PETITION UNDER ARTICLE 32 OF THE CONSTITUTION
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- Title
- PETITION UNDER ARTICLE 32 OF THE CONSTITUTION
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1.
List of Dates
2.
Writ Petition with Affidavit
Annexure-I
3.
RF_DR_25_SUDHA.pdf
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* F1
1
37
38
45
46
48
49
55
56
62
63
69
70
76
77 -
81
82
85
86
89
90
94
Note on History of Net-Oen
4e
Annexure-II
Mode of Action & Effectiveness
5,
■Annexure-ITT (Colly)
(i) Hormonal Control of the
Menstrual cycle
(11) Bleeding Problems
6.
Annexure-IV
Cancer Risk
?
Annexure-V
)
The Tragedy of Des
8.
Annexure-Vl
Effects of Progany
9.
Annexure-Vli
10.
Note on Discontinuations
Annexure-Vl it
Note on Return of Fertility
11.
Annexure-ix (Colly.)
Copy of a poster and a phamphalet
issued by Sawai Man .Singh Medical
College Jaipur,
12.
Annexure-X (Colly,)
13.
Guidelines for use of Norethisterone
Enanthate,
95
Anne xu re-XI.
14.
Problems of Service delivery
Annexure-XIi
Copy of letter dated 18.10,1985
15.
Co de Numb e r .■
CMP No.,
11
107
108
111
112
113
114
117
of 1986
An application for Ad-interim
ex-parte stay.
/7
100
of compiling
References
16.
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LIST 01/ DATES
This petition raises substantial questions of law
of General Public Importance in the realm of
family planning vis-a-vis Art, 21 of the Constitution*
The questions are sa)
It is not the obligation of the State to
conceptualize and built institutional
structures with programmes that would ensure
free and rational exercise of fertility
control by informed choice, by women
themselves, which would be in furtherance of
the mandate under Art. 47 of the Constitution ?
If so, any State action to the contrary which is
blind to such an obligation will be unreason
able and contrary to public interest and thus
unconstitutional vide Kasture Lal's case(1980)
3 SCR 1338 ?
b)
Whether it is justifiable for the State to
administer any drug or device to healthy
women to control a normal physiological
process such as pregnancy and thereby bring
r
about a serious disruption in all bodily
functions of women administered the drug ?
Is it not a violation of Art* 21 of the
Constitution ?
c)
t
When the existing family planning programme
which entrusts the matter of fertility
control entirely to the medical profession,
professional social workers, and population
control agencies, all bound by target realizations
and wherein thus exposes women to the abuse of
such devices, is it justifiable to introduce
a new method of contraception, which has a
greater potential for abuse than all other
methods ? will such an action not be
violative of Art* 21 ?
d)
When serious contr-indications and disagreeable
and disruptive side effects of the injectable
i
- iicontraceptive Net-Oen have been clearly
noticed even during the phase III clinical
trials leading to high drop out and dis
continuation rates, and when adequate data
tjill now is not present to rule out serious
long-term health hazards for the women and
their progeny/ which data must be available
before further phases of trials are under
taken and without ^jhich demonstrable data
they cannot be undertaken, is it not
arbitrary and unreasonable to proceed into
phase IV trials as is sought to be done by
the respondents ?
Net-Oen is hormonal injectable contraceptive produced
by schering,
a West German drug Company.
Schering
began clinical studies of Net-Oen in 1957.
is a
Net-Oen (Nor ethisterone oenanthat)
synthetic hormone which is similar in structure to
progesterone a natural female hormone.
dose of Net-Oenz
When a high
a synthetic proge sth rone,,
is
administered/ it totally disrupts the cyclical
integrity of the natural hormonal balance in the body/
just one of the effects of this disruption being the
prevention of ovulation i.e. the contraceptive effect.
1967
The drug under the brand name ot Norigest went on
market in Peru.
1971
It was withdrawn in 1971 and field trials were
suspended after pituitary and breast nodules were
found in experimental rats treated with Net-Oen.
It was irrationally concluded that the
findings in rats w-rc not applicable to human
beings and the drug went back in the market*
1983
Though Net-Oen was known to be available in at least
35 countries/ most of them in the third world/ many
aspects about its safety and efficacy are still
unknown*.
iii
The Twelfth Annual Report of the WHO
1983
states
"... there are a number of questions on the
effectiveness and safety of Net-Oen that
continue to require research: optimal time and dose
regimens, effects on lactation and progeny, long
term sequelae, effects on tipid metabolism, and on
endometrial bleeding, and performance of these
injectables in the normal service situation."
One of the affects of this high doese of
progesterona is to1 create
a major disruption in the
.menstrual cycle. This is exhibited in
the form of
what is termed as menstrual chaos i<,e
o irregular
bleeding. spotting,, changes, in the
frequency, duration
and amount of bloodI loss#
heavy and prolonged bleeding
or a total absence of
<
bleeding.
•Since the mechanism of action of Net-Oen is
not localized to the
overy and both the hypothalamus
and pituitary gland
are equally affected, a disruption
is experienced in
several other bodily systems controlied by these centres such r
as regulation of body
temperature, hunger and feeding,
thirst., sexual
function and emotional changes,
That such bodily
changes do take peace with Net-Oen is
apparent from
the manifestation of
symptoms such as headache, diZ2iness, weight gain, anxiety/depression, fatigue, hyper
tension, decreased libido.
and abdominal distension.
A possibility of irreversible damage and
atrophy exists among long term users of this drug.
■lath qnnugj. Report of the WHO, J9R4
• Little Information from human studies is available''!
on long acting Injectable contraceptions and the risk
o
neoplasia, although results from animal toxicology
city1"5 haVe ralSed OOnOern about Possible carclnogebi'-
i
*D'
i v..
Animal studies are important because virtually
every substance that is confirmed as a carcinogen in
humans also produces cancer in animals.
Furthermore,
about 1/3 of all known human carcinogens were first
identified in animal studies.(e. g. nicoline coal tar)
When a definite risk of cancer has been
established in animal species indicating a potential
risk in humans it is unjustfiable and unethical for
ICMR and unconstitutional and unreasonable for the
Government of India to have a sanctioned the project of
WHO to administer Net-Gen, to several thousand Indian
women for a period of so long as 2: years, with the
question of cancer risk remaining unanswered.
The issue is so serious that It-canoQt-be
dismissed by saying that trials/studies on rodents
are unapplicable and not extendable.
There is a defenite liklihood of risk of
Oen affecting children born to women using Net-Oen
as a contraceptivee
As happened with DES((a= Di-ethyl Stiblestrol
harmonal preparation given to women to prevent
spontaneous abortion)
the children born to women
using Net-Oen may develop serious health problems when
they (the children)
grow u^.
DES daughters developed
a rage form of vaginal cancer when they were in their
teens.
Some progestins particularly those derived
from testosterone like
Net-Oen cause birth defects
such as masculinization of external genitalia in
female children.
These risks of congenital malformation
assume greater significance in the Indian context
where both the family planning services and the
health care system especially for claves and section
at the periphay of the society are far from satisfactory.
•E 1
-v-
The scientific bodies and Drug control agencies are
thus very callous in the matter either by underesti
mating these very real and serious hazards or by
disregarding them by a wave
of hand on 33sumed and
biased
one sided social gOals.
The report of the phase III trial of ICMR
states
"as compared to published studies elsewhere,
higher method failure rates were seen during
the first six months of Net-Oen usage.
The report clearly indicates that as many as
70% of
VvUiiic^
in
contraceptive
cOe.
study did not find the injectable
Net-Oen as an acceptable method of
contra cep tiorie
There are other serious contra indications
for
the use of Net Oen such as s—
Liver disease
Incidence of serum hepatitis
Amoebic hepatitis
Damage to the liver by afflotoxin
Known or suspected genital malignancy
Known or suspected breast malignancy
Suspected pregnancy
Considering that a number of questions
regarding the long term health hazards of Net-Oen use
remain unanswered.
The respondents have no
authority of law to proceed into phase IV trial,
The phase IV trial is conducted as part of
family planning camps,
rthen the injectable is
offered along with other approved methods of
contraception making it appear that the injectable
Net Oen has already been approved for general
use.
(annex, ix) P.P. 95-99
(
‘F’
vi
18-10-1985
Letters were addressed to the Hon’ble Minister for
health and the Drug Controller of India, on tehalf
of petitioner No.l, requesting the banning of all
experimentation with the drug.
received by the petition.
No reply has been
A true copy .of the said
letter is
Annex. XII P.P.108-111
7th April,
1986
Writ petition filed.
i
•Hi
\
■■
IN THE SUPREME COURT OF INDIA
(EXTRAORDINARY JUKISDICTION)
WRIT PETITION (CIVIL) NO.
^^0
OF 1986
In the...matter,Qfl.
A petition under the Article 32
of the Constitution for enforce
ment of fundamental rights under
Article 14/ 21 of the
Constitution.
AND.
In the matter oft
1.
Stree Shakti Sanghatana
through Convenor
Dr. Susie Tharu/CIEFL Campus,
Hyderabad.
2.
Saheli through
Ms. Nalini/
Defence Colony,
New Delhi.
3<
CHINGARI through
Gita Shah,
c/o 2/ Gandhibag/
Ahmedabad.
4.
Dr. Shyama Narang
5.
Dr. Kamala S. Jaya Rao
6.
Dr. Davayani Dangoria
7.
Df. A.K.< VAsudevan
8.
Dr. Ramah2i> Dhaxa.
6
... Petitioners
9.
Mrs. Vimal Balasuoramanian
-Versus1.
Union of India through
its Secretary/
Ministry of Health/
Nirman Bhawan,
New Delhi.
2.
ICMR, through its
Director General/
Ansari Nagar/
New Delhi.
2
State of Andhra Pradesh
through its Secretary^
Department of Health and
Family welfare/
3.
e•• Respondents
To
The Hon’ble Chief Justice of India
and his companion Justices of
The Supreme Court of India.
The humble petition of the
petitioners abovenamed most
respectfully
SHOW^Tri?
That this is q petition under the Article 32 of
1.
the Constitution for the issue of the writ of mandamus
or other appropriate writ order or direction restraining
the respondents from further testing/ or recommending
for use and administering the injectable contraceptive
|
Net-Oen which has jaot been proved as a safe drug for long
term use and .
• Mi III
I"
••'•■"■■■I
is
*—»*-*;.
found to be a definite health
,v.jT-^r/-rrr- ■■■_—■
... ..
hazard when used even for short term use:under Indian'
conditions
2.
That this petition raises substantial questions of
law of General Public Importance in the realm of family
planning vis-a-vis Art. 21 of the Constitution.
The
questions are:
a)
In it not the obligation of the State to conceptualize and build institutional structure with programmes
that would ensure free and rational exercise of
fertility control by informed choice/ by women
and
themselves//particularly by women/ in various
(
3
conditions cf unfreedom, due to social relation
ships, backwardness, poverty, illiteracy etc.
which would be in furtherance of the mandate
under Art. 47 of the Constitution?
If so.
whether any State action to the contrary which
is blind to such an obligation will be unreason-
able and contrary to public interest and thus
unconstitutional vide Kasture Lal’s case.
(1980)
3SCR 1338
b)
Whether it is justifiable for the State to
administer any drug or device to
healthy women
to control a normal physiological process such
as pregnancy and thereby bring about a serious
di sruption in all bodily functions of women
administered the drug?
of Art
c)
I s it not a violation
21 of the Constitution?
Is it justifiable for the state to introduce a
new method of contrception which for women does
which
not have any clearly demonstrable benefit.
poses a definite
risk to their health and a
potential risk to their progeny and which does
not satisfy the criteria of a spacing method of
contraception?
d)
which
When the existing family planning programme
entrusts the natter of fertility control entirely
to the medical profession, professional social
workers, and population control agencies, all
bound by target realizations and which thus
exposes women co the abuse of such devices. is it
4
justifiable to introduce a new method of contra
ception/ which has a greater potential for abuse
than all other methods?
will such an action
not be violative of Art. 21?
e)
When serious contra-indications and disagreeable
and disruptive side effects of the injectable
contraceptive Net-Oen have been clearly noticed
even during the phase III clinical trials leading
to high drop out and discontinuation rates. and
when adequate data till now is not present to rule
out serious long-term health hazards for the women
and their progeny, which data must be available
before further phases of the trials are undertaken
and without which demonstrable data they cannot
be undertaken, is it not arbitrary and unreason—
able to proceed into phase IV trials as is sought
to be done by the respondents?
Phase III and
Phase IV trials as under:
i
5
Whether is it not constitutionally immoral to
f)
conduct phase IV trials/ which are still a stage
of experimentation, in the form of Family Planning
camps where women are lured en mass to participate
in the trial on the basis of biased incorrect and
incomplete information designed to conceal the
experimental nature of the exercise, the serious
consequences of the drug and where women are
unwittingly recruited as guinea pigs without their
informed consent?
Whether is it not unethical to conduct phase IV
g)
trials in this biased fashion and in health centres
which are ill equipped to screen women for serious
in
contra-i'&ications or to deal with complications
that may arise from the use of this drug?
Whether it is not both unscientific and unethical
h)
d)f on the basis of this biased data the drug is
approved for general use in the Family Planning
Programme with full knowledge that the health
services in our country are far from adequate to
deal with the complications of this drug and know
ing full well that the majority of the women to
whom this drug will be administered will be unable
to voice their problems or seek medical relief due
to their social and economic constraints and cul
tural inhibitions?
Currently the 2nd Respondent/ Indian Council
3.
of Medical Research (ICMR) is conducting Phase IV of a
clinical trial with the injectable contraceptive, Net-Oen
jjuii
.i_.i. I-.,
--i—
••—~■
■■ |---- »iw■ i■
-------------------------------------------- ---------:
-6(norethisterone oenanthate) .
The study was started in
August, 1984 through 45 primary. health centges.JPHCS)
attached to 15 medical colleges in different parts of
A total of 2, 250 women are to re covered
........
... .
by this experiments. Earlier Phase III had cove re d._X/5.53
the country.
subjects in 1983^ while the initial 1981-82^ pilot study
by ICMR had enrolled
2,602 women.
This experimentation
with a hormonal contraceptive drug on several thousand
’•
a*
'.'Indian women is-unethical and unsafe ’and should be
s topp ed i mme d i a tely.
< <----The Petitioners have therefore come to this Hon’ble
4.
Court motivated by basic human concern.
They have
definite knowledge and understanding of the abuses and
coercion involved in family planning programmes and the
plight of poor uninformed and backward strata of Indian
women who suffer due to woeful lack of basic health care
They are not opposed to family Planning
facilities.
as an abstract proposition.
They are however concerned
with the set-backs and disrujbticbns in the normal function
ing of bodily system of women, which will set in due to
the use of injectible contraceptive Net-oen.
They are
thus concerned with the ethics and morality of choices of
fertility control by the State, in the face of proven
oontra-indications and of side-effects of such choices.
J
They are concerned with the promotions of standard of
living and the raising of the level of nutrition and
the improvement of public health of people which will be
be tter foundations for free and rational Family Planning
than mere forced thrust of invasive methods in the back■
.1
i—I
Mi
ii
■■■ ,
, ■-
ground of lack of adequately equipged_^nd health care
7
facilities, and existence of ill •"equipped, health care
systems/ and unconcerned professional personnel guided
The /question is thus one
by target realisations.
I of blind Malthus ianism Versus liberty to deal with one's
i own body rationally, in the context of being a member
j
•••—
—■
. of a political society and the mutual obligation if any
arising therefrom.
5.(i)„ The first and second petitioners are Stree Shakti
c*
Sanghatana, and Saheli, two women* s organisation
•» Hyderabad, New Delhi
established in
respectively taking up issues of harrassments/
discrimination and cruelty to women.
The groups
also join with other Civil liberty organisations
on issues of atrocities to the oppressed. The •
third pe-tdStionex^pl.aced' at- Ahmedabad is also
engaged in taking up causes of women through
(ii)
street plays, poster exhibitions etc.
The fourth petitioner is Dr. Shayama Narang, bom
on 26th June, 1951.
She passed her M.D. from
Moscow and then worked in India and abroad in
various specialisations.
In Hyderabad,
she has
worked as a Pool Officer at the Govt. Maternity
Ho sp i tai •
(iii)
The 5th petitioner is Dr. Mamala Jaya Rao, born
on 27th May, 1937.
After obtaining her MBBS#
MD & ph. D. Degrees from Osmania University.
She worked at tr.u National Institute of Nutrition
for 21 years.
At the time of her voluntary
retirement in March, 1984.
She was Dy. Director
and Head EndoScrinology Deptt. of the said
*• Institute.
8 -
(iv)
The 6th Petitioner is Dr. Devayeni Dangoria, born
in 1933.
After passing her MBBS/ course in 1956
and the DGO in 1959 from Osmania University^ she
was in Govt. Service from 1959-69.
370111 London.
took the
has been in private practice.
In 1970 she
Since 1970 she
She worked for the
CSI Hospita, Medak between 1976-79 and has started
her own rural clinic at Naraapur.
She also has a
private nursing home in Hyderabad.
(v)
The 7th Petitioner is Dr. A.K. Vasudevan, born on
27th October1948.
Having passed the final MBBS
examination from Osmania Medical College, Hyderabad
in June,
1972.
He has been in private practice
in Secunderabad, from 1973 and is today a well-
established and reputed practitioner in the city.
(vi)
The
8th Petitioner is Dr. Ramana Dhara, born on
14th
November, 1953 passed his MBBS exam from
Pune University in 1976.
He has established a
private practice since 1979, in an industrial area
on
(vii)
the outskirts of Hyderabad.
The 9th petitioner is Mrs. Vimal Bal a Subrahmanyan
both on 26th April,
1943.
After graduation (B.Sc.)
from Madras University she has been working fore
some years as a Journalist with the Times of India
group since 1980 she has been a freelance Journalist
writing on nealth, population and issues connected
with women’s rights/
in India and abroad.
for several reputed journals
9
6.
HISTORY OF net
Q£NX
NebOe*! is a jjggiopjl .AHje.gjtabie...contraceptive produced
by Schering,
Timi rt-m.ninr r«w*i»iii»nnniiMrii^m_nii un_f.
Schering began
drug conpany.
clinical studies of Net-Oen
first major
field trials were conducted in Peru and in
196 7 the drug
under the brand name of Norigest went into
the market in
Peru. It was withdrawn in 1971 and field trials were
suspended after pituitary and breast nodules
were found
in experimental rats treated with Net-Oen,
Although
iInternational norms require that safety be demonstrated
I in a rodent model,
was irrationally concluded that
the
I findings in rats were not applicable to human
beings and
;the drug went back in the markkat.
7.
D6sipte the fact that Net-Oen has been marketed
and ^^j:983^ was known to be available in at
least 35 countries
>
- f' •
■
v ■
-
.
-
'
in the third world, many world.
safety and efficacy_a^reJstiTf^nkown-
Annual Report
The
ii
of the WHO, 1983 states:-
the5e are. a number of questions on the
-TIT
eff!^£XS?ess and
- r-rn- _,
r-
—
^Net^en. that continue
research ’ Optimal time and dose regi
mens, effects onlactatlonjndprogeny, l^-tem
effects on Elpid metabolism,
and on
endometrial^ bleeding, and performance., of these
injectables in the normal service situation. “
CPP 45-46)
ir Advancedcountries which have stringent safety standards
V
and where vocal health and consumer movements also exist,
d^g. regulatory agencies have either not approved the use
have set UP Public Enquiry
10
It is
commissions to review their earlier decisions.
; significant to note that these public enquiry Commission
H ----------
were set up inspite of^/the /act that the scientific
11
”
' advisory boards in these countries and the WHO had
recommended that Net-Oen could be used safely in the
j------------------ -- ------------------ ; -it.............
Family Planning Programmes.
- T-............... .
.
■■■
A note on the history of
Net-Oen is annexed hereto as Annexure I.
8.
c de
r"'1
-- ----------------------------- ---------------------------------------------
.
- jt 3$ -A2..
WHAT IS NET-OENt
---- ------------Net-Oen (nor ethisterone oenanthate) is( a synthetic ,
( hormonejwhich is (similar in structure to pro^ esterone/a
urmonv.
natural female
The physiological balance of
the reproductive system in women is maintained primarily
by two hormones oestrogen and progesterone.
This is a
finely tuned system in which these hormones are released
cyclically in specificz_controlled quantities/ during
the different phases of the menstrual cycle.
The level
■ of one of these hormones determine the inhibition or
' release of several other hormones affecting the reproducI
tive system.
This conplex and delicate harmonal balance
is controlled by the brain centres/ the hypothalmus ahd
the pituitary gland.
When a high does of Net-Oen/ a
synthetic progesterone^ is administered/ it totally
disrupts the cyclical integrity of the natural hormonal
balance in the body, just one of the effects of this disruption being the prevention of ovulation i.e. the
contraceptive effect.
