r-

s.st?-”-«

t^nly'.ycar Pcr’od
(hat the
relative
a
°m areas with a
Muabty of Ihc smear and TaV'08"*"’'"' ’ ..... e where the
h‘8hd aboratory standards
— —s are
«>nXed ' whcn° fOrimP,0r,anl risl factor t-

importance of propcr f "d who understand the
forcytoIogicalrL™
fi**l>on should take a
continuing basis.
,nal,On- Gaining should be on a

negative reports as low a

P (hc nurnbcr of fakr

P01ici^

“-a. canX-s^.pX'hPed coXX"^"
are Under age ->S

sS U',h

in
by
^e*
only those who are spCd^r]u CnSUrC Rood quality
cc,°endoc=XX„T?,nedlO5^PleX’

to be

of'X

developed anH J

"Fhcr

thorough $arn^i° ai}5olu(e criteria |O cnnC

p

?

e

whX’" ,',C '"XX

^Ons Ihe screening staff a E.Xchan8‘ng

^-“XrC°Ura8P:

slides

COmPar'nS 'hC

^blejdi agc
or
^;/hc/c » remains fairly
whXh" 8 ShOU,d b' “i-ed a 7hXh " mav decl.^

o.her xonps ,n

id^s;:xr ,5

"-SS screening pro^Xes OXbnOrn,a' s"'=a ‘ -n

I
quonty^i^' Orsani'a'iO"
and

oology laboraio'y

XXT5?0 pc^' -«'

r" com'>'°X';^

gist, c—
lollou......

screened m a

ro' owini

J a cytopatholodiagnosis
cytology reports is r- of IPa,i'™ Wilh abnorm;i)
10 a clinician and
mandatory before'-Cytology
‘■'n be made
,|lc
•' cyiolo^y.
r an,.... J ' any dec,s’on
'olutne of
,Jl-'KiH"tic C|in,ci !e ;»»« ‘‘Pjuupnate
‘■cturah/.cd. A |.iigV
should be cestablished
• • ,rcainien!.
•'hon of a Cy .vz„
^'■''nccologydepa,.,,,.;,he
successful opci.
in
‘bvisior, of labj,
ol
regional
I
'J. k, level referral bos.,,, ,
‘■, ioital hospitals and
, - •* spcciah/ed
'
• -....
uhnorrnal smears
"“li abnormal cyio|(...v r- "A ,o
*’ ‘a,“
“*l>t
‘l,( those
'hose patterns
,cP'c.scniing vlri ,lr^C nun,ber ol
"!l1 help to maimam’tire\
cvt<
.
ous paihologies
colpo.scoj " O'n rbagnos '
n'C' ,Od
he,ng" -o,
w"eral. laborator,es , ,, i '^I'nologists’ sk,|h h
1'’ram'ns annually , '
pa'bo/ogy faethtL considered.
sl.X'p' Add'"onal "hi"?
Xm "rr"Cf ,han
WK)
ill 7? be
7 co"ildered as the
7^", Ci,htr a ■lining
; "-c„,a„dc„nnoi “,C™,„S operation ss should
•h also
place
hn'■"se sc, vices.
'
,,l;lcccai,a workload
llPjrl)ologjsf Pi cl ci abb
■
X " T

cy.X7,';,','u,ei

^ned nnd'd.^feX''^;^''' [ound sbotdd be

7 T1' A

ul

■c‘-'"<bng
’■ uper\7eX7"r",''!'''LO,n,,,
ld‘-d' maierial io a
■ Usually, single
' 'areas or health?'’'
n<’' he- placed in iso.
'''‘""'"'''’^'heu'Zbd'nm ’ '■'■™ "ell uained
‘■'I’o.scd l0 a Iargc

i

'

r

^'Ologyy|ab°ra[o!i«’o U "’7' ** dc''cl°P«i in

Protection is h hca,“ aPParem
«n‘«lly organted sc X'

undePr",rC'n'

613
number °f P05*^^ specimens,
vision.
Caching and super-

........................ ■

«k/H of [|lc

-’<cni)inc (hc
''-"net. '(,‘x
"d :",o',di^a"d
'fquiied; a

-■ U/CC/F,1S'nndafdizcd
"'n Againsi Cane,cr/i.nzse
° ^’Ucrnational
gynecology a,uj (>b..
M/-’. /'/). or alternatively
' " AJC (A,„er,c„„.. ,
..... Co'”m«Uce) syMem (/J)

X-"0" of

I

i
i

r
o!4

¥

I

A WHO MEl.TING

Screening should not be undertaken at a level
beyond which facilities for diagnosis and treatment
become inadequate. Information of the incidence of
the disease should be available for planning and
estimating the resources that will be needed. If
screening is concentrated on women over 40 years of
age, the largest proportion of cases found will be
cancer as opposed to dysplasia. If screening is
directed to the younger age group (20-40 years), cases
of dysplasia will predominate. As the treatment of
these two groups differs markedly, planning of treat­
ment facilities will depend on (he age of the popu­
lation being screened.
All patients with a confirmed diagnosis of
dysplasia (mild, moderate or severe), carcinoma in
situ, or invasive carcinoma must be adequately and
promptly treated. An accurate histopathological
diagnosis of preinvasive or invasive disease is
essential. If colposcopy is not available and invasive
carcinoma cannot be ruled out by random biopsies,
then a cone biopsy must be performed.
The great majority of cases of mild and moderate
dysplasia can be treated on an outpatient basis with
electrocoagulation, cryosurgery or CO; laser if high
quality cytology, colposcopy and histology arc
available. The same therapeutic approach may also
be used in selected cases of young women with small
severe dysplasia or carcinoma in situ lesions which arc
totally visible on the ectocervix. All cases must have
at least three normal cytologic and colposcopic
follow-up examinations at 3-6-month intervals after
the treatment procedure. After that, annual rescreening is mandatory.
The method of choice in management of severe
dysplasia and carcinoma in situ is conization of the
cervix uteri performed commonly in an inpatient
clinic. Although cone biopsies are primarily
diagnostic, they may also be therapeutic. This is
important in the management of young patients
because it preserves fertility. Management of women
with preinvasive disease (dysplasia and carcinoma in
situ) on an outpatient basis .should not be under taken
unless expert colposcopists aic available and
complete follow up is expected.
'1 hr ireatineiii ol choice lot midoinvasive cancer
with a stromal invasion not exceeding 3 mm. and
without cancerous emboli in vessels, is total
hysterectomy with extirpation of the upper third of
the vagina; this results in a five-year survival rate of
95-98%. Preservation of the ovaries is possible in
women of reproductive age. Cases of microinvasivc
cancer in young women with stromal invasion less
than I mm should be singled out- for study of the
efficacy of wide cervix uteri conization.
Treatment of invasive cervical cancer (stage I-IV)
usually involves radiotherapy or radical hysterectomy
and must be done at a centre by trained specialists

In spite of the possibility of early detection of
cancer of the cervix uteri, more than 6O^o of patients
in developed countries are initially diagnosed with
evidence of considerable local spread, metastases to
the regional lymph nodes of the pelvis, or more
advanced disease. Information on staging and end­
results of more (han 32 (XX) patients with cancer of
the cervix uteri from 120 cancer centres from
primarily developed countries worldwide has been
collected by the International Federation of
Gynecology and Obstetrics (M). The stage distri­
bution was stage 1. 33°^; stage II, 36°7o; stage III,
27%; and stage IV, 4%. The five-year survival rates
by stage clearly show the benefit of early detection:
stage 1,78%; stage 11, 57%; stage 111, 31%; and stage
IV, 8%. Long-term survival among properly diag­
nosed and managed cases with dysplasia or carcinoma
in situ is virtually 100%.
When cervical carcinoma is found in the late stages
of the disease, the emphasis should be shifted from
the attempt to cure using cytostatic agents, which
have been shown to have no value in prolonging life,
towards an appropriate regimen of pain relief and
palliative care.
Where radiotherapy facilities already exist in
developing countries, efforts should be made to
acquire a remote after-loading brachytherapy kit.
Training at these centres should include courses for
both the gynaecologists and the paramedical
personnel. When radiotherapy is not available,
radium needle importation should not be en­
couraged. Acquisition of a brachytherapy unit is the
recommended first step.
Countries should endeavour to develop at least one
radiotherapy unit where none exists currently.
Whereas training opportunities for persons from a
developing country in the past have been primarily in
developed countries, it now appears more desirable
that such training should be done in the local environmcni. Regional training centres should be cncouiagcd; international health bodies have a role to
pla\ in piomolmr. mi* h 11 .lining el lot Iv hquipnicnt
lor these new centres will include one or two trlct hci ap) ir i ad lai ion nun Innes initialls. Sealed ixoiope
units, either vobalt-<>(' ot caesium, arc recommended.
I incar accelerators arc likely to present considerable
operational diflicultic^ m any newly formed centres.

I \Al u AT ION

A cervical cancer control programme should not be
initiated prior to the establishment of adequate
evaluation procedures, it is essential to assess
progress of the screening programme periodically
both from the procedural standpoint, to determine
how effective the operations actually arc, and in

£.

(

CONTROL OF CANCER OF THE CE1*VIX UTERI

615

------- Of ^'Svtmcnl'J0 ana|yse the extent to which
niorbidity

monahty have been reduced in the
Population group covered. The following aspects
should be
considered when evaluating the
Programme:

P0PUlati°“ 11,31 has

programme has been implemented Th^

rr

Shave SendyT"* pr°8ramm“.-

^vecancerlSSS"^"'

the notificationoFfi^ “7 laK,ne 01 Sm'ars until of^Ss^
■he not'XboT^n-^ Jhe lakin* °r

ProSn V0™01 " Cy,Ol°8y '^oratories (e g

* regarded ’as Mur™"?

7dvanccd

can

of advanced-stage
cases of

on the incidence of invasive

(g) screening history of th.
’n^,verrcanccr of the cervix;

>

cancer

°n mor,a,il>' ^om invasive

xxi xv?~

mechanism of recording all
rc®'s,rallon '» a
Uterine cervix This miH , J
J °f
°f lh'
of the centres'that follow u^Xd tre/tlT'’^'^

indicator of the intenshv rf?Cn,ng’ bul on,y as an

I

olgZIlld^lXln?"6"""0^^
screening activities wcr/inT151^5 CXIStcd bef°re the
simultaneously with the sX’31
dcvdoPed
of the primary imnX
5 Programme. One

■-.eabse^XX^X^^'10^-"

covelagc^lo'^^1^ PrCCis' '”can’of evaluating
population. Although il^o°C/1,n’PlC
°r ,hc
expensive, and could enrn cou’1Ir*cs this could be
some women’s llci ' t
7 d,fr'cul"« due to
cervica. stud/‘X* ’f
’

provide information on risk ' s“ch.surveys can
socioeconomic status, of those woXnT-’ *
by screening, which m iv not b
bf'n8 ml“ed
routine data collection. '
' “satiable from
In order to properly determiinc the effect of »
. screenmg programme it is necessary that data on thl
frequency of screening and on ccXie
° n el
netdence and mortality should be available for th"
lime periods before, during the start, and after the

not prevent the
such information should
ahernahve to compX 11'0"
A"

a5X»^.|**>?SX5

Present. It would be preferabl ‘”fV^’VC d,sca$c mi«hl 1
^ere included in such a record
°f discaic
distinction between in sifu ,ng.Systcrn'furlhcr. the
crucial.
and ,nvasivc cases is

PRIORITIES FOR CERVfCAL CANCER CONTROL

—
broad scale a J Unfor,lJnaPr
"l,'>'mary
not Pfeasible
on or
a
of the associa.ton be'weenmsexuaTbVh’edUCali°n
cervical cancer and the use of barrier
'°"r and
could he of substantial value in
" contraceptives
certain countries,
As the early detection of
cervical cancer has been
proved to be effective at a
reasonable cost, the estabrecommendcd wherever j
organization and
utilization.areThe'^eTabbs'l
“"d
The establishment
and implementation body
of precise j-----Sow tongcaX'
screening
out in df''clopcd countries.
Cost-erfectiveness coni
resource

Programme design in all
IO,u p,a? a ro,c in
necessity, stronger in the d 0 r‘CS,.but lhis role is, by
the developed countries r,CVC Oping COl,ntries than
J « countries. Because of the need for

.4

616

A WHO MEETING

focusing on population coverage and careful
utilization of the cytology screening and laboratory
resources, the following stepwise scheme of screening
levels is recommended:

(i) The aim should be to screen every woman once
in her lifetime between the age of 35 and 40 years.
(ii) If additional resources are available, screening
should be once every 10 years for women aged 35-55
years.
(iii) If additional resources are available, screening
should be once every five years for women aged 35-55
years.
(iv) An ideal or optima! screening schedule would
involve screening once every three years for women
aged 25-60 years.

I*

Screening should not be encouraged at a level
beyond which the diagnostic and therapeutic facilities
become inadequate.
RECOMMENDATIONS FOK RESEARCH

Primary prevention
(1) Research should be directed to clarify the exact
role of human papillomavirus infections in cervical
cancer and to the analysis of the natural history of
these infections and their interactions with host cells
in the development of malignant tumours. The
contribution of other potentially carcinogenic factor's
(e.g., smoking, mutagenic metabolites of bacteria
and protozoa in chronic inflammation, infection by
alphaherpesviruses and exogenous hormones) and
their possible interaction with papillomavirus
infections should be studied.
(2) Once the etiological role of human papil­
lomavirus infections in cervical cancer is confirmed,
research in the development of suitable vaccines for
immunoprevention and immunotherapy should be
pursued with high priority.
(3) The association between sexual behaviour and
cervical cancer in developing countries should be
investigated to ascertain the extent to which multiple
sexual partners and early onset of sexual intercourse
are relevant in these populations.
(4) The protective value of genital hygiene and
barrier methods in contraception deserve further
attention and study.
(5) The present inconclusive data on oral and
injectable contraceptives, intrauterine devices, cir­
cumcision, and nutritional imbalances in modifying
the risk for cervical cancer should also be sub­
stantiated by further investigations.

Early dctcciion

The first five research needs listed below were
identified at a U1CC workshop on screening pro-

!

c-

|

i

• <<

J______ X. •-

grammes held in Lyon in November 1984 (J6) and
were endorsed at the present meeting.
(1) Applied research is needed to develop
appropriate screening strategics for developing
countries where the incidence of cancer of the cervix
remains high and where the resources for disease
prevention may be limited.
„
(2) The natural history of precancerous lesions
should be clarified in developing countries and in
younger women in developed countries; the long­
term effects of screening in women at all ages should
be studied.
(3) Research is needed on the etiology of cervical
cancer to provide useful markers of women at very
high risk.
(4) The long-term effects of different methods of
treatment of precancerous lesions and the optimal use
of colposcopy and local ablation should be inves­
tigated.
(5) Operations research, including economic
aspects and cost-benefit analyses should be con­
ducted, particularly with regard to alternative re­
screening intervals.
(6) Various strategics of organization of screening
at the community and national level should be
studied.
(7) The reasons.why certain women fail to attend
for screening, and why resistance to screening may
exist in certain populations should be identified.
(8) The effectiveness of using air-dried smears
should be investigated.
(9) The role of laser therapy in the treatment of
early lesions should be determined.
(10) The feasibility of down-stage screening, i.e.,
the visual inspection of the cervix by paramedical
personnel in an attempt to find cases in an earlier
stage, should be studied. This approach should only
be contemplated in areas where cytological screening
would not be possible for many years.

LIST OF PARTICIPANTS

J. V Bokhman, Oncogynaecological Department,
Petrov Research Institute of Oncology, Leningrad,
USSR
D. A. Boyes, Cancer Control Agency of British
Columbia, Vancouver, B.C., Canada (ViceChairman)
S. Eckhardt, National Institute of Oncology,
Budapest, Hungary
G. Geirsson, Icelandic Cancer Society, Reykjavik,
Iceland (Co-Rapportcur)

f!'

I

4*'

j. i!:. 'K

.

- x- u- ••

.

It

p fl ’
"PS.

f

i
CONTROL OF CANCER OF THE CERVIX UTERI

A. Kalache, Department of Community Medicine,
London School of Hygiene and Tropical Medicine,
London, England
Z. Kulcar, Institute of Public Health of Croatia,
Zagreb, Yugoslavia
J. Luande, Tanzania Tumour Centre, Dar es Salaam,
United Republic of Tanzania
U. Luthra, Indian Council of Medical Research, New
Delhi, India (Chairman)
A. B. Miller, National Cancer Institute of Canada,
Epidemiology Unit, University of Toronto,
Ontario, Canada’
S. Moss, Institute of Cancer Research, Royal Cancer
Hospital, Sutton, Surrey, England
P. Ngendahayo, Faculty of Medicine, National Uni­
versity of Rwanda. Butare, Rwanda
R,.- Prado, Service for Cytopathology and Control
df Cancer, University of Chile, Santiago, Chile
(Rapporteur)
L. D. Sanghvi, National Cancer Registry, Indian
Council of Medical Research, Tata Memorial
Hospital Annexe, Parel, Bombay, India
J. Sulianti-Saroso, Indonesian Cancer Society,
Jakarta-Puzat, Indonesia
P. Uyanwa, College of Medicine, University of Lagos
Teaching Hospital. Lagos, Nigeria
Wu Ai-ru, Department of Gynaecological Oncology,
Cancer Institute, Chinese Academy of Medical
Sciences, Beijing. People’s Republic of China
* Alio repreirntmi the International Union Against Cancer.

617
t

Jnicrnationa! Agency for Research on Cancer

i

N. Munoz, Unit of Analytical Epidemiology

I

WHO Regional Office for the Americas
H. Restrepo,
Diseases

Regional

Adviser

for

I

Chronic

WHO Regional Office for Europe

L. Dobrossy, Regional Officer for Cancer

WHO Secretariat
G. Antal, Programme of Sexually Transmitted
Diseases, WHO, Geneva, Switzerland
J. Kierski, Maternal and Child Health, WHO,
Geneva, Switzerland
K. Stanley, Cancer Unit, WHO, Geneva,
Switzerland (Secretary)
J. Stjernsward, Cancer Unit, WHO. Geneva,
Switzerland
H. Tamashiro, Microbiology and Immunology,
WHO, Geneva, Switzerland

Observer
M. Bodo, National Institute of Oncology, Budapest,
Hungary-

r£sum£
LUTTE CONTRE LE CANCER DU COL DE L'UTf.RUS

Le carcinomc spino-ccllulairc du col de I'utdrus est la
principale cause de dices par cancer chcz la femme dans les
pays en ddvcloppcinent et une cause importante de mortality
dans les pays d^vcloppes. Ce type de cancer frappe souvent
des femmes rdativement jeunes, contrairemcnt A d'autres
cancers, et mdrile A cc titre un rang dlcvi de priorite.
Dans certains pays dcvcloppes, des programmes de ddpistage cytologique du cancer du col de I'utdus sont en cours
depuis de nombreuses annecs. Une diminution importante
de la mortalitc, de I'ordrc de 50 A 6O°/o, a de observec IA ou
sont executes de vastes programmes bien organises de ddpistage. Ccs bons rdsultats tiennent pour I'cssentiel A i’ablation
des Idsions inira-dpithcliales. qui permet de prdvenir
I'apparition de tumeurs invasive*.
Le carcinomc spino-cellulaire du col de I'utdrus est
4troitcmcnt Ite A un comportemeni sexuel caractArisi par la
prdcociti et de multiples partenaircs. Le comportcment
sexuel du partenaire masculin joue ^galemcnt un rdle. Des
donncesrccenicsprouveni I'cxistence d’une relation de cause

a effci entre ccrtaincs dci lesions qui precedent Ic carcinomc
du col de I'utcrus ci ccrtaincs infections A papillomavirus.
Malgr^ les preuves d’une relation entre le cancer du col
de I'utcrus et Ic comporiemcnt sexuel et les rdsuliats
promciteurs obtenus sur le rdle des infections humaines i
papillomavirus, sculs des programmes d'^ducation ont etc
jusqu'ici rccommandes comine strategic sp^cifique appli­
cable a la prevention piimaire du cancer du col de 1'ut^rus.
Ricn ne prouve que I'histoirc naturcllc du cancer du col de
I'utcrus varie suivant les populations. Aussi, I'etudc des
antecedents naturcls sur laquclle reposent les programmes
de depistnge nyanl fail leurs preuves cst-clle vruiscmblablement applicable dans tous les pays. L'dtcndue des ope­
rations de d^pistage varie sensiblement A I'ichcllc mondiale.
Dans de nombreux pays en developpement, Ic depistage du
cancer du col de I'utlrus est incxistant ou au plus sporadique
alors que dans certains pays devcloppis, il est tres pratiqud.
II est important de notcr que Ic nombre des frottis prdev^s
nc rcflcte pas la proportion de personnes cffectivcment

i. .'■V''

I

/^5

1

4

?

I ■ 1

w

;

TF T JY

7R J

!

EVALUATION REPORT

i
t

ON

FAMILY PLANNING PROGRAMME

f
hi

i
I

J

3

.I1

I

ti

Is

MAY

1986

PROGRAMME EVALUATION ORGANISATION
PLANNING COMMISSION
’ GOVERNMENT OF INDIA
NEW DELHI

I
f

h/

1

• /

;■

.

.•

'

r-

f ■ r.-jwajh

746
20

2.15

The phenomenon of actual deployment of staff

falling short of the sanctioned strength, particularly at
the district and PHO levels, indicated that the degree of
I

organ is at ional coordination reoained below the optimum and
planned levels•

The sizeable number of posts in all cate-

gories lying vacant at the district level were a drag on
the full-scale implementation of the programme, as either
SOlilC

portion of the work to be looked after by the incumbents

of these posts accumulated or, as in the case of field staff,
(

the areas to be covered by them remained inadequately attended

or unattended.

Similarly< the vacancies in the middle rind

lower categories of posts at the PHC level*, such as those of

the Lady Health Visitor and Auxiliary Nurse-Mid-Wife, meant
that the services which would have been provided, if the
incumbents were in position, were in fact not made available.

Appropriate action to remove this deficiency is, therefore,
called for by the States concerned.

Reasons fob Posts Remaining Vacant
(

2.16

The- main reason for the posts remaining vacant at

different levels was stated to be administrative delay. The
process of reenuitment (it was reported) was usually slow and tint

consuming. In some cases, the posts were held in abeyance or a

Contd,..21 /-

>

^/7

-:-21 Iban was imposed on filling up the vacant posts as an economy
measure

In other cases, the posts remained vacant due to

the non-availability of suitable candidates, i.e*, candidates
fulfilling the required qualifications.

2.17

In as much as the successful implementation of a

crucial programme of national importance, like Family Welfare

programme, rests to a large extent on the full complement of
staff being in position at all levels, it is imperative that

ways and means should be found to cut down admin .is trative
delays in the filling up of the posts<

2.1M
i

i

The adequacy of the existing staff structure for the

implcincntation of the programme was discussed with the concerned

officials at the State/Pistrict and FHC levels.

In nine out of

the 16 selected States (Andhrapradesh, Haryana, Himachal Pradesh,

Karnataka, Kerala, Punjab, Rajasthan, Uttar Pradesh and West
Bengal), the view was expressed that the existing family planning

c

staff at •different

levels,
levels, particularly at the district and

lower levels, was inadequate.

time
i

The concerned officials emphasised
dis trie t/HIC
the need for strengthening the staff at the. / levels keeping
in view the size of the population to be serviced and the
communication facilities available♦

Therefore, keeping in view

the magnitude of the population to be serviced and the terrain

end communication facilities available, the State Governments
.;?iould review the strength of the staff required for the purpose
it

ifier^-nt levels of the operation of the programme and

Contd...22/-

22
accordingly take steps to strengthen it.

alone In, however, not adequate.

Creation of posts

Available posts, new or on

transfer, should be filled/expeditiously.

The district and

junior level posts, being operational level posts, should be

filled up with a sense of urgency.

It should be the endeavour

to fill up the posts falling vacant within an outer limit of
three months.
.Z^ajjiing of Faaily Planning Staff

The training of the staff in the basic

2,19

technical and administrative aspects of a programme has a key
importance for the successful implementation of any social

development programme•

This is particularly so for a programme

like Family planning, having medical socio-psychological and

cultural implications.

The family planning staff should,

therefore, have proper and adequate training so as to enable

them to project the programme effectively and also to cater

to the needs and requirements of eligible couples having d if fere:
socio-cultural background as well as psychological attitudes/

Keeping thia aspect in view, information was collected on the

orientation and inservice .training undergone by the family

planning stuff in. position at various levels at the time of the
study.
2.20

State Level;

At the State level, as on 31st-March, 198?,

information regarding special training in family welfare, If

•my, undergone by the technical staff was available irr respect
Contd...23/-

t

T

/Q9
66
5'.O6-

Out-of 4^7 ncn-adopters■ reporting subsequent

contactCs) by.official agemdies,;%.8 per cent reported

d

’contact by only one category of staff» 28.6 per cent

y

33

two; and 54-6 per cent by three (or more) categories of

staff.

Appendix table 5.2 gives the distribution of

d

these non-adopters by the category of staff who contacted

them.

It would be observed there-from that out of 437

nonxvdoptere.who reported having been contaoted subsequent
en/' les.

of the

toMThe

• to the first contact, 38.2 per cent reported having been
contacted by auxiliary nurse-mid-wife, 30.9

cent by

other family planning staff, 21.3 per cent by motivators,
21.2 per cent by Village Health Guide, 18.3 per cent by
nt to

Lady Health Visitor/public Health Nurse, 15.6 per cent by

’adopters’,11.2 per cent by Extension Educators and the
I

riots

' rest by others, such as

friends, doctors, relatives,

community leaders, block staff, etc.

Those contacted by

voluntary agencies comprised only 0.2 per cent of the total
(79.4)

number of non-adopters.

Voluntary agencies, thus, played

practically no role whatsoever in propagating family planning.
' (^'6)
Awareness of pamily planning Methods
(1C0.0)

.66/-

*

5.07

Between. 79 and 8? per cent of adopters as well

as nonr-adoptera aaid that they were aware of more than one
The position in. this regard between
family planning method •
districts was found to be
progressive and non-progre salve
dissemination of information.
similar. Thia indicates that the
Contd.. <67/*“

-H-Wiiwfc*,.

F

150

I
I
i

6?
about family planning was being directed to all people
under the programme.

This aJjso shows that the non—

' adoption of family planning methods was not for want of
knowledge 'about these on the part of non-adopters but

because of other reasons.

With a view to ascertaining the level of

5.08

knowledge as to different family planning methods,
eligible couples were asked to name the different methods

known to them.

Appendix table 5.5 gives the distribution

of all sample adopters and non-adopters, for all the

selected districts/States taken together, according to

their knowledge of these methods.
5,09

It would be seen from Appendix table 5.5 that

. tubectomy .was known to the largest number of the selected

respondents, viz;., 80.1 per cent of the adopters and
67.7 per-cent of nonr-adopters.

Vasectomy was known to

between. 52 .‘and 55 per cent of adopters as well, as non.adopters.

However, the number ox
of wose
those knowing about the

other major family planning methods_was much higher in the.
case

of adopters than, among non-adopters.

Thus, whereas

44.7 per cent, of,-adopters knew about, IIID/Copper-T, only
27,9 per cent of, non:-adopters knew of it.

i
!

Similarlyt

whereas 40.5 per cent and 15.0 per cent of adopters knew

of condoms and oral pills respectively, only 25.0 per cent

and J.O per cent of non-adopters knew aboait these methods.
Contd. • .68/-

l

/5/
.68.

pie

is for other methode, via., foam table ts, Jelly /cream
tubes, MTP (Medical Termination of preenancy), rhythm

t of

(safe period method), wlthdrawl, abstinence, etc, only

u.t

a fraction of both adopters and non-adopters knew about

these methods.

As regards the knowledge about terminal

(viz., tubectomy

and vasectomy) and non-terminal (viz.,

IUD/C opper-T, condom

, oral pills, foam tablets, cream and

in evidence in case

e -xods

diaphram, etc.) methods, this was more

but.’

of adopters than among the non-adopters.
of adopters reporting knowledge

to

of different family

marked variation as

planning methods did not show any
districts.
between progressive and non-progressive
the ir

that

for non-adopters, the extent of/knowlodge

Lected

family planning methods

1

that of adopters in progressive
to

>1

in the

jreas
nly
t

knew
r cent
thods#

r

-

Aa

of different
to

vas in general comparable
ae well as non-progressive

districts •
5.10

■t the
< _ 1

The percentage

It ia evident from the foregoing

account that

methods among
the knowledge of different family planning
mainly confined to
adopters as well non-adopters was
tubectomy and vasectomy followed by

terminal methods of
, .and condoms, in­
the non- terminal methods of IUP/Copper-T
to reflect
This
could
be
taken
that order of importance.

on these methods in the

the relative degree of emphasis
pt is surprising that the
operation of the programme.
cent of adopters and
rhythm method was known to only 1.2 p&r
Contd...69/~

. - •

A-

I

IS

69

0.2 per cent of non-adopters.
i

Likewise, MTP was known

to 0.4 per cent of adopters and 0.2 per cent of non-

l

This points to a rather lop-sided approach

(adopters.

.in'the matter of propagation of different family planning

methods.

The heavy and practically exclusive emphasis

■ori;terminal methods of tubectomy and vasectomy also sheds
t

some light on .a pertinent point as to why there is such a

1

large percentage of hon-adopters despite the family

planning programme having been in operation for over three
decades now.

Obviously, if a large enough percentage, of

©li&^ble coupled did not want to 'terminate* their option !
rto have children later on and were not well-informed
regarding the other non-terminal methods available,

f

especially like the MTP method, they remained non-adopters f

due to the sheer lack of knowledge as to the availability 1
of methods which could be suitable and acceptable for them,
(

5.11

The above suggests that it should be the endeavour

of the agencies/functionaries concerned with the family
planning programme to inform the eligible couples on all

methods of family planning, clearly differentiating between

the ‘terminal* end ‘non-terminal* options available to then,
instead of putting all out emphasis (in terms of persuasion

and incentives) on terminal methods simply because these
happen to be certain and irrevocable.

If it is known to tt-

eligible couples that,there - are methods of family planning
Contde..70/-

I/

5 DAP/AS Ci PHO. Ji-C r

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B

■

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■■■'

PROBLEMS GF FiELD WORKERS: STUDY OF

‘i
--

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£

.'

■■

■

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i

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.

.

fGHT PRIMARY HEALTH CENTRES IN FOUR STATES
•

.

-

•

■■■

'

y

■

'

■

■

•

it
|

#
|

T

i

I

G. NARAYANA

J. ACHARYA

s
I

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t

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«

i
CENTRE FOR HEALTH AND POPULATION STUDIES

I

ADMINISTRATIVE

STAFF COLLEGE OF INDIA
H Y D E R AB A.D - 500 4 75

BELLA VISTA,

•'

.

'V! ..Jy

..■.A*

' ‘

C

I-

I
:62:
/

i

here, like the female workers, their supervisors also place
emphasis on certain job duties*

Ono of the most important

B
f

area from the point of view of supervisors is the number of

r

Family Planning cases motivated by each worker, closely followed

by HCH and immunization activities#

r

Least importance is -

I

given to the maintenance of records, treatment of minor ailments,

registration of vital statistics and other activities#

However

the emphasis of one supervisor differs from the other#

While one

i

i

supervisor stresses family planningj the other supervisor may be

<
interested in immunization programme or PICH activities#

Similarly

there may bo significant differences in the instructions given in
regard £o record keeping»

While the Medical Officer gives one

proforma to uset the BHE may ask the workers not to use#

In some

cases differences are also noticed in the instructions given by

‘i

l

the PHC Medical Officer and the District Medical Officer#

I

WORKLOAD ASSESSMENT
I

This means that tfce female workers are given more work

than they can possibly do.

It is therefore necessary to assess

the work load of the female workers#
I

i

One way of doing it is

to take all the job duties and ask the female workers to inform
us

of the time spent on each activity.

The information we got

on these aspects was la^er found to be less comprehensive and
i

reliable#

.•

Hence we have here tried to first calculate the

total time available per year#

Out of the 365 days available in a year,,*
I

48

and 12 days respectively are Sundays and second Saturdays

ir w

Y

V TUSMT ’

¥

T

/55
:63:

r

There are as many as 14 Gazetted

which are general holidays.

holidays.

We have considered the average figure.

owed
%

4

I

This loaves 291 days in a year available

Out of the total 291 days available, some days are

■

ne
1
i iy bt^

utilised by workers as casual leave, earned leave, maternity
■

leave and medical leave.

(
lilarly

/en in
Dne

3
i some

II
I

Number of days of casual leave each

worker can ’avail in a year depends on the state.
the cases, it is 14 days.

casual leave or not.

In most of

However the workers may avail the

Wo havo taken the actual number of days

availed as casual leave by each worker in each PHC and the

j

1 n by

averages are calculated for each state.

In Rajasthan and

West Bengal, each worker on an average availed 12 days

,e

I

casual leave to 6 days in AP.

The average figure for all

the four states is 10 days.

iC

£

days are holidays.

A total number of 74

for female workers to perform their duties.

Tents,

:ver

However the figure varies from state to state.

e wr$

Unlike the casual leave which cannot be accumulated

lLl sess

and encashed if not utilised, the earnod leave can be

s

h form

encashed.

I

got

30 days of earned leave in a year.

nd

to be accumulating earned leave to cither avail or encash

I

Each worker may avail according to leave rules

it at a later date.
de in a yoarJ

Most of the workers seem

Number of days availed as earned

leave by each worker varies to a great extent.

»ys

91
-JSW XT

As we

■

■

:64:

calculated the casual leave , we havo also taken into account
the number of days of earned leave utilised by each worker,

averages are calculated for each state.
the actual position is not available

maintained properly.

Then

V

In case of West Bengal,

since the records are not

In such cases we have taken the actual

number of days each worker can avail as earned leave.

in soma cases the recorded number of

However,

days utilised as earned

leave does not reflect the actual number of days.

In quite a

j

few cases > it is noticed that the workers
go on leave even

without Informing or getting sanction from the appropriate
authorities.

possibilities.
centrate

This is done mainly because of encashment
But there is

no alternative except to con-

on the official figure recorded at PHC.

However it is

necessary to koop in mind that this figure is lower than
the actual figure.

The Gained leave availed by workers

differs from state to state.

It is as high as 20 days in

Andhra Pradosh, closely followed by Rajasthan with

Uttar Pradosh with 15 days.

15 days and

The average figure for all the

states is 18 days*

i

Besides earnod and casual leave, the female workers

1

can also avail maternity leave, medical leave, leave with
half pay and leave without pay.

Wo included all those four

kinds of leave into one general category

’other leave’.

7

T
d
w

ec

ar

th
to
nui

7

a

:65:

1
Average

Again the figures for West Bengal are not available.

:ount

number of ’other leave’ used by the female workers is 7 days
Then

cor.

in Andhra Pradesh, 4 days each in Rajasthan and West Bengal.
; Bengal, ■

’

The average figures for all the four states is 4 days.

ire not
TABLE: 1

;tual

lowever,

Figures showing Average number of working days per Female Workers

i ri»—I

Andhra
Pradesh

Rajasthan

UP

W.Bengal

Average

Second Saturdays

60

60

60

60

60

Gazetted Holidays

10

15

16

14

14

Casual Leave

6

12

10

12

10

□n-

Earned Leave

20

18

15

30

18

rar it is

Other Leave

7

4

4

103

109

105

116

106

Total No. of days
in a year

365

365

365

365

365

Total number of
days available for
work

262

256

260

253

259

yen

Sundays/

ate

;n
(

in

4

i

.‘ays

u

the
-i

i3

The combined figure of general holidays (sunday and

3 workers
i

second Saturdays),

Gazetted holidays, oarnod leave, casual leave

th

and other leavo gives us an idea bout the non-working days.

four

this total figure of non—working days is subtracted from the

If

total number of days available in a ynoi?, wo got the figure of total

number of working days (ae shown in table 2).

The number of

/STS

j-

:66:

working days (as shown in table 2). The number of total working
ays differs from state to state marginally. The average figure
for the state of Andhra Pradesh is 262 days, Uttar Pradesh 260
days, Rajasthan 256 days, and West Bengal 253 days. For all the
four states, the average figures is 259 working days.
i

j

i

r

9
j

L
h
o

r.
id

iy

Lr
2

iJ

One of the main duties of the female worker is to
regularly and periodically visit all the households in the
villages in a sub-centre area for the purposes of extension
education, motivation and service delivery activities. The
c her functions like record keeping and preparation of reports
is done at home after coming back from the field visits.
In
fact, she prepares a tour programme once in a month, to cover
at least each village once in a fortnight.
However, the tour
programme to villages-is interrupted by a series of other
specific activities like visits of high officials, subcentre
= ^1nS’ cond^tion °f deliveries, PHC monthly conferences and
cpompanying the sterilisation acceptors.
Here we have
calculated the number of days she actually spends on all
the atfove mentioned activities, leaving tho rest of days
actually available for house visits.

• ,Thefe Qre I'fcJ9ular visits to subcentres by ths high
officials from ths centre, state and district levels.
lm°st all the female workers said that high officials visit
them but the frequency of visits vary.
In case of nearly
one fifth of subcentres the visits are almost twice a
month. The visits of high officials are once in a month
in case of 37.9 per cent subcentres.
Other female workers
informed that their subcentres'are rarely visited. The
frequency of visits depends bn several factors.
One of the
more important reason is the accessability of the subcentres.
Subcentres located on the National Highways or main roads
are more visited by the officials. The other reason may the
better performance of the subcentres compared to other
units in thp PHC.
Actually in each PHO there are some
S^7Cen^res uhich are used as showpieces for the visiting
officials.
All these reasons lead to the differences
in visits made by the officials to subcentres.
Wo have
calculated the average figures which comes to almost
one visit by an official every month. This means 12 visits
by officials in a year to the subcentres.

i

:6?:
i

j or king
figure
i 260
all the

,e
.on
he

•ports
In
jet

rour

r
ntre^
os and

subcontros do not
to tho
officials
All tho visits of
Only siigh^y
programmes.
of tour
result in the cancellation
programmes
their tour
cancel
half of the field workers
more than
accompany tho
visits of officials. They
to accommodato the
field workers
Since half of the
this tour.
officials during
.
o^ncellations arc
actual number cancexxu
their programmes, tho
cancel
In this case it comes
the offic^3^3*
total visits by
half of tho
of calculations.
the purpose
for
up to 6 days in a year

Ono

the

of tho areas

which regularly

attending
official tour programme is

delivery cases by

There are two main ways
tho field workers#

of cancollation of tour

U-

in tho registers

ors

deliveries

conducted by each

fomalo worker.

Tho other method

fiald worker herself•
from
the
elicit information ‘
i3 to directly
the actual
and calculated
methods
0e have tried both tho
programmes.
cancellation of tour

the
res.
ids

1?y

number of

J^ing

i'53
Each

field worker

isits

average conducts 29

i. ‘

extremely l°w

ic

4

programmes*

figures givon
the actual
basiQ
on
the
One is to procood
of
in regard to tho number
at
PHO
maintained

I

)

of calculating to

know the actual number

/is it
,‘ly

intervenes with

in all theso four states

deliveries in a

compared to the

gubcontre area.

total number of

on an

This is

deliveries

d iffcrooces in
also substantial
There
are
in a given area.
conducted from
Df dolivorios
number
regard to tho average

t

I

I

:68:

state to state*

conducts 48 deliveries in a

One female worker

year in Andhra Pradesh, 31 deliveries
deliveries in Rajasthan and around 16

conducted durinQ the day time.

of the 29 deliveries are

More than half of the female

workers cancel their tour programme

during the day timo.

So the

deliveries in West Bengal.

half of these deliveries aro

All the fiold workers agree that

during day time which means 15

in Uttar Pradesh, 20

to attend the deliveries

total number of cancellation

of tour programmes comes to 7 days in a year.

Tho female workers on the

spend significant number of days

i

during the day timo.

c

attending delivery

i s

total interviewed spend

Ono fourth of tho

of them more than 4 days*

The average number of days spend

I

by each female worker is 3 —
for 42 days in a year.

(
tour programme

5 days a month which accounts

Note than half

of them cancel their
!

frequently to attend the delivery cases.

4 3

*?

the number of cancellations in this may

jf >•

c

)

year*

Thoro are some major

I J

So

come upto 21 days in a

difficulties in accepting either

of these above two cancellations.

K

' cases

fourth upto 3 days and the rest
upto 2 days a month, another one

i

i •

other inform that they

Tho first one based on

aoebndary material i.e., rocorde and roports informs us of the

id
j

official figure only.

<

9

Sometimes the dolivery cases conductod

by the female workers are not rocordod.

In a few cases, tho

r

:69:

dullvory cases conducted by the local dais are included in the

ries in a

It also happens that the female

list of the female workers.

h, 20

workers if busy in other activities neglect the MCH areas*

est Bengal*

However it is important to note that the female workers who

rios aro

attend either early morning or day time cases, do not usually

re

go to field on that day unless the tour programme coincides

female

with the place from which request for attending delivery case

ivories

comes*
;ii.

This is not a frequent happening*

the second figure of 21 days in a year into account for the

<

purposes of further calculations*

Hany of the female workers

are reluctant to give the information on whether they cancel

they

their tour programmes or not.

cases

This may bo a result of the

fact that there are no clear instructions on what should the female

wed spend

workers do if the delivery case is during the day time.

d the rest

Should

they cancel the tour programme and attend the delivery cases?

spend

Should they attend the delivery cases and also visit the field

jnts

according to the schedule?

:he5

• n.

Hence wo have taken

It is evident that most of the

female workers do not perform any other job duties when they
-

have to attend a delivery case.

ays in a

This shows general interest

of the female workers in attending delivery cases which are

jithcr

i

both remunerative and satisfying than other job duties*

on

; of tho
Besides motivating tho family planning cases all

ducted

9 the

I

workers accompany the motivated cases to the PHC or Taluk
hospital wherovor tho facilities are available for sterilisation

/Z2
:70:
filling the pruscr?-.'
the C3S0
only
register
asked almt's: *
operations. They not
operation. vihon
for
the ease
£
but also prepare
forms
accompany tba family
informed that they
all the female workers
The amount of ti1^
time with them.
i
and
spend
planning accept or
depends on several factors like
case
and
field workers spends por
of cases motivated
to PHO, number
of proximity
f emale
the dogr00
believed by the
It
is
often
iroments.
other general requ
accGptors, more
tiTO they spend with the
-•
that
more
workers
This adds to
to tho
tho reputation
will
bo.
satisfiod tho village^3
|b
facHitatos in goi^ ib9
times
I’field worker and some
workers spend
of the
of the female
three fourths
Nearly
• more cases.
fourth of uorkots jy
the other one
average whils
each on an
a day Per
of days each female

B'

I

(/

I

spend two or

more days.

worker spends in a year

The average

number

doponds on tho number

of cases she

motivates.
of cases
in the number

if

motivated

I

variations
There are
mot ivatos on an
each
worker
IfIn Andhra Pradesh
Pradesh
the workers.
in
Uttar
by
in Rajasthan -|0 cases,
a
year,
for all
average -15 cases
The average figure
Bengal 7 cases.
5 cases and in West
Each worker spends
|
por
year.
is
10
cases
thoso four states
noarly 10 days are
which
moans
ono day per case
sterilisation casos.
on an average
the
and
preparing
accompanying
spent on

I

B

I
II

:71:

Tho Hcdical Officers of PHC are supposed to conduct

jru scribed

r

r.

1 almost
imily

hardly followed in practice.

However this rule is

Out of 48 sub-centre clinics each

(nodical officer is supposed to conduct only 30 are conducted.

r time each

This is duo to various factors like nonavailability of tho

Like

medical officers, field workers or drugs during those particular

and
fe-

clinics once in a week in every sub-contro.

days.

■

le

The field worker during tho clinics days prepares the

clinic and stays with tho medical officer till he completes

3
■

■

examination of all outpatients.

t ion

£
4

ac nd

So nearly 30 days are spent

on the subcontre clinics in a yoar.

Besides these above reasons

for cancellations of tour programmes, the field workers are
supposed to attend the PHC monthly conferences in the first

f workers

wook of every month, which moans thoy spend 12 days in a yoar.

female
e

1

TABLE No.3
TABLE SHOWING THE NUMBER DAYS OF CANCELLATION OF TOUR PROGRAIWES

5.No.

Item

VIP -visits

Pradesh

1.
2.

or all

3.
4.
5.

tiw-ccd

Periodicity
(per yoar)

No. of days
lost

on a^«

Delivery cases
Family Planning cases
Subcontre clinics
PHC monthly conferoncos

12 visits
42 times
10 cases
30 clinics
12 conferences

6 days
21 days
10 dgys
30 days
12 days

ids

aro
os.

J

Total days

79 days

Total working days
available

259 days

Total days now
available

180 days

’W w w.

16^

'1

I

:72 s

■

With 6.days per yoar oach field worker spending on

■

1

VIP visits, 21 days for delivories, 10 days for family planning

cases, 30 days for subcentre clinics □nd 12 days for PHC monthly

conferences - altogether 79 days in a year.
days that remain for field work.

Thoro arc only 180

It is this time that the

field worker can effectively use for visiting all tho households
in villages periodically.

However it is important to know how

much time each field worker can effectively spend pur
household to perform her other job duties,

Tho analysis below

indibates the time available for each field worker por day,

tho number of households in oach subcentre and the time
effectively available per household.

Tho actual starting time from homo to go to the
I

villages differs from one field worker to another.

Slightly

moro than one third of tho fonjale workers begin thoip working

?•

day at about seven in the morning.

More than half of tho

workers start from eight in tho morning while a
/I

eight.

remaining few after ‘

The time at which each worker starts from home depends

on tho distance one has to travel and modo of transport
available.

f

Somotimes seasonal variations also play a role.

However, the average time one starts from home is
in the morning.

I

around oight

i■

!b 5
:73:

Similarly the time, they return back home also

varies.

ing on

While ono fourth of the workers reach back before two

in the afternoon, another one fourth return at three in the

Planning

evening.

3 monthly

The-rest of field workers reach home after throe.

The averago time of reaching back homo for the field workers

□nly 180

is around 3.30 hours in the evening.

:hc
Duscholds

Considerable amount of time is also spent by the
1OW

field workers to go to villages from home and to reach back.
In most of the cases the public transport system is not

5 below
S’

Jay,

available and the field workers go to tho villages varies

to go to tho villages by walk.

I
g.
io

The distance from subcentra

to the villages varies to a great extent.

tho casos tho distance is below 5 kilometres and in another
one third cases, more than 5 kilometres.

jhtly

In two thirds of

Tho time t^kon to

cover the distance also differs from ono field worker to another.

jrking

While 70.7 por cent of total interviewed taken pearly one

ic

hour, the rest of them more than two hours*

iig few after

taken is one hour 40 minutes to cover tho distance oneway.

lupe nds

Jo.
eight

I

The average time

/6b
:74«
♦

TABLE NO.4

TABLE SHCWING THE AVERAGE TIME AVAILABLE FOR THE FIELD WORKER

PER DAY

1.

Average starting time

0800 hours

2»

Average time takon to roach the village

1 hour 40 minute-

3.

Avorago time taken to roach home

1 hour 40 minute*

4.

Average time reaching home

3.30 p.m

5<

Total time available

7! nuurs
hours au
30 minuta
minutu ;,

6*

Total time takon for travel

7.

Time available to visit families

i

t

3 hours 20 minute ?
4 hours 10 minute '

c

Now it is possible to calculate the total average

n

timo available with each field worker to spend her timo per­

forming her duties in tho villages (as shown in tablo No.4).

£

3

The avorago starting time is 8.00 clock in the morning and tho
1

avorago timo reaching homo is 3.30 hours in the evening.
( h

total timo available is 7 hours 30

minutes in a day.

3

J
i

Tho

Howovcr

the average time taken for travel to roach the village is ono

hour 40 minutes.
back homo.

Tho samo amount of time is takon to travel

Therefore tho total time takon for travel both ways

i

is throe hours 20 minutes.
>0

If wo subtract the total travel

timo from the total timo available in a day, wo got the timo

each field worker effectively spends in the field.
it is 4 hours 10 minutos por day.

I

In this

i

r

/c 7
:75:
t

total
of
calculating
tho/timc
Thorc is one more way
_D WORKER

available for each field worker.

We have made an attempt in

selected subcentros to reach tho villages of the field workers

according to their tour programme.

hours

4 0 minut.f

it

All necessary precaution

is taken not to reveal this information to tho field workers.

jr 4 0 minuUi

In most of tho cases the field workers reached the villaQ0

n m

at

min/ 11;

irs

10 in the morning and left tho place at about 12.3 0 in the

afternoon.

According to this, they

rs 20 minutiil

hours in

each village which is far

rs 1 0 minute

earlier.

However, this

all the villages
it to say
average

only spend two and half
below tho figure calculated

counter checking cannot bo done in

due to lack of time and resources.

Suffice

here that the average time of 4 hours 10 minutes

the most optimistic figure.
per day calculated earlier is

mo por-

No.4).

With 100 days available in a year for field work and

3 and tho
on each day 250 minutos to

The
Ho’
\

/or

.i is one

I travel

j both ways

tlmo available is 45,000 minutos of 750 hours per year.

Given this figure it is necessary to see how much time
they can effectively spend per family in a year.

Bubccntro and the average number of families in each subcontro
(see table No.5).

time

this

for this,

wo have calculated the average population size each PHC and

ravel
q

contact the villagers, tho total

I

/6&
:76:

TABLE No.5

TABLE SHOWING AVERAGE NUMBER OF FAMILIES IN EACH SUBCENTRE

Ci

No. of
subcentres

No. cf K
familL*

Subcontros
Population

S.No.

State

PHC
Population

1.

AP

1,35,645

15

9,043

2fO1Cf

2.

UP

1,11,368

9

12,374

2,71: |

3.

to.Bongal

1,33,529

8

16,691

3,7S E

10

9,234

i
2,05^

Rajasthan

4>

92,336

i

■in

■

<

T otal

4,73,198

42

47,343

10,521 r

Average

1,18,299

10.0

11,829

2,62::

L

There are variations in the population size of average I

PHC in all the four selected states.

Tha average size of Andhra

PHC is 1,35,645 persons of Uttar Pradesh, 1,11,368 of West Bengal

1,33,529 and of Rajasthan 92,336 persons.
population, the average number

the

Irrespective

J

of the subcontros also differ

with a maximum of 15 subcontras in Andhra Pradesh and of 8 in

i

i

West Bengal.

As a result the average size of the subcentro

differs from ^.stato.Wo have calculated the number of families

tt.

in each subcentro taking the average family size :as 4.5 persons,
t

*

For all the four states the average subcentro population is

11,829 persons with 2,628 average number of families.

To

calculate the average time each field worker can offactively

k$

I
;r'’

WIRE

:77:

opond over family, wo divided the total timo available by total

numbor of families in each subcentre.

-res
:ion

No. of
famillK

Total time available per year

Time available per family =
2,010

Total number of families in each
sub centre

2,750
180 days x 4 hrs x 10 min

3,709

Total Average time available °- ^>628 families
per family per year

2,052

= 20.9
minutes
per
family

According to the above calculations the average time

( >0,521

each field worker can effectively spond per family in a given
2,620

area is 21 minutes per year»

These calculations do not take

into account the amount of each field worker takes to walk from
one house to another.
Jf average

It also excludes some of the possible

calculations of tour programmes particularly during the family

>f Andhra

planning camps, film shows and family planning exhibitions etc.

st bongal

If we take the timo observed on the basis of our field visits
•of the

without informing the field worker, each worker has only less

ffr

than 10 minutes to spend with each family per year in a sub0 1

centre*

All those calculations show how impossiblo it is for

:ro

the field worker to communicate, motivato and promote various

ilies
health and family planning aspects in the villages.
jersons.

It is also

totally unrealistic to expect thQ field workers to visit all the

8

is
villages, to maintain contact with all house holds and to
perform all job functions.

oly

Even if the aroa of operation is

drastically reduced, the amount of time available for the field

worker is not going to make much of a difference.

■a
-—7
■'

T-T?
...................................................

’

L

i
I.

-■
■'

■ ■

■

■s

- •-'

/7O

X 9 '

■

WORLD HEALTH
ORGANIZATION
! SPECIAL PROGRAMME
OF RESEARCH
DEVELOPMENT
‘ AND RESEARCH
TRAINING IN HUMAN
REPRODUCTION
r
. ;’if i--:

•:?..r'<5S‘ '?• -

a.-.ftAy •

■ ''W
i-V; : m. -''

(

I

:

?

12" Annual Report 1983
■
-:....

VC
_

......................................

■

I

I

! J . I 'v
....

.............

I

1 7/

Twelfth Annual Report

findings"!? thfs ^udTwfo hCCTd \neW family pIanninS ,aw’ bascd on the
g
this study, which will authorize non-physicians to insert nine

duStaof’h'014' °f \5 rS°"sF^7eX?ned

May° 98? Tte

duration of he practical period was extended one week to include the teach nJ

for Scoure' wil

primed' r'<,"eS' °r"’e M,”iSt'7 °f Hea"h' The

Integration of family planning with health services
bee?rmad1c

at both administrative and

asmatLai altd

family planning more acceptable but facilitate its provisionIncreasingv
I

I

address tins issue m India, Kenya, Peru, the Republic of Korea and SriTanka
I
H

Kenya

ii
i

<

f
il
c

(

,inT,1C Atudy !n KcnVa is showing clearly the result of making services more
IX mnnH
COnvcnicnt t,lrough an integrated MCH/FP programme. After
nths ot operation of the four rural clinics about 21% of all eligible
women m the study area were current contraceptive users This” well above
he national average of 5%-7% of eligible women, which was also the rite
averagin^TO^ for anrOJe?l ‘T'1’ ?°ntinuatl0n
were remarkably high.
Over half of all elfoih meth°ds’ and duJing the last 12-month period 76%.
•be injectable XS^dTd^^TtheluD.S'
36%rCf°SC

under fire yeareCofda»eICd th ‘'“'d "‘"“''l“rvi“s- Nearl>'
c

r
r
i;
!•

22

children

A

Research and development

the
IDs.
with
cm-

a total of 15,800 visits to clinics during the first 18 months of operation, with
an average of 3.8 visits per child. Antenatal care was the second most important
activity. During the first 18 months 1075 expectant mothers received antenatal
care in a total of 3,889 visits (an average of 3.6 per woman). During the last
six-month reporting period there was an average of 63 first visits for antenatal
care each month and about 184 revisits per month. These figures, as those for
other services, reflect a general increase in use of services as the year proceeded.

ling
two
jdy,
irch

>ups
nng( (
lual

India

and^
uch
ake
giy>
not
are
g is
•doion,
im*'
ika.

orc
tier
blc
ove
ate
gh,
.%.
osc
nic
ren
igh
ide

The first phase of the project is due to end in February 1984. A second phase
is presently being planned, during which all project activities will be trans­
ferred to two Ministry of Health clinics in an area about twice that of the
original study area. Project activities in the second phase will be integrated
with the other services of the Ministry of Health clinics and carried out
jointly by project staff and Ministry personnel at the outset. Over a period
of two years full responsibility for maintaining the MCH/FP services at the
same level of efficiency as achieved by the project will be shifted to the Ministry
clinics.