A note on the mode of action
c of............
. .........
the drug and its effectiveness is annexed hereto as
Annexure II.
pp-
11
9.
DISRUPTION OF HORMONAL BALANCES;
Since a high doee of progesterone inhibits the secretion
of oestrogen and other hormones necessary to maintain the
normal menstrual cycle, lone of the effects^of this high
Ah^dO' se of progesterona is to create a : major disruption in
t
_..— —————
... .....
pp the menstrual
This is exhibited
in the form of
.......cycle.>
.-------------___
what is termed as ^menstrual chaos), i.e. irregular bleeding.
spotting, changes.
in the frequency, duration and amount
of blood loss, heavy and prolonged bleeding or a total
absence of bleeding.
According to the WHO, with Net-Oen
"approximately, one half of the users report at least
ore normal cycle during the first year", .
In other words,
with Net-Oen users
.s, approximately one half of the women
did not have even one normal menstrual cycle during the
first year
This estimate is probably lower than tohat
happens in reality as the studies/ generally do not give
\
.
C tT
”
e the number of women who experience menstrual disturbance
----------at the end of the different injections due to menstrual
abnormality,, which is of importance to the FamilyPlanning programme but not to the individual woman who
suffers the consequences of the drug.
p
It is also impor-
4tant to note that the incidence of menstrual abnormality
jJl
“' ’
'
.......
"
-j jincreases with each successive dose of the injection.
n Further, till now there has been no effective treatment
------------------ --------
-
' xi-1
•. worked out to manage the bleeding problems.
Scientific
bodies recognize only the effect of unpredictable
bleeding vis-a-vis the social and cultural nuisance but
dismiss lightly the effect of such disturbances on the
health
women users which ought to be the fundamental
12
calculus.
For instance, WHO notes
that amenxrrhoea or
frequent bleeding providing it is not heavy, is tifclikely
to pose any health problems for women although the scien-
tific evidence to back up that assertion is totally
„
inaemia>
Xr missing. However in a country like ours {where anae;
xM1, iss_____a common problem in women of the reproductive? age>
,.*?
even a minor increase in the blood loss during the
menstrua! cycle can spell the difference between life
and death.
10.
- V'
< .
- \
r’
zi
J r ■<
A-'1'’
Similarly, since the mechanism of action of Ne%—
Oen ls..H?t localized to the ovary and both the hypothalamus
and pituitary gland are equally affected, a disruption
is experienced in several other bodily systems controlled
by these centres such as: regulation of body temperature,
hunger and feeding,
:changes.
sexHa^- function and emotional
That such bodily changes do take pl ace with
Net-Oen is apparent from the manifestation of symptoms
such as headache.
sS/ weight gain, anxiety/
depression, fatigue, hypertension, decreased
and
abdominal distension.
11.
Further, since Net-Oen suppresses ovarian,, uterire,
.f- Pituitary a nd hypo thalamic function a possibility of
c.’r
irreversible damage and atrophy exists among long term
users of this drug.
The fact that all published docu- •
ments reviewing the acceptability of Net-Oen, are
strangely silent on the possibility of such irreversible
damage, especially in the light of Pituitary tumors
in experimental rats, is just one indication of the
callous attitude of scientific bodies with regard t/>
13
women’s health.
'V
Notes on the Hormonal control of the
uustrual cycle and the Bleeding problems due
administration of the drug are annexed hereto as
Sb—(t> %
Annexure III (Colly.).
12.
LONG TERM EFFECTS UNKNOWNt
A>
Cancer Risk
♦
Information about the potential of a drug to
cause cancer comes chiefly from toxicology tests in
laboratory animals and from epidemiological studies in
humans.
The 13th ar—Pep?rt of the WHO,
1984 stats.
,,L
thuma n s tud i e s: is available on
long acting injectable contraceptions .and the risk of
neoplasia, although results from animal toxicology
studies have raised concern about possible carcinogenicity“4
a
.^J:®,..it.n5>ortant because virtually
l!v^.substance that is confirmed as a carcinogen in
humans also produces cancer in animals,
Fu rthermore,
about 1/3 of all known human carcinogens ^e.g.: nicotine,
> coal tar) were first identified in animal studies.
The
fact that animal studies., with Net-Oen have so far shown
increased risk of pituitary and breast
nodules in rats,
and endometrial cancer\jbi monkf . ysf poses definite risk
of similar problem occurring in women.
The Petitioners
respectfully submit that when a definite risk of cancer
i
has been established in animal species indicating a
potential risk in humans it is ,unjustifiable and unethical
for ICMR and unconstitutional and unreasonable for the
jGovernment of India to have
. sanctioned the Projects^WHO
14
to administer Net-Oen,
to several thousand Indian women
for a period of so long as 2 years, with the question of
cancer risk remaining unanswered.
The issue is so
serious that it cannot be dismissed by saying that
s/studj.eS-on
are inapplicable and not
rodents
S^ich a statement apart from being scientifi
cally unsound is even socially unacceptable.
A note on
cancer risk is annexed as Annexure IV.
p p. C3■
B.
■1 f
Effect on Progeny
There is a definite likelihood of risk of Net-den
tut
affecting children corn to.
women using Net-Oen as a
contraceptive Tlrese can be due tos
(i)
failure of contraception
(ii)
failure to detect early pregnancy at the time of
administering the drug*
(iii)
residual effect of the drug in women who conceive
soon after discontinuing Net-Oen.
(iv)
through breast milk.
The kind of health problems such exposure to the
drug can create ih children are:
(i)
birth defects
(ii)
later sexual development of children (specially
females) at puberty.
These factors assume grave
importance in view of the fact that so far no
studies have examined the outcome of pregnancy after
exposure to Net-Oen or that no pest marketing
surreilence after introduction of the drug is
available to dispel the high probability
of effect on the progeny.
15
4
As happened with DES
Di-ethyl Stilbestrol (a hormonal
preparation given to women to prevent spontaneous abortion)
the children born to women using Net-Oen may develop
serious health problems when they (the children) grow up.
develoPe^ 3 rare form of vaginal cancer
when they were in their teens,
A compilation on effects
of DES drawn from studies and reports is annexed hereto
es Annexure
70-7G
V
All drugs are potentially teratogenic unless
proved otherwise.
Some progestins/particularly" those
derived from testosterone like Net-Oen cause birth defects
such as masculinization of external genitalia in female
child ren. when administered in the
first trimester of
pregnancy.
It is well founded suspicions such as these
relating to progestines which prompted United States
Food and Drug Administration in 1978 to not ppp rove of
the DMPA (another injectable contraceptive similar to
Net-Oen) in the United states.
An expert Dr. Alan K-Done
who reviewed more than 70 clinical and epidemiological
studies dealing with the administration of progestins in
early pregnancy and birth defects/
and found, "the majority
of the studies are positive for an association of progestins
with birth defects at any reasonable level of statistical
significance.
The remainder/ it should be remembered/
simply fail to answer the question
They do
not show that there is no association.“
Another leading expert in the study of birth defects
Dr. Alan Goldman/ is convinced from a thorough study
of available research that
Progestins (which includes
16
..Net-Oen) present "a slight but definite risk of an
increased malformation rate.*1
r,|-' -$£1
13.
no
The Petitioners
reiterate
that
---- ---------------so far-study has
-—- ---- - --------
| examined the outcome of pregnancy after exposure to Net
* Oen and el imniated beyond doubt or even by reasonable
v probabilities t±Lq>ost-user pregnancy-progeny linked
effects.
These^risks of congenital malformation "assume
greater significance in the Indian context where both the
;family planning services and the health care system
especially for classes and section at the periphery of
the society are far from oatirfactory.
The scientific
bodies and drug control agencies are thus very callous in
the matter either by underestimating these very real
and serious hazards or by disregarding them by a wqve
of hand on assumed and biased one sided social goals.
14.
Besides exposure of the foetus to the drug in
pregnancy, children, can also be affected by the drug
^via breast milk.
It is an established fact that small
!quantities of the drug are excreted along with breast
milk.
The WHO itself has expressed definite concern
! regarding such exposure of infants to this drug through
the breast milk and therefore has recommended that breast
I feeding mothers should not be given Net-Oen till six
months after delivery.
However in India studies
conducted by the National Institute of Nutrition has shown
*. .. ..
...r—.
- -■
■'
to. IM
; that women on an average breast feed upto two years.
“
"•
-
-W— -
—-
— —-
”
■*■*“ ’
'
'
-
'
T""“
the drug is harmful to the breast fed infants, then
| there seems to be no ligic in recommending that the
drug
-be given after six months of delivery.
If
MB Ito ■
—•
«
17
It is precisely_J^j~s. cQPcern about exposure of
infants through breast milk that has prompted the West
Germa
Federal Health Office in 1983 to revise its
decision regarding the use of Net-Oen as a contraceptive.
One new restriction is that.
to prevent "the threat of
an injustifiable health risk “Net Oen may not be used
lactation.!t is significant to note that Schering
whichjaanufacturers Net Oen is a West German firm.
note on effects on Progeny
15.
A
annexed as Annexure V£. IT’ T/^\
Why Phase IV trials -If such factors stare us on
t,te._-5acc£?
In August,
1984 at the request of the Ministry of Health
Indian Council of Medical Research (ICMR) decided to
co nduct a ?j2?se
trial which is termed as Pro9ramnie
introduction^ study.
I CMR
Both the Ministry of Health and
seem to have felt that it is Justified to
proceed into phase IV trial on the basis of results
obtained in the phase III trial conducted by ICMR.
The
waramranna
report of the phase III trials of ICMR states Maimui »■■■■—iai» wowarMMMu*
★
M.<vcant*
as compared to published studies elsewhere, higher
method failure rates were seen during the first- six
■«null— .1, rmnin
months of Net-Oen usage
when all women were receiving
the drug at 60 + 5 days internals.
The reasons for
this ??±screpant observation in the present study cannot
be explained.
*
The interim results on 3100 subjects enrolled for the
•--
study showed that 90% of the menstrual cycles observed
were abnormal.
* Discontinuation due to excessive / prolonged bleeding
was 15.6 per lOOusers at 24 months of usage.
•■wV
- 18 -
* £^-scontin^ation due to jamenorrhoea (No bleedina) were
- - --Per 100 users at 2 4 months of usage,
discontinuations due t«riTrregui“ar"^leeclXn^[ were 12.1
perlOO users at 24 months of usage,
•' «hr
inwi
*o verall di sconti nuation rate due to ^menstrual disturba-
43.J5jDer 100 users at 24 months usage and had
risen in geometrical progession over every period of
six months.
*Apart from the discontinuation rate due to menstrual
disturbances/ another 29.7 women per 100 users dropped
out for personal reasons while 11.7 per 100 users and
4.9 per 100 users dropped out because of “lost to follow—
up" and ’’late for fcbtoibow—up” respect!vely.
*By the end of the study period i.e. 24 months a total
of 68.6 women per 100 users had discontinued.
16.
The above data clearly indicate that as many
I as 70% of women in the study did not find
the injectable
—
I
contraceptive Net-Oen as an acceptable method of
contraception.
The study also indicated that thin
built under-nourished women (who would form the majority
of our countrysj women population) are at an increased
risk of pregnancy while on Net-Oen.
This finding becomes
all the more disturbing considering that the possibility
I of congenital malformation coccurring in children exposed
——
—--------------------------- -—---------- -
j to Net-Oen in utero is not -------ruled1 out.
17.
There are serious contra indications the case of
Net-Oen such as s
*liver disease (there were 1/38/101 reported cases
infective hepatitis in 1983
and even by conservative
19
estimates the actual incidence is probably at least
ten times highej..*
* incidence of serum hepatitis carrier state, a desease
spread through injections is 4-S5 % of the. population.
♦ Amoebic hepatitis is rampant although no tests are
available to detect it and therefore there is no easy
way of screening patients with this disease.
♦Damage to the liver by afflotoxin is another signifi
cant and common problem in India.
It is important to note that specialised equipment and
highly skilled laboratory technicians are required to
detect many of theconditions.) .
*
Known or suspected breast malignancy (second most
common cancer among women in India)
♦Known or suspected genital malignancy.(average incidence
of cervical cancer alone is between 12 to 51 per
1000 women) .
* Suspected pregnancy (the facility for detecting
I pregnancy in the early stages does not exist^ in most
I Primary Health Centres.)
18.
Having regard to these factors almost 70% of
women
discontinued from the trial by the end of 24
months and considering that a number of questions
regarding the long term health hazards of Net-Oen
use remain unanswered.
The respondents have no
1
-
-------
-------------------------------- -----
---------
authority of law to proceed into phase IV trial which
is just an operational research intended to find out
the logistical problem of introducing a new drug into
20 -
the family planning programme.
The ICMR has not
discharged its responsibility to advise the Government
about these factors and thus its phase IV trials, are
without any valid sanctions and hence unsustainable.
A note on Discontinuations is annexed hereto as
Anne xu re
19.
<
WHY THE INJECTABLE:
From all the available information the injuctable
contraceptive Net-Oen does not offer any substantial
advantage over the other existing methods of contracep
tion available for women.
Net-Oen is being offered as
yjas
—rspacing.^method^xor
. ....
women between the
18 to 40 years.
age groups of
To be effective and less disadvantageous
a spacing method has to have the following characteristes.
it should bu acceptable to women as a ne thod of
contraception for a minimum of 2*3 years.
it should have proven return to fertility i. e.
the woman should be able to conceive and carry
to term a pregnancy if she desires after
discontinuing the method.
it should be a safe method for breast feeding
women as a substantial number of pregnancies
occur during this period.
the method should not have serious contra-indi
cations which would need specialized skills to
diagnose.
It should not be a method that would cause long
term
irreversible
damage to the.............
health of women
---------- ---... --- ---
or their P^ogpnjn ' . .
2J- -
NeR°t fulfill any of the above criteria.
{J
Th.e..?etitioners firmly believe that it cannot be intro-
I dyced into 1:116.. f
,w
.................................................................................................................................................................................. ..........................
Programme as a spaci ng
jI
hI -e1^?_d_°£.,??.?™66ePti?n*
------------------------------------------------------------------------,------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ■
A note on return to fertility
is annexed as Annexure VIII.
20.
|2p-£6—$>9-
UNETHICAL MANNER IN y/HICH PHASE IV TRI^S ARE
BEING CONDUCTED
The first and second petitioners have a definite
^nOwledge that the Phase Iv trials are being conducted in a manner which is designed to conceal
the fact^that women are participating in an experi-
ment.
The_trial is conducted_ag_£>ftEfc„pjL £aMlY
?£SBBlBSF_oan£s^ when the injectable is offered
alongwith other approved methods of contraception.
Making it appear that the injectable Net-Oen
has already been approved for general use
which
are wholly contrary even to the Guidelines laid
down by the Government of India for use of Net-Oen.
(A copy of a poster and a phamphalet issued by
I Sawai Man Singh Medical College Jaipur,
handling
the matter precisely within objectionable manner
90^^
is annexed hereto as Annexure .
e
Further,
according to che ICMR protocol for phase IV trials /
written informed consent.
Is not required.
i
- Sa Both these action
violate
. . -.j y #
guidelines laid^down
by WHO1 sJL964 Helsijnk£ declaration /later
revised at the world-Medical- Assembly,
Tokyo, Japan, -1975) .
Every biomedical research project involving
human subjects should be preceded by careful assess-
ment of predictable risks in comparison with foreseeable
benefits to the subject or to others.
Concern for
the interest of the subject must always prevail over
the interests of science and society.
Doctors should obstain from engaging in research
projects involving human subjects unless they are
satisfied that the hazards involved are believed to
be predictable.
Doctors should cease any investiga
tion if the hazards are fould to outweigh the
potential benefits.
In any research on human beings, each potential
subject must be adequately informed of the aimp,
methods. antipated benefits and potential hazards of
the study^ a nd the discomfort it may entail. He or
she should be info med that he or she is at liberty
to abstain from participation in the study and that
he or she is free to withdraw his or her consent
to participation at any time.
The doctor should then
obtain the subjects freely even informed consent
preferablyTin writing. 1
When obtaining informed consent for the research
2i
project the doctor should be particularly cautious if
the subject is in a dependent relationship to him or her
or may consent under duress.
In that ease the informed
consent should be obtained by a doctor who is not engaged
in the investigation and who is completely independent
of this official relationship.
The research protocol should always Contain a
statement of ethical considerations involved and should
indicate that the principles enunicfcfeted in the
present
Declaration are compiled with.
Similarly the *irst petitioner Stree Shakti Sanghatna
I were
witnesses to the iinlhical manner in which the
yhase IV trials were conducted in
a Primary Health
-----------Near
; Centre at Patas Chen^/Hyderabad. The Guidelines
I
mentioned above and the phases of during trialst are
annexed as Annexure ■ X.
F
I
21.
No infpimed consent:
The experiment is being conducted without the
Informed consent of the women recruited for the trial.
The drug has not been appjfroved for general contraceptive
use in either UK or USA.
The WHO scientific group
convened in 1977 to review neoplasia and steroid contra
ception concluded that “there are no adequate data from
studies in women to assess whether progestogens used
as
contraceptives in the form of progestogen - only pills or
as injections have any effect on the risk of
neoplasis"
(Memorandum from a WHO meeting in Oct., 1981 reprinted
in Bulletin of WHO, 60(2)
s 199 210 (1982).
It is not
conclusively proved that the drug is not cancer-producing.
24
The drug* s immediate side-effecte are unpleasant in the
countries where it is being tried outz and has been a
major reason for discontinuation by India women recruited
for the ICMR trial.
These recruits come from among the
most depriyedj illiterate sections of society,
women
seeking abortion are also recruited for this trial/
’
-
.........................
-
~
I-.."-
'
— -V
■
their participation being spelt, out as a condition for
getting MTP (medical termination of pregnancy) •
This
attack on human rights must stop.
We believe that every individual is entitled to
knowledge of. end uccess tO/ safe birth control.
The
women who are receiving the injectable in the current
trial are not give an opportunity to make an informed
choice.
Nor is their consent to participate in the
trial informed consent as spelt out in the guidelines
Igid out by
WHO *s 1964 Helsinki Declaration (late#
revised at the World Medical Assembly/ Tokyo/ Japan,
The Petitioners were witnesses to the manner in which
it was propogated and trials conducted.
On April 1/ 1985 Members of the 1st petitioner
organisation/ Stree Shakti Sanghatana/ visited the
Patancheru Primary Health Centre near Hyderabad/ where
a ‘camp* was organised to inaugrate the injectable
contraceptive Net-En.
This Primary Health Centre
was selected by the Osmania Medical College for the
Phase IV trial.
The paramedics with whom the
I
Petitioners spoke/ said that they had been assigned
task of procuring 20 recruits for the trial from the
nearby areas.
1 .
v<
;5 4
‘‘
-
4
They told the
petitioners that if they had informed any of these
women that they were subjects of an ejqjeriment or that
there were possible side-effects# no-one would have
'volunteered.
The women who assembled that day at
the PHC were from the poorest class.
They told the \
petitioners that the only information they had been
given was: “Injection lelM# bachcha nahin hoga. "
i
^xjThe Petitioners believe that by experimenting on Indian
|women with the injectable contraceptive, the ICMR is
|only serving the interests of the West German drug firm,
Schering A*G
Berlin
Schering A#G,
is a subsidiary
agency of German Remedies and some of their well known
products are Anovlar-21, Cols^par, Cumorit Oral,
Testoviron and so on, most of which are hormonal
preparations.'
The promotion of Net-Oen is part of
the larger pernicious practice of Western multinationals
which are durrping in Third world countries, products
that are banned or heavily restricted for use by their
own governments.
The following facts from authentic sources will
prove that ICMR's experiments with Net-Oen disregards
the true interests of the women in this country, their
health and their well-being.
gti ng _p a st mistakes}
No Programme promoting an inyasiyei contraceptive
method (like injectable. Pill or IUD)
is safe or accept*
able without sysmpathetic medical care.
Women in this
26 country do not get even minimum Primary health co re;
they still have no access to safe obstetrics or safe
abortion.
This being the case they are not likely to
get adequate counseling in a high-pressure contraceptive
injectable programme.
The pre-conditions which did not exist in the 60s
for a safe IUD drive do not exist even today in the 80s
for a safe injectable trial.
The ICMR has no right to
continue repeating it past mistakes at the cost of the
i^palth of this country's women.
In addition -co an the above arguments# it is
important to place this issue of the injectable trial
in the broader perspective of people’s control over the
technologies that effect their lives.
Article 21 of the Constitution
23.
And this is what
all about.
Potential for abuses
It is easy to see why the Government is
eager to introduce
the injectable.
From active decision makers (regarding
contraceptive choice) women can be rendered into passive
especially in a milieu where anything coming
.®.needle is equated with "good medicine".