(

The Indian family planning programme has been in operation for more
than three decades, yet the general level of family planning acceptance remains
low. Moreover, there are large variations in family planning use, both within
and between states. This study was undertaken by the Indian Council of
Medical Research in collaboration with the Operations Research Group
and the Population Research Centre, Baroda, to identify problems and
deficiencies in the existing MCH and family planning services and to measure
their impact on family planning acceptance; to ascertain service factors which
contribute to differentials in family planning acceptance and continuation;
and to formulate intervention strategies which would improve family planning
services and increase their use. The study was carried out in the states of
Gujarat, Rajasthan and Uttar Pradesh. Gujarat is a relatively high acceptance
state while family planning acceptance is low in the other two.

Interesting results have emerged from the first, diagnostic phase of the study.
Originally, the Primary Health Centres (PHCs) concentrated on the control
of communicable diseases. MCH and family planning were subsequently
integrated as essential components of the programme, and the survey sought
to assess the impact of integration as seen through the eyes of the health
workers, and also in terms of actual performance. There was variation in the
proportion of workers (51% in Gujarat, 78% in Uttar Prasdeh and 93% in
Rajasthan) who said that integration had benefitted both the MCH and
family planning activities. They felt it did so mainly by improving rapport
with patients and clients and increasing their confidence in the health per­
sonnel. Those who did not think that integration had been beneficial-objected

23

/ 73

Twelfth Annual Report

to the perceived greater workload and felt a need for additional traininc
to cope with the variety of responsibilities. They also said that integration
had adversely affected the malaria and nutrition activities.

k7

The study has shown severe under-utilization of government services.
Service providers ascribed this to sporadic and inadequate supply of medicines
and contraceptives, the distances that patients and clients had to travel to
the PHCs and the populations illiteracy, lack of knowlcdec ol services avail­
able and their adherence to traditional practices and‘beliefs. Additional
training of extension workers was needed to improve education and motiv­
ation. The survey of married men and women confirmed the lack of know­
ledge of services available and showed that distances to PUCs were con­
sidered great enough to make them effectively inaccessible. Governmental
services were thought to be less adequate than’those offered by private and
non-governmental facilities. Users complained, among other things, about the
unavailability of medicines and proper treatment at government clinics and
singled out the behaviour and attitude of PHC staff, lengthy waiting periods
and the non-availability of physicians as reasons for not using the PHCs.

Little use was made of ante-natal services and the great majority of deliveries
took place at home. In Gujarat some 62% of the children under five years
ol age received BCG, and about 38% received al least one polio dose and
DP f injection, but almost none were given the boosters. In Rajasthan and
Uttar Pradesh, levels of primary immunization were much lower. In Rajasthan.
12% received BCG and the first polio doses, but only 2% got the first DPI ;
in Uttar Pradesh, an average of 20% received each of the three, and -1%
were given boosters.

<

Not only did integration not make for very effective MCI I care, it did not
seem particularly to promote family planning practice. Less than half of the
eligible couples in the three states used any method of contraception. Users
of all methods constituted 43% of the couples in Gujarat. 33% in Rajasthan
and 28% in Uttar Pradesh. Sterilization was the most widely used method,
with male and female sterilization accounting for 88"<>, 81% and 55% of all
family planning methods in the three states. Between 23% and 46";, of IUD
and sterilization acceptors had problems after insertion or the operation,
and-PHC staff follow-up was said to be not very satisfactory. In the case
of sterilizations, only about 10% of the clients in Gujarat and Rajasthan
were satisfied with the follow-up; two-thirds were satisfied in Uttar Pradesh.
Great variation was shown in knowledge of the different kinds of services
available at government hospitals and PHCs.

On the basis of the information collected, a second phase has been desiimed
to test the impact of two intervention strategies. One will consist of training
service providers to increase their ability to educate and motivate community
leaders and the population. The second intervention will attempt to over­
come the problem ol distance by expanding outreach activities through the

24

/74

Research and development

ling
lion

use of mobile teams that will visit designated sites at regular intervals. The
interventions will be evaluated after a two year period, whereupon recommen­
dations will be made to the Government for the reorganization of rural health
and family planning services.

ces.
ines
I to
zailmal
>tivow-

Introduction of methods into programmes
The Programme continues to receive requests from governments for col­
laboration in conducting Phase IV studies of injectable contraceptives. These
studies involve both the Task Force on Service and Psychosocial Research
in Family Planning and the Task Force on Long-Acting Systemic Agents.
Phase III studies have indicated that both depot-medroxyprogesterone
acetate (DMPA) and norcthisterone enantate (NET-EN) are effective,
sufficiently acceptable and safe for contraceptive use. Phase IV studies are
conducted to devise how best to introduce these methods into a national
family planning programme. A variety of aspects are examined: the method’s
acceptability, in terms of continuation of use, use-effectiveness and side­
effects under usual family planning programme conditions; the program­
matic implications of its use, including logistical considerations, the need for
referral services, additional staff training and/or supervision; and the accept­
ability of the method to the clinic staff.

ntal <<
and
the
and
ods
ICs.
ries
*ar<
and
and
lan,
PT;
4%

Some governments have initiated Phase IV studies of NET-EN alone
(Bangladesh, Mexico, Pakistan and Tunisia), since less is known about NETEN than about DMPA, and India will start such a study late in 1983 in 40
post-partum clinics located throughout India. The study in Mexico has been
completed, and results included in last year’s report. Egypt has begun a
comparative 8 centre field study of NET-EN and DMPA, and a similar study
may begin in Indonesia late in 1983 or in 1984.

not
thnan
od,
all
JD
on,
asc
lan
?sh.
ces

NET-EN in Pakistan
The Phase IV study of NET-EN in Pakistan was completed this year, with
a total of 2313 subjects, in some 40 urban and rural clinics located in two
provinces of Pakistan (Sind and Punjab). NET-EN was administered every
60 days. No pregnancies were reported. The preliminary tabulations of the
results showed an overall discontinuation rate of 30.8 per 100 women at
6 months and 45.0 at 12 months. The most common reason for discontinu­
ation related to menstrual disturbances taken as a group: there was an 8.8
per 100 women rate of discontinuation for amenorrhoea at 12 months, 5.8
for irregular bleeding and spotting, 3.0 for heavy and prolonged bleeding,
2.9 for heavy bleeding and 2.4 for prolonged bleeding. The next most common
reason for discontinuation was returning too late for an injection (13.4 per 100
women at 12 months). One of the main objectives of the study was to assess

led

ing
lity
'erthe

25
1

I

Twelfth Annual Report

ir™ S' nTS iS S far "° “P1™1™ r°r
high rate of pregnane
•n the J.. Sl 6 months. Tne pregnancy rate was verv low in the neriod 6

recommended against {ise of the 90 dav J

,nvc^,galors 1’ave therefore

an^M SwHA7„£n’a,C°tnfCtiC SU“fa
I" Hangzhou. China
meohtn A *2. "on SetVn S‘,1 S1°rd<l’",m-.'"i'?
«»*. «" »■=
In Hangzhou 20 of ?ho or J‘
’herefore on Us duration of action,
whirh k
’ ~
t lc
su^Jects showed decreasing circulating NEJT levels
sohieets"X pSTo"^“1-“ S
SSen on"|i2rsub;P,i1 C" T '" r'1'” "'bj“‘S' 7'hc Slockl»l»> sludywas
subjects receiving-;
'i^ro
NlnC St,b'ects flowed circulaling levels ot NET greater Ilian O^nnud

"j'S!;?ENf <>vulali™ als°play a"
t

Effects on lactation and progeny

Short-term ellects of hormonal contraception were studied in the recentlv
completed mult,centred trial on the ellect of steroidal conln'c ,dm, ™ ?
tation described above m the section on oral contraceptives conducted in
Szeged, Hungary, and Bangkok and Khon Kaon in Th iihnd In ihr u

mmhe .
d
dlffcrences in growth as compared with those whose
others used non-hormonal methods of contraception even though milk
volume was s.gmficantly decreased in association !vith cmnHned oS
contoeeT 1V?S
c ianges In nidk volume were seen in the DMPA and proses
togcn-only oral contraceptive groups.
** °t'cS

50

' -•—T^B,;

» /'o

THE

Journal of Obstetrics & Gynaecology
of India
ft

VOLUME XXXV No. 4

AUGUST 1985

SAFETY OF LAPAROSCOPIC STERILISATION CAMPS

‘ft

JOY

Laparoscopic sterilisation camps in
rural areas originated in Maharashtra in
1973. Very soon it spread to Gujrat. In
the last six years or so laparoscopic steri­
lisation camps have spread all over the
country and millions of laparoscopic
sterilisations are performed on camps
every year. This reflects the inherent
advantages of laparoscopy when employ­
ed for sterilisation in camps. But are
our laparoscopic sterilisation camps safe
from the patient’s point of view?
There is no surgical procedure which is
without complications. Laparoscopy is no
exception. A mortality of 1 :100,000 may
be expected during laparoscopy. But
from all accounts the mortality on our
laparoscopic sterilisation camps seems to
be at least 10 times higher than this. Can
we accept this with equanimity? The
exact cause of death in individual case of
mortality can be pinpointed only if post­
mortem studies are carried out. For vari­
ous reasons this is not always practical.
Sensitivity to local anaesthesis is com­
monly implicated as a cause of some of
deaths. Perhaps it is not responsible for
all the deaths attributed to it. But even
if a death or two are proved to be due
to it a test for sensitivity to local anaes­
thesia -whatever be its worth, need to
be carried out in every case. Deep seda­

tion causing respiratory depression and
some degree of hypotension no doubt is
contributory to many a deaths. The dose
of sedatives administered should be the
minimum required and must take into
consideration the low weight of the pati­
ents commonly encountered on the
camps. Gentle handling of the patients
and allowing adequate time for optimal
action of the sedatives and/or analgesics
will go a long way in optimising their
dosage. Vascular injuries caused by the
pneumoperitoneum needle or the trocar
are most lethal. Insertion of pneumo­
peritoneum needle or the trocar is often
taken lightly and entrusted to the most
junior member of the team. Why should
it be so when this aspect of the procedure
needs as much care and expertise as the
rest of the operative steps? Certainly
there are many other areas that need our
watchful and critical attention. Each
and every one of the deaths occurring on
our camps must be scientifically in­
vestigated, thoroughly probed and critically analysed if we wish to avoid repeti­
tion of similar occurrence. Above all,
every camps must be adequately equip­
ped with personnel and paraphernalia to
promptly treat any complication that
may arise unexpectedly.
What is the morbidity that develops in

-

«f

the patients who submit themselves to
! ' laparoscopic sterilisation on camps? I am
;
afraid, no one knows it precisely. But on
[! all counts, it must be much higher than
tolerable, considering the scant attention
to asepsis and neglect to properly steri­
lise the laparoscopes in between two
cases. No one can get away with ignoring
the basic principles of surgery. In an elec­
i
tive surgery like sterilisation which is not
i
intended to deal with any pathology the
morbidity is governed by—(i) amount of
I
preoperative screening of the patient (ii)
attention to fundamental principles of
surgery (iii) care, skill and meticulous
attention to details as provided by the
il
surgeon and (iv) post-operative care.
All these areas need an unbiased and
critical look. There is ample scope for
improvement in each of them—if we
wish to minimise the morbidity.
What is the failure rate of laparoscopic
camp sterilisations? Not many care to
know. We have hardly any authentic
studies wherein at least 90% of the pati­
ents are followed up for a minimum
period of two years. It is feared that on
some camps the failure rate it unacceptl ably higher—possibly 15 to 20 times
I higher than the reasonable maximum.
; The standard failure rate with laparoj scopic sterili.’Uition is 3 per thousand. It
should never exceed more than 5 per
thousand. There is a common tendency to
blame the quality of the ring employed.
We must, no doubt know the failure rate
with a particular ring as depicted on
aproperly executed clinical trials before
ahat ring is introduced in our programme.
I ;

i

77

Incidently, the physical dimensions an
the memory of the ring can be chec 'e
by anybody with the help of a micro­
scope with a micro-scale inserted in the
eyepiece. The ring applicator is as crucial
as the rings for achieving effective steri­
lisation. One can readily find out at lapa­
rotomy during hysterectomy or at mmilap for puerperal sterilisation whether
the ring applicator gives a tubal knuckle
of minimum 12 mm length both when
the first and the second ring is released.
No doubt the substandard type of the
ring and the kind of the ring applicator
must account for part of the high failure
rate. Certainly, part of the high failure
rate must be due to lack of care and skill
oi the part of the surgeon. It is mand.ilory that the surgeon assures himself
that the ring is applied precisely on the
tubes to his entire satisfaction. But how
many surgeons look for this check in
each and every case?
There is tremendous scope to elimi­
nate mortality, to minimise morbidity
and to reduce the failure rate at our
laparoscopic sterilisation camps. Ihis
calls for determined and sincere efforts on
the part of everybody involved with these
camps—administrators, organisers and
surgeons. Yet there is so much that the
surgeons can do by themselves. Utmost
attention to asepsis, adequate sterilisation
of laparoscopes and other equipment and
precise execution of the surgical steps
in making
will certainly go a long way m
our laparoscopic sterilisation camps >ar
safer for the patients.
__ Maliendra N. Parikh

.. i

i
V

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f
I
3

t

tev
&•!r

7
h
4.-.

r/3

XXM1I ALL INDIA OBSTETRIC AND GYNAECOLOGICAL CONGRESS
HELD AT DURGAPUR 21ST TO 23RD DECEMBER 1384

Presidential Address
Learning, unlearning and relearning

hr
Mahendra N. Parikh*

(

i

I
I(

I

h; 5
remained
unshriken
Our honoured Chief Guest, immediate democracy
past President of the Federation Dr. C. S. through more than one crisis. And
Dawn, all our past Presidents who found- this week we are going to the polls
*• < d and nurtured the Federation bringing to elect our eighth Parliament. We hope
it to its present glory, Dr. N. G. Mukher­ the new government's commitment to
jee, Chairman of the Organising Com­ health care and population stabilisation is
mit tee, and his hard working colleagues absolute and total,
whose sweat and toil has brought th:-,
Congrcs'. to reality, distinguished emi­ Gratitude
nent guests, varied participants of the
Friends, 1 am indeed very happy and
Congress, special invitees, .and my dele­ proud to be your President. I am grat' ful
gate colleagues—
to you for electing me to this high office
My
predecessors, all of them without ex­
V> c are meeting here under the gloomy
shadow of the brutal assassination of our ception, were giants jd our profession
beloved Prime Minister, Mrs. Indira with remarkable achievements. I have no
Gandhi. Over the last two decades she such pretentions to greatness. But 1 have
not only shaped the destiny of India but complete faith and confidence in your
i.'so contributed in no small measure to co-ojjeration and help. Armed with these,
the cause of World Peace and Happiness. 1 hope to conduct the affairs of the
11 was but natural that the appalling Federation creditably. Believe me, the
ghastly murder shook the whole world thing 1 love most is to participate in the
and saddened alike the hearts of millions activities of the member bodies of the
in India and billions outside. FOGSI joins Federation and to meet FOGSI members
the entire humanity in praying to the Last year, I had the privilege of partici­
Almighty for Eternal Peace to the soul of pating in the various activities conducted
our departed leader. Ours is the largest by nearly half the members of the Fededcniocrncy on earth. Our complete com­ ration. I hope to do better this year. At
mitment to and our absolute feith in this stage, I would like to acknowledge
my deep gratitude to many who shaped
*NoxrTusjrc XVad-.a Maternity Hospital, Romand moulded my professional career, i
b(ii/-4'»') 012 Seth G S Medical Collcpc, ffc/tnbnysimply love mathematics. Forty years
400 012 and Snshni5/v> Citifns' Cooperative
back when one’s choice of profession did
Ho'p tai, P<Tmbni/“40002S

/

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-

!<?/

3^

Q' -^7

'2'

Av J y

/y^s I

t
Jk

I
J

I

i

fresidektial address
JOURNAL OF OBSTETFiCS A’

3

3Y:<.‘.ECOLOGY CF INDIA

not go mucji beyond medicine and engi­ and we will perhaps take it in our stride.
neering. I U-as expected to take to engi­ But we will certainly not survive unless
neering and was almost pushed into it. It we curb our growing numbers. We have
is to my obstinacy that my parents ulti­ a long long way to go to bring down out
mately relented and permitted me to birth rate to even 25- Zero growth rate is
pursue the lengthy and expensive medical too distant a dream. A growth rate : one
studies much against their will. But for is a realistic ambition at present. Tne job
their generosity of granting my choice 1 of population stabilisation is not easy.
would not have been a physician at all. But let us remember that the difficult is
Thereafter, it was the joy and happiness possible and the impossible only takes a
of delivering women as a student that longer time.
prompted me to take to Obstetrics and
Our Contribuiiaii
Gynaecology. Late Dr. P. C. Daruwala
The involvement of gynaecologists in
and Dr. Juliet DeSaSouza taught me to
love and respect my patients and treat MCH care and family planning is just
them with dedication. Eh. Eustace natural. No gynaecologist can remain
Sequeira not only gave me an inquisitive aloof from it even if he wants to. Ideally
mind to conduct medical research but speaking, spacing should be the backbone
also taught me the fundamentals of medi­ of family planning. But an ideal contra­
cal writing. Dr. K. M. Masani and Dr. ceptive-simple, safe, cheap and universal­
C. G. Saraiya revealed to me the plea­ ly acceptable—is not in sight. Sterilisa­
sures of teaching and writing, and imbib­ tion is bound to play a crucial role in our
ed into me the ethics of medical practice. programmes, at least till the turn of this
Dr. B. N. Purandare and late Dr. V. N. century, although spacing methods will
Sb’rodkar exposed me to the art and skill assume slowly but certainly increasing
u. surgery. Dr. Dina Patel opened the importance, More and more sterilisatagates of endoscopy and microsurgery to tion^ will have to be carried out year
me. Lastly while Dr. Ajit Mehta initiated after year. Although vasectomy, being
me in the affairs of Bombay Obstetric and simpler, easier to organise and cconomiGynaecological Society, Dr. C. L Jhaveri cal to execute, is theoretically far better
painstakingly trained me in the compli- than tubectomy for a mass programme,
cated handling of organisational respon- for all practical purpose* tubectomy is
sibilities. I shall forever remain indebted the central pillar of our programme acand grateful to them all.
counting for 85 per cent of the sterilisa­
tions. Male chauvinism, ignorance, tradiPopulation Stabilisation
t:on and social attitudes all conspire to
make tubectomy more acceptable than
The Task
vesectomy. The crucial role of gynaeco-

Our great nation has only two ills—one, logisls and hence of FOGSI is obvious.
our evergrowing numbers and two tha
i/La pa roscupic Sicrilisanon Camps
corruption eroding the very fabric of our
More than half of the female sterilisa­
society. If by some magic wand we could
get rid of these two ills we would be on tions are bein«.performed laparoscopicaitop of the world. We have now learned to ly. Bui if you exclude puerperal sterilisalive with the all pervading corruption lions
t----- —which, for all practical purposes.
.

should be beyc.u.. the scope of the laparo­ no heed tc asepsis and disinfection on
scope—laparoscopic sterilisations would laparoscopic sterilisation camps.
account for ’.he substantially great bulk of Silastic Berras
the remaining, i.e., interval and periaAn equally disrurbi-g development in
borlal sterilisations. This wide acceptance
the field of laparoscopic sterilisation is the
of laparoscopic sterilisation in very pleas­
mushrooming of different brands of silas­
ing to me since way back in 1973, I along
tic band without any mandatory quality
with Dr. Dina Patel, initiated laparoscopic
control. The manufacture and marketing
camp sterilisations against ali odds and
of simple aspirin tablet is governed by
despite great resistance from many quar­
many restrictions and rigours of quality
ters. But certain undesirable though
control. But an important item of public
avoidable developments in laparoscopic
health and well being viz., the silastic
camp sterilisations make me feel uneasy.
band is free from any such controls.
The craze fur numbers dictates the affairs
Why? Perhaps we do not know the opti­
from the very top to the very bottom ir.
mum physical parameters of the silastic
cur sterilisation programme. This is very
band. Perhaps we are not equipped to
unfortunate, for this inevitably lays great
judge and assess the quality of the silastic
importance on quantity al the cost of
band. Perhaps legal position in the matter
quality.
On laparoscopic sterilisation
is not clear. Does silastic band come
camps this has led to using the laparos­
copes without disinfecting them and to under the perview of the authorities as a
drug? Law is not clear. There may be
performing the operations without due
ample excuse* not to act, but the fact that
care. The result is unavoidable mortality
poo: quality bands would lead to increas­
and morbidity. It is obligatory for th?
ed failure rate and destroy the laproscopic
government to eliminate this monster of
sterilisation
programmeis adequate
numbers. The government’s action in this
reason to act—and to act expeditiously
direction does not go beyond issuing guide­
and effectively. Where there is a will there
lines regarding laproscopic sterilisation
is a way. We should insist on biological
camps. Merely issuing the guideline*
efficacy as the most important proof of the
without ensuring that they are followed
quality of the bands. On laparoscopic
rigidly amounts to actively encouraging
sterilisation, camps only those bands
the number game to ll.e detriment of
should be permitted to be used whose
women undergoing the operation. The
failure rate is convincingly proved to be
pious guidelines must be enforced rigidly.
less than 3 per thousand. Secondly, it
If the government has the will to make
should be made obligatory for a silasticlaparoscopic sterilisation camps safe for band manufacturer to mention at least the
the acceptors, it should immediately re­ dimentions, stretchability and memory of
strict monetary’ disbursement at such the bands on the packing. If a piece of
camps to the maximum permissible num­ toffee needs its constituents to be pro­
ber of operations as per their own guide­ claimed on its wrapper, why not the band
lines. While I am urging the government at least its physical nature? I have studied
to act effectively, may I request each one the physical properties of a variety of
of you never to use the laparoscope with­ silastic bands and find that they differ
out adequate disinsfection. Let it not bo from each other. Logically, their bio­
said of any FOC-SI member that he paid logical cfhcacy must also vary and this

pj^sIDL2 CTLUL A^DDFuL' F

JOURNAL OF CBSTTiTUCS ANr: GYNAECOLOGY OP

<5

could reflect cz the.r uuure rales. Silastic
bands used or. the camps must be tlie best
and no: the cheapo:. Unless prompt and
effective actirn is taken to curb the
menace of numbers and to conlrol the
quality cf bauds, l.-.parrscopic sterilisation
programme will prove self-destructive
and like • the illfated lippes loop pro­
gramme. • the laparoscopic sterilisation
programme too would ultimately end as a
me teor—bright and luminous one moment
and gone the next.
Du/y ETcmption

Another important thing is disturbing
our minds. When a double puncture
laparoscope can be used as effectively and
as efficiently as a sing-e puncture one, 1
just cannot understand why oniy single
puncture equipment is duty free. Strange
logic, if there be any. On behalf of all the
five and half thousand FOGS1 members
I reques: the government to make second
' •.ncture equipment duty free in the inte­
rest of the national family welfare prograannoe.
•' -ucing

Spacing methods are tts vital to populauon stabilisation as surgical sterilisation.
It is phasing to see the revival of intra­
uterine contraception, thanks to the copper
devices. May 1 ask you to try my tech­
nique of stitching an intrauterine device
to me uterine fundus at the lime of caesa­
rean delivery? This technique gives an
expulsion rate of about 5% only. Com­
pare this to the very high expulsion rate
cf immediate postpartum insertion viz..
207c to SOfl. Spacing of pregnancy in
women needing caesarean deliveries is
very important. And the technique I just
mentioned is an effective way of doing it.
In the field o: hormonal contraception, injectables do have merits and need to be
taken more seriously.

y.icTOS'argical Recanalisation
Sterilisation—male or female—is the
most effective weapon in our fight for
population stabilisation. We are urging
people to get sterilised with only two
children. But the high infant mortality
necessitates some of the sterilised people
to seek recanalisation. The demand for
xecanalisalion is not insignificant. In fact,
it is much more than what one is inclined
to feel. I', is the moral obligation of the
government to provide best possible faci­
lities for microsurgical recanaiisalion as a
part and parcel of the family welfare pro­
gramme. Every state must develop a few
centres for microsurgical recanalisation.
This will - boost the sterilisation pro­
gramme and increase its acceptance.

i

'
[

I

Continuing Education
Modem Practice
Today’s obstetric practice is far diffe­
rent than the one of just a quarter century
or so back. Thanks to biophysical and
biochemical monitoring of the foetus,
ultrasound facilities, amniocentesis, foetoscopy, laboratory skills of prenatal screen­
ing, chorion biopsies and progress in
neonatal management we can offer ex­
cellent service and care to the pregnant
woman and her foetus. It is often said that
modern gadgets are eroding the clinician r
skill and judgement. The reality is far
from it. Every good clinician knows that
gadgets and laboratory facilities are excel­
lent servants but horrible masters. Wo
are fully aware that gadgets and machines
cannot dictate clinical management. They
only provide us vital information that we
just cannot obtain by using our five senses
even when backed by the best clinical
experience. To say that modem diag­
nostic facilities will'take away our clinical
sense and judgement is as absurd as say-

i
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!

i

II

i

irg that the advent cf diagnostic x-rays therapy inevitably implies the need to ac­
made physicians poor clinicians because quire new skills and fresh knowledge.
they no longer diagnose pulmonary dis­ Besides, medicine is expanding by leaps
orders by percussion and au.scultahcn and bonds. New information is pouring
alone. In fact, modem day developments in every day. A part cf what we learnt
have turned a good clinician into a better as medical students is fast becoming
clinician arid a safer one for his patients. obsolete. A physician cf today must keep
On the other hand, a poor clinician tend^ pace with new developments and rapidly
to place too much faith in the machines altering modes of patient management. To
and expects too much from them. This is achieve this one must read journals and
detrimental. It is for us to make good use new books. How many cf us have time
of the modern day facilities and improve and inclination to do this? All of us must
our patient care.
Knowledge derived do this anyway. I would most earnestly
from modern technology must be coupled appeal to you to spare at least cne hour
with the wisdom of clinical assessment every day m scanning new medical litera­
experience and expertise. Another com­ ture. This by itself is no: enough. It is
mon cry is that modern day facilities are necessary to grab every opportunity to
expensive and our poor country’ cannot attend conterences like our present con­
afford them. In my opinion, any govern­ gress, clinical meetings, guest lectures,
ment that cares for the health of its people symposia, panel discussions, etc. It is an
should strive to give them the best important function of all memberbodies cf
possible in medical care. At least all FOG SI to arrange such programmes as
referal centres must be equiped with the often as possible for benefitting their
most sophisticated facilities.
members. I promise all possible help
If obstetric practice has changed so from FOGS! to its memberbodies to en­
dynamicaUy, gynecological practice has able them arrange academic programmes.
not lagged benind. It has advanced radi­ Memberbodies should vie with one an­
cally.
Many new developments have other in organising conferences, ntinuity
completely revolutionised the management of education programmes and mass educa­
of patients. Laparoscopy, hysteroscopy. tion activities. In the final analysis, the
vaginal
cytology,
colposcopy,
radio­ continuity of education programmes are
immune assays, ultrasound, microsurgical intended to improve patient care in all
techniques,
in-vitro fertilisation,
and directions. It is, therefore, equally hnnewer drugs like clomiphene citrate, portant to pass on relevant new medical
gonadotrophins, danazol, bromoergocrypknowledge to family physicians. Better
tine, etc. have all altered patient’s care to
patient care w’ill go a long way, if parti­
her great advantage. The world of today’s
cipation of family physicians in the educa­
obstetrician and gynaecologist is totally
tional programmes arranged by member­
different than that of his predecessor of
bodies is encouraged and ensured. Mem­
just a few decades back. He can serve his
berbodies
could also distribute a monthly
patients far better and with greater
bulletin or newsletter to all their members
satisfaction.
conveying to them salient new informa­
Learning—New SkiVs
tion appearing in medical journals. Such
The advent of newer techniques of publications can be made financially viable
diagnosis and changing concepts of and be made to reach beyond the mem-

h

P
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£ciXl^ r=

I

INI RODUCnON QU
INJECTABLE CONTRACEPTIVE (NET.OEN.200 mg.) IN
NATIONAL FAMILY WELFARE PROGRAMME THROUGH
POST PARTUM CENTRES
i

~

♦

STUDY PROTOCOL
(ICMK)

/

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<

sC0'

: 1 t

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Indian Council of Medical Research
Ansari Nagar./New Delhi 110029
in collaboration with
Ministry’of Health and Family Welfare
Nirman Bhavan. New Delhj

■ r-

•’-IF’"’'

-r^-* r • ->—<

L: ' ■ ■ W ■

1%^
;I

------T" (NEr.OEN.200 rag.)
IOTKCDUCTION OF INJECTABLE CONTRACEPTiyE
post-pakium ce^es
IN NATIONAL FAMILY I------

'■ r

.1

RATIONALE:

I

The strategy of the national family planning programme is to offer
a wi^ variety of contraceptives to eligible couples to assure as far as

possible that each couple will be able to find a method that meets the
particular needs. Currently the national family planning program
offers sterilizations, IUD, Oral Pills and conventional methods. Injec­
table contraceptives still

-t form a part of program.