Women
C^lOAl?.oJr9et'. the injectable like they can forget
th?
^_or throw it away if they can't tolerate its
sAd.?-®fleets.
Nor canJLt be pulled out like on IUD when
it causes infection and bleeding.
The injectable ensures
from the hands of the user to the
1?a.?dl.oj:.the .health personnel who wield the syringe,
The
possible scope for abuse in a system where health personnel
are pressurised to achieve targets is_ tremendous.
There
I
27 is recorded evidence of similar abuses in the past when
different methods were 'pushed' at different points of
time in particular, abuses in IUD promotion and
sterilisation are well documented.
Women receiving an
injection need not even be told that it is a contracep-
tive drug they are getting.
In fact this kind of abuse
of the injectable have been widely documented in UK
j where the recipients have invariably been poor, coloured
• women.
The ICMR’s own study strengthens the petitioners'
fear in this issue.
Tne Circular to medical colleges
selected for the Phase IV trial refers to high disconti
nuation rate during Phase III.
The ICMH1s own deduction
is that the women discontinued because of the absence
of counselling, lack of educational mterial given to
subjects, and “very casual behaviour of clinical staff
A note on the problem of service delivery is annexed
hereto as ftnngxure XI.
pf J6O-I07
When the disastrous IUD drive of the 60s was eval
uated. the same reason was revealed lack of back-up
medical care for the rejection of the IUD and its fall
in popularity after the initial spurt.
The code numbers
given in the compilation of references is set out at the
end of the Petition.
24.
-Women as Targets?
Besides, the question;the rationale by which
decisions regarding contraceptive research are made.
According to press reports, ICMR is currently experimenting
with the hormonal implant, prostaglandins for abortion
- 28 -
and the anti—pregnancy vaccine.
Clinical trials are
going on with all these methods# and all methods# signi
ficantly# are female methods.
We wish to know* which
women are being persuaded to participate in these trials.
It is hard to believe that these women know that they are
being used for experiments with drugs whose safety is
under question.
Also, in case of method failure result-
| ing in pregnancy# there is no assurance that the women
compensated or that they will be granted Medical
;: will be conpensated
j Termination of Pregnancy without difficulty.
After
’.’hen r. political disaster for the
then ruling party was precipitated by the coercive vasectomy campaign, population controllers in this country
►
are aggr&sively directing all FP programmes at women in
totaldisregard of their health and human rights.
Women
seeking abortion are being compelled to accept Pill,
IUD or injectable.
(One woman had three IUDS pushed into
her on different occasions which were detected when she
finally got synpathetic medical treatment for excessive
bleeding.
This has actually been witnessed by one of
the doctors in the petitioner group).
^”2?^
sre not opposed to scientific
research, being undertaken on human being with the
necessary precautions#
However# they feel it is time »
that serious and systematic research into male
contraceptives be undertaken.
After all men are also
responsible for reproduction.
Perhaps the authorities
are confident that despite the abuses in FP programmes
aimed at women, because they are women they will not use
29
the ballot box to express their anger and rejection^
This is the most obvious reason for the shift in emphasis
on female contraception despite its risks and dangers.
25.
Who desides Family Planning Policy:
It is true that women are the ones oppressed by
frequent pregnancies and are better motivated than men
to seek contraception.
I t is the /right of all women J
to be able to use' safe birth control methods and we fully
support the need for a humane IP programme designed to
respond to felt needs.
However, women are rarely
consulted when the directions in FP policy and research
are decided!
A
In the advanced countries where women have exper
ienced the side-effects of both IUDS and the Pill, there
is today a major swing back to barrier methods.
V-
Barrier
methods such as condoms, diaphragous , cerical caps.
spermicidal d^-ly and fo^m tablets are being used
with great success in these countries.
Yet no effort
has been made to popularize them as part of the mass FP
programme in India.
It is surprising that such sinple
nethods are ignored and more conplicated ones experimented
with.
Again, the evidence from public hospitals is that
even when women seek abortion or sterllsation they are
ofen tinrned away on the whims of the health personnel in
charge.
And yet, when the samehospital organises a
‘camp*, women are recruited by the hundreds, lured with
incentives, to “come and be sterilised".
The entire
j philosophy of the FP programme appears to be the
I
; achievement of its targets rather than genuine response to
I
women* s needs.
I
^/demand
--n° -
y^o^greater emphasis to develop better barrier
methods; greater emphasis on meeting fejt needs; as
much emphasis on safe child bearing as there is on
birth control; an end to all quotas# targets and
incentives which lie at the heart of all FP abuses.
The FP programme should exhort men to share the respon
sibility of contraception and sterlisation.
26.
.Ethics of experimentation:
Finally the petitioners demand that the whole
issue of medical experimentation fee debated publicly
and safeguards against abuse introduced.
--
..........................
. . .3 .
.
,<
—
The Petiti
•
oners know from press reports as well as from sources
within the medical research fraternity that in India#
>
as in many other Third World Countries# the concept
of 'Informed consent' is non-existent ih practical terms#
though many paper guidelines pay lip-service since the
70s and 80s after press reports have been exposing
trials with human guineapigs.
Thifcd Workd Populations
are ideal research material for field trials# especially
(
since the norms for such research are extremely
stringent in the advanced countries# and the public
there are far too vocal and well-informed to allow
rampant trials of potentially risky drugs.
The
research establishment in our country# wittingly or
unwittingly, collaborates with the drug multinationals
in conducting human trials to get the data and feedback
required by the firms.
conscious
It is only the literate# socially
country who can protest
and put an end J:o this unethical practice since the
- 3$ -
siibjects_q^tli^fie._.ej©erimentx are ignorent and unaware
that they even have a say Jin thijS..matter.
We are often told by senior medical researchers
that there can be no medical advance without human
That all trials on human beings are
experimentation.
only for ’’their own good”.
conten^pn] i s:
that the researchers recruit
articulate, well-ififkrrmed. literate volunteers from the
middle and upper classes/ recruits who can give truly
informed consent, who will be vocal in demanding back-up
j medical care and who will reject a drug or device if its
side-effects are intolerable.
H7on-ble°WV5*19/5' iet^S W!r,e-'Pressed
nun ore Minister for health and
to the Drug Controller of India, on behalf of Petitioner
No. 1 requesting the banning of all expermentation
with the drug.
Peti tioner.
No reply has been received by the
A true copy of the said letter is
annexed hereto as Annexure
I
28.
.
rr
The Petitionees have not filed any other writ
petition with reference to this matter earlier.
The Petitioners submit that administering of the
injectable contraceptives is deleterious to the health
of women and against public interest more particularly
in the interest of uncared for or taken for granted
women’s health in this country, who constitute half
of the population.
The petitioners are constrained
to approach the Honourable Court under Article 32 of
the Constitution, on the following among other
- 33- •
i.
That it is the obligation of the State to
conceptualize and buil^ institutional structures with
programmes that would ensure free and rational exercise
of fertility control by informed choice. by women
abd
thems el ve s, /p a rt i cul a rl y by women, in various conditions
of unfreedom. due to social relationships, backwardness,
poverty, illetracy etc. , which would be in furtherance
of the mandate under Art. 47 of the Constitution,
If so.
any state action to the contrary which is blind to such
an obligation wxj.1 bt^ unreasonable and contrary to publfcc
interest and thus noconstitutional vide Kasture Lal's
case. (1980)
>-
He
3 SCR 1338
Ihat is it not justifiable for the State to
administer any drug or device to healthy women to control
a normal physiological process such as pregnancy and
thereby bring about a serious disruption in all bodily
functions of women administered the drug?
Is it not a
violation of Art. 21 of fche Constitution?
/not
III.
That i-o i ^/justifiable for the State to introduce
a new method of contraception which for women does not
Z ana
have any clearly demonstrable benefitZwhich poses a
definite risk to their health and a potential risk to
their progeny and which does not satisfy the criteria
of a spacing method of contraception.
IV.
That the medical profession and the Health
Ministers in the state and centre are not entitled to
sanction any programme for administing any contra cep tiws
to women without publishing adequately the nature of the
“
33 -
contraceptive, the experiments conducted, the names of
the expert bodies that granted approval, with reasons
as women have the right to be informed about matters
effecting their personal health which is a fundamental
right under Article 19, 1 (a) of the Constitution.
V.
That the respondents have no right or authority
to inflate methods of contraception purely for statisti
cal purposes and without adequately equipping the rural
and urban health centres and adequately trained staff
for providing a coirpi ate system of follow-up.
VI.
That the respondents have no right or authority to
experiment with these contraceptives on women in this
country as this would be violative of Article 21 cf the
Constitution and ’life' as interpreted by this Hon'ble
r
Court means not mere anfnial existence and includes all
factors which would enable a healthy life.
VII.
That the herding of women, mostly illiterate and
poor,
for purposes of experimentation without any
criteria or guidelines for selection for the administra
'I
tion of this contraceptives without detailed legislation
on the question of use of contraceptives, protection of
women against abuse and provision of punishment for
negligence, culpable or otherwise is violative of Article
21.
The executive has no authority to embark upon a
programme of promocmg injectable contraceptives banned
in some countries and for restricted use in others,
^^mission irj that the respondents despite their
knowledge of the dangers inherent in the drug have
wittingly agreed to undertake these trials that have
Our
34 and will produce havoc in the lives of thousands of
women who are being experimented on.
This is arbitrarys
unreasonable and recklessness in the matter o^fiealing
with other* s bodily systems#
VIII.
That the petitioners submit that in this regard
wbmen who are treated as chattel and their consent taken
for granted, and on ill advised ideas and are not
recognised as human beings_have a right to know and
right to take decisions in respect of matters of their
life and liberty.of the said fundamental rights are
infringed by fertility control Programmes*
Any action
which refuses to recognise this fact would be a practice
derogatory to women and contrary to the provisions of
Article 51A of the constitution.
And to put on end
such practices is a fundamental duty of every citizen
of the constitution of India.
All citizens have a right
to question the Implementation of policies which amount
to practices derogatory to women.
IX.
That the absence of any legislation in this regaid
the Helisinki Declaration to which India is al so a
signatory/ as said Declaration would be in consonance
and
observance of which by the
re^ohdents would be one of the fundarr^taY'obllgations
set out in Part 4 of the Constitution.
X.
Population control may be one of the laudable
objectives but while
agencies have no authority to violate human dignity or
i
the right to be informed or the right to a heal'thy"
life.
Which is one of the directive Principles of
State Policy.
This Hon'ble Court in Kasturi Lal’s case
36 -
has held that any State action which is contrary to
Directive Principles of State Policy will be perji^e
unreasonable and contrary to Public interest.
It is therefore Just and necessary that
this Hon'ble Court be pleased to:
a)
Call for full and complete information
available with the respondent on the use
of Net-Oen including the report of the
i*For] 1
cl. .
2
b)
h Organisation.
Appoint a team of eminent and socially
conscious scientists and doctors as well as
representatives of women's group and
ho investigate into the
issues raised and submit a report to
thls non'bie Court within a stipulated
time to be fixed by law.
c)
Pending submission of the report of the
programme with the injectable contraceptive/
direct the Respondents not to carry on
the said programme.
d)
on consideration of such
materials/ directing the respondents
tO~.d;i:®C:?.ntin?e use of the injectable
contwceptive net-oen; and
36'
e)
pass such further or other orders
as this Hon’ble Court may deem
fit.
FILED BY:
R• VENKATARAMANI
ADVOCATE FOR THE PETITIONERS
FILED ON:
ZfchAprll/i986
J
SUPREME COURT Of INDIA
/37 /
Extraordinary Jurisdiction
Writ Petition (Civil) No.
of 1986
In the matter of ;
Stree Shakti Sanghatana & Ors.
••.Petitioners
-Versus
Union of India and ors.
••.Respondents
AFFIDAVIT
1/ Ms. Nalini d/o Banarasi
Das Banot aged about
24 years r/o Saket / New Delhi do hereby
solemnly
affirm and state as follows :
1.
That i
Cjlli
ene of rhe Office bears of the
Petitioner No. 2 in the above
writ petition and as such
I am well
acquinted with the facts of the case.
I had
read a copy of the writ
petition and the petition for
stay and understood their contents.
2.
That the contents of
paras 1 and 3 to 28 of the
Writ Petition are facts true to
my knowledge and rest
are submissions and
prayers to this Hon'ble Court.
3.
That the contents of
paras 1 and 2 of the
petition for stayase facts true to
my knowledge and
the rest ae submissions and
prayers to this Hon1ble
Court.
4.
That the annexures to the Writ
Petition are
true copies of their originals.
deponent
verification s
.
Verified that the contents
c- '
of the above
affidavit are facts true to
r
'
u my kno wl e d ge, no part
false nothin9
ha;
_j been concealed
Oelhl!rl£led thls the 25th day of March,
deponent
1986 at
ANNEXURE I
HISTORY OF laJECTlBLE OONTRACEPTIVES
'
Date
NET-qen
1953
Injectible progestins developed
1957
Reference
by Karl Junkmann
11/19
Synthesised by Schering AG
11/19
1963
1965
Field Trials
1967
Marketed in Peru-Norigest
Early
70's
Evidence of link between blood clots
11/19
and oral contraceptives caused
concern about safety of all hormonal
contraceptives in UK/USA
70's
11/19
Studies showed some progestins in
cluding DMPA (another injectable
hormonal Contraceptive) caused breast
nodules in beagles (dogs) •
This
cautioned US/FDA.
1971
11/19
Withdrawn from market due to concern
about nodules in pitutary glands and
breasts of rats.
7/1
Was put back on the market, because
it was held that rat studies were not
applicable to humans.
1975
7/1
7-year beagle and ten year monkey
studies started.
Schering had plans
11/19
to register Norigest in 70 countries.
NET-EN approved for use in 40
1981
countries
c
6/200
- 2 -
1982
S3
Toxicology Review Panel of WHO
said NET-en safe for use in
programmes.
1983
7/2
SMPA- controversy has raised larger
issues about testing and use of
contraceptives.
11/20-21
are-
How much reliance should be
placed on animal studies?
Which animals should be used?
How much evidence from human
studies is necessary for regula
tory decision^
Particularly if
animal studies prove harmful effects?
What about post-marketing studies
in humansfc
Who should conduct, who
should pay?
What uncertain!ty about potential
risks is acceptable in view of
benefits?
Controversy extends also to interna
tional arena.
What role should decisions of
developed country regulatory
agencies especially US/FDA play
in the policy decisions of develop
ing country regulatory agencies or
family planning and health
programmes?
ii/20 2
3
* Should
doner agencies supply drugs
or other products on request to
developing countries if the product
is not approved for Use in the
donor country?
*
Should national donor agencies try
to restrict international organisa
tions in the methods of family
planning that are supplied?
1983
According to Schering Information Service
NET-EN is not registered in UK/USA
because of DMPA cont;ro.Yey.gy.
At least
one doctor claimed that NET-EN was
7/2
licensed for short-term use and clinical
trials in UK.
Published Clinical Studies
also support this#
1983
International Planned Parenthood
Foundation began supplying NET-EN
on request to various family planning
11/19
programmes#
Toxicological tests on NET-EN on
laboratory animals are underway#
US/
FDA has approved start of trial on
women.
1983
West Germany provided uhconditional
Umr i--------
current approval of DMPA and NET-EN.
The Federal Ministry of Health is
holding hearings to decide whether
use should be restricted.
11/20
4
1984
UK has not ruled specifically on
NET-EN
1984
Federal health office of Federal
it
-i-ni
u
Republic of Germany has revised the data
?A
sheets
Di
NET-EN ffti&owing its
decision to restrict the approved indica-
in women
who cannot tolerate other preparations*
Contraindications now include pregnancy,
•
-
- ----- *----
'thrombo-embolic disease, the immediate
post-coerative period, hypertension,
car—•.‘inoma of breast and
^terus, distur—
bances
in lipid metabolism, severe hepatic
*•« i 1 ii irtm 11 ii nr>i
dysfunction, metabolic disease, jaundice and
'^^pruritis.
Warnings are also directed to its use by
patients with perphyria, liver dysfunction a
history of thrombotic disease, and by lactating
mothers.
Cited adverse reaction include
menstrual disorders, spotting and ameno.rr^oea
It is noted that ovulation may be
inhibited,
occasionally for as long as one year after
withdrawal.
/
Tbeuse of medroxy_progesterone acetate in
injectable form as a contrac^tive. has been
prohibited in Zamoia
5Zta<|b6«!V. Mt
(See PM| Dl| 77,3, 7; 83.1, 24)
t/zZ,b.osaa^ Schedule a?
1
was given as a three monthly
ANNEXURS-"!!"
MODE, OF ACTION AND EFFECTIVENESS
Mechanism of action»
A.
Injectable progestias prevent pregnancy in
several ways.
They work primarily by
inhibiting ovulation in most women.
They also work by
making the cervical mucus thick and scant#
thus creating a barrier to sperm.
making the endometerium less suitable for
Implantation of a fertilised ovum.
possibly changing the rate of ovum transport
through the oviducts.
Two studies also indicate that NET-EnJp contraceptive
effect may stem from
hostility to early fertilised egg and there
fore a cycle of early conception and abortion
may be set up*
y-
B.
ten Egyptian,women who were using the injectable
contraceptive (NET-EN) for at least 6 months were
monitored weekly for a period of 12 weeks by
measuring 3 pituitary hormones (
31/41
LH and pro
lactin) and 2 ovarian hormones (oestradial 17-B
and progesterone)
prolactin levels were constantly low.
pSH levels were variable with no
-2unlform trend.
However they were never
the mid-luteal phase levels and
no peaks reminiscent of the ovulatory
surge was encountered.
31/43
LH levels were again variable with no
recognisable pattern.
However/ on no
occasion was an ovulatory range of
LH encountered.
Oestradial 17-B had no recognisable
but v/cre never above that of
the early follicular phase.
Progesterone levels were always in the
follicular phase range.
31/48
(Our) findings support the view that the
Injectable NET-EN acts on the hypothalamic-
pituitary complex suppressing the FSH ancj
..LH release and therefore preventing ovulation^
Results fro® two pharmaco kinetic studies conducted
in Haugzhou, China
nd Stockholm, may shed light on
10/50
the mechanism of action of NET-EN and therefore on its
duration of action.
In Hungzhou,
20 of the 20 subjects showed decreasing
circulating NET Icv^Ig which became un-measurable on
or before 60 days, while in the 6 remaining subjects
1
there was a plateau of NET of 2-3 n mol/1 for 40-90
-3-
days# indicating significant secondary depot effects
in these subjects•
The Stockholm study was undertaken on 12 subjects and
10/
confirm previous data that about 33% of subjects
receiving NET-EN ovulate before the end of the 60 days
inje-ction interval.
9 subjects showed circulating
levels of NET greater than 0.2
at 60 days/ at
the time the study was terminated*
It is clear from
these data and the fact that relatively few pregnancies
occur in the C? f
rsgimen/ that mechanisms other
than Inhibition of ovulation also play an important
role in the anti-fertility effect of NET-EN.
a
based upon measurements of estradial and progesterone in
blood# it has been shown that about 32% of women will
ovulate within 60 days of injection of Norlgest and
a-
that this figure increases to only 34% within 70 days I
thereafter ovulation appears to occur more frequently
and# by 90 days after injection/ 51% of treated
28/34*
women will have ovulated and presumably be exposed to
the possibility of pregnancy®
Pharmacology and factors affecting effectiveness.
Nor -ethind--rone en.anthate/ £a progestin derived from^
*^?*tes to sterone#^ is prepared in an oily solution* Un
like the microcrystalline suspension used for OMPA#
oily solutions do not have a fixed particle size*
• 1 ,
. .c •
11/24
Ja
s
I
I
i
46
-4-
As a result/ the rate of release from the
injection site and into circulation may cary widely.
Many of the disadvantages of the presently available
*
Injectable depot contraceptive relate to unpredict
I
able pharmaco kinetics.
i
of action rather unpredictable, but the initial
Not only is the duration
9/593
plasma levels that are reached are far in excess
r
of these needed for the desired purpose.
The effectiveness of the injectables. particularly
I
NET-EN may vary, perhaps depending on
-
timing of the injection relative to the
11/25
menstrual cycle
-7
iI
I
rate of metabolism of the drug.
the women's weight,
injection techhlque.
Injections given in the cycle (first 5-7 days of menst
-
rual cycle) may be more effective in preventing later
conception.
(study with DMPa of Thai women).
Factors governing the rate of metabolism of contra
ceptlve hormones are not well understood.
Women in
different population groups may metabolise an injectable
■ ■
progestin at substantially different rates «
Clearly/ the mean body weight of women who became
3
pregnant while using NET-EN was substantially lower than
the mean body weight of women who did not become
3
4
I
pregnant.