Heaver,

injections as a delivery system is popular among Indian wsnen.
Council is currently conducting a Phase III study at 46 centres in

the country. /The interim results on 3100 subjects enrolled for the st y

c"

suggest that inspite of 90% of the cycles being abnormal only 30% wcmen
discontinued due to nenstrual problem. These included arenorrhoea in
„% (approx.) cases. The pregna^ rate is 1.05 with this method and
is quite ccnparable with available spacing methods.

This study has ccsp-

leted its target of recruitment but the followup will continue for

another one year.

7 a ongoing Phase III study it is
In the light of these findings of
problems of logistics and back up
quite appropriate to look into the [
be required when the method is included into
facilities which may
Hence what is being proposed at this
National Family Planning Progranme.
introduced into the family planning
stage is to see how NET. OEN. can be
progranme based on the available experience in the country.
(.

1.2

OBJECTIVES:

Overall Objectives:
into the Family Planning
introduction of NET. OQ4. injectable
Specifically following
■•’rograime under existing operational conditions.

i

aspects will be studied:r

A.

I

I
B.

I

r

1.3

i

Logistics requirements for this method of Fertility
Regulations., This has following components:-

I.

Training of Medical and Para-nedical staff

II.

Education and motivation potential for the clients

III.

Follow up needs and mechanisms

IV.

Management of side effects including referrals and
backup facilities.

V.

Data recording requirements

VI.

Other local operational aspects like transfer of
staff, supervision, etc.

Acceptability of NET. OEN. as a method of fertility
regulation by the providers and the clients.

SIMILAR STUDIES:
A completed WHO Phase III multicon tre ccrparative trial of

Norigest and Depo-Provera given every 12 weeks, showed that although

the termination rates for amenorrhoea and '’other medical" problems
were lower with Norigest than with Depo-Provera, the pregnancy rate
I

with NET. OEN. was significantly higher than with DMPA (Contraception

15, 5:513-533, 1977). This study also showed different continuation
rates for the Indian centres.
It was found that most pergnancies with Norigest occurred during

the third month following the first injection of the preparation,
l-iirthermore, pharmacokinetic studies of norethisterone oenanthate,

suggested that satisfactory blood levels were only maintained for a
period of approximately 8-9 weeks after the first injection - (Howard

et.al., 1975; Winer and Johnson, 1975, Gerhards et.al., 1976).

This led

WHO to initiate a second trial to evaluate the use effectiveness for

Norigest given every two months during the first six months of treat­
ment, and then at a dosage schedule of two or three months for the

remainder of the study.

Results obtained so far indicate that the preg­

nancy rates are lower with this new regimen, although terminations for

-other nodical reasons" seem higher than was the case

"amenorrhoea"

nonthly dosace regimen. (Contraception 1982, Vol. ,
with the three
XCMP hiitiated^rly 19^ through its netvork of
No.1)Research Centres (HRRCs) a randomized clinical
tax u
Reproduction
contraceptive efficacy
safety of
evaluate the
different treatment sc^dules of 60 days and 90 day^
'given in tw
received 2 ronthly injection for initial
non
subjects having
with 12 months of use indicate that there are no
preliminary analysis
plications. The pregnancy rate of 1.05 is
serious life threatening
Changes observed in the menstrual pattern
within tte acceptable ranges,
due to these reasons are on the higher side
tlie
discontinuations
and
^iHonging and by June^^L.thGrt;
(30^) . Hoover follow up is
which treatment schedule_can_be
I

reconunended.
1.4

Pt.line of Design andjjethodologx:

Overall Design:
will be conducted in 12 States in the country, In each
The study
centres (Type B&C)* will be identified. A total of
3-5
postpartum
state
.) will participate in the study. The
40 postpartum centres (approx
has been done in consultation with the state
selection of the centres
of Health. The basic criteria are that
administrators in Ministry
recruit the requisite number of subjects
centres have the work load to
total of 4,000 wonen will be recruited into
in the stipulated period. A
the study (each centre to enrol 100 subjects).

1.4.1

I

1
I

OEN

will be given every 2 nonths (60-7 days) for the first

’
four injections.

ThG drug schedule thereafter will be decided on basis

of the results obtained

from the Phase III ongoing study.

f

)
! & Il for background on Postpartum centres
*Kefer to appendix
load of selected centres.
including the work
3

US

i

APPIWIX IV

J

PHASE III CQMI5AR?1I’IVE l^TlUiATICN OF THE CV^TRAEEI’TIVE
LFrliCTlVENESS OF l^RETHIbTEfOx’E OtMANIHATE (200 mg.)
GIVEN EVERY TWO OR THREE M3NIHS.

-1

INITODUCTICM

National Family Planning Programme in India is being supported
and strengthened through research and development in methods of contra-

ception by Indian Council of Medical Research.

The research strategy-

at 1CMR involves the evaluation of never and better methods of cunt ra­

ception keeping in view the varying socio-economic and cultural lack­
ground of our [Ajople.

Through a network of Human Reproduction Research

Centres located in different parts of the country.
rlx.-rc has been increasing interest in the use of injectable

cent racept iv( • as they offer long term contraceptive protection unlike
ora J

pills wlvn tl»c dziily intake of pill is cumbursome and result? into

liiglier dropouts.

Availaljlc data on previously undertaken mult teenier

trial with Wore t hi sterone Oenanthatc injectable contraceptive given
once in 3 month indicated that a substantial majority of tlic pregnan­

cies have occurred during the third month following injection.

Interim

results of t'ne WHO trial with NET Hl (200 mg.) given at two or thre^e
nont lily .interval shewed that tvo monthly schedule considerably lowers

tlie incidence of pregnancy as compared to three nonthly schedule.

(

Through, a network of Human Reproduct ion Research Centre's (HRRCs) .
the Indian Couiicil of Medical Research has initiated a randomized cl inical trial

to evaluate the contraceptive efficacy and safety of Inj.Noiu-

tin sterone Oenanthate 200 mg. given in two different treatment schedule
of 60 days and 90 days.

40

I

I

{

The present coinnunication reports upon the preliminary results

!
of the study upto 12 months of contraception use.
Study design and methodology

4 The study was initiated in March *81 at 16 Human Reproduction
Research Centres of Indian Council of Jfedical Research.

The study

design involved recruitment of 2400 healthy, informed female volunteers,
observed for a period of 30 months of contraception use by the partici­

pating centres.

Each subject was screened to ensure that the subject

meets the following eligibility criteria:-

1.

Aged between 18-35 years

2.

Of proven fertility

3.

Frequent exposure to risk of pregnancy

4.

Willingness to rely upon this treatment of contraception

5.

Willingness and ability to return for follow up visits.

6.

Regular menses

7.

Ability to kt'ep menstrual diary card

8.

At least one menstrual period after MPP.

<

i

Contra-Indicati ons
A previous history of throndx) e’llxd i< di.'^jrdcr

(

2

Rjccnt or severe liver disease

3

Known or suspected breast malignancy

4

Suspected gen it a1 ncopla si a

5

Susp -c t cd pi egnancy

b

CXigoing lactation of less than 6 months duration
Zii’iy hormone therapy within one month of admission

8

lostpartum case within 6 weeks following delivery
(they must have at least two menstrual periods).

9.

Women with lib

8 gm.%

41

i

/9’7
/

*

A

•n

I

i
Subjects were then a ilocated to either of the treatnent schedule
All the subjects received
(60 days or 90 days) by random allocation,
The first your injec~
first injection within 5 days of menstrual cycle.
60+5 days and thereafter either at
tions vere given at the interval of
on their allocation to treatment sche60+5 days or 90+5 days depending
fol lowed for a period of 30 rronths.
dole. All the subjects vould be

S

1

taken and physical.
At each follow-up visit a medical history was
were required to ccmpictc a ircnsexamination performed. TI-jc subjects
and follow-up information was recorded
trual diary card. nic initial
on an uniform standard proformac.

e
I?

the discontinuations due to
Ihu present analysis•> focuses on
used to calculate the gross
various reason a I .i Ic -1 ab 11 ■ teehnique was
The tests of statistical significumulative discon t inua ti on rates.
degree of freedom. Thv' cut off
cancu arc based on Chi-square with one

date tor present analysis was 30th September, 1982.
I

*

ftesult

A total

30t h
of 2602 subjects w_?re
ux-^re enrolled for the traal tii.

2 enrolled for 60 days schedule ((■« ••up 1)
Sept. 1982, of tlK.sc 1291 ware
Table I shows the enrolwrd.
and 1311 for 90 day schedule (Group II).

I

f

centres.
by each of LlK participating
of the acceptors was 25.3 years and their ... in
T!k? iiY'an age
44.5 kg. and height 150.6 cms. (Table 2)
parity war. 2.8. ;vtan weight was
There was only one case
Majority of the- cases had normal blood pressure.
;:;ion (BP 162/92) which was discontinued iaU
of suveru hypr-tui
•n .1 lec.u <’d
On .idmr.sion there was no difference K'twucn the whim
IO I VX) I ieat nrnt

x-lvxiulc with respect to age, pariiy, wei'ibl

I k-Bihl . .

Ii
42

I

gjMMMg

• I
■i'

Every attenpt was made to enrol subjects who met the eligibility

criteria.

However, tliere
Uiere was protocol violation in few cases.

i.

54 subjects were above the age of 35 years

ii.

There were two nulliparous women

iii.

Two wonen were enrolled within one month of delivery

iv.

41 woiren had lib 8 gm%.

1
i

These cases wre not excluded from the trial.

f

4-

However, ten cases wore deleted from the trial; 6 enrolled
during lactational amenorrhoca, 2 during pregnancy which was detected

r

Jater and two post MIT.

Cne case had moderate dysplasia, The repeat smear was done and
first follow up visit.
the case was discontinued from the trial at
• I
D i scon tinu.it ions

Twenty five pregnancies have lx-on reported to date.

In Group I
■i

all the 11 pregnancies occurred, within 6 months, while in Group II,
10 pregnancies occurred within 6 iiDnths and 4 occurred after the subjocts were put to 90 day schedule. Of these 4 pregnancies, 3 occurred
during the third month after the injection and one during the first

i

I

montli after the injection (Table 3) .

I

!
Gross discontinuation rates for pregnancies at 12 month were
1.05 and 1.80 per 100 women for Group I & Il respectively (Table 4) .
not statistically significant (X? = 1.72).
Tlie difference was

f

p
I!

Discontinuation rate for excessive or irregular bleeding was 18.3

II
i

[xr 100 wonen in both the groups.

Discontinuations because of amenorrhoca wore 11.02 and 9.38 for

*■

t

Group I and II.

Tiie

difference was not statistically significant

(X? = 0.79) .
43

ii

■

Ii
1

/

■

-

.

F1

6

ri

!

I
pregnancy, husband objected, separated from husband etc. accounted for
j
13 per 100 waien.
Discontinuations for personal reasons such as desire for further

i

Discontinuations for medical reasons like Jaundice, Alergy,
Palpitation, iiausea and Vanltting were 1.89 and 2.35 per 100 wem^ iri
Group I & ii respectively.

The difference was not statistically signi-

fleant (XI = 0.37).

The total discontinuation rates for all reasons were similar in
both the treatment schedule (38 per 100 wesnen) .

Around

of the wonen w-e reported as lost to follow-up dur inc

the study period of which 2.3% were never seen after the first injection.

Furtl.er 4% of the subjects wore not given subsequent injections as they
could not report to the clinic within the scheduled period incite of

the repeated home visits.

These were discontinued as late for injection.

msCUSSION:
A total of 2602 subjects constituting 17,370 wmen months were
observed for 12 Jionths. Of these 1291
women were enrolled for 60 day
schedule and 1311 for 90 day schedule.
There was no significant difference between subjects allocated to either of the two treatment
schedule with regard to age, parity, weight and height.

<iily 25 involuntary pregnancies have occurred giving a rate of
1.05 and 1.80 per 100 users for Group I and Group

II respectively,
the 25 metlwd failures, 21 occurred within first six months of tin

of

contraceptive exposure when all the subjects received norethisterone

oenanthate at a interval of 60 days.

'Ihe
'Ihc remaining 4 pregnancies have

occurred in women who received injections at a intoi"val of 90 days and

Of these 3 occurred during 3rd month of the use.

I
I

44

1

i

I

• 90% of
subject
reatnent schedule, had

^^KSWBw- ■' •

irrespective of their

as

.' L'.

■

■ *1.? ■■jjir t -f j jfjr frffMrftf*ai
;ver the rate of disconti­
Wither excessive bli^
nuation due to these catplication were only around 25 per 100 users.

Probably the conplications in the group of women were either severe
enough or psychological to warrant a discontinuation from the trial.

Interestingly the decision of discontinuing from the trial was taken by

the subject herself in all the cases except in one who continued into
I

one year anenorrlioea and the investigator decided to discontinue the

subject fran the trial for further managenent of the amenorrhoca.

No severe life threatening complications have been reported so

■‘far.

Tie minor menstrual conplication continued to be on higher side. /

The pregnancy rate was within t lie acceptable range.

Data collecttd so far, does not -have sufficient fexi»rience with

two or three nonthly treatment schedule and therefore the above findings
needs to be validated on much larger sample of observation.

It is cxpec-

tM that by July, 1983, the prospective observation may accumulate upto

about WOO wbnun years of obsiervations (12000 vrimen month) for each of
the treatansnt schedule and the conparative assessment of efficacy and

safety at that stage would be more meaningful.

(

I.

45

. i

$

/-

I

i
Vt>i.

-1

1

No. i4

EIMTORiAkS

?

i.he New BnrlsnG
Journ.il of Medicine
Official <)t gut, of
J...' Massachusetts 5.’•die;.! S«xicty

F

J

Founded in iX) 2 as the New England j oi rnal or
Mfdk.tnt. andSurgj.ry and continued in 1328 as Vol. 1 of
the Boston Medical and Surgic.alJuUrn al

Publesiifd Wei key by the Committee on Pi kucai ions
OF 3 Hl Ma.SSACHVSETI S MtDICAL SOCIETY

ClauoeE. Wei ch. M.D., Chairman
Bentley B. Colnxk, M.D.
Samuel Progcr, M.D.
James F. McDonough. M.D.
Saul S Radovsky, M.D.

1’ranzJ. higelfingrr. MJ).. I.diiou

(

4

Assoc,ate Earrows

Jane F. Desforges. M.D.
Jan Kcxh-Weser. M.D. ’

Ronald A. Malt. M.D.
Arnold L. Smith. M.D.

GeorgeS. Richardson. M.D.. Book Reviews
Rolx'it O'Lx’ary, Assistant Editor
F.niTORfAi Board

Walter H. Alx-lniann. M.D
Park S. Gerald. M.D.
W. Gerald Austen. M.D.
George A. Jacoby, M.D.
Herbert L. Gao|xr. M.D.
John /\ Mannick. MJ').
KoIm ic E.Johnson, MJ).
William B. Hood, Jr., M.D.
Jeiome P. Kto- iicr, MJ).
Roland H. Ingram, MJ).
<ieoi gc F. Cahill. Jr., M.D.
Olli S. Micuincn, M J).
Emil Frei, 111, M.D.
RoIkti S. Schwartz, M l)."
Armen H. Tashjian, Jr.. M.D.

*

Milton

>

rc an®' ;

Paige. Jr.. Rpsisess Manager

Ai i noH%-pr**p;n mg nianuscript.i for submission io the Jt/urmil should consult ■■Information for Authors.” 1 Jus material
may lx- ton nd in the first issue of every volume of the Journal, or
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relrrcmc io articles repotting ciosriy related eases. A very short '
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731

CAN THE PILL CAUSE BL TH DEFECTS?
The difficulties in documenting causal relations
between environmental agents and birth defects arc wcH
recognized. Epidemiologic survevs and survm'Lmce
studies should, in theory, be productive approaches to
identifying environmental teratogens. In practice,
however, a gradual accumulation of clinical reports by
alert practitioners, followed by retrospective studies of
cohorts assumed to be at risk (and infrequently by pro­
spective studies), lias proved more successful. Because
there may be multiple causes for similar defects, the de­
finition of a specific cause is greatly assisted
there arc
clusters of cases, unusual i/£ characteristic anomalies, or
other unique features to attract the attention of the in­
vestigator. J he rubella anti thalidomide synth tunes arc
cases in point.
Suspicions regarding a potentially teratogen., role for
progestogen/estrogen have been voiced for srvcr.-i years,
but reports have l>een conflicimg. The recognition <>l a
pattern of multiple anomalies1 s and an ir.crcascd fre­
quency of congenital heart defects13 associated wan
maternal progestogen/estrogen exposure has lx*en
followed by surveillance data suggesting a possible in­
crease in esophageal anomalies4 and by epidemiologic
data from a collaborative jjcrinatal study,5 revealing in­
creased frequency of congenital heart defects. Their arc
also data to dispute the positive findings expressed
above.®
1 he unique features that first attracted our attention to
the potential teratogenicity of progestogen/rstrogen1
were the associated anomalies now covered by tlie *
anonym VACTERL(V stands for vertebral. A tor anal. C
for cardiac. T for tracheal, E for esophageal, K for renal,
and L for limb). These anomalies of simultaneously de­
veloping and simultaneously vulnerable structures re­
capitulated the systems involved in the thalidomide syn­
drome, but presented a somewhat different pattern. 'Fix*
com parison for maternal progestogen/estrogen exposure
of patients having three or more of these major anomalies
with various control groups isshown in l ablc 1.
Janerich and his co-authors, in this present issue of the
Journal, provide further evidence of an ctiologu i elation
between oral contraceptives and birth defects, spccilu ally
limb anomalies. Adding these data to that previously re­
ported for the association with limb anomalies.11
esophageal anomalies,1-*-4 and cardiac anomalies1 3 5 in­
creases our suspicion. One may speculate that a nmnlxT of
factors may influence whether or not an anomah will <x cur as a discrete malformation or in ass<x iaiion with othri
anomalies — among these are hereditary pi (’disposition,
dose response and precise inning of (lie infill. From i he
point of view of recognizing causality, it is the iharaiterislic .moinalies or patterns o! anomalies th.it ma\ prove
useful
A unique featui e of the data of Janei ich ci al. is thai al!
patients who had limb-toluciion anomalies assixiatcd
with maternal oral contracepuve cxposuie wire male
This is a useful "cluster” of patients, and it is not i .< . cssai >
that every investigative group find such a strikingly hip ■

i

Oct. 3, 1974

T HE NEW ENGLAND JOURNAL OF MEDICINE

r

' /^2»
Table 1. Comparison of 15 VACTFRL Patients with Four D:L
lerent Control Groups for Progestogen/Estrogen Exposure.*
(JuMfAMikON

Progestogen/
estrogen
vulnerable

VACTJJU.

9

Chmomowmal
Anomai it*

2

FvmcT1ONAL
Mvamvks

Drvsis Atlanta
Tore -Purelaiiun“ cation"*

3

period’
No progestogen/
estrogen

6

13

27

293

3¥7

vulnerable

period
Progestogen/

1
!

estrogen;
entire pregnancy
1st trimester

Chi-square

Probability

24
46

5.17
<0.025

10.3
<0.005

38.3
28.5
<0.001 <0.001

‘Adapted (ror: Nora A None’
* Vulnerable pcood defined with respect to heart lesions, with range being from 14 to60
days.

frequency. We have reviewed our own data and have
ound a pi eponderan<x*of males: 10 of 15 VACTERLpadcnts were male, and 10 of 13 of these who had limb
anomalies were male. The majority of our patients with
limb anomalies have lesser deformities, the spectrum
varying from absent leg and arm to proximally displaced
thumb. Oneof the interesting conclusions ofJanerich and
his colleagues is that a hormonal insufficiency may be pre­
sent in the mothers in his scries. This is consistent with tlx:
pt oposal of Mitchell et al. regarding etiologic considera­
tions in transposition of the great vessels. Mitchell’s con­
clusion was reached in an earlier report of the coll.ilxnativc perinatal study8 discussed above?
/Xt present there are a number of groups, including our
own, investigating the role of progcstogcn/cstrogcn as a
potential cause of birth defects under a contract program
through the National Institute of Child Health and
Development. Both retrospective and prospective studies
arc in progress. For a drug like thalidomide, which pro­
duces a high frequency rate of malformations, a large pro.■.|x*ctivc study is not necessary. However, available data
suggest that, if progcstogen/cstrogen produces malfornations, it is at a low frequency rate probably acting on
's~ predisposed persons. 1'be epidemiologic impact of these
hormonal agents would thus not lx: related to high risk for
each individual exposure, but to the high number of exjxisurcs from widespread use. Therefore, prospective
indies of hormonal contraceptive teratogenicity must
contain large numbers of patients, and this takes time to
accumulate — perhaps thr ee or more years.
There is an inipoHa:*’ ace for rcuospective studies
such as that of Janerich cl al. in lact it may turn out that
prospective studies cannot pr ovide enough cases within a
given time to t each a meaningful decision regarding cause
and effect. J’hougbtlul and careful retrospective studies
in tv provide the ear liest definitive answers. But there are
p.’i hills. I he analysis of data and correct < out fusions are
. •.-•xtricahlv Ixrund tothe accuracyof the primary input of
data. Adequate tetatogenic histories do n<»r apjxrar in
routine mcdicttl cliarts. Only one third of out patients who
*

fiad documented progestogen/eurogen exposures at tlxvulnerable period of embryogenesis (as recorded by
trained research assistants obtaining detailed histories at
personal interview) had records of such ex|x>sures in their
charts. Hormonal pregnancy tests, “breakthroughs/' in­
advertent initiation of hormonal contraception early in
pregnancy and even hormonal treatment in pregnancy
for past history of spontaneous abortion are either poorly
understood or poorly remembered and reported by many
mothers. The teratogenic history taking must be very pre­
cise and very specific. “Quick and dirty” retrospective re­
views of maternal histories not taken as part of a study to
look specifically at all potential exposures to hormonal
contraceptives and precisely related to the vulnerable
period of embryogenesis for given malformations ai e like­
ly to be uninformative at best and erroneous at worst.
It is hoped tliat those possessing resources of data in
which there lias been a careful and precise primal y input r
will be motivated to share the information they have to
hasten the time when confident conclusions may be
reached. These conclusions may < ome from the weight of
evidence gradually accumulated by a number of groups
through traditional retrospective analysis. Perhaps the
primary input and retrieval of data from the collaborative
perinatal study will meet the measure of a specific pro­
spective study, despite the fact that the study was designed
in die 1950's and concluded in the 19G()’s. Or |>erhaps we
may have to wait until recently initialed rctrospcclivcand
prospective studies designed specifically to answer the
question of progestogcn/estrogen teratogenicity are com­
pleted.
In any case, as we have earlier stated, and as janeri< h
and his co-workers have concluded, it is prudent to dis­
continue the use of hormonal pregnancy tests. We add
tliat is also prudent to emphasize the need to demonstrate
the absence of pregnancy before oral-contraceptive
therapy is initiated. Further work on the hormonal con­
traceptives to develop products that will essentially
eliminate breakthroughs would also be indicated if
teratogenesis is documented beyond reasonable doubt.