1/530
There was e also a significant difference
-5-
in the ponderal index of pregnant and non-pregnant
woman using NET-ENo
it- was also an unexpected aM apparently para
doxical finding that subjects who became pregnant
with NET—EN had a significantly lower mean body
1/530
weight than those who did not become pregnant.
Of the 15 women receiving five or more injections
of norethisterone ©enanthate. 12 had levels of NET
in the plasma? during the period from
28 to 90 days
after injection, higner than the mean levels ob
tained in the group of women receiving their first
injection
In addition. the rate of decline of cir
culating NET? in patients having multiple Injections
was significantly slower, suggesting a decrease in
the metabolism of the steroid.
30/4
The nature of this
alteration in metabolism in ob&ure.
It is not known
aftdr 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 NET by the liver is not Increased
by serial injection, then the
total amount of NET in
the body will progressively increase with each subse
quently injection.
There was a wid^
between individuals in the rate
at which NET-EN was metabolised.
There was no signi-
flcant different between the mean ponderal index of the
30/5
two group studied suggesting that a possible
storage of NET In a secondary fat depot is not res
ponsible for the finding of higher circulating
levels in women receiving multiple injections#
The
long term clinical sigBlficaoea of high circulating
levels of NET is not known#
In ICMR’s phase III trial t
Two of the eleven centres contributed substantially
to the high number of pregnancies reported/ recruiting
!
only 14% of the total subjects but reporting 50%
of the pregnancies
ANNEXURE
I
HORMONAL CONTROL OF THE MENSTRUAL CYCLE
The normal human menstrual cycle is dependent upon
a complex system containing several components#
Including higher brain centres# the hypothalmus# the
pituitary
gland# the ovaries and the uterus.
The
cohesive function of these components is integrated
by a positive and negative feedback signals and the
endocrine system in the female.
The hypothalmus
(part of the brain) secretes a factor
called the gonadotropin releasing factor or hormone.
This is released into the hypothalmic - hypophysehlport*
al system (the blood vessels that connect the hypo
thalmus with the pituitary) in which they are transported to the anterior potuitary.
At this site they
stimulate the synthesis and release of LH (lutenising
hormone) and FSH (follicular stimulating hormone).
The pituitary synthesises three gonadotropic hormones
FSH/ LH and prolactin (PRL)
The role of FSH and LH in the menstrual cycle is
better known than the role of PRL.
Current opinion
is that PRL is necessary for the production of
steroids in the ovary.
The primary effect of FSH and LH is to stimulate
the growth of the follicles in the ovary (See Note 1)«
Both these hormones must be present in adequate amounts
t
.0
-2-
in order for reproduction to be normal.
These hormones
ovaare ultimately responsible for the production of
rian hormones which in turn control the release of
gonadotropin releasing factor from the hypothalmus.
These hormones also control the release of gonadotropln releasing factor directly by acting on the hypo-
thalmus.
The average length of the menstrual cycle is 28 days,
By convention the day of initiation of bleeding is
In the ovary the new
designated day 1 tSee Note 2)
follicle for the new cycle starts to develop (approximately 2-3 days) before the onset of menstruation,
just before or during menses. the cells of the deve-
loping follicle proliferate and the follicles increase
in size, soon to exceed 1 mm in diameter. Many do not
attain this size but atrophy.
most sensitive
The follicle that is
to FSH stimulation gets a lead that
it never relinquishes.
The rising levels of FSH
stimulate the follicles to grow*
As the follicle grows. it starts synthesising and
releasing estrogen.
The locally produced estrogen in
turn stimulates the further growth of the follicle which
grows upto the size of €mm in diameter.
The
next ;
la r ger foil'-..
The concentration of estradiol (the major biologically
active estrogen) in the general circulation rises from
-3-
50 pg/ml on day 1 to about 75 pg/ml on day 6 of
the cycle.
Estradiol concentration increases more
sharply to reach levels of about 150 pg/ml on day 9.
A sharp rise/ usually called a surge#
surge/ then occurs# to
reach a peak of about 350 pg/ml on day 11.
Estradiol
levels decline rapidly to values of about 250 pg/ml
on day 14«
The estradiol concentration then gradually
rises again.
I
The central nervous system —
hypothalmlc-pituitary
axis is stimulated as the concentration of estradiol
in the blood stream • rises (when the follicle in the
ovary is developing).
An acute surge of FSH and LH
at midcyle is induced by estradiol.
( In order to
stimulate this release a circulating level of
100 -2 0 0 pg/ml is required).
In primates/ including
humans/ the interval betweeri the estrogen peak and the
LH peak is 14 to 27 hours.
Ovulation (release of ovum
from the ovary) follows the LH peak within 11 to 24
hours.
Shortly before ovulation/ circulating levels of proges^
terone ( 17 - hydroxy progesterone ) produced by the
ovary increase.
Just after the onset of LH surge
( 11-12 days ) levels of progesterone coming from the
ovary also begin to rise.
With ovulation/ the collapsed
follicle produce progesterone in increasing amount,
The highest
levels of circulating progesterone are
reached on cycle days 18-<23«
-4-
To summarize
A normal menstrual cycle is characterized by the
following hormonal changes#
!•
The estrogen peak precedes the LH peak.
2.
The estrogen secretion attains appropriate
levels.
3*
The LH peak occurs at-least 13 days prior to
the onset of menses.
4.
As the level of LH rises* there is an initial
rise of circulating progesterone.
5.
With the LH surges the circulating progesterone begins to rise further and reaches a
maximum 6-8 days after LH peak.
Control of the production of these hormones
Estradiol is the most potent gonadotropic inhibitor.
Moderate levels of circulating estradiol as seen in
the early phase of the menstrual cycle, maximally
inhibit
the output of gonadotropin
In the normal
menstrual cycle, a change in estradiol levels in either
direction
Peither an increase or a d ec re a se) stimulates
the hypothalamic hypophyseal axis to synthesise and
release gonadotropic hormones.
Thus 2 days before the onset of menses, circulating
levels of estrogen is at its lowest level.
This stimu-
lates the hypothalmus to release the gonadotropin
releasing factor.
This in turn stimulates the pituitary
-5-
to release FSH.
FSH acts on the ovary and stimulate
the growth of the follicles,
At the same time
pituitary is also secreting LH in basal
amounts. Thi
LB stimulates the follicle
estradiol.
the
to synthesise and release
As estradiol levels inorease it acts on
pituitary and inhibits the release of FSH.
As
FSH levels decline, except for one
growing follicle^
the rest regress.
Estradiol synthesis in the growing
follicle increases dramatically and in
response to
the sustained Peak of estradiol/
a surge of store LH
is released from the pituitary due
to the stimulation
of hypothalamus
the release of gonadotropic hormon
A smaller increase of FSH also
takes place.
Thus
estradiol inhibits the hypothalmus in the early part
of the menstrual cycle and stimulates
the hypothalamus
at midcycle•
After ovulation the basal levels
of LH stimulate
secretion of estradiol ani
progesterone by corpus
luteum (the collapsed
follicle after the ovum is released)• The combination of
estrogehand progesterone
are potent Inhibitors of the hypothalamic
gonadotropic
releasing factors. The corpus
luteurn regredses after
12-14 days if the ovum is
not fertilized and implanted
in the uterus. This causes the level
of estradiol
and Progesterone to fall
which again stimulates the
hypothalamus which stimulates
the pituitary to release
FSHe
-6-
Note 1
During foetal life the surface of the ovary is covered
by a layer of small cubical cells.
These cells multi**
Some of
ply and grow into the substance of the ovary.
these enlarge and change
form the ova.
The ova is
surrounded by a single layer of cells ( membrana granu*
losa)•
Each ovum plus its surrounding cells is called
the primordial follicle.
At puberty full follicular growth begins.
Towards the
end of the menstrual cycle ( i«e. 2-3 days before the
onset of bleeding ) many follicles start growing. One
of them is always larger than the rest.
With the
stimulation of the hormones released from the pituitary
glary?/ this one follicle enlarges maximally while the
rest atrophy.
This
Graafian follicle<
enlarged follicle is called the
At the time of ovulation
the
follicle ruptures and releases the mature ovum.
The
follicle without the ovum then collapses to form the
corpus luteum.
The corpus luteum would continue to
function if the ovum gets fertilized and is implaneted#
Otherwise it also atrophies.
Once again the follicles
in the ovary start growing before the onset of menses*
ENDOMETRIAL CHANGES DURING NORMAL
MENSTRUAL CYCLE
Note 2
When the damage resulting from the menstrual period hem
I
-7-
repalred (on about the
been fully
fifth of sixth day)/ under the influence of increasing
levels of estradiol produced by the follicles in the
ovary, the inner lining of the uterus starts thlcken-
ing.
Blood vessels also increase and blood supply
Increases In the lining®
As progesterone is released increasingly into the
circulation, the inner wall becomes thicker and glandular.
The blood vessels are congested/ and clear or
slightly blood stained fluid Is released.
It is
preparatory to implemtation of the Ovum.
If the ovum
is not fertilized then there is a fall in estrogen and
progesterone levels in the blood.- due to the atrophy
'"'it
of the corpus luteum.
This causes the blood vessels
in the wall of the uterus to contract.
without the
blood supply the lining of the uterus dies and Is
shed off with the blood as the menstrual blood flow.
6
Disturbances of menstrual bleeding represent the
. [1 M!
..
* ———«'*'• 1 1
.
111 '
"
'
,.mum in..»<■«.
.. .....................
greatest reason for discontinuation of long^
8/9
acting progestogens, but most information on the
treatment of endometrial bleeding is
Effect of disruption of menstrual cycles on the
woman's health•
Although there are no known adverse health effects
of either irregular bleeding(if not heavy or prolon ged)
or amenorrhoea unpredictable bleeding or spotting can
6/204
be incoveni^-nt and of concern to the women, and
heavy or prolonged blooding may lead to depletion of
iron stores.
WH3 notes that amenorrhoea or frequent bleeding, providing it is not heacy.
7/4
unlikely to pose any
health problems for women, although the scientific
evidence to back up that assertion is missing.
Nevertheless, a woman who finds the disruption in
he menstrual cycle intolerable, in terms of her
social and cultural environment. has little choice
but to live with it. for once the injection is given.
she will have to wait until the effect wears off.
I
“
...
.
■
■
Women with menstrual disturbances may be upset
because of fear of disease or preganancy,
ligious practices, fplk bliefs and other
rumours,
But, poor nutrition and short birth
intervals in developing countries make regular
• .. ./7
9/59 2
ANl^XURr; -XI
Colly)
BLEEDING problems
■Some definitions.
Amenorrhoea
is defined as he absence of any
bieeding or spotting. Tts duration is divided
into two categories; more than 45 but less
than 90 days. and 1 total
ame norrhoea through
out an entire injection interval,
All subjects
with total amenorrhoea are, of course,
excluded
a
from/nalysis of bleeding and spotting.
v\)uo
Bl ceding
s defined as vaginal blood loss
requiring normal sanitary conditions.
Spotting
is defined as vaginal blood loss which
did no t require such precautions.
An episode is defined QS
bleeding or spotting
which starts within an injection interval
the mean number of episode per 90-day interval
provides one index of the frequency of bleeding
and/or spotting.
The total number of days of bleeding and
spotting
occuring within an injection interval is used
as an index of the durationt of bleeding or spotting experienced during the 90-day interval.
The Iliean..length__qf bleeding and/or spotting
episodes during an interval is defined as the
number of days of bleeding or spotting divided
by the number of episodes starting during that
interval.
This provides an index analogous to
2
the average duration of a menstiural period.
Since,
an episode may start in one injection interval and
extend into the subsequent one, the total number of
days associated with such an episode is included.
Cycle Length -
is defined as the number of
bleeding and/or spotting days plus the number of
bleeding free days prior to the onset of a sub
sequent episode.
A normal cycle
was defined as cycle of 26 to 35 days’
duration in which the bleeding/spot ting lasted for 2
to 8 days.
II.
The definitions of menstrual cycle & irregularities
as given by ICMR are as follows:■BE FT NT TIP NS?
For the purpose of the study use the following
definitions:
1.
Menstural Cycles
a. Regular Cycles
i.
Normal:
Cycle Length
- 2 2-35 days.
ii.
Short:
Cycle Length
- 15-21 days.
iii. Long:
Cycle Length
— 36-45 days.
b. Intermenstrual bleeding/spotting
Bleeding or spotting occurring in between
two well defined cycles.
c. Irregular Cycles:
Complete disrruption of normal menstural pattern
/3
3
such that it is not possible to differentiate
between regular cycles and intermenstrual
bleeding.
d<
Amenorrhoea: No bleeding for more than
45 days.
2.
Amount of bleeding:
a•
Excessive bleeding:
Bleeding is profuse
and/or prolonged as compared to pre—treatment
cycles.
1/
b.
Scanty bleeding: The amount of bleeding is
less than pre-treatment cycle.
c.
Spotting: Blood staining not requiring any
protection.
Pattern in the disruption of menstrual cycle in
women receiving NET-PEN.
The(menstrual) irregularities take two forms: either
frequent bleeding or spotting; or an absence of
7/4
bleeding(amenorrhoea)•
Most women experience some menstrual cycle disruptions
while using injectables.
Normal menstrual patterns
may be replaced by amenorrhoea (absence of bleeding)z
irregular bleeding and spotting, or changes in
the frequency, duration and amount of blood loss....
(with both NET-EN and DMPA), changes in menstrual
patte£9.®.. are largel y impredictable .....
NET-OEN users experienced a shift from relatively short
11/K26
4
"Cycles" during the first
injection interval to a
predominance of long” cycles" in excess of 45
days during
the third injection interval.
2/10
During the first three injection intervals
(with the
90 day regime) the mean number of
bleeding and
spotting days combined are 20(+ 12)
, 16.8(+11<4)z
Table
2/9
15.2(+ 9.9) days respectively.
There was no obvious difference
between women who
developed long period-s of
amenorrhoea andthose who
experience frequent and
lengthy bleeding episodes.
(no one can predict which
28/338
women will have amenorrhoea
and which develop bleeding
problems) .
Incidence of disrunHnm
------- -H-^^uPUon of menstrual cycle.
A WK? Study notes that
one-half of the
with NET-0EN,
users report at least
’'approximate! y
one normal cycle
during the first year".
. °rz in other words, with toe NET-0EN
users. approximate!y
one hal f of the
women did not have even one normal
menstrual cycle during the
first year.
Cause of
the menstrual cycle
Little is known about the basic
mechanisms of bleeding
di sturbances. especially those
rel at ed to steroidal
contraception.
Neither the blood level of
progestrogensz
nor the endometrial morphology
appear to be related to
the bleeding patterns.
i*
/5
5
The fact that circulating NET persists at higher
levels than expected might predispose to amenorrhoea
20/5
I
in seme cases.
I
Further studies are required to exclude
long-term clinical and metabolic effects of raised
i circulating NET levels due to multiple injections.
Management(treatment) of menstrual irrequ 1 arities,*
Attempts to prevent bleeding irregularities caused
i
by progestin only injectable are generally unsatis—
While routine estrogen supplements were
factory.
once widely used. no controlled studies have shown
that they reduce or stop menstrual disturbances...*
11/K26
Most clinicians do not recommend routine use of any
estrogen supplements with injectables.
*
Suppl err. ent al
estrogens eliminate some of the advantages of inject—
ables.
Women must remember to take a pill.
Al so.
estrogens can cause dizziness and nausea and may poste
a risk of
blood clots- Counselling before and during
use may encourage continued use better than giving
estrogens
A WHD publication recommends that a
woman experiencing heavy and/or prolonged ble-^ Ing
should first be examined for causes of the Reeling
other than the injectable ....bleeding diminish(with
treatment) in one or two cycles/ the women should switch
to another method of contraception.
A satisfactory approach to the management of p.':_onged
or heavy bleeding due to injectable contraceptive has
not yet been developed.
/6
6/204
G\
6
Disturbances of rn?nstrual bleeding represent the
greatest reason for discontinuation of long-
8/9
acting progestogens, but most information on the
treatment of endometrial bleeding is anecdotal.')
Effect of disruption of menstrual cycles on the
woman's health.
Although there are no known adverse health effects
of either irregular bleeding(if not heavy or prolonged)
or amenorrhoea unpredictable bleeding or spotting can
6/204
be incovoni^-nt and of concern to the women, and
heavy or prolonged bleeding may lead to depletion of
iron stores.
*
WH3 notes that amenorrhoea or frequent bleeding, providing it is not heacy.
7/4
unlikely to pose any
health problems for women, although the scientific
evidence to back up that assertion is missing.
Nevertheless, a woman who finds the disruption in
*he menstrual cycle intolerable, in terms of her
social and cultural environment. has little choice
but to live with it. for once the injection is given.
she will have to wait until the effect wears off.
Women with menstrual disturbances may be upset
because of fear of disease or preganancy.
ligious practices, fplk bliefs and other
rumours.
But, poor nutrition and short birth
intervals in developing countries make regular
• • • </7
9/59 2
h
menstrual patterns the exception rather the rule and
if reassurance is given and fears can be eliminated
many women will tolarate e.g. amenorrhoea.
Haemoglobin (Hb) 1 evels .jn-Saab..SibJect wer
At the time of
monitores throughout the study.
enrolment, 13.3 per cent of the subjects had Hb
levels ranging between 8 to 9 gm % and the remaining
86.7% had Hb more than 9 gm %•
Of these, 48.7% had
Hb lev el s over 10 gm % ( n orm aj. for I n c3i an.. wpn^ n) .
Though a large number of subjects discontinued from
the trial because of excessive menstrual bleeding etc»z
16/8
the Hb levels at the time of enrolment showed no
significant difference with the levels at the time
of discontinuation.
Similar, observations were seen
in the subjects who had discontinued from the trial^
The above observations.
because of amenorrhoea.
indicating no relationship of Hb level with the
— III w ^.Iir.
-
1
W®'** i-1’-**"* r
—
•.•’Til u’—_imxwM»M*******>« —1«» ■■ i»
,
type of menstrual disturbances \rernain to be further
established! since in this trial the method of Hb
e st imat ion_^as.r-not
any external quality control -
? lure adopted.
im—i li
*-* ' • J'
-0-0-0-
©
e-vdud
y
Xv d
_____ )
IxMuV 4 ) At
-A/J.
AoXt.
AO <\wv
z>>*
V^Vj
- — -•*
II),
.
i-e
Annexure
CANCER RISK
Information about the potential of a drug to
cause cancer comes chiefly from
in laboratory
11/31
toxicological tests
animals and f id m apldamiologic studiea
in humans.
ANIMAL STUDIES are used for several reasons:-
effects without
they may reveal adverse
any risk to humans.
than the
Animals can be given dosed far larger
doses for humans.
It is assumed that a drug
including cancer,
whicn causes adverse effects#
or more often when given
will do so faster.
in larger doses.
Thus adverse effects could
in animals than in
be identified more quickly
of drugs may be
humans. In fact. larger doses
intention of causing
given to animals with the
Researchers then have a better
adverse effects.
idea of what to look for in humans.
Animal studies can be more carefully controlled
than human studies.
So that othvr possible
risk factors can be excluded.
hormonal contraceptives be-il/32
The US FDA requires that
tested in three animal species- rats* dogs (beagles)
and monkeys.
On the basis of body weight.
the drug equivalent to
RATS must receive amounts of
human dose for two years.
1 or 2, 10 and 50 times the
..../2
2
must receive 1 or 2, 10 and 25 times the
human dose for 7 years.
MOhIKKYS must receive 1 or 2, 10 and 50 times the
equivalent human dose for 10 years.
Hith Net—these animals studies have found
11/32
higher rates of tumours in treated animals than
in control animals.
RATS:
breast tumours, benign and malignant and
pituitary nodules.
BSAGLSS:.
(information not yet available)
endometrial cancer. (Information
on breast changes if any, in monkeys
is not yet available)
The UK-based co-ordinating group on Depo-Provera
Says:
^A company which runs successive carcino-
genicity studies in animals, all of which
are positive, and then argues their
inapplicability to the human situation
streches credibility to its limits1’.
The practice of giving high doses to a small
number of animals in an attempt to provoke cancer
i
is a standard method of screening any chemical
or drug intended for widespread human use.
Vi r-
tually every substance that is confirmed in humans
also produces cancer in animals.
2 5/box
I tern
Furthermore,
about l/3rd of all known human carcinogens were
/3
3 •
first identified in animal studies such. as
I
e
those for Depo—Provera.
Fifty times the equivalent human dosage does
seem massive.
But in 1976 almost three years
before the monkey cancers were discovered,
25/box
It^eia
researchers in Sweden investigated the difference
between women and monkeys regarding their re sponse
to depo-provera.
Findings were published in the
prestigious “Contraception0 Journal(:) The Swedish
doctors found that monkeys require ten times as
much Depo-Provera as women to achieve the same
level of it in their blood stream.
Thus,
50
times the equivalent dose by weight is apparently
no more than 5 times the equivalent effective dose.
Monkeys also appear to metabolize Depo-Provera much
faster than hurnans do.
Malcolm Potts of the International Fertility
Research Programme in a private IFRP discussion
report that completely contradicts his public
25/box
position, explains the scientific reasoning for
I tern
the large dosage method ,l We must recognise that
the reasoning behind giving high doses of a
drug to a few monkey is to highlight a lower
risk that might apply to very large numbers
of woment”
Data are Just becoming available on olong-term
sequelge among women using DMPA and studies are
6/20 3
1982
WHO
now being undertaken on the potential long term
|.
............ /4
I
4
effects of Net
Although the risk of developing certain tumours
has been shown to be related to endogenous hor
mones the relationship between exogenous hor—
PiOP^e {such as 1
CIABL.£•£>,
10/5152,
1983
WHO
.and the hsk of
neoplasia is not fully known.
Little information from human studies is avail
able on long doting inj^ctabl^ contraceptives
and the risk of neoplasia. although results from
8/1 •
1984,
WHO
animal toxicology studies have raised concern
about possible carcinogenicity.
Problems with existing studies on human;-
Unfortunately, most of the human studies
that have tried to find any effect of
DMPA or Net EN on
7/6
quoted
from
a WHO
journal
10/52
the development of
cancer have been poorly designed and
therefore. do not provided useful information."
No controlled studies have been P-
j'
undertaken on the relationship between
the use of injectable contraceptives and
the risk of cancer. In a ,P£pulation where
the use of injectables has been wi despread
reasonably long time.
studies on
subject (neoplasia)
/5
10/52
5
have been conducted in developed countriejs
where risk factors to various diseases,
[
_
-—mJ . .» j- i J1. n r " i .i.. ■!■•! Ju auaaa aia ii.. -.
m
10/52
including neoplasia, are different from
mi ii
“
“
I-.., j-.ii-uw.owr ~m j-
-•
those in developing countries.
Mi>st of the studies.
all of which have been on
DMPA/ have involved short-term users and so would
not be able to detect risks for long term users.
11/33
if such risks exist.
While no evidence can conclusiveley prove a lack
of risk, carefully controlled research on large
numbers of women is now underway to provide a
7/6
stronger scientific basis for future regulatory
■
>
deci sions.
(This is a case controlled o study.
multinational by WHO on DMPA (1978-^988) .
The
study was designed to examine the possible
association between the use of ooth oral and
injectable steroid contraception and the risk
of cancer of the breast. cervix, uterine corpus.
ovary and liver.
The preliminary findings of
WHO researcher provide no evidence that
increases the risk of breast cancer ,
however. the study of more than 8000 women in
Kenya, Mexico and Thailand did show a doubling of
risk of cervical cancer in women who sused DMPA
.■
for 5 or more years.
Final results of this
collaborative study will be available in 1985.
Jean Robinson of the Co-ordinating group on
i
Depo-Provera noted the particular need for research
/6
I
6
on cancer of the cervix in relation to inject-
ables.
This was due to cervical cancer being
the major cancer killing of women in the third
wo rl d, the fact that in most industrialised
countries, cervical cancer is more prominent
amongs poor working class women; that studies
have shown that women most at risk of developing cervical cancer are also those least likely
7/6
to attend regular screening clinics; and
that some early research found a higher than
average rate of cervical cancer amongst poor,
black women with large families who have been
using BMPA.
The preliminary findings of the WHO research
provide no evidence that DMPA increases the risk
of breast cancer; however.
the study of rr-.ore
that 8000 women in Kenya, Mexico and Thailand did
show a doubling of risk of cervical cancer in
7/6
women who used DMPA for five or more years.
CfSan Robinson, of the co-ordinating group on
Depo-Provera noted the particular need for
research on cancer of the cervix in relation
to injectables.
This was due to cervical
cancer being the major cancer killer of
women in th
thi rd world; the fact that in
most industrialized countries.
cervical cancer
mote prominent amongst poor working class women;
/7
7/6
7
that studies have shown that women most at
risk of developing cervical cancer are also
that least likely to attend regular screening
clinics; and that some early research found
a higher than average rate of cervical cancer
amongst poor, black women with large families
who had been using BMPA.
-o-o-o-
ANNSXJRE - "V
M
THS TRAGEDY OF DE3
DieViyl S-tlitrestrol (DES)
is a synthetic non—steroidal
estrogen synthesized first in 1938.
At first it seemed
t^ revolutionise therapy in cases of tlireatened abortion^
prematurely etc
as till then it had been difficult
to purify natural estorgens
which were in any case of f^f
low potency when given by mouth.
Sopn^ DESZ and other
chemically^modified, natu,ral. estorgens were being used
to treat threatened abortion r premature labour, as pre—
ventivc therapy in women with )>ad obstetrical history^ in
________ ~ —~>-v jm jin nt ii m l~ -.-—j..-... ,
>
the management of pregnant women withdi.abetes and even in
cases of normal pregnancy ds a general pro; hylactic
measure.
IBut it
.Vfeia. pulx. in 1970,1a clear 22 years
after the^drug had been in wide use ta.t a mador
came to light.
Researchers in Bostan
noticed that a
previously exceedingly rare malignant tumour, clearcell
------- - ----------- ---------------- -
-
— ---------
} adeno—carcinoma of the vagina almost universally occurring
in ol
men, was being seenln young women and adclescents.
A r-
ring of ante natal histories of the mothers of
these women indicated that a significant number of them
*
had been given DES right from the first trimester.
Between 1945—1970 approximately 3 million women had
receive 1 DES to prevent miscarriage although the scienti
fic lit-r rire alrealy containe’ reports of 6 studies to
i
show that DES was ineffective in the treatment of threa
r
tenod abortions.
!
ai<itionz ran international registry of clear cell cancer
Following the discovery of the asso-
2/-
5
6
on cancer of the cervix in relation to inject-
ables.
This was due to cervical cancer being
the major cancer killing of women in the third
wo rld/ the fact that in most industrialised
countries/ cervical cancer is more prominent
amongs poor working class women; that studies
have shown that women most at risk of developing cervical cancer are also those least likely
7/6
to attend regular screening clinics; and
that some early research found a higher than
average rate of cervical cancer amongst poor,
black women with large families who have been
using WA,
The preliminary findings of the WHO research
provide no evidence that DMPA increases the risk
of breast cancer; however.
the study of more
that 8000 women in Kenya, Mexico and Thailand did
7/6
show a doubling of risk of cervical cancer in
women who used DMPA for five or more years.
CTOan Robinson, of the co-ordinating group on
Depo-Provera noted the particular need for
research on cancer of the cervix in relation
to injectables.
This was due to cervical
cancer being the major cancer killer of
women in tli^ third w^rld; the fact that in
most industrial!zed countries.
cer..’tcal cancer
mbfe prominent amongst poor working class women;
/7
7/6
f
7
that studies have shown that women most at
risk of developing cervical oencer are also
that least likely to attend regular screening
clinics; and that some early research found
a higher than average rate of cervical cancer
amongst poor, black women with large families
who had been using DiviPA.
-o-o-o-
2
of th© vagina and cervix was establishedw
By the late 7Q*j - ,
the registry had documented 333 cases and the data showed
^■hat some two -thirds had been exposed in utero to DE S.
"*“ro
***
iiiwub__________________ ____________________ _
The
treatment with DES had commenced before the 45th day of preg
nancy ©nd together with observer! changes in the genital trac-
suggested that the clear cell cancers were probably amal~
formations tather than neoplasms*
in addition* virtually
—manifested after the onset of puberty, suggesting
interplay between in—utero exposure and the onset of
SXLdQcenoux secretion of estrogen at the men.irchc
Whether the tumours were to be regarded as malformation or as
malignancies , their clinical behaviour was that of malig—
nancies.
Similarly, whatever may be the nature of the inter
relationship) between DES an 1 subsequently endogenous estrogen
metabolism/ there was little doubt that DES exposure during
tne^ : : rat tribes ter of pregnancy was ac«use of clear cell
adenocarcinoma of the lower female genital tract
The esti
mates of incidence of this cancer attributable to DES is
betwe- n 0.1 and 1 per 1000 upto about 22 years of age.
data
Iso
The
confirm that the incidence begins to rise subs
tantially at the beginning of adolescence Cthe youngest
recorded case occurred at 7 years of age)
age of 19 years.
and peaks at the
By 24 years of age it appears to have
The incidence data is probably an
un1 ler egtimate because reporting at the ministry is incomplete,
dropped substantially.
some cases were exposed to unidentified medications
some of
which may have been DES and because of incomplete
records
and faulty memory. Alongwith the recognition of
the asso—
ciation between DES and clear cell cancer, other changes
)
i
3
in the vagina and cervix were also noticed*
There were
changes in the vaginal glandular epitfeolulm (adenosis)
,
transverse ridging of the vaginal wall/ abnormalities of
the vaginal and, cervical mucosa/ and partial or complete
obliteration of the vaginal fornix*
Overall/ virtually all
of the DES —exposed and about one—half of the non—exposed
had cervical abnomalities•
It was also noted that vaginal
epitnelial changes were most closely associated with the
timing of the onset of exposure/ total dose and duration of
exposure.
A convincing demonstration of adenosis progressing
to adeno carcinoma on follow-up is
still lacking/ even
though it is logical to assume that adenosis Mis the bed
* or soil from which adeno carcinoma asises”.
■k
Studies on men with testicular cancer also seem to indicate
DES exposure in utero but these need to be substantiated.
There is also suspicion as to the relationship
>f DES with
cancers at other sites in the female genital tract or in
the breast.
A study showed that a significant number of
male offsprings of women expose'?
DES in pregnancy/ had
difficulty in passing urine and atr^rmaiities ofthe penile
urethra (stenosis or hypospadias) but this needs to be
corroborated by other studies.
Another study showed that
of the 30% of the DES —exposed malest as against 8% of the
placebo—exposed had one or more abnormalities of the uro
genital tract.
No malignancies were identified.
There also
seems to be evidence to show that nhe DES—exposed male
offspring may have increased rates of infertility.
There seems to be an association between uterine deformity
(principally T—shaped uterus) and grossdefects of the cervix.
These findings raise questions about the future fertility
of DES-exposed daughters.
There is also evidence albeit
fragmentary that the risk of spontaneous abortion and ectopic
pregnancy may be increased - tri the.^ DES—exposed daughters.
There
now can be little doubt that DES specifically,
has profound effects on the lower genital tract of the female
Qfprobably on the male genital tract as well.
In
the female, these effects include clear cell adeno canalnoma
of the vagina and cervix, as well as an assortment of other
changes, some of which ar^- reversible.
The possible risks
of cancer of the uterus, ovary and breast, of infertility and
of complications of pregnancy await evaluation.
In DES
exposed, malesf the analogous problems include testicular
cancer^ congenital anamolies of the urogenital tract and
infertility.
health consequences of intrauterine exposure to
DES LancL.pe£.^^
derable.
hormones in general) are consi
It has been argued that the low incidence of clear
cell carcinoma attributable to DES is reassuring»
Also based
upon estimates of the prevalence of DES exposure-and the
absolute incidence attributable to DES, the total number of
cases is likely to be in the hundreds or, at the upper limit
probably no more than about 3000
(assuming the highest esti-
mated absolute incidence rate and two million exposed females)•
Nonetheless, the necessity for long term follow-up carries its
own burden.
A onnsiderable proportion of the female offsp ring,
and probably of the males as well, can expect some abnormality
• ...SA
5
of the lower
geniral tract to be diagnosed., which may in
turn require more intensive follow-up to ensure that
malignant changes are detected as early as possible.
The
social cost of lohg-term follow-up might be Computed in
terms such ^s the actual monetary costz or some other index
it is likely to be high.
The psychological impact/ with
the attendant problems of knowledge of a genital abnormality
and of anxiety about the future cannot be measured, but it
is bound to be great.
****
-4*
•
<.«U,
.4
j-s tragic is that these were grounds to be concerned
■
'■
——
.
—
-. —,.__ _
about the extensiye use of DES in human populations as
thri year that the discovery of the drug was
10 the same Year it was reported that the drug
was/carcinogenic in animals.
Further, only about a decade
a5te5 DES therapy was first advocated, the scientific basis
/I -*••'** •
tv.
, Ia-«
for its claimed beneficial effect was evaluated and rebutted
C*——v~-L.. r_
*”*
r>_tr
Not only was the drug without
a cHnlcal. experiment.
demonstrable benefit, but it may well have exacerbated
***M * 4^b' -A, —• «T •
those effects it was supposed to have prevented*
A therapeutic misadventure might have been
rr 1 led if more
rigorous scientific criteria had been required, of those who
advocated the use of DES to treat pregnancy.
ia»>nnuMr*Mfni(MBMR«NKnanaMiMiiti<**a»» n»*•»««•»
And although the
^anuMsru^.
evidence is not yet in for other female hormone supplements,
*-> - An-* j-u.0_jwm wxjwcKuar
the burden rests upon their advocates to -demonstrate their
"**** ■**
■
»nsM«
-
•
........
.
......
,
efficacy and safety*
The response of a drug regulatory authority and medical
establishment to this whole tragedy is(quite enlightening
6/-
6
To begin with none of the public health agencies in the US
(FDP, National Institute of Health, National Centre for
Disease Control, American Cancer Society, National Cancer
Institute) were willing to initiate a national effort to
contact women who had been exposed to DES in utero
In
addition, many hospitals and doctors refused to give indi—
vldual women information on whether or not they had been
given estrogens during their pregnancy
i As if the history of this drug was not sufficiently distressing
'NTH awarded ten universities research., grants in the early
1970s to test DES as a=* n'morning—after” pill (a contraceptive) .
The FDA—approved experimental dosage as a post coital
'contraceptive was massive : 250 mgs. for five days.
By 1972, an NIH official announced that the morning-after
pill was being given by most University Health services.
The papid adoption of DES as a post coital contraceptive
was stimulated in part by an article in the
American Medical Association.
Journalof the
To the embarrassment of the
—patientsf from the University of Michigan Health
Centre, where the study had been conducted, read the report
and started an investigation on their own because the report
f lid not fit the facts.
Some women had discontinued the
full five day treatement because of severe nausea.
Others
who took the medication properly had remained pregnant.
A subsequent investigation revealed that out of a sample of
69 rx.3 patients, only 1 in 4 had ever been contacted by the
health service after being given the pills.
After the
□JAMA/g study had been severely challenged, Lilly, the prime
maker of DES, made a concerted effort to inform doctors
7/-
that since the drug’s safety and efficacy had not been
proven, it should not be used as a post—coital contraceptive
j-
twill»»’• -
iiM'tiiru-r-.*
'•U"
1****,®fl 1 ■ fl®
(Lilly continued to supply DES to Tablicaps, the company
that marketed morning—after pills as an ideal contraceptive) .
The FDA took no action. however, to limit the use of DES for
non—approved uses or to warn doctors and women to stop
using it
In May 1973, the FDA mailed a bulletin to physicians approving
DES for use in preventing pregnancy under restricted conditions;
in September, reporters received a similar press release.
Nonetheless z in 1975, FDA Commissioner revealed that FDA was
fust about to approve DES as a post coital contraceptive.
However, an FDA physician testified that the
FD/k had issued
a statement published in Sept»1973 that 25mgs of DES could be
used as a post—coital contraceptive-
In fact hundreds of thousands of women. including many DES
daughters were receiving DES.
And because the treatment was
not always effective, a whole new generation of children was
being bom that had been exposed to massive doses of the drug
in uteno.
Two of the FDA physicians, testified that they were shocked
that the FDA (their employer) had allowed the Federal Register
to publish a new use for a drug without any study or investiga-
tion and one that was proving to be hazardous.
Excerpts from : "The effects of Exogenous Female Hormones on
the foetus"•
Epedemiologic Reviews, The Johns Hopkins
Univ School of Hygiene and Public Health,1979.
and "The Women’s Health Movement” Sheryl Burt
Rwzek, 1979,Praegar.
ANNEXURE ~”VI"
EFFECTS ON PROGENY
The likelihood of the drug affecting children born
to women using NET-EN can be due to :
failure -of contraception^,
failure to detect early pregnancy at the time of
starting Net-En as a contraceptive#
residual effect of the drug in women who conceive
soon after discontinuing Net-En?
through breast milk.
The kind of health problems such exposure to the drug
can create in children are ?
birth defects#
affect later sexual development/
as happened with DES (a hormonal preparation given
to wooen to prevent spontaneous abortion) the
children born to women using the drug may develop
serious health problems when they ( the children )
grow up.
DES daughters developed a rare form
of vaginal cancer when they were in their teens.
No studies have examined the outcome of pregnancy
after exposure to NET-EN.
No studies have systematically foliowad the health
and development of a large number of infants
exposed in utero to DMPA or NET-EN as a result of
contraceptive failure or the inadvertent initiation of
<
-2contraception in a woman with undiagnosed pregnancy. 6/205
Most information on the effects of progestogens on
fetal development and infant health is derived from
studies of oral contraceptive failures of progestogens
used as hormonal pregnancy tests or as treatment for
threatened abortion and premature labour®
There have been 3 reported cases of clitoral enlarge
ment among daughters of women who received MPA during
the first tx-masterc
Concern over potential teratogenic effects - that is#.
birth defects
was one reason given by the US/FDA
in 1978 for not approving DMPA as a contraceptive
in the US.
11/29
The concern arose not because of reports
that injectable contraceptives caused birth defects.
but because of suspicions about other progestins used
in higher pregnancy.
In the 1950s and -^ariy 1960s large doses of various
progestins were given to pregnant women to try
to prevent threatened or habitual abortion.
ll/3t
This
treatment was never proved effective and is no longer
recommended •
Some progestins, particularly the
progestins derived from testosterone, occasionally
caused mascullnizaticn
of the external genitalia
(enlarged clitoris and/orlabial fusion) in female
children when the progestins were administered in the
-3~
first trimester of pregnancy.
Recent studies have suggested that prenatal exposure
•to hormones may cause other# nongenital anomalies* 11/3S* A leading expert in the study of birth defects#
Dr. Allen Goldman# is convinced from a thorough study
of the available research that all progestins
(which would include both DMPA and NET-EN) present
"a slight but definite risk of an incr^Hsed.mal-
formation rate".
7/7
Another expert# Dr. JAlan Dine#
reviewed more than 70 clinical and epidemlolocial
studios dealing with the administration of pro
gestins in early pregnancy and birth defects# and
found
” The majority of the studies are
positive for an association of progestins
with birth defects at any reasonable level
of statistical significance.
The remainder#
it should be remembered# simply fall to
answer the question
They do not
show that there is no association.M
As stated In the Annual Report for 1982# nothing
is known about whether synthetic progestogens have any
effects on normal hormonal changes in the early in- 10/5
fant which may in turn affect later sexual develop
ment.
-4-
IMPACT GN INFANTS THROUGH BRfiAST MJfjK
Although the impact of injectables on infants via
breast milk has not been adequately studied to
arrive at
7/7
firm conclusions# a 1981 WHO technical
report pointed to some of the reasons why this should
be a major concern.-
“Mothers using hormonal contraception
during lactation will expose their children
to the hormons being used via the breast
milk.
On theoretical grounds, this small
amount of hormono may be potentially import
ant since#
first# the brain is not fully developed
at birth and is particularly sensitive
to hormones ;
secondly the blood brain barrier is
functionally immature •
thirdly/ capacity and the affinity of the
neonatal sex storoid binding protain is
less than in later life ;
fourthly, the Immature liver has a slow
elimination rate and consequently a higher
level of the steroids may be found in
the blood and this may result in a longer
exposure
than would occur later in life.1*
-5-
When a breast-feedlog woman uses any hormone/
small quantities of the drug pass into breast milk
and are consumed by the infant.
will suffer
Whether the infant
any long-term ill effects is unknown
and is now being studied.
Sexual development has been delayed in rate exposed
to high does of DMPA in rats’ breast milk.
Studies
following humans through puberty have not been
11/30
conducted .
Another concern when giving a drug to a nursing
mother is the possible transfer of this drug or
its metabollties to the infant and some studies
link neonatal jaundice ( hyperbilirubinemia) to
the steroid content of breast milk.
This becomes all the more significant when we
consider .that Indian Childhood
ceirbossis is a
serious and common disease among children in India.
*
9/59
ANNEXURE
«vllw
DISCONTINUATIONS
The second WHO trial reported life-table continua
tion rates for NET-EN of 50 per 100 women at one
year/ for both the 8 week regimen and the 8/12 week
regimen.
A multicentre phase 111 clinical trial was under
taken/
to compare noreth1sterone enantrate (Net-En)
given by 2 different regimens.