L.
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J AME.sJ . N GRA, M.l).

University of Colorado Mcdival Center
Denver, CO80229

■

A L’DREY H . N ORA. M. D.

t

References
1. Nora ]]. Nora AH: Both defects and oral contraceptives. 1 an*-i
1:941-942. 1973
2. Kaufman RL: Birth defects and oral <ot:ti.<cepti\es. Lancet 1:1?'‘">.
1973
3. Levy EP, Cohen A. Fraser 1 C Hormone treatment during pregnancy
and congenital hcai t defects, luincet 1:611, 1973
4. Oakley GP Jr, Flynt WJ Jr. Falck A: Hormonal pregnancy tests and
congenital midformations. Lancet 2:256-757. 1973
5. Hook EB, Heinonen OP. Shapiro S. ct al: Mar- rr.al exposure to oral
contraceptives and other female sex hormones, relation to birth defects
ni .t prospectively usccitailed <uhort of 50.2X2 piernancics. Teratology
9(3) A•21. l'/74
6 Mulvihill JJ. Mulvihill CG. Neill CA: Prenatal scvhorrnuac exp? a-e
and cardiac detects in nuni. Teratology 9- ’>:,-v?u. 1^74
7. Norn AH. No.a JJ A syrdrv: ic ol rnui pic congenital anomalies asxociated with teratogenic c.\|H.’sure. Arch Environ Health (in press)
K. Mitchell SC. Sellmann AH.’A e'.’ph.il MC. ct ■’ 1-ti- - ••gic corrcialesin a
study of Congenital heart div 'C in 56.Hv births. Am J Caro
28:653-657,1971

I

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5

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i

SCIENCE
INDO-US VACCINE PROJECT

Fears of Misuse
Safeguards and assurances fail to still suspicion

N the face of it everytiiing seemed
tiiere would be no leakage of sensitive
I I perfect. The US, acknowledged epidemiological
.
o
information. S.C. Jain,
V-X leaders in the field ofmedicine, was the
’’s joint' secretary.
‘u department
J“
J. says:
not only willing to share its research on “The ‘Indo-US
‘
project would help the
various vaccines crucial to India but country’s health programme by devel­
would also pump in $7.2 million (Rs9.36 oping
.
new vaccines to combat diseases
crore) towards training Indian scientists like cholera, typhoid, diarrhoea and
Signing the project memorandum:
to carry out similar work. The pro- jaundice more effectively.’’
criticism persists
gramme also involved testing the new’
USIS
vaccines in India.
So when the two countries signed a
memorandum of understanding on the
Indo-US Vaccine Action Programme
this July, there w’as understandable ju­
bilation. But it proved to be shortlived. A
damaging report, put out a month later
by the Press Trust of India, a national
news agency, triggered off a storm
which is still raging.
The report written by the agency’s
Science Editor, K.S. Jayaraman, accused
the US of planning to use Indians ”as
guinea-pigs” to lest new’ vaccines. He
even suggested that many of the tests
were actually meant to find out the
Indian population’s immunity to dis­
eases to be used to wage a biological war.
In the days that followed the chorus
Scientists believe that the Indo-US vaccine
ofdissenters grew’. Last month when the
Science Writers’Association convened a
programme drawn up in July, will only result in the
seminar to discuss the vaccine pro­
use
of Indians as "guinea-pigs” to test new vaccines
gramme several eminent scientists
spoke out strongly against the pro­
developed by the Americans, and in the leaking out
gramme. leading theattack was Pushpa
of sensitive health data from the country.
Bhargava. director. Centre for Cellular
and Molecular Biology in Hyderabad.
Bhargava thundered: “Epidemiological
But this is disputed by health minis­ cines in I he country to bring down the
data on our immuno-competence is of try ^)ffici;ils. Despite massive efforts, cost ofimporls. Right now India imports
strategic importance and the (Indo-US) hardly 40 per cent ol India’s 24 million the polio and measles vaccines.
agreement compromises India's sover­ infants are covered under the Union
But the Indo-US project seems to
eignty in this regard." But there is an Government’s immunisation program­ have other priorities. For instance. US
equally strong lobby supporting the pro­ me. There are serious logistic problems. scientists are keen on testing a vaccine 1
gramme. A group of 18 well-known The oral polio vaccine, for instance, that they have developed against the
scientists even issued a joint letter in needs to be stored at below minus 20 rotovirus. one of the many organisms
September expressing their support.
degrees Celsius otherwise it would be­ that cause diarrhoeal diseases. But
The Department of Biotechnology, come ineffective. And the triple antigen health experts point out that there is
the programme’s nodal agency, then vaccine needs to be kept under refriger­ hardly any point in vaccinating children
clarified that no vaccine would be tested ated conditions too.
against diarrhoea unless a more com­
unless it was cleared by the Drugs ConUnfortunately, refrigerators arcdifli- prehensive vaccine was developed. As a
trolleroflndia and the Indian Council for cult toinstall and maintain in rural areas senior health ministry oflicial com­
Medical Research (icmic). The new vac- where power is a problem and break­ mented: “Most of the vaccines being ,
cines would also have to be first ap­ down of equipment is common. Vac­ developed would reach us linally with­
proved by the US Food and Drug Admin­ cines that can be stored at room tem­ out our involvement. Western compa­
istration. The department asserted that perature need to be developed but that is nies would have made them commer­
the trials would be conducted and super­ not part of the Indo-US project as yet.
cially viable in no time.’’
vised only by Indian scientists. And that
Another problem with the existing
Moreover, with vaccine research still

I
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i

I

immunisation programme is that chil­
dren have to come repeatedly to health
centres to take their vaccines. Since
drop-out rates for inoculation are high
in rural areas what is needed is a kind of
“cocktail vaccine” similar to triple anti­
gen (for diphtheria, tetanus and whoop­
ing cough) for protecting children from
more diseases. Polio has already been
added to the triple antigen shot in the
West but it has so far not gained mass
acceptance in India. And an equally
important factor is manufacturing vac-

I

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<NT«llU.R il. I*m7 « INIMA TOIIAV

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171

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SCIENCE
PHASKANT PAH.HAH

i

in its infancy in India, scientists fear they
might end up conducting clinical trials
instead of being involved in developing
vaccines. And despite assurances from
biotechnology officials, the system to
prevent researchers from using Indians
as “guinea-pigs” has several glaring
flaws. For instance, officials say that no
vaccine would be tested in India unless
the Drugs Controller of India and the
icmr clear it. Experts point out that in the
past, the drugs controller has neither
checked the sale of spurious drugs in the
country nor prevented banned drugs
from being marketed.
More importantly, thedrugscontrol­
ler is not bound to get iCMR’sclearanee to
permit the testing and marketing of new
drugs in India. Since it is easier to get the
drugs controller’s approval many com­
panies and institutions try to bypass the
icmr clearance.
The Lucknow-based Central Drug
Research Institute (cdri), for instance,
only got the drugs controller's approval
to test a controversial birth control pill
called Cenlrochroman. Even while
clearing the pill for mass use the drugs
controller did not ask the icmr to review

.3

1

•I

(

I

CLINICAL TRIALS

No Qualms
OW people are subjected to
clinical tests for new drugs
without even realising It Is Il­
lustrated by Vasundhara Sharma’s
case. When told by her friend that New
Delhi's All India Institute of Medical
Sciences (ahms) had a new contracep­
tive, she wanted to try it out. Mother of
a newly-born son. she wanted to have
her next child after two years.

Vaccine research In India: slow
cdri’s human clinical trials. The insti­

tute wanted the drug to be released by
Prime Minister Rajiv Gandhi recently.
But the Prime Minister's Secretariat
insisted that it lie cleared by the icmr.
The council is now reviewing the trials.
The problem doesn’t end there. Nei­
ther icmr nor the Drugs Controller of
India has an effective way of ascertain­
ing if clinical trials are being conducted

properly. The council has a Toxicologi­
cal Review Committee which chccksout
if the drug is safe for human use. And its
ethical committee merely lays down
guidelines for human clinical trials and
has no way of ensuring that these are
observed by researchers.
For instance, the ethics committee
insists that researchers must inform all
people undergoing clinical trials about
the side effects of the drugs being tested
and the risks involved. But in most trials,
this is rarely done (sec box). Admits
Professor N.C. Nayak. chairman of
iCMR’sToxicological Review Committee:
“We need proper surveillance teams to
check whether the tests are being done
ethically."
Meanwhile, the Americans are
piqued by the outcry. They dismiss all
talk of biological warfare as a lot of
“hogwash '. Philip Schambra. science
attache to the US lanbassy In India, says:
"We arc disappointed by the whole
controversy. If the vaccine programme
is stopped, the greater loss will be to the
Indian people.’’ Not many Indian scien­
tists are convinced about that.
—RAJ CHENGAFPA

Doctors in the ahms Gynaecologi­ ceptlve. After six months though she
cal Department told Sharma she wou­ wanted to stop the injections, the
ld be given an Injection which would doctors sent a nurse over to administer
protect her for three months. They It. Even after she stopped the injec­
assured her there would be no side­ tions, complications persisted. She
effects. What they didn't say was that stopped menstruating for a year. And
they were actually making a clinical when she finally got her periods they
trial on the new contraceptive, Nore- ' were very painful. Worse, she was
thisterone Enanthate, (net-en) to test unable to conceive.
Shanna finally became pregnant
its efficacy. Nor did they tell her of the
earlier this year—five years after she
known side-effects or risks involved.
Complications began soon after stopped the injections. But even now
Sharma’s first injection. Her men­ she is worried. "I don't know if my
strual periods became highly irregu­ child will be normal." she said.
None of the doctors who gave her
lar. a known side-effect of the contrathe injections are still with ahms to
BHAWMl SiNGH
”■ -I cross-check her story. But officials of
the Indian Council of Medical Re­
search, which initiated the trials, con­
firm they were surprised by the high
rate of acceptance in the tests done by
ahms. The doctors claimed to have
achieved the results by “motivating"
people to complete the trials.
But Sharma's case only shows
how doctors flout all ethical norms
and get away with it. If a premier
medical Institution Is so callous, there
is no way of ensuring that the pro­
posed clinical trials under the Indo-US
vaccine project will not be misused.

oufi. clinical <ri»l of a.
nqiv-contracephye on an
unsuspecting patient; ■

■ w
\ /

'

-St

’ige*

■M

—RAJ CHKNGAPl’A

1 72

INDIA TODAY ♦ nCTIIRKK >1. WC

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■

31? )
Upjohn's case clainlx£ tnat t.-e finding of naiignant endoaotrial tun ours in

□onxays exposed tc Depc-?rcvera (m?) ic.not relevant to the use of D?
in uonen is based cn six points set out in their Prelininary Statenent

(piz; to the panel hearing ir. Noveaber 1982. Each of these points vill be

♦

considered in turn.

• M
■ J

1' "the inherent dubiety of extrapolating free anitial studiee using nassive
dosages to expected buran performance using recocaended dosages9
c:.’

7E£

KC.TrTi

Leaving aside the question of why Upjohn designed a study to include a

502 human dose level if they consider it of no relevance to humans, their

aoove statement is relevant to all animal toxicology studies. Generally,

such studies vill include a high dose of the conpo’ind under study firstly.

i

to obtain a 'ballpark’ figure for onset of toxicity, and secondly, to

•pendent tczicolcrist

indicate vhether there nay be particular target organs for toxicity, so
that these organs nay be subjected to closer scrutiny in the lover dose

Si
’

■

groups or ir subsequent clinical studies.

: -mtssicned
.-or nearly all types of toxicity except carcinogenicity it is videly

ra

accepted teat there is a threshold for the onset of effects and that
veil-designed animal studies can help to define that threshold. Once a

tnrechold is reliably ascertained, application of an appropriate safety

1

margin may permit use of the compound in humans without Irreversible
side effects. With DP however, tne effect we are dealing with is foreation
cf malignant tumours, no reliable "threshold" has oeen demonstrated and

■4

- -i

tne "safety =«rgir.B, if ar.y, is ver*/ small - These points are expanded in

tne following p?.:

mms.

IA

j

St)

3/

unar. dose group, 2 out of 12 nonkeys sur-.iving to the end of

5
1

7 out of 16 monkeys surviving to the end at this dose level, statistical

the study shoved endoaetrial tunours that were agreed tc be ~a-■ t gn-x-,^ ~y

considerations alone tell us that an effect‘vith an incidence as high as

five different pathologists vho reviewed the slides. In one case, there was

351 could hive been missed. Similarly, extrapolation from the 50X human

evidence cf metastases in the lung and possibly invasicn cf other areas cf

dose data, using any mathematical model, vould indicate that 101 the

tne reproductive tract.

human dose vas not safe in terms of carcinogenesis.

Ince tne toxicity observed is careirore-e-.t

the "threshold" argunent cannot be applied. Even in the case cf epiga-.etic

carcinogens (the category in vhich cost carcinogenic homones are placed),

Other findings which throw doubt on the 10X hunan dose level being

it has tc be assured that there is no threshold or safe level, until proved

are the observations of decidualised cells in the endosetriun of nonkeys

oxher-ise.

treated at this dose level. These are the cells froa which the tu^nor;

at the 501 dose may possibly have been derived (see later under ii);
"•isk estinaxes for low coses cf carcinogens are frequently made by

6 out of the 7 monkeys shoved decidualisation varying from minimal to

extra.c.a-.tcn free high-dose results, and whilst the limitations of sucn

narked according to two of the pathology reports (Heywood and Moyer).

-echnutues are recognised, they are widely accepted as tne best estimates

At 10X the buran dose there vas also considerable variability in the

tnat can be made in the present state cf knowledge. In a case such as 2P,

response of the endoaetriun; decidualisation vas’variable, as were

where large numbers cf vocen nay be exposad for prolonged periods of time,

endoxetrial thickness changes, the number of glands present and the

®'Z2~ a

I

rusx estimate at therapeutic doses nay becone significant in

prcporticr. of glands shoving cystic dilatation. There is no reason to

suppose that vcaen night not be mua!ly variable in their response;

terms of the numbers ultimately affected.

the enormous differences in nenstrual patterns in women following LP

Pitting aside for the xoneat the "no threshold" argument for carcinogens,

injection indicates that vide l.-d-1,•■ridun] variation in utaHno response

-'•® area cf safety margins should be considered. The tvo turours occurred

is indeed the case in vonen.

at >CI tne r.unan dose. No eadonetrial tunours were observed at 19X the

X*

i

ne-i t

buran cose in the 7 ronkeys surviving to the end of the study. In the case

3iven the above considerations of the snail nun her of nonkeys

of a drug intended for long-tem administration to otherwise healthy

the variability of the endoaetrial response and the presence of decidual-

persons,

noreally at least a safety margin of 100-fold would be employed in

ised cells, no conclusions can be dravn as to the relative safety of

extrapolating from reliable animal toxicity data to derive ar acceptable

these dosages in the ccnkey, nuch less extrapolate the finding to htsnans.

husar. dose. Many workers vould feel the safety margin might be set even

'1

■ft '

tigner, say ICOC-fold. Assuming that the tumours observed in the monkeys
were due tc 2? and not spontaneous, then the upper
—a_fc-_

* for a safety

o« put at no higher teat 101 the human cose, cm cresent

der.

Sven tne .21 cumar cose be in.- regarded as "safe

4

II

i«.

the —xelir.ocu cf tne endometrial lesions nnving arisen mere froo

5/
epitne^ia. =e_ t;.-pe feund ir. monkeys but not human females....8
secretory

a-enocarcinoca with the comment that somo of the tumour appeared

One cf the • petmolcgis-.s who reviewed tne cata (Valerio, mac suggested that

I•
3

to arise from decidua, and the other tumour as anaplastic carcinoma. The

the carcinomas possibly arese from epithelial cells. Ice work cf -islccki
and Streeter (1938) showed tmt ir. tne pregnant rhesus monkey, cegir.-ing about
tr.e testh day of gestat

tee surface epithelium and the epithelium of g~

a-jacsxt tc and at the site of attachment to an
implanting blastocyst undergoes

I

fifth pathologist (Moyer, Southern CaliforrdLa) described one as a

i

moderately well-differentiated adenocarcinoma and the ether as diffuse

adenocarcinoma with areas of moderately well-differentiated gland structure

end other areas of undifferentiation throughout the lesion.

cp-th-_lal plaques. However, they were unable to conclude
vnetb-r c.-.emical and/or -ccnnnical factors were responsible for this prolifer-..
These inconsistencies in the opinions of the various pathologists who

eticn.^’hilst tne human does not undergo such extensive epithelial proliferation

s

reviewed the data were commented on at the recent FDA hearings in the USA (1963).
. sfttrue senkey to form plaques, epithelial proliforation dees occur at

Th.a picture has now been further confused by the testimony of Dr Dallenbach-

<-^zllar stage cf pregnancy (10 - 1$ days}, covering over the site of
Tellweg at t.-.ose hearings who says that the tumours are aicroalveolar
pcte^aticn of the blastocyst into tne endoaetriua \boyd and Hamilton, 1951}.

adenocarcinomas cf the endcoervical mucosa, a diagnosis which is consistent

it is my no means certain that proliferating epithelial*.

sells are

tte rserJi eonkey, though the extent of proliferation in tnat
—^y ve_A be greater tnan in otner species.

I

there is, however, nb agreesent anongst the j

patnouogists as to the derivation

to make if tne tumours were fairly advanced as certainly seeoed tc be th?
case

patno.ogist (Valerio; who proposed am eni’.-.slial

origin also said she could

zctall..- rule cut a stromal ccmponen-. as well’.

Another pathologist iHugtes,

criminally classified tne tumours as

aceEcesrcitcma- but later classified

1

*-® Uterint

Thus there is a largo measure cf disagreement as to the origin of tne tumours.

If they do arise from epithelium it may not necessarily be from a type of
epithelium which is unique to the rhesus oenkey. Futhersore, as one of the

witnesses at tne FDA nearings (Dr Morris) has pointed cut, if epithelial
plaque cells in the rnesus monkey are responsive to progestogens, why do

they regress after only a few days during normal pregnancy in'that species,

when progesterone levels are still risingl If the tumours arise from decidual
-•‘^’ther zcnkeys is tne 52* nuzan dose

I

Croup snowed pseudo sarcomatous deciuual transfer-sat ion of tne ezdonetrial

j

and acted V.e pretence cf clumps

stroma without encosetrial

the ccnkey, ar.c one which would explain the puzzling feature of lacr of
any transition between tne carcinoma and the atrophic endoaetriua.

of the tunours. Any firm conclusions about derivation would in fact be i

in one of the monkeys.

witn the zr.oi.T. effects of unopposed progestogen on the cervix cf women and

cinemas. Ar.ctme r setnologlst

.-.ey.-ccd,

eial lerly claasifiac tne tumour- as undifferentiated endometrial oarciacmes

f r.frc~*astic ce^ls in a dacidualise-i stroma

cells, tnen tnese are certainly present in both women and the rhesus monkey

during prernarcy and are responsive in both species to progestogenic
stimulation. If tne tumours are of er.docerwical origin, then these tumours
are also found in woien, albeit rarely, and,according to Dr Dellenbach-

.-.eliweg, occur in association with treatment by highly potent progestogens.

ia one of tie tcnxeys, Anctner ore

S 2.

i

P^fcrexces:

7/
ILL/ "difficulties vith the study protocol"

•islocki S3 tr.a Streeter 31 (1935) On the placentation of the Macaque

(Macaca zulatta.: fres

tine of inplanzation until tr.o formation of
The source, age and previous treatcent of the nonkeys used Ln this study

the definitive placenta. Ccr.tr. fcbryol. Cameg. Instr.. 27, 1.

were unknown. The two nonkeys developing carcinonas were also replacement
Bo-d JD

w.- (1952) cieavag., early develop...-.-, .xd

nonkeys for others that died or were sacrificed earlier in the study. These
ire aJi I unsatisfactory aspects of the study but presumably
were not regirded

er the egg. Chepw.- L. ix: Ma.-shall-e Phy.loloQ- cf Reproduction.

■

Silted by Ao rarkes, Ungears, Green c- Co, London, pp SC-€2.

i

i
rood and Lr-g iinixiszration: Depo-Prcvera. Public Soard of Inquiry.
ufficia_ -.rtxscript of proceedings, Vcluxe II, January 11, 1983.

at the start of the study as sufficient of a probles to invalidate any
results. They do point to the need for repeating of the windy under aore

controlled conditions. Ln the neartime, since there are no other conparable
data, the results oust be accepted as limited*
United* evidence that L? is

carcinogenic in the nonkey. The protocol deficiencies are not sufficient

w

grounds for dismissing the findings.

; j

/dCAy? i>

4®

♦ 'United1 is used here in the sane sense as it is used by the International
Agency for Research .on Cancer Monographs, viz. the experioental data are
■

restricted in scope such that a causal relationship is not fimly established.

I'/-.-

E

iv) "uncertainty as to unether Depo-?rovera caused the lesions in the first
place or whether they were of spontaneous origin"

■

w* ■

1

This caveat applies to any positive finding in an aninal toxicology study
where insufficient nuabers survive to the end to persit statistical

analysis. In such cases, other pointers have to be used such as dose-

response relationship, tunour site and background control data. The fact
that the carcinonas were seen only £n the high dose group, that both tunours

occurred at the sane site, and that the uterus Ls.ratureily responsive to

stiaulation by progestogens, all point towards the preaability that the
tunourn were caused by TP. In this context it is unfortunate that historical

background rata on spontaneous endoretrial tunours in the rhesus sonkcy

eitner has not been provided or has not been sought ’ey the nanufacPurer.
Accoming tc Tr . cr.es FTA r.earir. :*, l^SJ) suer, f.utcurs are very’rare.

-

s3

<*?

■

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ANO CANCER

Introduction

The topic of potential c,arcincgenicity of EKPA is a conplex area, both

biologically end epideni©logically.

present extensive evidence.

•

:

We have therefore not attecpted to

However, we are aware that for easy wosen, anxiety

ant

about possible loag-tem effects of any steroidal contraceptive ia a powerful

factor in their decision as to whether to use a particular aethod.

The

general public is now aware that the effects of

cn

cancer-inducing chesiicals nay
take up to 20 years or core before they becone evident in sufficient
numbers
of people to enable identification of the carcinogen. No assurances about

nx: lertxnony to "Z FIA ?utltc

the aafety of DKPA will be accepted by wonen,' properly inferned, until sore

of Inquiry re Lepo-?rovera,

tine has elapsed and sufficient nunbers of woaea who have taken the drug
for sone tine have been adeeuately followed up.

The rodent, beagle and rhesus sonkey carcinogenicity studies give no

reassurance on this issue.

A corpany, which runs successive careir.agen* rf ty

studies in aninals, all of which are positive, and then argues their

inapplicability to the Hunan situation, stretches credibility to its Units.

The potential significance of the beagle studies has been extensively
discussed by expert witnesses at the l?Sj FDA hearinrs.

The nonkey stud^

are considered in an appended paper, submitted at our request, froa an
■

independent toxicologist.

This shews that with the extensive dnaagreeueat

ar.ongst pathologists reviewing the slides/ Upjohn• s argusenta for ddssissing
the study cannot be accepted.

:

■

Statement of the actio:’, of synthetic gestagens

rr<-

on the hlstomorpholOGy of the er.docervical mucosa
in wemen and nonkeys

’*

t

•’

preventing adverse ^reactions of hormonal therapy, a distinct
*"
to onefuhe otter side aust te prev^ted.

Observations: In the last Io years we have studied 27 adenocarci­

rrom this aspect, a long acting unopposed gestagenic stimulation

nomas of the endocervix developing in women up to the age of So.
t22 of these women had taken oral contraceptives, in most instances

m a young healthy female with a previous hormonal.equilibrium
will cause a hyperproliferation of the endocervical mucosa which F

continously for up to 19 years, on the average for Io years.

night become a precursor of a carcinoma/ If however a postmeno­

During the same period of tine we cqllected 11 adenocarcinomas in

pausal patient with an endogenous hyperestrogenism is treated with

situ of the endocervical mucosa. Io of which developed after 1

a synthetic gestagen, her hormonal equilibrium may turn back to

to 2o .years of use of oral contraceptives. 13 of the 22 patients

normal without any adverse reactions on the endocervical mucosa.

f

with adenocarcinomas and 8 of those with adenocarcinomas in situ
had taken oral contraceptives containing norgestrel as gestagen.
The others had taker, either norethisterone acetate or lynestrol.

Zci adenomatous hyperplasia of the endocervix was diagnosed either
prior to or at the same time as the adenocarcinoma.
2 of 12 rhesus ccnkeys treated for Io years with medroxyproge­

£2ri^.f*BLoplnton'

,
POtent
(Norgistrel)
o. a very large dose of a gestagen with low potency (Medroxypro­
gesterone acetate) is contraindicated in young healthy females.
On the other hand both medications seen to be justified
and
therapeutical, helpful in postmenopausal patients with constant
hyperestrogenism and resulting precancero-ses of the endometrium.

sterone acetate at doses So times those prescribed, for women
developed the same types of adenocarcinomas of the er.docervix

(not endometrium!). In the same group of monkeys# none of the
normal controls and none of the 3o animals treated with lower

doses of medroxyprogesterone acetate developed a carcinoma.

Valuation:

1

Prof. Dr. cei Gistio OcIlanbsdbHellceg

studies suy^st the use of gestagens for cany years may be
ay related to the aevelopnent of the rare adenocarcinoaas of
efte eadocervix.
n.-________
anaocervlx. Since
adenocarcinomas of the endocervix developed

Morphoioghcha Ablcilung
dcr UncvsnifCh-rroucnlcIinilc
KUNIKUM WANNMEIM

following nortestosterone cderivatives as well as following derivarives of aedroxyprogesteroime, it seems likely, that not so much
rhe chenical structure but rather the potency anc^dosis of the
■

cedxeation is important for the neoplastic potential. Norgestrel,
the agent taken m r.ost of the worsen involved, is Oox more potent
:» f
than natural progesterone. Medroxyprogesterone acetate, the agent
|'
to the monkeys, only caused carcinomas in those animals,
I 1■ who received So :: the normal human dose. In consequence,
consequence, the dose

ii

seems to be the important factor.

lilMH

t hormonal equillbrlura is the most impertar.t factor in

1

h>

5

■ H ,

Vol. 64, No. 3, pp. 333-480
1986

Z7.-'

'> A
A* n

............

’■

<1

(

IPIpE a, ORGA^isAnc^.ri^bj^ESi& aA'fSANit'jrf
I
Update — Le point
M. A. Gemmell, J. R. Lawson,
& M. G. Roberts
V. Chalapati Rao,
T. G. Mek alf,
& J. L. Melnick

I
!

Control of echinococcosis/hydatidosis: present status
of worldwide progress
Virus humains dans les sediments, les boucs et les sols

I
I

333
34!

i
H HO Scientific activities — Activites scicntifiqucs QMS

I

(
?‘7

f

:

;
prajets de recherche tnomedu. ale cn I9.C .

—•

'"^1

...... .........

r^,

nu,lud!t i ^^'rhCiqut^ ■ / 'appm au <

361

Continued on outside back cover

i
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-----------

Suite nayc 4 de la convertare

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(M 37) 3»2

I
cancer: Memorandum from a WHO Meet) g

I

I

i

"SX

I

yarned bv coruini^ the presen^.ua:

I

'specific topics.

1NTRODUC1 ION

cancer that.
,hlis f:
,r demonstrated
PMPA havc.hus
far
demonsou,.
women receivingath
|opin& any
, riskA"
of dcve
developing
any type
type oj
of
no increase
m’ ,h'
ll controlled trials
- . "
„ 1"
he lack of wc
well
tr.als
cancer. ... because of the Uck o f
cancers, itjs

........
.......»•«>
fertility regulation '‘j1
b\. Membcr povernSpecific issues of s. •
‘
unilx arc investigated
b’Cn,S?'l,y;1:rcl^";mm'mZt3krnbv.be Pro-

1

I

I

mtd'also'evmnmed m meetup ol experts
convened to revicss the as.a a

•r io

*

^.cw by (bc

One subject
of Mcroid contra­
Programme is whctii
in 1977 the Pioccptives alters the..skoncop-

•.rtor-

-d

•

t

gramme convened .. . _
from studies
eluded that "there arc no adequ
u,jC(J ...
in women to assess whether P ^<;sio(,(.n.only pi||s
comraccpnves in the for
P b
o)

tumors in aminal toxicoa’i-s
1
for
(mls contraccpiivcs (-D
\v, |C).S Special
ic'.c.uch in this area As a
, . ..f
;' j
rl.>na.nnmemli..iled..;um:bei’-oimm
national collabo:atr.t t
■•■'d
1
n ..xk,
steio.d ‘ •mtr?.. eptne
dir iciatioaship
bc
’.sv -i> xti
i i'.k <>! selected m-' .plasm i -xs. ! all data, .isaibbk
I:. ’‘*S 1. t!. • Piramme ic\
,.\t this meeting U ’•‘■as
an uij’.,lablr contraceptives.
...... -$ liMcJ
’ ’■‘ud^X'.Phiin -a. ar.he.1 b. lbe 'ir"-"-",
i !>c(»;cnib-: !9S5
Uff.f.co cjr.toto.f □ V.H( > nu-cuuf in I - <•G-ru;il
-•
-;;
Profihr-»e of
for t i'tiiio khuulil be sen! t<’ niunn.v r. Human
R«v-r.h, (Rvdi'ptncia a"-f Rcsc-T'tli
1711 Gent'a -i.
*■ •-!duutnt.. Wotld Ikuith ()i
„.,n<h.ni* ' “I
Zetland A l itb.'a ltaiv.i.>,."i' 01 inis • <‘

’“£x i=;

monitor t...
among women
de«lopmen>”f;^
had
> noted that \
used DM I A
■ • .. .
livc studv on ibis issue,
illaborativc
study
recently m.uatcd a co! aboMuse stbpcn
prclnmnaiy results
and cervical cancers U.
published concerning bie .
A and
\ Other cpi^n>.ol^'calfs.ud.«ebecn.n.
,
ZXbnd

1

I
B

Costa Ric» -d Jamaica: results of

jn a number
Rcpubbc of

these studies are not yet aw» •>
Me.u-bdc.drug.egul

Of countries.
Germans. Sweden.

'l

’Kingdom and USA.
n virw to its approval as a

haveresu- 1
these reviews neoplasia has con
contraceptise
1 ‘C c
conccrn; lhe Probeen, raiser U „tb
gtammc has also rtcti
...s in both dcsclopcd
subject Hom Member pov
,iS .bcrcloTC considered
ar-ddcvclopmccountne. .
•
(o icvK.w
o-Xortunv to conscnc
bofiipub'.rhedand unjm '

.;

iciniolog,cal data
an)ina|

lr‘ '“"’'""J™: ",d been tlmto.tghlyrc-viewrd pretov.-o.or sti.1 •■<..• t.a
l981 j.jccung
vteusly tO- iota »• a‘inch.dmC the pre
.vere thus l''1'nl;’L
tl,. w'no collaborative study
liminary results Hom
.
lbe daIa reviewed
This Memorandum sum .
reeonUncndations
and the conclusions and p

1
II :

t

Ioi future research.

*n » laut iv.ur <>! tin- /<<///<■'•■■

*/.'S

375-

•i_. .

•. '-•«’•

■J

i

B': '
memorandum

376
COLLABORATIVE STUDY OF NEOPLASIA
THE WHO
AND STEROID CONTRACEPTIVES

1

coding and editing at each study
Tu?
includins range and consistency checks performed by
'"ompmer. was conducted at the coordinanng centre
in Seattle Potential errors, not correctable at the
coo^nating centre, were referred to the centres for

apr
V
frc?
ur?

i

di­

Methods

The WHO Collaborative Study of Neoplasia and
Steroid Contraceptives was carried out in 14 collab­
orating centres in 11 countries. The risk of cancer n
DMPA users was examined using data collected
three centres in Thailand, one centre in Kenya and
one centre in Mexico, which were the centres where
DMPA use was appreciable. Recruitment of subjects
began in October 1979 in the centres in Thailand ano
Mexico, and in June 1981 in Kenya. The most recent
analysis of data on DMPA and cancer ava.labk: for
this
wt.usv complete
this ’review
review was
was based
based on
on suojeers
subjects whose
data were available at the coordinating centre at the
„
— Cancer Research Center tn
Fred--------Hutchinson
in Seattle.
_
Washington, USA. on 14
14 June
June 1985.
1985
The study was restricted to women born after 1
in all the centres except Chiang Mai, Tha.land. In
Chiang Mai, the subjects were required to have been
born after 1925. which is due to the earlier availability
of DMPA in this area of Thailand. The study was
further restricted to women who had been resident
for at least one year in a defined geograph.cal area

rer;.

Claprovtsional diagnosis of cancer was made by one
pathologist in each participating centre. Stained and
unstained histological slides for each case were
reviewed again by a single reference
each cancer and classified using the WHO histo
logical classification of tumours. Analyses were
based only on cases where the diagnosis of malig­
nancy was confirmed by the reference Pathologist,
except for liver cancer, where clinical as well as patho-

Ste:
ou<
ere
ph
ar.
dii
in.;
an
us
ca
ih

^^na^^of breast and cervical cancers included all
lh(;conJrol subjecis from all four centres and used the
°ditiona| logistic regression model to estimate
risks controlling for potential confounders by enter­
ing them into the model as stratified variables.
VorThe other three cancers, cases were marched
with up IO eight controls on the year of birth centre
and year of entry to the study, and the cond,nona,
logistic regression model was used to estimate the
relative risks. For all analyses. 95"/. con^de"c'
intervals for relative r.sk esnma.es were ca culated
using the normal approximation to the exact
confidence limits <5).

ce
at
d:

«
12
O
ft

0
il
b

liver cancers among women in the eligible birth year
and residence areas were identified by momtonng a
admissions to hospital wards where these cancers
Bias and confounding
were treated, and by checking the records of oub
patient clinics and pathology departments m each
There is al least one potentially important
uncontrolled confounder in the WHO study and one
centre. Approximately two contro s per case were
.
potential source of bias. With regard to confounding,
- ----------selected from among women
m the eligible
birth y
;nformation on cigarette smoking was not collected in
and residence areas twho
— .had been admitted o o
.vn,^nlA0ical wards in^thc
the sa
earl parl of lhc study, but this has been initiated
than obstetric and gynaecological
hospitals for conditions that would no alter contra
recently. Several studies have shown cigarette
ceptive practice-i.e., excluding circulatory or car­
smoking to be associated with an increase m the risk
diovascular disease, diabetes, chrome renal disease
of cervical neoplasia (6-8) and a decrease
benign breast disease, previously diagnosed cancer
of cndomcrial cancer (9). The r.sk of breas. cancer
rhmmr liver
disease, and
and obstetric
chronic
liver disease,
obstetric or gynaecological
appears not io be related to cigarette smoking (9).
WPH|C few data are available on ,hc
dl Neither cases nor controls were interviewed if they
associaiion of ovarian or liver cancer wuh cigarette
had been referred from a family planning or fertility
prevalent
smoking. If cigarette smoking is more
clinic unless the visit that prompted the referral
among users of DMPA. as it is among userss of other
countries,
the woman’s first visit to that clinic.
steroid contraceptives in some
------- developed
.
.
A standard questionnaire presented to cases and
then failure to collect information on smoking and to
controls by a trained, female interviewer, was used to
ontroi for possible
IWH'll differences
• • w • - ---------- in it between users
elicit information on known and suspected risk
DMPA could overestimate the risk
and non-users of
g. .
factors for the various cancers bcmg studied, and on
of cervical cancer and exaggerate the apparent proobstetric history and previous use of conlraccp,’VCSn
:
\ on endometrial cancer. 1 he
tcctivc effect of DMPA
Recall of whether steroid contraceptives had been
of tobacco consumed by women in
small
amount
g. -----used was facilitated by showing samples of prepar
these countries suggests that confounding from this
ations available in each country.
nr/.iiminarv
source will not affect relative risk estimates
Data collection forms underwent preliminary

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377
pepot-meoroxypiocestekone acetate ano cancer

endometrial cancer

’^HhXrd -o

“«S and COn'rO1S rC < T/d

===•!=-

from rertHity or fanr.Iy Panning

'dXX

I
i

rnetrium to secretory or suppress Three
^'^epidemiological studies are bm.ted^ T re
descr.pt.ve ‘-^’^^^p^rertaken m areas of
from endometna cane
sludies showed no
DMPA T AX8e e fe o DMPA they pro-

I

“•="
cancers studied in the WHO study arc n.ore .tkc
thariSther serious diseases to bc.d'a8n0’'d'" $"ncc

u>»b -••••
’•- records of approxiHospital family planning
dime
.Mv <000 women who had used DMPA. One study

;................ .................. ..

XXXn" POten.iaHyimponantsuu.ee of

sxs: sa■-=
s^^Saasssi-number of cases exc u

n .nvkok no subjects

,

studies suggested an adverse ef

meaningful con-

■ r ^"h^u'ca^ordia^^Zs.^-.

were excluded lor n 15
wHh brcasl canccr,
subjects 'N,lJ.ccrv^. . . ol‘hcr three cancers were;
and zero subjects w h the oth
"JudC|<l °n:; wer e Cl ded for’his reason. Data on
cervical cancer were
ib(. c(.nlr(.

Cp ■□ly because of the small numbets msols^
eoVrendomcni^cV3Cnc‘eAssociated w.th

'nC an therapy for perimenopausal symptoms can
estrogen therapy rui y
iddilion of cyclical

exclusions >n
small number of subjects
Mexico are pending, inc
available
excluded in the centres for »b><*
rnk
maUs.tunlikelythat^mRnuurk^r^.^
estimates is serious y affede
cx;,,nmatio:I of
Further reassurance «0>n“
risk estimates
preliminary data showing ha rela
f.„ cervical cancer and eas
>«
ccp,ion

W!’C" '“"mosdi" iv o b« affected by -his potential
who
aualyscs A fi al com
ho seem most Wel..^n

■ ’ 1b.as
— > must, however,
eJusVn'abom'n-effect of' this
of excluded cases
await examination of the number c
and controls from all five centres.

.

- - -lof ihfl’ubhc Hoard af

• FoODANl.lUUGAVM.N.MWAriON. Ar/M'f

I9S1 (unpubliihcJ)Inquiry on Depu‘..............

•

-!
♦
__ ’’■ .--'•cr:
■
• ••
.

—

»-•■•-*

f

.t

f
- 378

MEMORANDUM

Oral contraccpiives, while indirect, suggest the hypo­
thesis that DMPA is negatively associated with endo­
metrial cancer.

accumulated insufficient data to assess the risk of
endometrial cancer in long-term users or the risk long
after initial exposure.

Results from the WHO study

(C

OVARIAN CANCER

Complete data on 52 cases of endometrial cancer
and 6012 controls were available for these interim
analyses. A total of 316 controls were matched to
individual cases on exact year of birth, year of entry
into the study, and centre. Only one of the cases, and
30 of the 316 controls had ever used DMPA, giving an
estimated relative risk in women who had ever used
DMPA of 0.3 (Table 1). This estimate was not
appreciably altered after controlling individually for
total number of live births, jota! number of
pregnancies, history of infertility, and use of
exogenous estrogen. Although this low relative risk
suggests that DMPA may protect against endometrial
cancer, the 95°?o confidence limns of the estimate are
wide (0.04-2.4) and the observed low relative risk
could be due to chance. There is no indication from
these findings that DMPA. as it has been used in the
past in the three countries from where the data for
this report were obtained, increases the risk of
endometrial cancer. However, this study has

Table 1. Relative risks of five neoplasms in women who
have ever used DMPA: results of the WHO Collaborative
Study of Neoplasia and Steroid Contraceptives
No. ot subjects
in the enilysis

c

Adjusted
relative risk*

C»nce' inn

C>*et

Control*

Endcmet'iwni

Breast

427

316
637
290
5991

0.3 (0 04-2 4)*

Liver

57
105
57

Cervix

820

5833

1 2 10.9- 1.51'

Ov»rv

0.7 (0 3-1.7}'
10 104- 2.0}*'

1 0 (0.7-1 5)'

* F-igu'es in pB'cnthe*** a’e 95% confidence mtervels.

* Control* metched with case* by »ge, centre, and year of
entry into th® study.
' Adjusted for total number of live birth*, history of infertility,
oral contmcept-ve use and IUD use. controls matched with cases
by ago. centre, and year of entry into the etudy.

The two studies using Grady Memorial Hospital
data, which attempted to examine the relationship
between DMPA use and the development of ovarian
cancer, did not indicate any adverse effect of DMPA
in this regard (IJ, 12). However, both had methodo­
logical limitations as mentioned above, and produced
insufficient data to allow meaningful conclusions.
Nine studies have demonstrated a negative
association between oral contraceptive use and
ovarian cancer (16). This effect is thought to be
mediated through ovulation suppression (18). Since
DMPA usually prevents ovulation, the negative
association observed with oral contraceptives, if due
to ovulation suppression, suggests that DMPA is
negatively associated with ovarian cancer.

Results from the WHO study

A total of 105 cases of ovarian cancer, largely
epithelial carcinomas, and 6206 controls were
available for the present analyses. From among the
controls available, 637 were matched to individual
cases on exact year of birth, year of entry into the
study, and centre. Seven of the 105 cases and 74 of the
637 controls had been exposed tc DMPA. The
relative risk in women who had ever used DMPA was
estimated to be 0.7 (95^o confidence interval,
0.3-1.7) after controlling for the potentially con­
founding effects of parity, history of infertility, use
of oral contraceptives, and use of an IUD (Table 1).
When the analyses were confined to uomcn of proven
fertility (at least one live birth), the comparable
relative risk was found to be 1.0 (95”o confidence
interval, 0.4-2.6). Insufficient data were available for
more detailed analyses. These preliminary findings
provide no indication that the risk of ovarian cancer
is altered in women who have ever used DMPA. as
this contraceptive has so far been used in the three
countries from where the present data were collected.
Data are, however, insufficient to assess the influence
on risk of ovarian cancer among long-term users or
risk after long-term exposure.

Adjusind for ore! contraceptive use and IUD use; controls
matched with cases by centre, age. end year nf entry into the

study

com.
year
Scve
ever
age
ever
0.37
troll
able
and
tha:
pow
risk
expc

raise
SUCl

cam
con
brer
the
pub
ado
crea
breh
179
Hot
exp<
(rcl;
give
estn
Th:
infea s
con srur
11 O'
I
werpro
si a:
of
des
wh*
typ
ob\
(23

LIVER CANCER

* Adjuxied ‘or •yo. centre, ape at first live birth, total number
of live b>r:hE. oral contraceptive use and IUD use.

‘ Ad(usted for age. centre, total number of pregnancies,
history of vaginal diacharge. age at fit*! «exunl relationship
number of sexual partner*, number of Pap •meart, oral contra
ceptive use end IUD use

Results from the WHO study

A’r

Complete data on 57 cases of primary liver cancer
were available for analysis. Two hundred and ninety

1
av.

./

!
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I

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^6
s
379

DEPOT-MEDROXYI'ROGESTERONE ACETATE AND CANCER

controls were matched to individual cases on exact
year of birth, year of entry into the study, and centre.
Seven of the 57 cases, and 34 of the 290 controls had
ever used DMPA, giving a relative risk adjusted for
age and centre of 1.0 (Table 1) in women who had
ever used DMPA (95% confidence interval,
0.37-2.85). This estimate was not altered by con­
trolling for a variety of potentially confounding vari­
ables. including history of jaundice, use of alcohol,
and other factors. These results provide no evidence
that,DMPA alters the risk of liver cancer, but the
power of this study to detect small alterations in risk,
risk in long-term users, and risk long after the initial
exposure is low.

Table 2. Relative risk of breast cancer in relation to
durction of DMPA use; results of the WHO Collaborative
Study of Neoplasia and Steroid Contraceptives
No. of subjects

Relitive risk*

Months of use

Cases

Controls

None

385

5290

1.0

1-12

17

220

1.1 (0.7-1.91

13-36

13

156

1.2 (0.7-2.21

9

157

0.8 (0.4-1.71

37

Figures m p.rcnthe»e. .re 95% confidence mterv.li.

BREAST CANCER

c

(

Limited experimental data in beagle bitches have
raised the possibility that injectable progestogens,
such as DMPA, may increase the risk of breast
cancer. The relevance of these findings to women is
cpntroversial, but they underline the need to evaluate
breast cancer risk in epidemiological studies. Until
the preliminary results from the WHO study were
published (3). there were no publications with
adequate data to determine whether DMPA in­
creases, decreases, or has no effect on the risk of
breast cancer.
In a comparison of 30 cases of breast cancer and
179 controls derived from the Grady Memorial
Hospital in Atlanta (/P). the frequencies of DMPA
exposure were 5 (17%) and 32 (18%). respectively
(relative risk estimate 1.0; no confidence interval
given). For oral contraceptive use, the relative risk
estimate was 0.3 (95% confidence interval. 0.1 -0.7).
This studv had little statistical power and almost no
information on long-duration exposure. In addition
a significant reduction in breast cancer for oral
contraceptive users has not been found in any other
study, raising the possibility of bias in the Grady
Hospital data.
In all other studies (//. /2, 20-22), the findings
were difficult to interpret because of methodological
problems. Among others, these included inadequate
statistical [ owcr, short duration of exposure, absence
of appropriate comparison groups, and sparse
descriptive data In one study, among 19 H75 women
who fcccivcd DMPA. no breast abnormalities of any
(w, c were diagnosed in any of the women, suggesting
obvious und- 'ascertainment of breast pathology
(23).
Results Jratn the H HO Study
This ieport is based on interim anabscs of data
available lor 427 cases and 5951 controls, of whom 39

cases and 557 controls had ever used DMPA. The
relative risk in women who had ever used DMPA was
estimated to be 1.0 (95% confidence interval, 0.71.5), after controlling for the possible confounding
effects of age, centre, age at first live birth, total
number of live births, use of oral contraceptives, and
use of an IUD (Table 1). Risk was not found to
change appreciably with duration of use (Table 2) and
was not altered either in women who were first ex­
posed before age 30, or in women initially exposed at
an older age. Too few women used DMPA before the
birth of their first child to assess the influence of such
use on risk. These findings suggest that DMPA. as it
has been used to date in the three countries from
where the present data were collected, has not altered
the risk of breast cancer. However, the data currently
available are insufficient to assess the influence of
DMPA on the risk of breast cancer in long-term
users, and the risk long after initial exposure.
CERVICAL CANCER

It is difficult to carry out satisfactory epidemio­
logical studies of the relationship between steroidal
contraceptives and cancer of the cervix. First, the
information about potentially confounding sexual
variables is likely tn be inadequate, especially about
age at first sexual intercourse and the number ol
sexual partners. Furthermore, (he sexual histones of
the male partners may also be important. Secondly, it
is known that occlusive method of contraception
offer some protection against cerv:cal neoplasia, so
ihc use of these methods should be taken into
■iccount 1 Im div. almost all pre-mvasive lesions (and
some invasive ones) arc detected by cervical cyiolop
cal screening. I uriheimoie. treatment of pre-mvasive
lesions is .believed to reduce the risk of invasive
disease. Thus, any substantial difference in the

i

*

I

*

.

a* M. 4kMS.

^07

z

3 SO

MEMORANDUM

pattern of cytological screening between groups being
compared could lead to incorrect conclusions.
Finally, histopathologists vary greatly in their inter­
pretation and classification of pre-invasive lesions of
the cervix. This could lead to bias if any one patholo­
gist reviews a disproportionate amount of material
from women using a particular contraceptive
method.
Very few published studies have examined the
relationship between use of DMPA and cervical
cancer; only two, other than the WHO study (4), arc
mentioned here. Powell & Seymour followed up 1123
women in Texas who used DMPA for a total of
14 000 woman-months (24); only 51 of these women
accumulated more than 4 years of use. Both'the
abnormal cytology rate and the rate of biopsy-proven
carcinoma in-situ were higher in the DMPA users
than was expected from past experience in the same
centre, but no allowance was made for the effect of
confounding factors such as age, social class, race, or
sexual behaviour. A study conducted by Dabancens
ct al. (70) in 1974 in Santiago. Chile, included 2409
IUD acceptors and 2684 comparable women who
accepted injectable contraceptives (2234 with
DMPA. 445 with chlormadinone). Of the women
using mjcctablcs, 331 accumulated more than 4 years
of exposure. In total, 9 women in the injectable
groups (I.26/J000 woman-ycars) and 6 in the IUD
group (I.82/IOOO woman-years) developed preinvasive or (in 2 eases) invasive lesions of the cervix.
Although reassuring, this study is handicapped by its
small size.

f\es:i!ls from I he WHO study

(

These interim analyses are based on 920 cases of
invasive cervical cancer and 5833 controls with
complete data at the coordinating centre as of 14 June
1985. One hundred and twenty six cases and 54S
controls had ever used DMPA, giving an estimated
relative risk of 1.4 after adjusting for only age and
centre
However, after adjusting also for the
potential confounding effects of total number of
pregnancies, history of vaginal discharge, age at first
sexual relationship, number of sexual partners,
number of Pap smears, use of an IUD, and use of or al
contraceptives, the relative risk of invasive cervical
cancer in women who had ever used DMPA was re­
duced io a non-significant 1.2 (95% confidence inter­
val, 0.9-1.5) (Table I). This small elevation in risk
could be a result of residual confounding due to im­
precise information on sexual behaviour of the study
subject, or to confounding by other variables not
considered, such as smoking or sexual practices of the
subjects’ husbands. As shown in Tabic 3, the risk did
not increase with duration of use, which also suggests
that non-causal factors may be responsible for the ob­

public
rnetri
strait
becau
provi

Table 3. Relative risk of cervical cancer tn relation to
duration of use of DMPA: results of the WHO Collabor­
ative Study of Neoplasia and Steroid Contraceptives
No. ol subjects
Months ol use

Cases

Controls

None

1 0

782

5184

12

58

216

13-24

20

92

1.2 -'0 7-2.0)

25-60

17

127

0.6 <0.4-1.11

61

26

86

1.4 (0.9-2.2)

1

Tb?
ducte
matic
data •
liver,
of Di
are C
cancc
There,
term
reass
Foworn*,
confi
trend
certa
An eloral
insta
adjus
Tc
worn
have
on c:
conti
tic nr
any
appe
stud

Relative risk*

1.4 (1 0-2.01

** Adjusied
centre, year
year of
of entry.
entry, total number of
Adjusted toi
lot age,
age. centre,
pregnancies, vagmal discharge, age at h-si mtercourt '. number
c.t sexual pannets, number of Pap smears, oral contraceptive use
and IUD use Figures in parentheses arc 95% confidence

intervals

served small increase in relative risk.
Although the risk of cervical cancer among long­
term users (use for more than 4 years) was no greater
than among short-term users (use for one year or
less), the subgroup Or long-term users was examined
further because earlier, published analyses had
indicated an increased risk among this subgroup (4).
Among women who had used DMPA for more than 4
years, the relative risk of developing cervical cancer
before the age of 36 was estimated as 2.3 (95% con­
fidence limits, 1.5-3.6). Among women aged 36 to 45
and 46 to 60 years the risk was estimated as 1.7 (95%
confidence limits, 1.4-2.1) and 0.4 (95% confidence
limits. 0.2-0.8), respectively. A relative risk estimate
of 2.4 (95% confidence limits. 1.9-3 0) was observed
among women who had first used DMPA before the
age of 30 and who had used it for more than 4 years,
whereas (he risk for women who had first used
DMPA after the age of 30 and had used it for more
than 4 years was 1.3 (95% confidence limits, 1.0-1,7).
However, it should be noted that these arc prelimi­
nary data, the number of subjects in the subgioups is
small, and the significant findings are a result of mul­
tiple subgroup analyses.
The magnitude of the risk elevation.- among young,
long-term users of DMPA is similar to that reported
for cervical cancer in young, long-term users of oral
contraceptives. These findings might indicate an
effect of the steroids on risk; an alternative explan­
ation is incomplete adjustment for confounding
factors.

Sup.
M

R. (
M
C. f
B. f‘
U.

CONCLUSIONS
1

Until recently, there were no adequate studies of
the effects of DMPA on cancer incidence. The

4 Li
■

-

f

381

DEPOT-MEDROXYPROGESTERONE ACETATE AND CANCER

published

data concerning cancers of the endo­

Kenya, Medical
Kenya

Research Centre, Nairobi,

V. Odlind, University Hospital, Uppsala, Sweden

because of methodological limitations, these data

Tieng Pardthaisong, Chiang Mai University, Chiang

provide only limited reassurance.
The multinational case-control study being con­

Mai, Thailand
D. Pctitti, University of California, San Francisco,

ducted by WHO provides the first reliable infor­
mation on DMPA and neoplasia. The preliminary

CA, USA
G. Rubin, Centers for Disease Control, Atlanta, GA,

data concerning cancers of the endometrium, ovary,
liver, and breast suggest that there is no risk in users

USA
S. Shapiro, Boston University School of Medicine,

of DMPA. The relative risk estimates for these sites
arc 0.3 for endometrial cancer, 0.7 for ovarian

Brookline, MA, USA
Siporn Silpisornokosol,

cancer, 1.0 for liver cancer, and 1.0 for breast cancer.
There is still only limited information about long­

Chiang Mai. Thailand
D. Skegg, University of Otago,

term users of DMPA, but these interim results are

Zealand
Suwanee Srisupandit, Siriraj Hospital, Bangkok.

reassuring.
For cervical cancer, the adjusted relative risk in

I

P.

metrium. ovary, breast, and cervix did not demon*
•strate any increased risk associated with DMPA bur.

women who have ever used DMPA is 1.2 (95*70
* confidence interval, 0.9-1.5). There is no consistent

trend with duration of use of DMPA, although
certain subgroups of women show an increased risk.
An elevation of risk has also been observed in users of
oral contraceptives in the WHO study.

Chiang

Mai

University,

Dunedin.

New

Thailand
B. Stadcl, National Institute of Child Health and
Human Development, Bethesda, MD, USA
D. Thomas, The Fred Hutchinson Cancer Research
Center. Seattle. WA, USA
M. Vessey, University of Oxford. Oxford. England

In both

instances, it is possible that this is due to incomplete

adjustment for sexual risk factors.
To date, in the WHO study only a small number of

WHO Secretariat

P.

tional studies focused on these specific topics. Since
any effect of DMPA on cancer incidence might not
appear until after a delay of many years, further
studies will need to be carried out in the future.

Special

Programme

of

Research.

Reproduction. WHO, Geneva. Switzerland

have had a long interval since first use. Information
on cancer risk in these women can only be gained by
continuing the present study or by initiating addi­

Corfman,

Development and Research Training in Human

women have used DMPA for prolonged periods or

E.

Diczlalusy,

Special

Programme

of Research,

Development and Research Training in Human
Reproduction. WHO. Geneva, Switzerland (Con­
sultant)
P. Hall. Special Programme of Research, Develop­

ment and Research Training in Human Repro­
duction. WHO. Geneva, Switzerland
S. Hat lap, Special Programme of Research, Develop­

I

ment and Research Training in Human Repro­
duction, WHO. Geneva, Switzerland (Consul­

!
I

Supawat Chutivongse, Chulalongkorn
Medical School, Bangkok, Thailand

Hospital

R. Gray, The Johns Hopkins University. Baltimore,

MD. USA
C. Hill, Institut Gustave Roussy, Villcjuif. France
B. Hulka, School of Public Health, Chapel Hili. NC,

tant)
S. Hoick, Special Programme of Research. Develop­

ment and Research Training in Human Repro­
duction. WHO. Geneva, Switzerland (Secretary)
L. Mehra, Maternal and Child Health, WHO,

Geneva. Switzerland
M. Ten Ham, Pharmaceuticals,

WHO,

Geneva,

Switzerland

USA (Chaitman)

REFERENCES

I
I

I. WHO Technical Report Series. No. 619. 1978 {Steroid
' contraception and the risk of neoplasia: report of a
WHO Scientific Group).

2. Facti about injectable contraceptive*: Memorandum
from a WHO Meeting. Hullciin of the World Hrahh
Organization. 60: 199-210 (1982).

"7^'

<r

f

J

t-’S

7

7

5 I

^7

SF.X HORMONE EXPOSIRE DLRING PREGNANCY
AND MALFORMATIONS
M

H

BRIGGS AND MAXINE BRIGGS

Ih ai tn I ni\cr\it\ Hclmnnt. l icioria. Autiraiia
and
I h< (hrlunv Hospital (itrlonv, l ii toria . tu.\irtihu

■

•*

I. (general Considerations ...
II Animal Studies .
. .

in
i\

v

7

\ irilization and Feminization in Humans
Chromosome Abnormalities.
Somatic Malformations . .
Conclusions .

\ i.
References
Appendix: Some Recent Studies .

51
52
55
5x
64

77
79
R2

I. GENERAL CONSIDERATIONS

■

■■

■

Mi

The implantation and development of the fertilized ovum requires an
adequate supply of maternal sex hormones. It may therefore be questioned
why it is necessary to suspect sex hormones, in certain circumstances, of being
teratogens. The reasons are twofold. First, the amount of sex hormones
received by the developing fetus during early pregnancy is relatively small. It
is therefore a reasonable question to enquire what will happen to the fetus if
the supply of hormone is multiplied severalfold. Secondly, it is. or has been,
common practice to administer in certain clinical circumstances during early
pregnancy not just the natural sex hormones of the woman, but also their
synthetic analogs. Obviously, there can be no guarantee that the possible
teratogenic properties of sex hormone analogs are identical to those of the
naturally occurring steroids.
There are three major circumstances in which a developing human fetus
max be exposed to sex hormones administered exogenously during its early
and critical period of embryogenesis. The first of these is where hormones are
administed as a pregnancy test. This practice has been largely superseded by
the use of immunological pregnancy tests, but hormone preparations are still
available in a number of countries. The use of hormonal pregnancy tests was
very widespread a few years ago. Table 1 provides a list of hormonal preg­
nancy tests that have been available.
51

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INDIAN
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XS*\\r
OF
MEDICAL RESEARCH

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Annual Report of the
Director-General

1978

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(immediately after expulsion of placenta) and post-partum (within seven
days of delivery) groups and CuT 200, Nova T, MLCu 250 and Lippcs
loop in the interval group. Preliminary analysis of the data reveals that
acceptance of IUD in the post-partum and post-placental groups is very
poor. The incidence of expulsion in all the devices is found to be very
high in the post-placental and post-partum groups. Expulsion in the post­
partum and post-placental group was highest in the first three months,
gradually decreasing and becoming comparable to the interval group in
the fourth month. There was no significant difference in the incidence of
pregnancies and side effects with all the devices. Continuation rate was
poor in the post-placental and post-partum group due to high incidence
of expulsion. These trials arc in progress.
Robini Merchant’s Device

1

I

This device has been designed by a leading gynaecologist of
Bombay. In view of the favourable preliminary report by the designer,
a pilot trial with a plan to enroll 100 women per centre at 4 centres was
started in December 1977. A total of 151 women were enrolled till July
1978. Of 151 women, 42 had the device inserted immediately following
abortion, 12 had within 2-20 days either after delivery or abortion while
the remaining 97 were interval cases. Three women became pregnant
within five months of use (interval group).