After 18 months of
observation. preliminary findings are reported for
7S0 women who received NET-EN, 200 mg every 60 days.
and
796 women who received NEr*EN, 200 mg every 60 days
for 6 months. then 200 mg every 84 days
The overall
discontinuation rates per 100 women were similar
for
the groups over the 18 months observation
( 61-8-63,5 per 100 women.
For both DMPA & NET-EN, the continuation rates very
markedly among different populations ranging from
12/17
15% at 1 year.
The most frequent reason for discontinuation of....
NET—EN as well as the most frequently reported
6/203
side effect, is the disruption of the normal menstrual
cycle that occurs in the majority of
women using
these drugs.
Dis-satlsfaction wltn injectables stem largely from
disruptions in menstrual patterns
Bleeding irregula-
rities cause 20 to 25% of women wo stop using in- 11/K35
jectables.
-2~
ry
Y)
Tolerance of menstrual disturbances varied.
For
example/ bleeding patterns were very similar among
women in the two Indian cities/ Chandigarh and
Bombay/
11/35
but di scon tinuatdon for bleeding problems
was 3 to 10 times greater in Chandigarh.
In an ICMR study unfertaken to compare the efficacy
of NET-EN 200 mg given 2 monthly and 3 monthly/ the
following resultswere observed s
Reasons
(1)
Treatment
Discontinuation Rates
Schedule 6 mths
12 mths W mths
(4)
(5)
24,^'hs
(2)
(3)
___________________________________ 10 /
Menstrual dis
turbances
>
Loss to follow
up
Personal
Late for follow
up
Pregnancy
2 r'0mg/60
d ays
7.4
21.2
31.0
43.5
200 mg/90
days
8.8
19.5
31.2
42. 2
200mg/60
days
7.6
10.3
11.2
11.7
200mg/90
d ays
7.3
10. 0
11.0
11.5
200mg/60
d ays
5.1
11.6
22.0
29.7
2 00mg/90
d ays
3.5
9.2
16.9
23. 1
200mg/60
d ays
1.7
3. 3
4.9
4.9
200mg/90
d ays
2. 3
4.7
5.9
5.9
200mg/60
d ays
1.2
1.2
2.1
1.4
200mg/90
daps
0.7
1.8
2.8
6.5
-3-
(1)
(2)
Ocher medical
reasons
200mg/60 days
0.9
1.5
2.7
3.2
200mg/?0 days
1.2
2.3
3.7
4.4
41.5 56.9
68.6
40c 2 55.5
67.4
Total disconuatlon
rate
200mg/G0 days
200mg/90 days
(3^
22.0
(4)
(5)
(6)
Discontinuation due to menstrual disturbances which consisted
. of amenorrhoea, excess!ve/prolonged bleeding and irregular
cycles/spotting were the major reasons for drop outs.
Some of the reasons under this category (personal) given by
the subjects were desire for pregnancy and objection from
family.
Every attempt was made to keep the discontinuation
rates for "late for follow up" to a minimum and the annual
rate of disctohtinuation due to this factor did not exceed
2 per 100 users.
(There are no comments in the report about
f
the category "loss to follow up" which is the second highest
rate for discontinuation)•
Although DMPA was associated with more frequent spotting
and fewer normal cycles than NET-EN, the discontinuation
rates for
drugs.
" bleeding
problems" were comparable with both
Apparently statastically significant
between these drugs in this regard
Important.
were not
di fferences
clinically
w
4
Although it is important to know what happens
It is essential
to patients continuing use/
treatment as
to know why patients discontinue
5/5
this might aid the selection of contraceptive
fthis report is about patients
for patients
who discontinued treatment.
>
*****
■4
I
i
i
ANNEXURE - VIII
RETURN TO FERTILITY
NET-EN is being recommended as a spacing method of
fertility regulation.
In conclusion/ the results of the present study (ICMR
clinical trial) indicates that 200mg Net EN given at
60+5 day intervals provides adequate contraceptive
16/last
protection and offers an additional spacing
page 1984
method for its possible use in the National
Family Planning Programme.
Net EN should be used primarily for spacing
21/2
However/ sterili-
GOI
satidn or other forms of contraception should
1984
prognancy in younger women.
tee considered for women not desiring any any
more pregnancies.
Since the contraceptive effect of Net EN is said
(our
to be caused by
comment)
inhibiting ovulation
making deervical mucus thick and scanty
making endometrium less suitable for
Implantation of a fertilized ovum
changing rate of ovum transport through
oviducts
possibly through early conception/abortion#
return to fertility would mean that all
these effects are reversed after withdrawals
-2-
of the drug within a reasonable period of time.
Also the woman should be able to
carry to term aod
prod uce a healthy normal child*
As subsequent fertility has not been studied following
up the use of either DMPA or Net EN/ nulliparous (women who have no t conceived even once)
women who wish to have children at a later time
might be advised to use other methods.
6/207
1982
WHO.
As yet/ only one study has examined the
return of
fertility following discontinuation of Net En.
Although the , results of this study are difficult to
interpret/ it showed that of 5 5 wome n who a we re
followed for 6 months after discontinuing
Net En, and not
using any other contraceptive method/
14 became pregnant. ( Emphasis ours).
(The above mentioned
study was published in 1973 and WHO
says/ that till 1982 that was the only study done,
In
the Intervening 8-9 years this aspect could easily
have
been researched).
With Net Enz as with DMPA/ the
average time between
discontinuation and ovulatic n seems to
vary in different
populations.
Study on ten Egyptian wome n who
> w’ere using the inject-
able contraceptive NET OEN for
at least d months
31
• 41
concluded that NET-OEN is a strong ovulation
inhibitor .
at least after its use for 6 months
.i
- 3
Doubt about the prompt return of ovulation
after injection of depot gestagens used for con
traception is causing anxi^^i^oth in countries
ishere the method is used extensively as well
as in western countries where there long term
use has not yet been sanctioned
(The) results
3 4/450
suggest that inhilition of ovulation is the
principal mode of action of intramuscular
nore
thisterone canntuate but that 90 days (3 months)
after the injection. ovulation has returned in
half of the subjects and is likely to return
soon in most of the others
It is
known however, that in women taking daily low
doses of gestagens orally. morphologically
and histologically normal corpona lutra may be
produced but their capacity for synthesis of
unltro
is
diminished
both
progesterone
inviuo
34/5 41
Whether (in such cases) the exogenous gestagen would
be adequate to prepare the uterus for implantation
should ovulation and fertilization take plaee
is unknown (comment; This point is important
both for effectiveness i.e. failure rate during
injection interval as well as to predict if the
woman would carry to term if fertilization and
implantation occur)
This study has only consideree wemen having one
- 4
injection of noretnisterone oenatuete.
There
is evidence of a decrease in the rate of meta-
bolism of noretnisterone with subsequent
injections and there may be accumulation of the
steroid after more than seven injections* Thus
it is possible that there may be a consequent
delay in the return of ovulation in women
receiving multiple injections*
7
er a n n ouncinq the Injectab le Cent racept.i ve
New Method of Family Planning
Injactable Contraceptive
Easy method of Family Planning:-
Easy method.
Not related to Coitus.
Eliminates problem of buying or keeping
in the house.
Eliminates the problem of taking daily
unlike oral contraceptives.
Unlike Oral Contraceptives/ has no problem
of vomiting, nausea, thrombosis, or decrease in
breast milk.
Infact it increases breast
milk secretion.
When pregnancy is desired, just stop taking
the injections.
Unlike loop there is no
need for a trained personnel for its removal.
Who can receive the injection:-
Those who are between 18 to 40 years of age
Breast feeding women whose child is more than
6 months of age.
^hose who can visit the health centre at
the right time for the injection.
Those who want
to choose the injectable
contraceptive.
/2
I
Points 'co keep in mind
In the intial period of injection, there may bo
irregularities in the menstural cycle, either
a decreased flow or inter—menstrual spotting.
Sometimes blood flow may be increased and some-
times blood flow may stop, these bring not unusual.
Some women may have headache, weight gain and
abdominal pain.
accounts.
There is no need for anxiety on these
Even then, is there are any problem s
inform the Doctor or the health worker at the
A
health centre.
Department of Preventive & Social Medicine Savai,
Man Singh Medical College,
J aipur.
Pumplet announcing the injectable Contraceptive
Free family planning camp being conducted by the
Senior specialists from the Janana Hospital, Jaipur,
at Rural Health Training Centre, Naila on 1/3/86.
In this Camp:-
Laproscopy and other methods of Female sterilization.
male sterilization as well as post operative
will be given.
Insertion of Copper T.
/2
I /
3^-
- 3 -
For the first time in Rajasthan an injection
for contraception.
Immunization such as DPT, Polio for children.
Sd/—
Dr. V.N.S. Thomar
Head of Department, Preventive
& Social Medicine Sawai,
Mansingh Medical College Hospital/
Jaipur.
Sd/Dr. S.R. Mehta,
Principal,
Preventive & Social Medicine Sawai^
Mansingh Medical College Hospital,
Jaipur.
I
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-- -------------------------------------------------------------------------------------------------------------------------
.
3T7 iWrjfelHmn a^T^T
‘.M
’ A-'
.
.•
.,
I
HU'P' * 1
ANNEXURE X ( Colly J
Government of Jndia
of Health & Family welfare
GUIDELINES FOR USE OF NORETHISTERONE EimJTHATE, AN
INJECTABLE CONTRACEPTIVE FOR ITS USE IL GOVERNMENTAL
AND NON-GOVERNMENTAL FAMILY PLANNING CLINICS;
Criteria for selection;
Healthy informed
seek Family Planning
services to be selected if they fulfill the following
criteria:-
1.
Age between 18 to 40 years
2.
Proven fertility
3-
Exposed to risk of pregnancy
4.
Willing to rely only on NET-EN as a method of
fertility regulation.
5.
Regular menses (variation of not more than 10
days between the longest and the shortest
menstrual cycle during the last 6 months).
One cycle after M.T.p.
The following record of
the women to whom the
..1.S—administrated should be maintained.
j
1.
Age at menarche,
2.
Regularity and length of cycle
3.
Duration and amount of menstrual flow
4.
Occurrence of abnormal bleeding
5.
Data of last menstrual period
2he Qbstetjcal history should contain the
following informations
1.
Regarding parity
2.
Abortions
%
2
3*
Data on last delivery•
4.
Present lactational status
5.
Gestational diabetes.
Contxa-indicatjons-to the use_Qf jJET-Enanthate:
1.
Cancer of the breast
2.
All genital cancers (Except as treatment for
endometrial cancer) •
3.
Undiagnosed abnormal uterine bleeding.
4.
Suspected pregnancy.
5.
Should not be given in lactating women.
6.
Cases which require medical supervision e.g.
-v"'1
undiagnosed breast lump, abnormal liver function
pr recent history
of (liver disease Including^;
i
o J- J
'-’J- iXA-vti.
- j. * • y i
jl
Jf-*............
a
a
.V-’W- .
....... .
-J
Hlo Jaundicejin pregnancy or jaundice during the
last six months/ H/o or evidence of cardievascular
disease, congenital hyperlipidaemia, H/o
infrequent bleeding, amenorrhoea, diabetes
millitus or H/o gestational diabetes."
The following cornmon side-effects to be
explained to each womans
1.
Irregular bleeding and spotting, sometimes
prolonged.
2.
Amenorrhoea.
3.
Delay in becoming pregnant after discontinuing
NeT injection.
4.
Headache and weight gain.
It is of great importance that adequate
expalanations of the(long term effect!veness\of the
•
product, its possible side-effects and of the impossibility
3 ~
Of 2?
to
effects
Potential
■guratj £nof
H
Petiodi c
adverse
continued.
given H
Uses^
Tf the
reveaj. any
^fL^Jection are
users#
clini cal
effeots,
ev®iuation doe
s not
the
^ePication
N^'T4.§h"Wirl MM
pr®gna ncY in
^-2322^
or other
fonns of
women
no t de si ring
years of
age,
oo^sidered.
1 s ■tecommended.
for
sPacin g
satlon
contraception
should be
eny more
other fo rms
An Annual
■
Ho„ever/
can be
c°nsidered
Pregnancies,
of contr.
eception
examination
Of
Beyond 40
should be
PGi vis and
the br^ast
I
e
r i
for
on.
The initial ■
he
^2nject1&n
during the
of
fi rst
should be
Pays of
gi ven
w^man should
the ^nst.
rual
be re■Period.
examined
The
for the
Problem and
womd
devel opment
receiv e the
of any
8
^eeks of
next inJection
Use.
after evexy /
n
t
on;
■Since
care should
be
is a vi
^aken whiie
SCOUg
s°iuti °n/
fecial
g it into
in
the syringe
OrdGr to
"’eteriai
en
sure
ls ejected
that all
from the
the
occurs
3yrlnge and
a-^ound the
that no
nie^dlee
1©akage
in Tow
If the
temPeratu
vi
al
^as been
rQz
it is
stored
advisable to
givin g the
injection.
warm it
bofore
The
hy deer ■
Pneparation
1 ae5P int
shomd be
“ramuscuiar
injection,
given
gluteal
IH^scles.
^ffferably
The inject!^"
into the
fliassa ged.
site should
not be
7
and Purin
g
injection
<
Vx I
- 4
Erecautionst
If any of the contra-indications to use appear,
further injections of the drug should not be given.
Similarly, if any of the special problems
requiring
medical supervision should develop, the advise of the
trained medical personnel should be sought prior to
giving additional injections.
Warnings:
Do not administer an i^J^ctable contraceptive
when a pregnancy is suspected.
but may interfere with the
baby.
It will not cause abortion
dGVGl°Pment of the
(POLLY)
ANNEXURE
Phases of drug trials in human beings
Phase I
a drug is given to a small member
— —[—rB—JJ-J lml
of {healthy ihuman volunters with theprincipal objectives of looking
for evidence of toxicity and deferII IWIH—
• ... ..................
minc^ the^ basic prosperties of the
drug in mano
Phase II
The drug’s effects on a small
population of patients with the
appropriate disease (or, in^the case
of contraceptive^ ^healthy people^
are examined to determine^,its effi
cacy and to detect any adverse
effects on possible toxicity.
Phase
Consists of larger-scale testing to
less common side effects and
cover
to approximate more closely the
type of drug utilization that would
—
------------- -------------- -i-
- - — — __ miinr--*'. '
occur in medical practice if the
drug were marketed ’****'**'•*-*<*•-*. ..« warn
Phase IV
3
U 'r‘.
-k -w- . .«-•*
Programme Introduction stuly to
assess the accept abi1i ty of the
drug under existing family planning
programme conditions with a focus to
MMMkll.Ua .1—.
WM-rJU
identify the operational requirements
and logistics^
******
10 o
PROBLEMS OF SERVICE DELIVi^Y
WHO advises th? cautious approach, with proper
counselling, a careful medical examination and
On counselling, WHO suggests
adequate follow-up*
the following procedure:
" 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 DMPA OR NET EN then the
nature and type of 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 doubts that may arise.
It is a recommended practice to rake
the woman awaro of the possible side
effects of EMPA OR NET EN rather. than
to let her believe it to be free of any
problem."
WHO ALSO calls for a detailed medical history and
physical examination.
There are, of course problems with suggest-
ing that injectable contraceptives should only be used
/2
7/11
in carefully cc trolled situations with adequate
|o|
First, it required carefully designed
follow-up.
family planning programmes with well-trained staff
who are not assessed on their efficiency “processing’1
a pre—set number of women per day, month or year— but
oni their ability to provide adequate, objective
cP unselling and support for women who come to
them for advice.
Secondlyz it requires a much
tighter system of control over the distribution
of injectable cort raceptives to avoid then
7/12
becoming available as over the counter drugs which
i
can be purchased without a prescription or examination. as has been reported in Honduras and
Peru •
The Cocrdinating Group on Depo-Provera concluded
that if DMPA was to be used as contraceptive in the
UK
"the circumstances in which it is
to be available require farm more
stringent controls than both
the current licence and the recent
recommendations by the Committee
on Safety of Medic ines are able
t o achieve. “
The likelihood of those controls
being in place in developing countries is even
more remote.
That, combined with deficiencies
in the basic health infrastructure in many
countries has to cast a serious shadow on the
/3
3
suitability of injectable contraceptives.
In
1982z the Swedish International Development
Agency( SID&) f adopted a formal policy against supplying
DMA.
A SIDA official said the reason for the
decision:
"was not medical but the fact
that it would be difficult and
expensive to control its proper
use in rural areas in developing
country os-"
If injectable contraceptives are included in
large scale family planning programmes, it is very
likely that women will be encourages to choose them.
Therefore, it is very necessary that informed debate
on this issue takes place at the national and
international levels before such an even occurs.
Recently, concern has been expressed in India
that NET EN will soon be introduced into the
population control programme. An article in the
Lancet notes that:
ti
mindless pushing of birth control
methods has failed in India.
The IUD drive of the 1960s failed
miserably because of poor back
up health services; the vasectomy
programme of the 1970s ended in
political disaster
for the Govt.
of the day«
The fear now ig that
the 19 80s have been earmarked for
hormonal injectables and pills
and that the major casualty in such
a policy will be the health of
women • "
One of the reasons often cited for family planning
programmes is the improvement of women’s health.
Indeed, contraception is one of the essential
elements that can lead to better health for women.
But in many instances. the waman is left completely
outside the decision making fr rimework which sets
the guidelines for a family planning programme.
Maaza Bekele a UNICEF consultant and former head
of the Social Services Department Planning
Commission Office in Ethiopia notes that:
“the past experiences of many family
planning programmes have shown that failures
to gain the acceptance of women were
in part due to the attitude or insensiti
vities of the health workers-special 1 y
males- tfho do not take into account women's
feelings about such intimacies, or about
their relationship with their partner. In
sufficient attention was also given to what
woman want or prefer as far as contraceptive
methods are concerned.”
-5She also makes the impor—tant point that ccntraceptiom
on its own will not/ and indeed cannot/ brings about
a change in women’s position in society/ thereby
assuring them beter opportunities for education/
employrpent/ prospects/ adequate housing/ and access
to proper nutrition* It is the lack of these basic
elements that leave many of the world’s women trapped
in poverty/ and it is the effects of the poverty which
forces many women to rely on large numbers of children
aS some sort
f
for the future*
As Bckele
puts it.-
"enhancing women’s status is a most
important factor in successful responsible
parentho.d programmes.”
It isdifficult to see how Net-En , or any other injectp-
able contraceptive/ enhances women’s status* This is
particularly so if the women receiving the injection
are not warned about what to expect. As can be seen
from some of the case studies the "result can often
be frustration/ depressicn/ anger/ powerlessness
and a feeling of having been abused - in addition to
the distresssing physical side effects which make it
difficult for women to fully participate in their
community or family-
While some health workers and the pharmaceutical
companies Involved argue that there are no reasons to
worry about the wide-spread introduction of injectablesj
-6-
other
health workers# women’s groups/ consumer
groups ark! even some governments have found ample
cause for worry.
WHO gays the scientific evidence
is lacking to Justify restricting injectables# but
recognises that there are large gaps in knowledge.
WHO also acknowledges that social factors and the
need for adequate health infrantructures should play
an Important role in arriving at any decision about
the use of injectables.
"Particular concern has^lso been expressed
regarding the potential for ab?se by persons or agen
cies providing injectable contraceptive/ including
6/2
their administration without the woman’s consent
4
or knowledge
11
(The 1978 fl^ntraceptive Prevalence Study in Maxlco
found)
n
pharamacles.
most users obtain injectables from
Injections are often given by
11/20
’injectionists’ practitioners with little or no formal
v >
training who specialise in giving injections."
In some programs/ particularly where access to
family planning service is limited/ women are given
Injections at any ti-rme during the menstrual cycle. 11/30
When an early pregnancy is possible/ women should
be counselled that the potential for risks to the
fetus is uncertain.
In a field study of fcfet-En in Pakistan/ the overall
discontinuation rate was found to be substantially
A
* ' f—
higher than expected
(75e6 per 100 women at 12 months)
due at least in part to a larger number of women
returning for
stifled.
an Injection after the time period
This reason accounted for 25% dlscontlnua—
tion per 100 women at 12 months.
One of the main problems associated with of
dmpa
or
Net-En/ particularly in countries where health care
ds not readily accessibly/ is to ensure that the
appropriate time Intervals
12/31
Health workers should
thus particularly emphasize the need to return at
the designated tine# for the next injection.
Since our two trials were conducted over different
4
periods of time/ variations in injections technique/
which is important with a viscous formulation such
28/342
as Norlgest might account for the observed differences.
The 8 week schedule of Net-En appears to be more
effective than the 8/12 week schedule but It has the
disadvantages of more frequent Injectdcas » greater
11/25
cost and higher drug load.