$

HORMONAL CONTRAC I PI 1VES

1

Oral Contraceptives and Lactation

It was seen that when the steroids were given to lactating women,
substantial quantities of contraceptive steroids could be detected in their
breast milk. The significance of these findings can only be understood
by observing the children of mothers who had earlier been given steroidal
hormones during lactation at a time when such data on excretion of
steroid in breast milk was not available. Studies have been initiated at
IRR, Bombay, to follow up these children.

■j

Si

■

I
i:

J

-I
i

I

I

Steroidal Contraceptives and Sex Hormone Binding Globulin Capacity

Sex hormone binding globulin capacity (SHBGc) acts as a fulcrum
in the balance between androgenicity and estrogenicity. A study at JRR,
Bombay, showed that low SHBGc is a major finding in patients with
hirsutism as compared to SHBGc found in the normally ovulating control
group. Combination contraceptives are believed to act in two ways in

58

i

i

I

I

lithin seven
nd Lippcs
.cals that
is very
o be very
the post. months,
group in
id cnee of
rate was
•m idencc

•'L’ist

o(

I

this condition i.e. by decreasing ovarian testosterone and by increasing
SHBGc, thus making physiologically active testosterone less available.
The data indicates that norgestrel containing contraceptives decrease
SHBGc and those containing norethindrone increase it.

1

■■

b?

Evaluation of Probable Risk of Conception in Women Missing the Pill on
Two Consecutive Days

; P;

It is known that women who miss pills in a cycle run the risk of
conception during that cycle. However, there has been no well planned
study to indicate the likely days on which missing of the pill would lead
to escape ovulation and subsequent conception. Using progesterone
values as a parameter, it was shown in a study at IRR, Bombay, that
50 per cent of women who missed pills on the 12th and 13th days of the
menstrual cycle had escaped ovulation. However, the finding of reduced
cervical mucus and persistently suppressed endometrium indicated the
existence of some protection against conception in these women.

-

K signer,

<•

was

i.II July

. Ilouing
ji ttbile
. gnunt

a omen,

n their

Evaluation of Teratogenic Potential of Steroidal Contraceptives
t

In view of the clinical reports of congenital anomalies observed in
children exposed to steroidal compounds during foetal development, a
study has been undertaken at IRR, Bombay, to evaluate the teratogenicity
of a combination pill containing norethisterone and ethinyl estradiol in
Holtzman rats. Preliminary results indicated high embryotoxicity with
treatment during the early period of organogenesis at all dose levels
studied. However, drug administration after this showed a dose-dependent
relationship. Treatment given during the late period of organogenesis
produced feminization of the male foetuses, with reduction in ano-gcnital
distance. Female foetuses showed profound nipple development and
enlargement of the uterus. The postnatal changes due to this prenatal
treatment are being investigated.

f

K-.;

I

r
6

I

I lood

: oidal

of
at

il'. rum
■ 1RR,
with
< Jitrol
a\ s in

Immune Status and Hormonal Contraceptives

Studies on the effect of continuous intake of oral contraceptives
on immune status of the women revealed that there was no change in cell
mc<li.tied immune status of the women who had taken oral contraceptives
upto 2 years whereas humoral immunity to typhoid vaccine was slightly
diminished. Humoral immunity to tetanus toxoid, on the other hand,
was unaltered.

IIS
&

Studies V5ith Bio-absorbable Implants
Investigations have been undertaken at 1RR, Bombay, to study
the tissue reaction and release rate of bioabsorbable steroid-cholesterol

I

59

1
iISl

I

j ;

I

:xW.-/ •.• ■

'X ,

‘tat

- ;-

■

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i

WORLD HEALTH ORGAN^nON

<

PITT/DI/77.3

ORGANISATION MONDIALE DE LA SANTg
ORIGINAL:

*« «--thritis

ENGLISH

. ■ • :4

v.;, .

!

1

i

DRUG INFORMATION - JULY-SEPTEMBER 1977
■

A bulletin devotedI to international transfer
ol information <

on.current drug problems
-.: ■■

.;

4" -

•

: ••

CONTENTS

■ r

c
I.

page

5b

2

i

GEN’ERAL POLICY TOPICS

I

7' .

1.
2.

•s
II.

Prescribed drugs:

what information does the pa t lent -neetlSi .

Analgesics - Regulations controlling
their supply

3

REPORTS ON INDIVIDUAL DRUGS
Hormonal exposure during early

2.
I

Pyrazolones

pregnancy - the danger of birth defects

5

!

sensitisation reactions in Japan

3..

Aminophenazone -

4.

Spironolactone - the risks of treatment reappraised

possible cancer hazard?

III.

LIST OF PHARMACEUTICAL’ PRODUCTS APPROVED
DURING THE PERIOD 1 JANUARY 1977
30 JUNE 1977

IV.

OTHER RECENT REGULATORY DECISION’S

1.

Aminophenazone .

2.

Estrogens

8
9

J

10

16
16

V.

3.

Norethisterone acetate

4.

Oxyphenisatine .

5.

Phenformin

6.

Tetracycline .

16
16

16
16

OTHER PUBLICATIONS RELATING TO DRUGS

1.

Requirements for drug registration - a survey

17

2.

The Drug and Therapeutics Bulletin

17

« A

I

R 4 78 - R 379
R58O - 1ifii
The issue of this document does not constitute
formal publication. It should not be reviewed.
abstracted or quoted without the agreement of
the World Hauith Orgaim|iphv Authors alone
«'e resoonstble for view*
Jn signed

Ce document ne construe pas uno publication.
II ne doit faire I objet d'aucun cample rundu ou
r6«um6 ni cJ’aucune citation sans l autorisation de

,v‘"“ "

—

... .......................

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PDT/d!/77.3
page 5

11.

.

I

REPORTS ON INDIVIDUAL DRUGS

nS

me
•«. s

•A
This section provides background information on decisions resulting either in withdrawal
or restriction in the use of specific products in Member States.
For the benefit of
countries where access to this information is difficult a short review of relevant published
literature is provided in those cases where an apparent conflict of evidence exists,

founded,
serious
at ions
fere
icoagual so

I
||

HORMONAL EXPOSURE OCRING'EARLY PREGNANCY ~ THE DANGER OF BIRTH DEFECTS

1.

The diagnosis of early pregnancy became simpler, more rapid and more reliable when
hormonal tests first began to compete with pharmacological assays of urinary chorionic
Consequently, when orally~effective synthetic
gonadotrophin in the early 1950s.
progestogens replaced the earlier injectable formulations in 1956. these tests acquired
Their’act ion results simply from the induction
considerable popularity in many countries.
of menstrual bleeding when a high dosage of a progestogen administered over a period of two
ter five days (and in practice usually combined with a synthetic oestrogen) is suddenly
Failure to produce bleeding in these circumstances suggests, with high
wi thdrawn.
probability, that the patient is pregnant.

r» the
•tw

us «>•-

orking

The fact that progesterone itself and other progestogens had long been used (on
evidence that has recently been criticised as inadequate) to support pregnancies liable to
terminate in spontaneous abort ion^^ may have fostered confidence that, normal foetal

f -3
cis.

development was not jeopardised by transient exposure to these substances even during the
period of organogenesis.
Over ten years later however, in 1967, the possibility that
hormonal’ pregnancy tests carried a demonstrable teratogenic risk was raised by a group of
paediatricians in the United Kingdom.<2>
In a retrospective case-control study it was
noted that nineteen of 100 mothers delivered of infants with meningomyelocele or
hydrocephalus had been subjected to a hormonal pregnancy test, while only four of the 100
No important differences
mothers selected for control purposes had undergone such tests,
between the two groups were identified w ith respect to any other drugs taken in the first

t rimester.

Although the evidence could not be regarded as conclusive, it brought into serious
question the wider issue of the possible teratogenic potential of synthetic sex hormones,
A
whether used diagnostically, therapeutically or inadvertently during early pregnancy,
subsequent demonstration of teratogenic activity among steroid hormones widely used in
contraceptive preparations when administered to rodents(3) added a further dimension to these

misgivings but. surprisingly, no additional epidemiological evidence was generated for over
five years.
Then, within a period of twelve months, three independent retrospective
studies were pub 1ished(4’5'6> in which the effect upon organogenesis of any exposure to
exogenous sex hormones was investigated.

The prenatal histories of 76 children with transposition of the great vessels born
in Canada between 1942 and 1972 were compared with those of matched controls selected
from children with hereditary congenital defects.
Six of the case mothers and
none of the control mothers recalled taking hormones during the first three months

i

of pregnancy.

Evidence of similar exposure was obtained in 20 of 224 chi Idren_with unspecified
congenital heart disease traced by investigators in Colorado, United States of
(5)
America.A
positive history was obtained in only four of an unmatched series of
2G2 controls.

In a case-control study based upon information from registries compiled in New York
State, United States of America, prenatal exposure among 108 children with limb­
reduction defects (absence, in whole or in part, of a limb or digit) was compared
with that-among normal matcher! controis.(6>
A history of exposure was obtained ir
15 of the cnh.’ children as oppos'd tn lour of the controls
These data were of

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POT DJ 77.3
page 6
t

particular interest in two respects:
firstly the postulated effect appeared to be
spec; i f i c since
• •—- all eleven affected children exposed
orally-administered
- hormones we re ma 1e;:
secondly, 12 of the case mothers in contrast to only three of
the control mothers had
1
1 become
pregnant either while using oral; contraceptives or
within one month of discontinuation.

•
Although, in each case, an apparent increased risk of congenital defect following
exposure was identified, a consistent pattern of evidence failed to emerge because the
attention of each group was focused upon a different category of anatomical lesion.
Nonetheless the possibility that these results reflect a broad, non-specific teratogenic
action of steroids^jex hormones was subsequently supported by a survey undertaken in West
,erusa em
srae .
Information drawn from a large record-1 inkage system suggested that
the risk of major malformations was
increased rapproximately 25% by exposure to hormones,
was increased
no a i progestogens,
for minor malformations the corresponding figure was about 33%
Having regard, however, to
the exceptionally
exceptionally high
7.8% for the incidence of
to the
high estimate
estimate of
of 7.8%
abnormalities within the control group,
the general
general relevance
of
these results
group, the
relevance of these
results is open to
question.

it prog,
St «j L«s
progvs;
lyn-.t’
and
exp 1-s;.
the fir
pregnan
an expl
should
Physic!
part lew
mother
Reforcn

X> 3 f

Since the fallibility of r~
‘---retrospective
surveys is well recognised it must be conceded,
to give perspective to these findings,
„ , that much of the foregoing evidence suggests that the
risk of malformation following exposure is of the order of 1%(8
(8)' and similarly-designed
surveys have failed to establish
any association between hormonal exposure and congenital
(‘•-12)
defects.
Moreover, there is no evidence to suggest an important
secular change has
occurred in the incidence of birth defects over the past decade.6•13
Nonetheless, there
is a wide consensus of opinion that,
in the present state of knowledge, all unnecessary
exposure to steroidal sex hormones in early pregnancy should
be avoided.
Strong support for
this view has now been provided by r-------a prospective cohort study conducted in twelve hospitals
in the United States of America in which information was collected
on 50 000 women recruited
during early pregnancy between lf'58 and 1965.14Nineteen children with cardiovascular
defects (among which trunco-conal anomalies were common) were born to 1042 women who had
received steroidal rsex hormones during early pregnancy (18.2 per 1000).
The comparable
incidence of these defect
-- ^ts among the remaining unexposed children was 7.8 per 1000.

/

UX 2

. (

I

3

/

4

I

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I

I

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5

hi

6
J

The continued use of hormonal pregnancy tests has evoked specific criticism(15, 16}
particularly now that iimmunoassay
---- --of urinary chorionic gonadotrophins is considered to
provide a safe and reliable alternative test.
Hormonal tests were certainly implicated in
most of the surveys summarised above, and three more recent investigations (two of then,
conducted by groups responsible for the earlier publications) have provided confirmatory
•' v) dence:

7

8

9

A history of exposure to steroid sex hormones during the period of
organogenesis was
obtained in 13 of 19 cases of multiple congenital abnornaJities
seen in Colorado,
11.11 t'd 5:t at es of Amori ca ( 1 / )
Six of the hormonal exposures resulted from pregnancy
test s.

io

T went y-1 hrev of 1-lH random 1 y-sc) ect ed , seriously malformed children notified in
Ing land and Wales during 1971-72 had been exposed
in utcro to hormonal pregnancy
lests.^1^)
The exposure rate within
a group of prart're-matched" controls was
three-fold less.

11

W

N.

Sr

Oi

Mi.

12

Among a series of }(>4 infants with congenital heart disease born in New York State
between 1971 and 1974, 10 had been exposed prenatally to hormonal pregnancy tests.
6 to supportive hormone treatment, and two to inadvertent oral contraceptive usej19)
Only three of the matched control children were similarly exposed.

13

!■

I

. -x’zp.t;

14

..voral national drug regulatory agenclos. although
some other countries the tests remain
although in
i
vailable for uso in circumatancos whore a firm
decision has already been taken to terminate

a*

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page 7

a pregnancy, e„u
’ t ha.s
rnnfirn|^d
The Food and Drug Administration
States of Awurica
however, has now taken
.
f
1
of the United
p roges t ugeni.' 20 >
an additional step to regulate
lynestrene!.
^S7ox7p>^te^.on^tniSter0^e■ Cj
the use of aii
pr^rr r* <• » rs x-- -

appeared to be
x»istered

•

^ly three of

,-epri«'os or

•*

7

following

f.

cause the
■sion.

• *0 *- -* v UrVf IV 9

etynodiol, hyd roxyprogex terone.
and progesterone) by reouirin
.J megestrol, norethisteronc,
noretynod re1, norgestrel,
explaining to the patie’
tHf
* 163/160 bfl
these
---J drugs are
the first four months of p ‘ n.nT^56"
°f blrth
prescribed

they arc taken during

In addition, all recant

pregnancy.

“ they are used as

tfgested that
normones,
«’l 33k.

a test for
an explicit recommendation that
in h
x
"““n “^ted
to the physician
d not be
prevent
?
enCe Ot *d«^ate
must now carry
90
habitual abortion or to treat evidence of efficacy, they
threatened iabort ion.
particularly for entr^pUnn™” '7 P°S3lbillt>f
pregnancy before j--.
and
prescribing hormones
mcthor of the potential risk
pother
.
they bo taken
-•I during pregnancy to the foetus.
to inform the

I'-nce of

Rf f '• renews :

r. XX

eratogenic
ken in West

'

I
I
-1

en to
1

Smith,
e conceded,
’ts that the
-signed

^g^nital
hange has
i*ss,

Andrew, F D , f*
Christensen, H D.,
Williams, T.L.
°f Contraceptive
• - -4 Steroids in

!

there

O.w., Smith, G.v.s

(1949) Use of
from complications
c-’iethylstilbestrol
to prevent fetal loss
°f late pregnancy.
New Fngl.
Med . , 241. 562-568
2
Cai- I . Kirman,
B . Stern, 3. (1967) Hormonal
Mai formation.
Pregnancy Test s and
Nature, 216,. 83
Congenitai
3

/

essary

Mice and Rats,

•1

. support for
■ hospitals

(1973) Comparative *■
Teratogenicity
abstract. Teratology,
• Z.

Levy,, E.P.,

Cohen, a., Frazer,
Congenital Heart Defects,

1]

I

F.C

(1973) Hormone
Treatment taring Pregnency and
Lancet, 2. 611

J5 recruited
ascular
•'ho had

5

Nora, j.j.t

parable

Nora,

A.H.

(1973) Birth

941-942

I

Defects and Ora! Contraceptives.

Lancet.

X.

I1

6

I

•Janerich,

r
D “
T , Piper, J m.,
Glebat is,
Congenitai
--1 Limb-Reduction

DM (•(1974)
Oral Contraceptives
Defects. New Engl, .j'
and

=5.16)
7

ci to

!

rated 1 r.
thpwi
■w

Harlap, s . rPrywes,

291,
R

Progesterones
-..wj in

8

I

Sora

Teratology,

A H.

Lancet. 1, 682-683

l.i

Defects and Oestrogens
a nd

<1976) Contraceptive Hormones
and Congenital Hea rt

331-332

Di sease.

9

i

•*sis was
•ratio,

N°ra.

697-700

Davias. AM. (1975) B.ith

regnancy,

N.. Goujard, J . Hue 1, g . , •'
. Humeau-Rouquette
Teratogene des Hormones Sexuelle
■ -1972) Etude du R61
e
—js. Premiers rResultats d’une Enquete A
Po r t a n t sur 20 000 Femmes,
La Revue du JM«*d icine,
pidt'm iolog ique
-------- •
2683-2694
10
Oak‘e;V; G ”■•
W.^-. Falek
A

!

rregnancy

m

Lancet.

malformations.

2.

256-257

(1973) Hormonal

• ICY

I

.1

pregnancy tests and congenital

11

<*35

Mulvihill,

j

j,j

Prenatal Sex

• ^IvihiU. C.G.. Neill, C A
Hormones, Lancet, 1, i168

(1974) Congenital

12

State

Yasuda,

ws.

M..

Miller,

Transposition of

.^.<19)

13

Heart Defect s and

J r

(1975) Prenatal
Exposure to Oral Cone
racept ives and
the Great Vessels in
Man, Teratology, 12. 239-243

Department of Health and social

$

•Jblic Health.

■u 1
bl

London.

HMSO

Security. United Kingdom

(1972 ) The State
o f i he
i

Heinonen, O.P.,

remai n
re’na te

0" ''r",son- «
Hook. E B
Birth Defects
, Shapiro.
and Antenatal Exposure to Female Sex

296.

67-70

S. (1977) Cardlovascular
'-a Hormones, jjew Engl. .}; Mc.d

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Facts and Comparisons
St. Louis
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A DIVISION OF J. B. LIPPINCOTT COMPANY
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PHILADELPHIA • TORONTO
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Copyright © 1984 by Facts and Comparisons Div., J. 8. Lippincott Co.
■

Copyright© 1978, 1979, 1980 by Facts and Comparisons, Inc.
Copyright © 1981, 1982, 1983 by Facts and Comparisons Div., J.B.

Lippincott Co.

, p, ’ ii d-

;

an nghu reserved. No per. 0. .his
transmitted in any form or by anY
information storage or retrieval
5SSXX?;X'X?nvrriling horn Face.ndComparisens.

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the publisher.

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ISBN 0-932686-85-0

Printed in the United States of America

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111 West Port Plaza, Suite 423
St. Louis, Missouri 63146
314/878-2515

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251

__________________________________ PROGESTINS

(For progestins recommended only for their antmeoplastic action in endometrial cardnoma,
refer to the discussion of megestrol acetate and medroxyprogesterone acetate in chapter 11.
Warning:
Progest

..wr «'■*

3 z'.

''

nts are used beginning with the first trimester at pregnancy in an
- K.w.jnt habitual abortion or treat threatened abortion; however, there is
no adequate evidence that such use is effective. There is evidence of potential harm
to the fetus when such drugs are given during the first four months of pregnancy.
Therefore, the use of such drugs during the first foqr months of pregnancy is not
recommended.
. i
In the vast majority of women, the cause of abortion is a defective ovum, which proges­
tational agents could not be expected to influenca In addition, the use of progesta- v
tional agents with their uterine relaxant properties, in patients with fertilized defec- ;
tive ova may cause a delay in spontaneous abortion.
.. > t m
Several reports suggest an association between intrauterine exposure to female sex
u
hormones and congenital anomalies, including congenital heart defects and limb
<
reduction defects. One study estimated a 4.7-fold increased risk of limb reduction ..'V-vdefects in infants exposed in utero to sex hormones (oral contraceptives, hormone
withdrawal test for pregnancy or attempted treatment for threatened abortion), Somej
of these exposures were very short and involved only a few days of treatment;The
data suggest that the risk of limb reduction defects in exposed fetuses is somewhat A
less than 1 per 1000. If the patient is exposed to progestins during the first four
months of pregnancy, she should be apprised of the potential risks to thejetust

4

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Actions:
Progesterone, a principle of corpus luteum, is the most important endogenous progesta­
tional substance. Local reactions and pain on injection and the relative inactivity of oral
use have led to the synthesis of derivatives which are more effective or offer other
advantages.
Pharmacology: Progestins (progesterone and derivatives) transform the proliferative
endometrium into a secretory endometrium. They inhibit (at the usual dose range) the
secretion of pituitary gonadotropins, which in turn prevents follicular maturation and ovu­
lation They also inhibit spontaneous uterine contraction and induce secretory changes in
the endometrium. Progestins may demonstrate some estrogenic, anabolic or androgenic
activity, but should not be relied upon for these effects.
Pharmacokinetics: Absorption of oral and parenteral oily solutions of progestins is rapid;
however, the hormone undergoes prompt hepatic transformation.

I

Indications:
.
.
. .
Used primarily in the therapy of secondary amenorrhea and functional uterine bleeding.
Also used in endometriosis. Refer to the product listings for specific indications of individ­
ual agents.
Unlabeled uses: Medroxyprogesterone injection has been used investigationally to treat
perimenopausal and menopausal symptoms. Oral medroxyprogesterone acetate has also
been used to stimulate respiration in the obesity-hypoventilation (pickwickian) syndrome.

I
I

Contraindications:
Hypersensitivity to progestins; thrombophlebitis, thromboembolic disorders, cerebral apo­
plexy, or patients with a past history of these conditions; markedly impaired liver function
or disease; known or suspected carcinoma of the breast or genital organs; undiagnosed
vaginal bleeding, missed abortion.
Contraindicated as a diagnostic test for pregnancy.
Warnings:
.
.
.. .
, .
Ophthalmologic effects: Discontinue medication pending examination if there is a sudden
partial or complete loss of vision, or if there is sudden onset of proptosis, diplopia or
migraine. If examination reveals papilledema or retinal vascular lesions, discontinue use
Thrombotic disorders: Because of the occasional occurrence of thrombophlebitis, cerebro­
vascular disorders, retinal thrombosis, and pulmonary embolism in patients taking proges­
tins, the physician should be alert to the earliest manifestations of the disease If these
occur or are suspected, the drug should be discontinued immediately.
Animal studies: Some dogs treated with medroxyprogesterone developed mammary
nodules, some of which were malignant. The significance of this finding to humans has
not been established
Usage in Pregnancy Masculinization of the female fetus has occurred when progestins
! were used in pregnant women.
> Usage in Lactation: Detectable amounts of progestins have been identified in the milk of
mothers receiving them The effect of this on the nursing infant has not been determined.

rJ

(Continued on following page)

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Patient 'n^^^gert available with produ
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DEPG4WVEKA

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inject ab^ CDrut^cepmt

'

Depo-Provera

Information for Patients

3 ™"'hs -

....... tf

Name o! Product
Oepo-Provera

Unhke “the pill”, Depo-Provera
,
be t
used
in 2 ways:
ways:
ti
wd In
, va.
y
sp„„
— As a short-term method (for women
fibuction- has
stopped, and
for women who have been immunised against German me
)■
1___________________
«>ru4 Ini'wnmP

W“eenlieX aqueous suspens.on conta.n.ng 50 mg;ml medroxyprugesu.r r.e

rv’ ' AUS J a long-term method, where other contraception is unsatisfactory.

•

DATA SHEc

c

acetate

e

?M

Uses
’
cont.'sccp’.ion •Dng-te'm cpnirAcep’-ton
Progestogen ’o1
endomeinosis
z ShoH-term eoniracepbon Depo-Provera may
-/
comracepuon wnen an oral contraceptive .s conua-.noicaied
inappropriate »n me following circumstances
efor protection yr1
(i) For wives of men undergoing vasectomy.
(i.)
wn“a°rXng X’uniseq aga.nst -uoeHa. to prevent preqnau - v

btWions always ask your doctor before you have the injection.

. 1-

Sfessrs srwsM

afti
take
3 months or,. in some cases, much longer.
mnnth<;
e,. this may
..... 7 __
__________
•
fe '^sbepo-Provera is a long actingj drug any side-effects may also last for .severakmo
K jwS^ikel'yinflects are given below. These should be carefully considered before

f;*
V• '
'
•■_

most likely side-eflects are given
to use it.

S

Curing me period o! activity o’ me virus
0 tong-rermconrraceolron Deoo-Provera .sentenced lor long-jemuser-j
~
noica'.e- or nave q > : E
women >n wnom ctner coniracecPves
are
ctnerwse
unacceptaoies.ce-eUectsor arec
----------- --wnsabstaciofy
_
............ ■?-’?:.or!s o’ the :cnc ••
II ,s Ol me greates: ■moonance ma: adequate
.
3
r
-d
Gt
•he
imposssC
nature o’ ’he proc-ct. o’ «ts poss’ple jioe-fetec.s ad-e ■ p *• ’ ..
.
...............................
gnuat
users
anc
m-r.
.
t
•••
'
reversing me ehec:s ot eacn tmect.on are given to cotsnuat jSc's a'
' J.
effo
.c ’rmmacetce-surethateacr.-a^n.rece.vessucncounse.hnqastoe;^
receives sucn counselling as io
these explanations.
exc:anauons.
her to iuliv unce'Stanc these
n^pra; medica1 as ..
Cons.steni w.tn gboc cbmcal ccnuace^ve P'ad.ce. a genera, medua.
unceriaKen oe’cre aGrnin<sir«;*
as gynaecoios-CQi examination shouio oe u --- •
Depo-Provera ano at yearly inter .ais lnerea”e, feauiarcc-nsiaerauon
As with other ‘ong-’.erm normonal conuacect*’as
oe given to wneine' me previous‘ ueatment has resulted in.
First t.me -.grame or unusually severe neacacnes. acute .rsu.-.
1
disturbances oi any kind
Re-appearance ol depression
2
Pathological changes :n liver luncuon and no»mone levels
3
c. For the treatrr.er.t of endomethCSis

De^overa causes changes to your

* "irregular or breakthrough oleeamg. This may be nke a oeriod Howeve

fc” XgSXl■'RSfc SRSS5KSSXS&<»i
I There are other less common sioe-effects linked with Depo-Provera use. Tou may wish to
p your doctor about them.

W:
SW.n
T that you are not pregnant when yOu have your firs, won

,

ns are given every 3

Dosage and administration
i ennuia be noted thatu
Doses snouid oe
en oy deep intramuscular miecuon •
endomemos.s
d. lferent dosage reg.me w.tn nigner overall dosage .s reauired .or endomei q
man is recommenced lor contraception
ih? hrst i .<
Contracephon An mjection of 150 mg . m
0O0sl.pa?lum Fyn^e'
days ol a normal menstrual cycle or be o u
wiveso!^enunoercoi -g
doses should oe gr.en at 3-montn intervals * - fnorttns alter the lust may ue
vasectomy a second injeciion ol 150 mg i m . .
~ ••
d-r Snerm cc»' '*
necessary- m a small proportion ol pauenis where me husband . sp

timing of the first injection.

I

Be^ustDe^-Prov'erl ^iong-acting. it takes some time after the last injection for its effect to

wear off Vhis t.me vXs from woman to woman Most women must expect » wa't at leas. 6-8

to the length of treatment.

Because oHne’rsx of’heavy or profonged NeeO.ng m
.n some
some women, tne crug

.K,hX™"S5"r..v. already' gw.n you Id.^ddn •.MM. •"« « ~

should be used with cauhon m me puerDcr.um
,niect«on should
it the puerperal woman w.n oe c'east-leedi .g ..
me system •$ mondelayed until s-x weexs post-partum. when in«
\e ‘J * .mervais
fully developed Funner injections snouid oe x,1 e
Endometnos.s 50 mg . m once a week or ICO mg . m every‘wo weeks-O- mx

. why you might use it. Always ask your doctor if you would like any points in thio
explained or have any further questions.
; Depo-Provera contains 50 mg/ml medroxyprogesterone acetate — dose’3 ml.

i

=>
84
JK

month’s or longer

I

.-. ft-.

Contra-indications
Depo Provera is contra-maic^ted as a contraceptive ai the aoove dosaqe m
known or suspecied hormcne-dependant malignancy ol breast or genital
organs, and in patients with a known sensitivity to medroxyprogesterone
acetate
Depo-Provera should not be used m pregnancy, either for diagnosis or the'apy

Warnings, precautions and side-effects
Whether administered atone or in combination with oestrogen. Depo-Provera
should not be^j^xoioyed in oatients with abnormal uterine bleeding until a
definite diagnosis has been established and the possibility ol genital tract
malignancy eliminated
Doctors snouid therefore cne^k that patients are ng: pregnant before muai >
injection, and also if administration of any subsequent injection is overdue

-----

Medroxyprogesterone ano-'or its metabolites are secreted in breast milk but-----there is no evidence to suggest that this presents any Hazard to the child
A lew cases o’ breast ca’rce' nave been reported m women taking D.?poProvera. out no causal relationship nas been established
Endometrial tumours nave ce^e<ooed in monkeys given 50x the human doss but
(he relevance o’ this ic’man nas not been established
A very low incidence o’ ar.apnyiactoid reacbons nas been reported.
Patients wno nave a history o' endogenous depression should be carefully
observed and treatment discontinued if depression recurs to a sigmf cant
degree
A decrease m giucose tolerance has been observed m some patients treated
with progestogens The mecr.anism lor inis decrease is unknown Foi this
reason, diabetic patients snoufd be carefully observed while tece-ving
progestogen therapy
Interaction with ctner medicinal treatment has not'been reported, bu' the
possibility should be borne tn mind in patients receiving concurrent treatment
with other drugs
Patients receiving Depd-Provera may be subject to the side-ellects normally
associated with the use ol progestogens. in addition, it is likely that some or all
of the following effects may occur
1.
Delay m return to norma, menstrual cycling and transient infertility lasting
up to two years or longer may occur following continuous treatment with
Depo-Provera
2.
Depo-Provera may be expected to cause disruption of the ncrmal
menstrual cycle irregular, prolonged or heavy vaginal bleeding or
spotting may be experienced during the first two or three cycl-.s of
treatment The frequency of occurrence o< bleeding usually decreases
with subsequent injections After one year of treatment some women are
amenorrhoeic
Back pain.
3.
4
Weight gam
Fluid retention
5

I

Further information
The coniraceouve effect of ISOmgi.m Depo-Provera fasts approximately 90 ca
Provera «sa potent progestational agent with very tow toxicity’.pepo-Proverz
ideally suited to tne patient with endometriosis m whom oestrogen aancrogen treatment may be considered to otter too many drawbacks
grounds of intolerance or masculmisation
A 150 mg/mi strength of Depo-Provera ,»$ also available in a 3.3 mi viat
alternative indications

1"

Product licence number
PL 0032/0056

■ i

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Holder ol Product Licence
-—
Upjohn Limited. Fleming Way. Crawley. West Sussex.
Date of preparation or last review
August 1984

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£

Overdosage
No positive action is required.

Pharmaceutical precautions
Store at room temperature and protect from freezing Do not mix with other
agents
JLegal category
POM

Package quantifies
1 ml. 3 ml ana 5 ml vials

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Abortion and Sterilisation
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Bl iefing.. .Page. 7
■The human evidence available
on the effect of injectables
injectabl
on
To foetus is difficult, to
evaluate
primarily
because of a
lack of large- scale studies,
however, DMPA has been associated
with birth defect: and high abortion
rates in both humans and
yiJ,1T.'.-. (.16, p.gU) A leading
expert
in the study ol birth
defects. Dr A]]en Goldman, is
convinced from a thorough study
9; the available • OSes: ch that all r* ■>' 0
c 1*
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more than 70 clinical
‘,eillin9 ”ith the
"mho
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birth defects,
defects, and found
-i-soci'-inirit^ °f tlK' studies are positive for an
u.sociat on ol progestins with birth defects at anv
reasonaole level of statistical significance fS
remairxlor, it should bT^TTTtTansw^
retnembercxl, simply fail to
the question.... They do notI show
show that there
no
association.” (36, p.114)

bone,

Jthough the impact of

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" ’ l^r^T a“e<?uay^y studied to arri
t'-'
----’ve
e at
firm conclusions,

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is lunctronally

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- t.bi r-cily cap-.cr t y and the affinity of the neonatal sex
oLcto.d landing protein is less than m later lifebyrthly, the immature liver has a slow elimination
m /v tv’’'' COr
\SCqUCTt]y a higher
highcr leve]
°f the
consequently
level of
the steroids
-- J .in
, ‘
ouri
lri the
the blood
blood and
and this
this may result in a
)( < Afxxsui <• than would occur
in 1life.
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occur later
later in

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this should hf1C
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----- » reasons why
cpis snould be a major concern.
Mothers usjng hormonal contraception during lactation

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the
l() ,J|<- hormone being used via
unount o'Lf "i’ k' Ori ’heoretjcal grounds, this small
“t <>1 ho,wne nuy be- jxx.entially i.^or^nt since,
'
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Fopul u t j c
1 .n i ct ii a t .1 on It
<-g2 am at Johns Hopkins Uni V-.c :. _ t •,
■’pees tii .11 t: i,
ii c. con t r over s
over DM
PA and NET-OEN and trie
DMPA
1 e1 cac
; ft i i j, j j g
j r,
ngs in some animal
animal studies
studies versus .:om(
■- •• a n St .;(• i •
2' j s
■
1 nipor'..a n t questions about the re sea:-ch
n: . injcctaid es, and indeed,
all drug safety research:
”0 Which animals are relevant, models for
— —‘ studying a drug

used by humans?

o r

]<lrg<‘ arK] I1OW lon9 s}1culd human
studies be before
con t. ra o 'pt i ves o r otiier drugs that do
not. show adverse
f f oct 5; 1 n human.'; are
approved
for
use by informed
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1 r .»• | h< •my

1 a>.• ;(jh. 11 k(’t. 11 kj ;an vei 1 lance, if any, sixjuld
i>e unclei t uken t o look for rare or J
long-term effects
that would be difficult to identify except alter
widespread use?" (37, p.K18)

, :T d'i;’w' r; . ’ 1 those questions lie not only in an analysis of
scicntiirc .evidence-, but
but in
in the much more difficult
■ xamanat ion ol the moral,
socialz 'economic and even political
issues upon which the
whole subject of contraception is based.

Isi
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I

c2^5
Z biosoc. Sci. Suppl. 4 (1977), 165-179

Fertility regulation during human lactation

J

appearance of contraceptive steroids in
HUMAN MILK: EFFECTS ON THE CHILD

I

t

J. K. HARFOUCHE

Department of Community Health Practice, School of Public Health,
American University, Beirut, Lebanon

5

Summary. The realization that steroidal contraceptives administered
immediately after delivery to lactating women may be excreted into milk,
and adversely alfect the neonate, is a cause for concern. Most investigations
pn hormonal contraceptives have dealt with the efficacy of ovulation sup­
pression, and systemic side effects, but little is known about the appearance
of steroids or their metabolites in milk. Apart from the immediate side
elfccts on the neonate, unforeseen long-term consequences require special
consideration. Until research provides us with more information, women
should use breast-feeding and IUDs instead of steroidalcontraceptives during
the first trimester post-partum.

■

X

I

Introduction

(

In recent years there has been a surprisingly rapid acceptance of steroidal contra­
ceptives (oral and injectable). Today, there are about 50 million oral contraceptive
users in the world (Potts et al., 1975), and about 30 million of them arc probably
actual or potential lactators. The nursing infant may be the unintended recipient of
steroidal hormones administered to the mother, especially immediately after
delivery. The mammary gland is a relatively unimportant route for total drug
excretion from the maternal organism (Catz & Giacoia, 1972), but foreign com­
pounds which appear in milk will be ingested by the infant. The neonate has many
quantitative and qualitative differences from the mature adult, which make it
vulnerable Io the adverse effects of exogenous steroids or their metabolites in
breast milk and ingested in a biologically active form. Although immediate side
elfccts of steroidal contraceptives are important, it is the unforeseen long-term
consequences that arc of real concern (Catz &. Giacoia, 1972). We need a contra­
ceptive schedule which, while protecting the mother, is not detrimental to the infant
(Chopra, 1972).
In this paper, data on the appearance of exogenous steroids or their metabolites
in human milk and side effects on the infant are presented. The assets and short­
comings of some studies are considered, with emphasis on the missing links in our
knowledge about this important subject, and the urgent need for further investi­
gation.
165

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INDIAN
COUNCIL
OF
MEDICAL RESEARCH

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Annual Report of the
Direcior-General
1380-81

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Reproductive Biology and Fertility Control

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heahh have
Studies m tl

T

7 COnlro1 as
"^rnal and child
10 reCC‘Ve Pri0'ity “ thC C0UnCirS research ac,iviti«.

C l■ ns
a paS We7car™d out durin? 'he year, not only at the Coun1 s Institute for Research m Reproduction (IRR), Bombay, but at the All
Inuitu "’of' M °f
(A"MS)D--lhi, Postgraduate
.
ute of Medical Education and Research (PGIMER) Chandigarh
Calcutta O„ |,"St)’,’adualc Medical Education and Research (1PGMER)’
Ins itu c’sf M h.
eeSearCh ,nStitUlC (CDRI)’ Locknow, National
stitutc of Health and Family Welfare (NIHFW). New Delhi Indian

£

d e task fo.ee approach m these studies, in view of the problem
vXfs a k°f ''KrC:,SC W,"CJl haS been dcmandi'’f «^nt attention. The
ed pro ems in i?'3 COnS.UtUted ,hcse fic,ds
^ing the year and plann"d projects n the prionty areas, most of which have been initiated during
' uh'in ]t 51 o' arC| hcing
°l" ,hrou«h 17 Ce'>"« 'or Kethe cm. ri" Rcpr°duC"On S,lua,cd in di(rcrent geographic areas of

CONTRACEPTIVE RESEARCH
National Programme for Research in Human Reproduction
The Council had established in 1971, a network of Contraceptive
1 oting Units in different parts of the country. In view of the diversified
actixitics these units were renamed in 1976 as Centres lor the Evaluation
and Adaptation of Fertility Control Techniq
urgency of the problem of population increase,^he C^Inci^adopted^a

gorous poltcy for promoting research by launching a National Programme
f<r Rescatch in Human Reproduction during 1979. The Councifs Task
orecs tn contraception identified priority areas of research and formulated
wlo|US' ! WaS Subsequc,"1y felt that in order to involve the country as a
whole m these programmes, it would be necessary to have at least one-such

T8in wi,h’the number of the

units O1 CEAhCT has been increased to 17 and these

I

I1
I

62

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••

are now redesignated as Human Reproduction Research Centres (HRRCs).
The following arc the objecti\es and functions of these centres :
In the first phase, these centres will form a network of collaborative
clinical research centres for Phase III and Phase IV clinical evaluation of
fertility regulating methods including their psycho-social aspects.
During the second phase, at least one of these Centres is expected to be
upgraded as a Regional Research Centre to act as a nodal point in the
concerned regions viz. Northern, Southern, Western and Eastern. These
Regional Research Centres will be charged with the responsibility of con­
ducting Phase I and Phase II clinical trials, including the development
of newer fertility regulating methods and also introducing suitable modifi­
cations of the existing methods for their adaptation in the national p'o*• grammes.

Tlie central co-ordinating unit at the ICMK Headquarters and six
of the HRKCs have been set up in collaboration with the World Health
Organisation.
Norcthisterone enanthate (NET EN) injections (Phase III trials)

Eailier studies with NET EN 200 mg given every 3 months had
shown dial piegnancies occurred during (he third month following the first
injection of Nl.l EN. I his was probably due to the fact that in a majority
ol women, ovulation is restored by the third month. Results from a WHO
clinical tiial indicate that when NET EN is given every 2 months the inci­
dence ol piegnancies is reduced considerably. However, the results do not
cleaily indicate whether the incidences of menstrual irregularities and meta­
bolic ellecls arc altered in any way. In view of this the Council has initialed
a collaborative study at 12 centres, to compare the contraceptive efficacy
and incidence of side cllccls of NET EN given every two months for the
In.-a six months and then in 50 percent every 2 months and in the other 50
pci cent evciy 3 months. A total of 2403 women will be enrolled for the
siuily and followed for 2 years.
.Norethisterone enanthate in combination with different estrogens (Phase II
studies)

Available cxidence indicates that Ni l EN when injected al 3 monthly
intci\als (200 mg) is associated with a high incidence of irregular cycles. Il
is likely that the addition of a suitable estrogen may induce a withdrawal
bleeding as a result of the fall in estrogen levels, while progestoaen may
cnsinc conliacejjtive protection throughout the month. In order to evaluate
the contiaceplixc efficacy and side cllccls of various combination regimens,

I

63

w-'- -

-rfTO-rf,-’

-

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a collaborative study has been planned. NET EN 50 mg monthly alone
and in combination with estradiol valerate, estradiol benzoate and es­
tradiol cypionate (2 doses i.e. 0-5 and 2-5 mg) will be given. Five centres
will participate by enrolling 10 cases in each of the seven groups.

Return oj fertility following discontinuation of norethisterone enanthate

The injectable contraceptives constitute primarily spacing methods
and. therefore, there is a need to find out the interval after discontinuation
by which the return of normal fecundability is achieved. A prospective
longitudinal study has been planned to follow up all the subjects from Phase
III trials of NET EN who discontinued the use of NET EN after using it
for a minimum of one year. An equal number of matched controls will be
selected from the family planning clinic at the hospitals. The subjects of
the study group and the controls will be followed up for a period of one year
or until conception occurs.
Tubal sterilization with Filshie clip

Tubal sterilization is a widely accepted method of contraception. The
C ouncil’s Collaborative study on sequelae of tubal sterilization has shown
that comparatively younger women with low parity have opted for this
method in fairly large numbers (74-9%). In view of this, one may
expect that a fairly large number of women may seek iecanalisation. Il is,
therefore, essential to find a technique of ligation in the female which is
safe, effective and can oiler a greater chance of reversibility. The Eilshie
clip produces minimum damage to the fallopian tube (i.e. 1-2 mm in con­
trast to 3-4 mm in the standard Pomeroy technique) and hence can offer
higher chances of successful recanalisation. A clinical trial has. therefore,
been initiated with a view to study the efficacy and also the immediate,
short and long term mortality and morbidity pa!tern of interval and puer­
peral sterilization with Filshie clip by mini laparotomy approach. The trial
has been initiated al 10 HRRC’s. Each centre will be enrolling 100
cases which will be followed up for one year.

e

( oniparative studies on isapgul tent. Laminaria tent and manual dilatation

Data from several studies including the ICMR's Collaborative study
on short term sequelae of induced abortion have indicated that slow' dila­
tation of cervix prior to vacuum suction may achieve a substantial reduction
in complications following MTP. Laminaria tent being used for achieving
slow cervical dilatation needs to be imported and is expensive. 1 urthcr,
as it is to be left in situ for 24 hours, the women have to cither come back
after 24 hours or stay overnight in the hospital. This can impose practical
64

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j Vol. J] No. 12

December, 1981
E\ A I,CATION OF FERTILITY’

REGULATING METHODS IN WOMEN

Rapuily expanding population and limited
resources arc thought to be the most pressing global
problems today. 1-enihty regulation has. therefore
J become the major concern of people of all walks of
1 hfc. I he second half of the twentieth century which
wnnessed the most massive increase in population in
. the history of mankind also witnessed the discovery
and w,despread use of dependable effective contracepnvc methods
Prolonged use of contraceptive
methods by practically cvcry human being is an
essential prerequisite for the control of expandinu
population.
Tins means that lor the first time
enormous numbers of healthy men and women will
be exposed to contraceptive agents for long periods
of time. It is, therefore, essential that the efficacy
■md safety of contraceptive methods be evaluated
with care. 1 xhausnve studies on safety and efficacy
"ic uding ei.eet on progeny in experimental animals
at least one of which is a subhuman primate, precede
any studies on human volunteers. Preliminary studies
in binned number of volunteers for safety and effi­
cacy form the first two phases of evaluation of
contraceptives in human beings. These are followed
by Studies on acceptability, use effectiveness, clinical
and metabohe side effects. If these arc satisfactory
contracepines ,ue released for clinical use, however,’
epidemiological studies on short and long-term
sequelae, return of fertility ami possible effects on
progeny eiihe. because of accidental conception
due to method failure or ingestion of contraceptives
^xereted^n breast milk, continue over several years to

i

i

keep track of possible long-term
consequences of
contraceptive usage.
A summary of the work done in the contraccptjvc testing units of the Indian Council of Medical
Research (ICMR) especially the one situated in
Madurai and the National Institute of Nutrition,
Hyderabad, during the last decade witu respect to
evaluation ol low dosage combination pill, low <h
Js.iiie
injectable, intrauterine devices (ICDs) like
Eippe’s
loop and copper I device, and lubcctomy is
1'1 ven
in the next few pai^es.

Oral contraceptives:
Until about five years ago oral contraceptives
(DCs) were the most uideiy used contraceptive
method in developed countries. It was estimated that
over aO million women were using rhe combination
pill •
Ease ol medication and freedom from
immediate side effects were the major factors
responsible for the popularity of the pill. Prospective
studies during the last ten vears have shown that use
of OCr especially in women bc\ ond 35 wars, who
smoke and tend to use the pill’fnr longer than five

<

'cars, is associated with sumc health In/ards2 and
this has led to a fall in rhe numi ci <>: ()(.' users in
dc\ eloped countries.

In India, clinical trials conducted in the IC.MR
nCI W?rk -°f COntr:ICcPlhc TcslinP
during the

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ZmcK cncc varyng fro.n 1 in 10,000 to 1 in 100,000
Si m d.ffercnt rcg.ons.
However, lack of obvious
symptoms and chances of sudden, often lethal
5 haemorrhage in such women renders this one of the
F, most ethal neoplastic health hazards in OC users

.Several comphcated and expensive procedures like
,f liver scan or hepatic angiograms
•
have been suggested
7 and used as
screening methods for detection Jf this
' neoplasm >» OC users.
Most of the hepatomas
secrete AIT h is, therefore, possible that plasma A!T

measurement might sene as a simple screening
procedure for hepatomas in OC users.
.
D°s^
Lhe majonty of drugs is determined
: an he basis o. body weight. The doses of currently
used combmation pills have been tailored to suit the
needs of women in developed countries who weigh on
. .m average 5 5-60 kg. The average weight of Indian
T women from the low income group is only 45 kg.
J Wdl lover dose of progestogen and estrogen suffice
I for the Imh.u, womenThe question is far from
, . acadermc because metabolic side effects and health
f hazards oi
t
I OC use are related to the dosage of
f ingested steroids
Studies undertaken in NIN
. r .
. .
..
Hj deiabad indicate that contrary to expectation for'
. . tuiy
any given dose the steady state of the drug is lower in
undernourished
.... . .
women from the low income group,
his is because undernourished women excrete the
drug faster-'.
However, the dosages of estrogen
(and progestogen m currently available low dose
j eombmatmn pills are still sufficient enough to inhibit
ovulation and retain contraceptive efficacy.

Low dosaje injectable progestational contraceptives;
Dat.i presented so far, indicate that though OCs
are safe and effective contraceptives, acceptance•, use
clfvctiwncss and continuation rate for OCs arc |poor
:unong poorer segments of population in India.
Injections aie a popular mode of medication in this
segment of the population and injcctabic contra­
ceptives might, therefore, be a more readily accepted
method.
Injcctablcs are easier to administer and
monitor ar least in the urban communities.
The currently available estrogen progestogen
combination injecrablcs contain high, dose of estro­
gens and might be associated with metabolic side
fleets and health hazards similar to, if not higher
than the currentlv used ()Cs. Progestoecns are rmor,.

aJ
■-

VI

j .

d to be relatively free from these health hazards.But
the currently available injectable progestogens, depo
medroxy progesterone acetate (DMPA) 150 m" and
norethisterone acetate (NET) 200 m<r contain hi-h
doses of the gestogen, cause ovulation inhibition and
^X£I£_j!sruption of menstrual cvcle and some de' •
IT-TTIHID—of -icniliry after discontinuation ' •
LTl££Lions.
If dosage of the injectable can be
ucc that it acts like the progestational minipih
and not cause ovulation inhibition, mcnstiual and
metabolic side effects might decrease and there micht
be prompt return of fertility. Phase II clinical trials f
were started in the peripheral contraceptive testimj/
umt of JCMR at Madurai in 1972 to investigate
whethc^this was possible. Different doses of NET and
J)MP/A were injectedjancc a^month in volunteers.
Menstrual patterns, occurrence of pregnancy, changes
in target organs like endometrium, cervical mucus and
vaginal cytolog)-, plasma levels of the injected .steroid
and the endogenous steroid levels were used to
monitor these women. Data on these parameters in
women using norethisteronc 0.3 5 mg tablets daily
were used to find out whether the response to rhe
injectable progestogen is similar to the progestational
minipill. Studies were also undertaken to investigate
whether addition of small doses of estrogen would
result in reduction of menstrual disturbances.

Three doses of injection DMPA 10, 15 and 20
mg monthly and three doses of injection NE'I 10. 20
and 30 mg monthly were tested over the next two
years. Injection of DMPA 10 mg or MIT 10 mg
monthly did not have any effect on menstrual csclc,
or target organ and were ineffective as contraceptives.
Injection of NET 30 mg and DMPA 20 mg monthly
caused ovulation inhibition and marked alterations
in menstrual cycle.
Injection of 20 mt! of NT'J j
monthly and DMPA 15 mg monthlv were associated
with far fewer menstrual side effects - similar to those
seen in NE T 0.35 mg pill users. Addition of small
doses
Otestrogens
( ----------to either the injected or ingested
progestogen resulted in some improvement in
menstrual side effects but an unacceptable fall in
contraceptive efficacy,
Ibis might be attributable
to the fact that added estrogens at times nulli^cd
the effect of gestogen on target organs9
Net 20 img monthly prevented typical
< ci •. ical
mucus arborisation
durin midcyclc. Vaginal cyto--

jjnHBsrvc.srz

____________________________________ —

i

i

midcycle. Endometrial biopsy showed considerable
variation, in about 50 per cent of premenstrual
biopsies, glands showed typical secretory change.
Often a mixed pattern of secretory and proliferative
glands lying side by side was noted. At times glands
showed secretory exhaution. Stroma showed patchy
areas of edema and pscudodccidual reaction even
during the preovulatory phase. Changes in target
organs were similar to those seen in norethisterone
0.3 5 mg pill users1 °.

Estimation of plasma NET levels showed that
following an initial peak level varying from 4-6 ng/rnl,
levels often fell below 1 ng/ml. In the majority of
cases plasma progesterone estimations showed that
progesterone levels were above 5 ng/ml in nearly two
tldrds of the women confirming that ovulation had
occurred in the majority of women (Unpublished
data).

There was a prompt return of normal menstruation K{’
and
d fertility following withdrawal of NET 201 2.

Thus studies conducted over the last nine years
have resulted in evolution of a low dosage progesta- •>,’
tional monthly injectable contraceptive which appears !
to be effective and safe and is associated with
minimal menstrual and metabolic side effects.
Monthly injectable contraceptives arc easy to admin-j
isteriand monitor, at least in the urban set up. Prcli-'^
minary phase III studies also suggest that accept­
ability and continuation rates for this monthly :
injectable arc higher than those for OCs among
urban poor (Table II). If wider trials with this inject- i
able confirm these observations, the monthly inject­
able might form a useful addition to the contraceptive
armamentarium in the developing countries efforts '
to contain population explosion.
2C3
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Intrauterine contraceptive devices:

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Investigation of metabolic side effects of NET
20 mg users showed that unlike combination pill
use of NE'E was not associated with any alteration in
glucose tolerance. Total glucose as well as area under
the glucose curve remained unaltered in NET 20
users.
There were no alterations in triglyceride or
cholesterol levels, plasma albumin and total proteins.
Mineial ami vii.imin nutritional status remained
unaltered in NT T 20 users during the first year ol
use’ 1 . Sonic preliminary data suggest that use ol
NET 20 is not associated with any alteration in
laboratory parameters ot immune function nor any
alteration in morbidity due to infection. Phase III
clinical studies undertaken in Madurai and Hyderabad
confirmed the Phase II trial data that NET 20 is an
| effective contraceptive.
Among the pregnancies
reported there was one ectopic gestation.
I he
‘comparatively higher incidence of ectopic gestation
in progestational contraceptive users is well docu­
mented and this is most probably due to alterations
in tubal motility. The comparatively greater incidence
of ectopic gestation in NET users suggests that altera­
tion in cervical mucus is unlikely to be the major
mode of contraceptive action, because, if this were
so. ectopic pregnancy to uterine pregnancy ratio
.liouhl not get altered. Results of phase 111 studies
i.mtirmcd the c.ulicr data that use of NET 20 was
.('.sociatcd with minimal mcnsuuai disturbances.
I here was no progressive increase in menstrual
disim bailees w ith incrcasm:' duiation ol NT. I use.

Hormonal contraceptives, either pill or inject­
able, arc expensive and require sustained motivation
on the part of the women for continued use. On the 2;
other hand intrauterine contraceptive devices (IUDs)
are effective, safe, reversible, economical methods of ,
contraception that requires only the decision to get
the device inserted rather than sustained motivation ;
f<jr continued use. Because ol these advantages IUDs
form one of the most important methods ol mass
fertility control, especially among illiterate, indigent
3
women in developing countries 13. Ample evidence j
has any ■?'
exists today to show that no single inert IUD
1
• clinical
' 1 ]
definite advantage over the others. Earlv
trials have demonstrated that the second generation
bioactivc IUDs, especially Copper T devices (Cui)
max1 be safe and effective alternatives to inert
devices13. Clinical trials undertaken in tthe peripheral
contraceptive units of ICMP, during the earl} 70s
confirmed the safety and efiicao of copper devices
(Cui 200,220, 38OA and CuV’‘
Data from
these trials indicated that of these de\ices Cui 200
was associated with lower menstrual disturl .mces and

1

.II

As a result ot these
in
the National Family
data CuT 200 was introduced
th
the
introduction ot
Planning Programme and \\i
Cu i there was some increase in tin number of IUD

also higher continuation rates.

insert ions

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What is the ideal time
mder
M< H cate at the rin.c
segment ot ’Aomen come

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Goveri iijien t of.
Mi n:i. s l.i~y of Health &

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beleotion :

i:<.althy informed women who souk xomrly
ser'/jco;, co be selected it they lullixl t.**-. . o..crj (. er J a
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Ro^arding parity*

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Data on last del Ivory.

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1 r o ii un -L 3 tic t at i onu 1.

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Gebtational diabeiut.

!:. CtiLua •
Media
RF_DR_26_SUDHA.pdf

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