In a programme introduction study done by ICMR under
existing poet -part urn conditions
(urban clinics)/a
majority of the discontinuations occurred after the first
or second injection^ indicating lack of counselling or
educational material given to the subject and very casual,
behaviour of the clinical staff informs of the enrol-
ment of subjects.
The lack of active involvement of
the provisions and insufficient Information provided
/107/
-8about this method to clients may have influenced the
discontinuing from the study*
(out of 44 centres study on going in 27 centres)•
The overall discontinuation rates in this study are
3/40 much higher than a previous trial.
This
probably reflects difference in the centres and
populations/ and in the attitudes of the patients
or their physicians towards the exceptability of
injectable contraceptives.
★ ** *★
*
An nexure XII
\0o
To
The Drugs Controller of India
Directorate General of Health
Services
Nirman Bhavan
New Delhi 110 001.
To
The Minister of Health
Nirman Bhavan
New Delhi-110 001.
Dear Sir,
Dear Madam
Despite the heavy controversy that surrounds
the issue nationally and internationally, the
injectible contraceptive norethisterone enanthate
enanthate (Net-Oen) is being imported into India.
The ICMR is already conducting Phase IV of a clinical
trial with this drug as part of the Government
Family Planning Programme o
Net-Oen is an injectible contraceptive similar'
to Depo-Provers, a drug which has been banned both
in the UK and the USA.
Schering, the west German firm1that
produces the drug began clinical studies of Nte-Oen
4
in 1957.
The first major fields trials were conducted ,
I
and Peru and in 1967 the drug under the brand name of
Norigest went on the market in Peru.
It was withdrawn
in 1971 and field trails suspended after pituitary
and breast nodules were found in experimental rate.
Today Net-Oen is commercially marketed as Ncrigest and
as Noristeret when supplied to donor agencies.
Al though
it is known to oe 'available* in at least 35 countries.
it is not clearly known in how many countries it is
1 approved1 for use.
Clinical trials with Net-Oen
are going on in several Third World countries.
However, it is significant that in none of the
advanced countries which have stringent safety standards
and where there exists a vocal health and consumer
...2/-
-2-
movement,is net-Oen or Depo Provers (the two major
injectables) allowed for long-term contraceptives
have been used in some advanced countries in a racist
way on coloured immigrants and other disadvantaged
sections.
According to research findings the injectible
contraceptive causes serious of disagreeable and
disruption side-effects :
(1) Mcns'tzxi^l havoc (excessive bleeding ; irregular
cycles/ sometimes even amennorhea)
most commonly cited complaints,
is among the
We cannot stress how
serious a problem this is for labouring women.
Besides being extremely disruptive of working life
it heightens the risk of anemis which is a major
-4
di sease among women in this country.
(2)
Cancer Risk?
According to the WHO the cancer
causing effect of Net-Oen have not been adequately
researched into.
Studies are still being conducted
in different third workd countries (including India)
to assess the cancer risk.
This is the main reason
why the drug is not approved for use by white women
in advanced countries although it is being promoted
here*
(3)
Murn of fertility:
The return of fertility
after discontinuation has not been .prayed,
j---------------------- ___
Here
again the WHO recommend that it should
not be used
on women who wish to have children
later
The WHO gives a list of other serious
contraindications and says that careful screening
of prospective acceptors is needed to identify
... 3/-
\\i>
-3women at risk.
m the atomsphere of heavy pressure
on medical personnel and -general
i nd i f fe rence towa rd s
at risk will not be
patients we fear that the women
properly screened out while being recruited for the
trial*
The pre-conditions that did not exist in the
6O's for a safe IUD drinve do not exist even today
in the 80's for safe injectibles trial and use.
we
have no right to go on repeating past mistakes at
the cost of the health of this country's women.
Finally the whole issue of drug import and medi-
cal experimentation# which we believe to be necessary
should be debated publicly and safeguards against
abuse introduced.
We know from press reports as well
as from sources within the medical research
fraternity that in India# as in many other Third World
Countries# the concept of * informed consent1 is non-
existent in practical terms# though many paper
and 801s
guidelines pay lip-service since the 70*s
after press reports have been exposing trials with
human guinee pigs*
Third World populations arc
especially
ideal research material for field trials#
since the norms for such research are extremely
stringent in the advanced countries# and the public
there are far too vocal and well-informed to allow
The
rampant trials of potentially risky drugs.
research establishment in our country# wittingly^
’.or unwittingly# collaboration with the drug
. . • V-
»•
-4-
multinationals in conducting human trials to gQt the
data and feedback required by the firms.
It is
only the literate, specially conscious sections in
this country who can protest and put an end to this
unethical practice since the subjects of these
experiments are ignorant and unware that they even
have a say in this matter.
We are a women* s group that has over the
last seven years taken up several issues related to
women* s oppression in general and women’s health in
-4
p articular.
We stronly believe that Net-Oen is a
harmful drug for our country and that its import is not
in the interests of the women of India.
We request
that the drug be banned and that all experimentation
on Indian women with Net-Qen be stopped.
Yours sincerely.
Sd/xxx
Susie Tharu
Convener.
/True Copy/
I ’
CP DE Nu:
ER3 G^VEN v^HILE COMPILING REFERENCES
CODE NO.
1.
REFERENCE
YEAR
WhPs multinational comparitive
clinical trial
use effectiveness
sDMPA & NET^J i
( 90 daya»
2.
1977
Same as above - bleeding patterns
and side effects.
3.
WHO
Centric-
1978
. ccmparitive clinical
trial-PreJLiminary report.
(DMPAZ NET_EN_6O_day - 60/84 day)
4.
1982
^acts about injectable contraceptives
- WHO.
1982
4
5.
Was on want
NET EH the other
inject able.
1984
6.
Research
7.
WHO—I2t*h annual report of Spsecial Prof.
(WHO 13th annual report)1984
Res- Doc & Res.
8.
1983
in human reproduction.
PpjJiil^i£!^Rap_QriLs - Injectables
1983
Series K No. 2 May 1983
9.
Injectables Hormonal Contraceptives
Techinci al & safety aspects
1982
WHO No. 65.
• ••/2
-
2
IO.
WHO clinical trial — final report
1983
(see ref. 3)
Contraceptive 28(1) z Julyz 1983.
11.
ICMP - Phase HI Clinical trial
±2^
Introduction of NET EN in selected
PHC’S (Rome Scheme)
13.
1984
1982
Guidlines for use of NET EN in
Govt, and Non-Govt. F^P.Clinics.
Govt, of Indiaz Min. of H & F W
1984
4
14.
Nine Thai Wataen
had concern ~— 9
(DEPO)- stephen
Mother Jonas/ Nov. 1981
15.
Drug information - Jan.z March 1984
WHO.
1984
IN THE SUPREME COURT OF INDIA
(Extraordinary Jurisdiction)
OF 1986
CIVIL. MISC< PETITION NO.
IN
WRIT PETITION (CIVIL) NO.
OF 1986
I n the matter of s
An application for ad-
interim ex-parte stay.
AND
In the matter of :
1.
Stree Shakti Sanghatana
through Convenor
Dr. Susie Tharu
C I E F L campus
2.
Hyderabad.
Saheli through
Ms. Nalini
Defence Colony
3.
New Delhi.
CHINGARI
through
Gita Shah
C/0 2 Gandhibag
Ahmedabad.
4.
Dr. Shyama Narang
5.
Dr. Kamala 8. Jaya Rao
6.
Dr. A.K. Vasudevan
7.
Dr. Ramana Dhara
8.
Mrs. Vimal Balsubramanian
r..Petitioners
Versus
1.
Union of India through
its Secretary/
Ministry of Health/
Nirman Bhawan/ New Delhi
2.
ICMR/ through its
Director General/
Ansari Nagar,
New Delhi.
..2/-
-2-
3.
State of Andhra Pradesh through
its Secretary,
Department of Health and Family Welfare
Hyderabad.
• Respondents
To
The Hon’ble Chief Justice of India
and his corrpanion Justices of
the Supreme court of India o
The humble petition of
the petitioner abovenamed
Most Respectfully
SHO Whirl;
1.
That this day the Petitioner herein have
filed the accompanying writ petition challenging
the
mandamus or other appropriate writ order or direction
restraining the respondents from further testing.
or recommending for use and administering the inject-
able contraceptive Net-Oen which has
not been proved
as a safe drug for long term use and has been found
to be a definite health hazard when
used even for
short term use under Indian conditions.
The facts
of the case have been stated
in detail therin and
the Petitioners craves leave that the same may be
read as part of the petition for stay.
2.
This first and second petitioners have a definite
knowledge that the phase I—V trails are being
conducted in a manner which is designed to
conceal
the fact that women are participating in an experiment.
The trial is conducted as part of family planning
..•SZ-
I
-3-
camps.
When the injectable is offered along with
other approved methods of contraception-
Making it
appear that the injectable Net-Oen has already been
approved for general use.
3.
The first petitioner Stree Shakti Sanghatna
were witnesses to the inethical manner in which the
phase IV trials were conducted in Primary Health
Centre Near Hyderabad at Patan Cheru,
4.
Having regard to various factors almost 70% of
women discontinued from the trial by the end of 24
months and considering that
a number of questions
regarding the long term health hazards of Net-Oen
use remain unanswered.
The respondents have no
authority of law to proceed into phase IV trial,
which
is just an operational
research intended to find out
the logistical problem of introducing a
new drug into
the family planning programme. The ICMR has
not
discharged its responsibility to advise
the Government
about these factors and thus its phase IV trials,
are
without any valid sanctions
and hence unsustainable.
Prayers
In the premises it is most
respectfully
prayed that this Hobble court
may be pleased to :
a)
Pass an order restraining the
respondents
from proceeding with
any further experimenta-
tion or trials with Net-Oen, through its
project centra? chosen for the purpose
...4/-
I
-4-
b)
Pass an order directing the respondents to
submit to this Hon'ble court, a data based
JU -* ■ A, fjfr: r 0 Li.J
A
>»:•
report on the three phases of the trials
conducted so far with complete background
details regarding places of conduct of
trials, status of health care facilities at
those centres and follow up etc
c)
Pass an ad-interim ex-parte order in
terms of prayers (a)
above and confirm the
same after notice to the respondents.
i
d)
an pass such further or other order
as this Hon’ble court may deem fit.
FILLED BY;
R. venkataramani
ADVOCATE FOR THE PETITIONER
Filed on :
0 7th April, 1986
/
/
IN HE SUPREME COURT OF INDIA.
ORIGINAL JURISDICTION
WRIT
PETITION (CIVIL) NO. 680 of 1986
Stree Shakti Sangh a tana
and 8 others.
Pe ti ti oners
Versus
Union of India and 2 ors.
Respondents.
COUNTER AFFIDAVIT ON BBHALF OF IE
THIRD RESPONTENT, THE STATE OF ANDHRA
PRADESH,
THE WRIT ETIT1QJI.
I, Dr. B. Nanda Raj Singh son of Bahadur
Singh, aged U-8 years, resident of Hyderabad having
temporarily come down to New Delhi j do hereby
solemnly affirm and state as follows:-
D
I am an Additional Director, Family Welfare,
Medical & Health Department, Government of Andhra
Pradesh and I am competent to swear to this counter
affidavit on behalf of the third respondent in We
above Writ Petition.
2)
At the outset I respectfully submit that
this is not a matter which can be decided on the
basis of tho opinion and averments set out by the
petitioners in the Writ Pe ti tion.
It is a matter
to be gone into carefully, evaluated and decided
by a competent medical body of experts and. the
petitioners may be given the liberty to put forth
their views if they so desire before such a body
Gontd
©a®.
- 2 -
for evaluating the use of the drug Nct-oen in the
field of family planning as an Injectable
contraceptive,
I furtiicr respectfully submit
that the petitioners have not made cut any case
of violation of any of the fundamental rights
enshrined in the Constitution of India and the Writ
Petition would also not fall under Article 32
of the Constitution of India.
3)
I submit that the use of Net-oen injectable
contraceptive is being done on a purely voluntary
basis by the women who are taking
it and no kind
of force caf suppression of any information
regarding the use of the said Net-oen has been
resorted to as is being erroneously contended by
the petitioners in the Writ Petition.
In any
family planning device or drug the natural and
normal functioning of the human body is necessarily
interfered with and such interference with the
natural and normal functioning of We human body
is bound to have some side effects or roacticns.
It depends upon an individual to select and adopt
a particular method of family planning which may
have its own side effects.
V|hen the women are
taking Net-ocn with informs-ticn about the same and
voluntarily, the allegations made in the Writ
Petition lose all their basis .
The Writ Petition
has beon filed without reference to the actual
i facts and circumstances.
Con id
- 3 -
M-)
In all there arc 1? Medical Colleges under
Rural Orientation Medical Education (K)ME) Progranpe
in the country which are using Net-ocn injectable
contraceptive.
In the state of Andhra Pradesh,
Osmania Medical Collage, Hyderabad is the only
College which is participating under the said
Programme.
Two centres, Patancheru Rural Health
Centre and Athamakur Primary Health Centre, 'tro
participating under the Osmania Medical College,
Hyderabad in the use of Not-oen.
5)
The use of Net-cen at the Patancheru
Rural Health Centre came to be started under the
following circumstances*-
(a)
The injectable contraccptivo project at
Rural Healtii Centre, Patancharu has been
taken up as per the letter No. 12818/1/8l+-86/
AP, Government of India, Ministry of Health
and family Welfare, Nirman Bhavan, Now Delhi-
11, dated 2O.6.1981+ in which it was mentiomd
th?.t Osmania Medical College, Hyderabad
was one of the 1? Medical College under
Rural Orientation Medical Education ROME
Programme, selected for the injectable
ccntracop lives,
It was also suggested
to propose two names, for
supervising the
project. The Principal addressed to Director
Gontd.*.
t
- 14- -
of Medical Education in letter No. 211+/SPM/
0MC/8’-+, dated 3.7.198l+ proposing two names
of the Professors i.e. Dr.G.Anjaneyulu,
Professor of S.P.M. and Dr. Sultana Amir
Ali Khan, Professor of Obs to tries and
Gynaecology, PPP Government Matorni ty
Hospital Hyderabad, to be sponsored to the
■GOT, Ministry of Health and Family Welfare,
Nirman Bhavan, New Delhi for participating
in tiio Workshop on the above subject.
(b)
In the meantime, material on injectable
contraceptives was supplied to Osmanla
Medical College Hyd. from Indian Council of
Medical Itoscarch, New Delhi dated 5.12.1981+
in Lr. No. 73/6/61+-IB-21 and requested to
proceed ahead with proposed project and
further requested to send the particulars
of 3 PHCs and HiC which are under this
college.
Accordingly preliminary planning
was started for implementing this project.
Preliminary meetings with 1ho Medical Officers
for briefing on injectable contraceptives.
(c)
Two meetings wore conducted for all the
Medical Officers of IHC, Patanchoru and
FHCs, Kowdlpaiiy, Atmakur and Vargal
on 7.1.1985 and 31.1 .1985 to brief them about
Contd...
> 5 the proposed sr injectable contraceptive
project. Dr. Sultan Khan, Professor, Obs. &
Gyn. (PPP) Government Maternity Hospital,
Hyderabad conducted a Class on injectable
I
contraceptives selection of the cases, modus
operand! of the project etc, and clarified
all the doubts raised by them.
The Medical
Officers were all asked to submit information
required for the proposed project.
(d)
As per the instructions of G.O.I. & ICMR,
the PHCs under ROME
Programme namely Rural
Health Centre, Patancharu and primary health
centres, Atmakur and Vargal, keeping in view
of several factors like distance , availability
of personal,rccoiptivity of community,
monitoring facilities etc., were taken up for
injectable contraceptive. Dio PHC
though initially decided
Vargal,
to start the
programme, was withdrawn for want of spocilists
and monitoring services from the project.
(e)
Die injectable contraceptive Project at
Primary Health Centre, Atoakur was started on
1^.3.198?
Dio Superintendent and the
Professor, Obst, & Gyn. Government Materity
Hospital, Hyderabad screened the women for
injectable contraceptive.
Finally after
Contd..,
>■
- 6 careful screening and final examinations 10
women were registered.
T!ie first injection
was given on 'I5»3.'1985. All the acceptors
have been continued upto 30.5.1986.
No
compile a tions/c enrol aints were reported.
All
the kotiers/acceptors are halo and healthy.
(f)
The procedure followed at Rural Health Centre,
Patancharu was followed for screening,
follow-up of the cases etc., at Primary Health
Centre Atmakur also.
< 3)
launching of projsct at ric pataijchero?
At rural Health Centre, Patancheru, dtae
District Collector, Sangareddy inaugurated the
programme on 1.h-.l985.
The Superintendent,
Government Maternity Hospital, Prof. Obst.
and Gyn. Post Patum Programme, Principal l/c
of the Osmania Medical College, Professor,
SPft Dept., attended to tie inaugural function.
The professor of Obst. and Gyn. screened
the acceptors for injectable contraceptives.
In the
mean time organisers of Stree
Sakti Sangha tana arrived at the Rural Health
Centre, Patancheru and started protesting
the launching of the project.
Then the Distt.
Collector, Sangareddy interferred and asked
Contd...
- 7
Then the orjanisars of
for tlie details.
Stree Askti Sanghatana explained that this
drug Net>oen, 200 mg. wo-s a banned drug in
the affluent countries and enough experiments
wore not done in this field about its safety
and efficacy. So this should not bo
experimented over Indian women.
Listening th ci
their concern over the problem the District
Collector arranged a common platform both for
tho
organisers of Stree Sakti Sanghatan
and the Medical Profession, to voice their
arguments. The acceptors listened
the view
points on both sides. The District Collector,
Sangareddy
requested the acceptors to think
about and come to the decision afterwards.
The programme was postponed. The team of
This was infornnd to the
doctors returned.
Director of Medical Education and Director of
Health and Family Welfare, and Government of
India immediately.
For sometime no efforts
were taken to implement the project.
The field staff during their routine
visits to the villages came across several
women enquiring about tho injectable
contraceptives.
Like that JO women who
envinced interest and voluntored, wore
registered for tec injectable contraceptive
Gontd...
- e
project.
All the acceptors were personally
contacted by field staff alongwith Dr. G.
Nagiah, MEBS, DGO explained everything about
injectable contraceptives and clarified all
their doubts.
Ins true tions are given to all
the women registered about the duration of
injectable, possible side effeets etc..
(h)
preliminary exaiw-ations conwced
(1) Pa.p Smears Collected: PAP smears for all
the 50 women (Cervical smears) were collected
for detecting the element of cancer, out of
that 32 healthy mothers -were selected.
Dr.
Nagian, MBBS, DGO, Medical Officer, BBC,
Patancharu conducted all the investigations.
(2) Consent loros obtained.
For all the 32 healthy mothers consent
forms were obtained to participate in the
injectable contraceptive project.
(3) Medical 2 xamina tjon conduc ted:
Thorough routine medical examinations
both systmic and general were conducted for
all the 32 healthy monthers enrolled viz.
urine, B.P., Blood for HB, WBC, RBC and
differential counts etc.
Contd. ..
- 9 (>+) Individual case cards maintainadt
Individual case cards were opened for all
tee 32 healthy mothers, case history for
individual ccsos was recorded.
(5) First injection c;ivon on 23<-7.1985?
After thorough investigations, all the
subjects were administered with the 1st
injection on 23«7J985. The field staff visited
their houses during the first seven days after
their taking the injection to find out any
physic ad. and spychological disturbances.
Fortunately, everybody was sound in their
physical health and sound in their judgments.
(6) DISCONTINUATION of 'THE CASBg
Out of 32 cases registered 22 cases
discontinued as per the following:-
After 2 injections
19
9
After 3 injections
2
After 1 injection
At present there are 10 cases receiving
the injections regularly. They have already
had 5 injections and yet to complete the 6
injection in July 1986.
Contd..,
- 10-
,<7' General complaints for discontinuajace^
The reasons for discontinuation given
by the subjects arei
(i) Contraceptive failure-One case became
pregnant and delivered a male baby.
(ii) Menstrual irregular!ties-minor changes
in their menstrual period which is not worth '
mentioning.
( iii) Other complaints like backache,
weakness.
(iv) Migration (Change of address), objection
by husband, not interested in the
contraceptive etc.
(8) General Observation,
Uhe general observation is that 9 out
of 10 cases registered, gain in wei^it from
1 to 5 kgs during the period of one year.
In ono case,» increase inB.F. is noticed i.o.
150.100.
(9).
Follow up services.
All the subjects arc being examined
both for systemic and general medical
Contd...
- 11 -
examinations and every observation is
recorded on the case cards. The health
education is given to every subject. Dr. G.
Nagiah who is a Gynaecologist h?.s been
examining all the subjects whenever they
visit the RHC,
(10).
Visit by ICMS Team.
The ICMR Tbam visited the Rural
Healtli Centra Patancheru to study the progress
of the project during 12 and 13th August
1985,. They interrogated all the subjects
and inquired about their health conditions.
second visit by IQMR Ibam was during
Fob. 1986 (25.2.1986) They visited all the
regular cases, and inquired their health
conditions.
Particulars enclosed
Detailed project particulars are set out
in the annexure table.
6)
The situation obtaining at the Athmakur
Primary Health Centre is similar and the detailed
project particulars are set out in the Annexure
table .
Contd...
!7 >
- 12 7)
The use of Net-con in the State of Andhra
Pradesh under Osmania Medical College, Hyderabad
is being done as explained above under the
instructions from the Government of India, Ministry
of Health and Family Welfare and the Indian Council
of Medical Research.
It is a part of the programme
that is being, carried out rhrou^out the country
and is not confined to Andhra Pradesh alone as such.
The petitioners have chosen to make only the State
of Andhra Pradesh a party to the Writ Petition. The
programme is that of the Government of India,
Ministry of Health and Family Welfare and Indian
Council of Medical Bosoarch.
NEW DELHI
DAIED* 2.7.1986
DEPONENT.
I
PARTICULARS OF INJECTABLE CONTRACEPTIVES CASES
OF RURAL REAL TH CENTRE, PAWiCHERJ /END PRIMARY
HEALTH CENTRE. ATOMAKUH UNDER OSMANIA MEDICAL
colie (Si HYDEBkBAD
RHC
PAWCHE HJ
PHO
AWiAKUR
1.
Total Number of women
enrolled to date.
32
10
2.
Number of women still
continuing
10
8
3.
8
Number of women who have
(comple tin; by
completed 6 injections
31.5.1986;
and discontinued.
h-.
Number of womon dis
continued earlier by
type of reasons and
number of injections.
8
(a) Number of cases
discontingedt
After 1 Injection
Nil
1
/ifter 2 Injections
5
Nil
After 3 Injections
2
2
(b) Type of reasons for
discontinuances.
1 . Contraceptive failure
3
2. Menstrual irregularities
3
3. Medical complaints like
8
A. Other reasons*
Migrated from the village
and address not known
afterwards
2
Objection by husband
2
Not interested
2
Sd. 30.5.1986
■9
IN
THE SUIREME COURT
CF
iimu
ORIGINAL JURISDICTION
WRIT PETITION NO. 680
of 1986.
J.N ThE MATTER Oj'X
Strce Shakti Sanghatana & others.
... Petitioners
VS.
Union of India & Ors.
••• Respondents
COUNTER AFFIDAVIT ON BE 'ALF OF THE
RESTONEENTS TO THE ABOVE WRIT PETITION
I, Dr.D.D.Arora Late Sh. S.L.Arora agG
about 56 years, officer of the.Ministry of Health
afc present Deputy Commissioner(To) do hereby solcu
mnly affirm and state as underJ_
1.
That I am conversant with the facts of the
case on the basis of the relevant records I have
I
gone thyoUygh the writ petition and have understood
the contents I deny all allegations/averments made
JjC‘tition which are contrary to or
inconsistent'with records or what is being stated
hereinafter .Anything not specifically admitted or
dealt wife shall be deemed to have boon doniod.
In roplylcS: submit as under
2.
^Before traversing the averments made by
the petitioner in the writ petition the answering
CJ
contdi/_
I
respondents craves leave of this Hon’ble Court to
submit the following by way of proliminaiy sub rib.
s sions:
The answering respondent submits the
following Iparawise reply; to the writ petition.
3,
fara 1. -
It is incorrect to state that Norethis
I.
terone Oenanthate (NET OEN) is not a safe_ drug.
CjChc available .clinical trial data from the multioentre fhase IJI clinical trial of India Council
of Medical Research (ICMR). (copy enclosed) as well
as studies conducted by the World Health OrganrU
zation indicate that NET OEN in the docs of 230
mg given 2-monthly is cafe and provides adequate
I
contraceptive protection# 0?herc appears to be no
•W -
•
—
•—• *-•—■—.
—
-
- •
•
•
•
'
published evidence jto indicate that this durg is
(
i
i
I
associated with any adverse effects in terms of
i
metabolic or biochemical parameters. There arc
certain side effects e.g. menstrual irregularities
w llch are associated with any progestogen only
preparations - whether injectable or oral mini pillswhich are more of an inconvenience rather than
posing any health risk to the users. This method
is primarily being used as spacing method which
would be for an optimal duration of 2-3 years at a
time. There are no long term studios which arc cither >
................ .............. ....
'
................................... ..........
...................... ...... ■■
■'!!
cort d«/-
published or ongoing at the present time ’which
would indicate that this durg is associated with
health hazards. Such type af information can only i
be obtained from epidemiological studies provided
the drug is in long term use (more than 5 years of
regular use) in an adequate number of user population..
lara 2(a} in the ICMR; ongoing programme introduction
studies of NET OEN in selected Primary Health
Centres attached to Medical Colleges, the informed/
consent of the women is always obtained ^ior_to
the use of NET QEN, therefore, it does not violate
the article quoted by the petitioners.
para 2(b)- All the available .contrac eptives such
as Intrauterine Devices (IUDs) or oral pills do~
provide contraceptive protection [by altering body )
(
physiolqgj' in one way or the other. Therefore, the!
injectable contraceptive is no exception to this
rule.
Tara 2(c)~ The major benefit to the woeim with this
injectable contraceptive is that it provides adequate
contraceptive protection and thereby prevents unwanted
.. ....
child birth. The injectable contraceptive is not
associated with any potential risk to the health
of women as compared to the rik of child bearing ■
contd*/-
is Uftacceptability higher (maternal mortality 3-7
per 100 birth) in our country These injectable
contraceptives arc not associated with any potential
risks to progeny and this conclusion is based on
the(available published data on hprmona contrat
captives - oral pills and an another injectable".
drug-Dopo Irovera* The available data from the
.»»
■'
-
■ ■ ■ —-.1-^—
.
*
ICMR studies indicate that this method can bo
used for spooing since the return of fertility in
ox-NET users does not appear to bo adversel affe
cted as compared to IUDs /copy of manuscript "in
j
press"II enclosed) which supports the other published
studies.
fara 2(c0~ In the National Family Planning Progranuna various methods are offered on a vluntaiy
basisa To moot the need of diverse group of our
population, specially the young married couples,
it will bo essential to have a variety of spacing
methods which may complement the available spacing
methods in the National Family lianning Irogfamme.
Therefore, with all the safeguards of informed coru
,sonts and voluntary nature of -our fr.gramme, it is
not a fact chat the introduction of newer methods
of contraception specially for spacing, are viola_
tive of article 21. The present guidelines
1
isauod’ 'l’1
■ 'f pcfl • '■
ccntd#/*.
s.
■fay
the Drugs Controller of_India, require that
this injectable contraceptive is only available
on~the prescription by a Gynaecologist.
Therefore,
the question of abuse of this drug does not arise.
para
The published data from ..the ICMR. study
phase III multicentre clinical trial indicate
that under similar clinical trial conditions the
method failure rate (1.4 per 100 user at 24 months)
was~comparable to that of CuT 200 (IUD) which is
already an accepted method in our National Family
Welfare Programme. The continuation rates were
similar to that of Gul 230 at 12 months period,
however, they were lower at 21 months period. The
answer to the long-term health hazards and effect
^n the progeny has already been given in the pr
eceding paras.
Para 2(f) - The findings of ICMR phase III clinical
trial as well as studies carried out by WHO et<f.
in terms of efficacy, acceptability and side effects
associated with drug, do not discourage one to pro.
ceed with phase IV study. Correctly speaking, the
IV study actually consist_of; long-term monitoringand^ost^marketing surveillance of any drug-con
traceptive or otherwise-when a product is in actual
use. However, the -present study with NET OEN has
contd*/-.
•M l
a very limited objective to work out the logis
tical aspect of this method of contraception in
existing health care ddiveiy conditions. This
| data is essential for any programme administrator
before the drug can be recommended for wide scale
■
............................................
.. .......................................................................................................................... ........
i use in National Family Planning Trogramme. There
fore the objective of present study is to clearly
work out the logistical aspects and this study
should be correctly termed as pre-pro gramme intr
oduction study which is quite different from the
pha^O 511 _trials_an<i clEissicaiiy defined NIX ITT
phase IV studies. The copy of the phase IV study
protoqol is enclosed herewith giving the details
of the Objectives and design of the study.
'Wc are not aware of any scientific evidence
which would indicate that the NET OEN cannot be
used ill conditions provided the subjects are
properly -------screened by
trained personal for the use
..
of this contraceptive as per the guidelines providodjin informed consent is obtained from ethical
view point. In addition the present study design
and training programme for medical and para-medical
staff emphasis on adequate counselling to the pr.:>s_
poqtivo user which would provide her information on
the potential benefits and side-effects of this contra
ceptive.
contd,/-
-7-
Para (g)- The centres which are/currently involved ,
(in this study have gynaecologist to screen the
women for eligibility as well as to deal with the ;
complications that may arise from the use of this J
drug*
Paru 2(h)- The drug is not yet introduced for
—_—I
II
.1
- - •-I-
—
____
..
.
...
—
.
_
—— -- -
-
7
—
general use in the National Family Welfare Progranric* The question of approving the drug for go-
neral use in the National Family Pl aiming Programme^
would bo considercdfonly after results of prcsont._> j
■>--------------------- --------------------------------------------
...................................... -
■
-
;
ongoing studies being conducted by the ICMR arej
I made available to the Government of India,
i
...
-
■
The phase III clinical trial of the ICMR
was conducted at the Human Reproduction Research
Centres located in the Medical Colleges in the
different parts of the country. The major objective
was to find out the safety, efficacy and acceptability
in a well controlled conditions. Whereas the pre
sent phase TV study trial is essentially being
conducted in a larger population in the different
parts of the country, in order t. find out the
I
I
(
logistical requirements for the actual use of this
I.
■ ^.'J*'*■*''*
r
-—Kt I. HI If.. .
drug in the regular health care delivery programme
in the country in terms of (i) of training of
medical and para-medical who would be provides
of this contraceptive, (ii) the acceptability
of this contraceptive by the women users with the
contd./-
T
-EL.
available back-up counselling facilities in the
health care delivery system, (iii) back-up system
support of supply, storage and distribution of
drugs and (iv) the problem of the regular contacts
of both the users and provides due to the distances
involved, in terras of outreach'of health services.
In fact, the study in designed to help in
: driving our .services to.
Para 4- Injectable as a route of drug delivery is j
preterred in our society and culture.
As indicated
in above paras, the present ongoing phase 17
study, require the utilisation of trained medical
‘ and paramedical manpower who were the providers
of those drugs after adequate counselling and
obtaining the informed consent of the volunterr.
Para-5
No comments#;
lara 6 As per the report of the Toxicology Review
Tanel from the WHO page 202 (copy enclosed) both
| ? |
the rodents as well as beagle dogs are considered
to bo unsuitable models for studying the toxicology
of progestogons. The sicentific principles behind
this hypothesis is given elsewhere in the affidavit.
para 7 - At the present time, it is not recommended
to use NUT OEM in lactating .women for first six. months
contd*/-.
1
available back-up counselling facilities in the
health care deliveiy system, (iii) back-up system
support of supply, storage and distribution of
drugs and (iv) the problem of the regular contacts
of both the users and provides due to the distances
involved in terms of outreach-of health services®
In fact, the study in designed to help in
i driving our-services to*
rara 4- Injectable as a route of drug deliveiy is
preterred in our society and culture.
As indicated
in above paras, the present ongoing phase 17
study, require the utilisation of trained medical
and paramedical manpower who were the providers
of these drugs after adequate counselling and
obtaining the informed consent of the voluntcrr®
lara-S
No comi^ents®
para 6- Ls per the report of the Toxicology Review
Panel from the WHO page 202 (copy enclosed) both
|
the rodents as wall as beagle dogs are considered
to be unsuitable models for studying the toxicology
of progestogons. The sicontific principles behind
this hypothesis is given elsewhere in the affidavit.
fara 7 - At the present time, it is not recommended
to_ use JET OEN in lactating women for first six months
contd®A
-9-
after delivery.
We do agree that long term moni- H
H
v —— ■ ..
taring and surveillance is nocessaiy for any drug h
including this injectable contraceptive. As roco-
mmended in the XII Annual Report of WHO 1983
quoted by the petitioners, the performance of
those injectables in the normal service situations
is already one of the limited, objective of the
present study.
Para 8_ No comncaats
para g
Regarding the question of optimal time and
does regimes the ICMR conducted a Phase III mul-
ticentric clinical trial to compare the efficacy
of 200 mg NETWOEN given at 2 or 3 months. The
subjects were enrolled in two groups i.e. Group-♦_
The women who were given 200 mg of NET-OEN .every
60 T5 days through out the trial period and Group-
II- the subjects were given &)0 mg of NET OEN for
the first 6 months at 60 5 day interval and then
switched over to 90 day regimen. About 1300 women
in each study group were recruited and observed
for 28,500 women months. The method failure rate
were significantly higher in Group II as compared
to subjects in Group I(6»6
1.4
1.2 per 100 v/onon &
o.d per 100 women a-fa 2-1 months respectively).
Most of the pregnancies occurred during the 3rd
month of the injection interval in subjects recruited
contd./-
-10■
for Group II. This is further supported by the Ph
armacokinetic data that the circulating level of
Noretisterone is non-existant around that time.
The incidence of amenorrhoea v/as comparable
in both the groups at 6,12,24 months of use. The
incidence of anenorrhoeaj excessive or irregular
■bleeding were similar in both the group during
the entire period of observation. The discontinu
ation due to amenorrhoea during 2nd year of use
was high as compared to 1st year mainly because
of the preject guidelines to discontinue the sub
jects from the trial if amenorrhoea persisted for 5'
more than 1 year. -Wo agree that NET-OEN 200 mgs. I
causes disruption in the menstrual cycle in the
K-—
....
... . ....
|
form of irregular bleeding, spotting and amenorr-i
hoea. However, those menstrual disturbanccd did' pr
not cause any health hazards.
„ ‘
Para jO- The ether side effects due to its ^effect
on hypothalamus and pituitary- glands like headache,
weight gain, abdominal distention, anxiety, nervo
usness (have been rarely. I’cgarded as a problem. >.
The'cardivascuiar effects-associated with
the use of oestrogens containing preparations of
; ,.ral contraceptives have not been found with the
**'*•—_
—■
■■■ ■' ■■
......... . ..............
-
use of contraceptive containing progesterone only.
There appears to bo no significant change in bio;d
contd./-
v
coagulation, or the incidence of thromboembolic
disease which is related to the oestrogens# SciI.
'
entists/medical professional even recommends that
progesterone only methods are the contraceptive
of choice in women suffering with these compli
cations. The effect on the hlood pressure is
minimal*
lara 11 Possibility of irreversible damage and
atrophy (is not seen;among users of this contrace
ptive as shown by the fact that fertility returns
within
to 8 - months
after discontinuation
_<f
*------—*6 to_8
.
. .
. .. - - of
If
this method.
Para 12
Although'animal data has raised concern.,
about the safety)and long term side cffcctsjof
NET-OEN but certain animal models and the doses li
used does n^t appear to bo appropriate for stji.
dying human effects of these stofoids.Extensive
clinical and epidemiological studies among women
using these drugs havu thus a demonstrated"no'lift?
threatening side effects , including increased of
Neoplasia.
The \majjor..controversy Has been associated
with the interpretation of animal toxicology. The
f±r£?t problem in interpretation arose with the use
of beagle bitches as a possible predictive model
contd*/-
f
■
V
I
4 -< -
.A
.
I
-12for human breast cancer. These animals were treatc
with docs equivalent upto 50 times the human
dosage and followed for a period upto 7 years.
Since that time a large amount of scientific data
from animals and humans has accumulated indicating
that 'beagle bitch
_pqor model for
>
the study of progesterone for predicting risk of
thcabreast cancer in humans. There is also evi
dence that healthy beagle breast contain reservoir
of microscopic neoplasm which may grow and occ
asionally become malignant.
ThG ^?GOncl concern (from animal toxicology
came with the appearance~of a small number of
;cndometribl“malignant and"promaiignant lesions
in Rhesus monkeys treated with NET-OEN with a doos
of 50 times that of humans. Endometrial carcinomah
b*15 not been reported among women using JffiT-OEN,
[
in fact progostrogon are given for the treatment -f
endometrial carcinoma in considerably higher doses
than those used for contraception. There is a reason
that treatment .with these progestrogons
will actually reduce the long term risk of those
I c^cc£f..ln
It is also been observed thaf(l)
endometrial cancer in monkeys occurs in atrophic
endometrium whereas in humans it occurs in hypertro
phic endometrium and progestrogens suppresses this
hyperplasia. (2) Endometrial c^rcinomo. in mc-nkcys
contde/w
"
-13-
is of a different cell type. The cell make up of
those animals is quite different from that of
humans (3) Tumors in monkeys originate from epi
thelial plaques which are not present in human
uterus*
Studies on rodents have been carried out and a
drug related increase in the incidence
of
tumors
... ... .
-J-
- '
—»— ■ '
...
•■w*— —................................................................................................................................................................... **»...
.,.ww.
has been observed but it is due to the oestroge
nic activity of NKT-OEN in rodents, which is not
seen in humans* In view of the above findings in
the monkeys, beagle bitches and rodents, the tor—
icology review panel of WHO (Convened in 197C)
together with the expert scientists and represen
tatives of six drug regulaboiy agencies recommended
1
that ourrent and planned clinical trials of NET-
OEN phould continue since Clinical evidence from
more than 15 years of use as contraceptive
agent
shows no additional adverse effects, than those
found with other hormonal methods of contracep
tion. The particular advantages of IDT-OEN is that
it is . highly effective, long lasting and‘reversible j
contraceptive, make an important option that shouldk
be available for women desiring a method of ferti
lity regulation.
.t—
-
There is’.no similarity between 1
-— ------------------------fc
.'1»- -A
-
..............................................
NET OEN and Diethyl stilbesterol; horman preparation
because latter is oestrogen end NET OEN is a.pro,
******‘ww*’^
*-^
-
*
gestrogent
far a -]3 - No studies have systematically followed
contd«/~
I
i
-14the health and. development of infants exposed in
utero to NET OEM as a result of contraceptive fai.;
lure orthe inadvertent initiation of contraception
in a woman with undiagnosed pregnancy. This form
of contraceptive exposure is quite infrequent and
I it is difficult to identify sufficiently large
I
>r proper investigationS| How,^
number of infants
for
—- ------vrver it is observed that any teratogcniQ hazard
associated in efore exposure an progestogen is
i ■
i
negligible.' In the present study the injection
is being giving 5 days of menstrual cyijle and in
gase of method failure the MTT was adylgocU
fapa ^4- Effects of lactation
Effect of progestorogens on the production
of milk in women appears to he promotive. KiV? Q7%J
in particular has no adverse effect on lactation,
A recent study has shown that the level of
NET OEK 200 mg in the breast milk is in the order
of 3 mi^rogran/litre one week after injection while
by 8 weeks it is usually undetectable.
This would
given an estimate of total exposure of the infact
of approximately 05 per cent of the total intake.
The ratio’of NET-OEN in breast milk to. plasma is
11 10« In human subjects the measurement of NET OEM
was undertaken on plasma samplos from 4 breast fed
contd./-
-15-
infants 2 to 5 days after the injection of NBT GEN.
The drug could not bo detected in the plasma using
an assay system which has a limit of detectability
of 0.05 micrograr.i/litrc. Since there is (no infor->-U
(mation pn thg_Ppssiblo effects of progestogens on
i
i
maturation of hypothalamus and liver function in
the neonate, it has been recommenced that infants
should not bo exposed to these steroids during
h v•
the first 6 weeks post partum (WHO;. In the ICMR
study subjects who wore lactating for less than 6
months were not included in the study to exclude
all the possible risks of hormones on the foetus.
Effect on Lipid Metabolism; Thu_.cffoat of W-Og;
<
.200. mgs .on lipid metabolism is nr; minimal and
published and unpublished data indicate that it
2pads,to a small decrease in HDL»cholosterol.
Most investigations have found little or no effect
on liver functions.
farpi.. .15., 16 & 17
The phase Illclinicai trial ?f
the ICMR which shewed comparatively higher method
failures in first six months of drug use as compared
to the later period were within the acceptable di^
leal trial criteria ef the study. Although;the reason
for this observation is not completely ur. • rstood
ori£._possible explanation could be that it nay take
^ome time for the adaptation of the body physiol;
to the pharmacological effect of this injectable
contd</-
-16preparation. As regards to 90% of the menstrual
If
cycle being abnormal, this particular statement I
was not reported in our publication of phase III;’
clinical trial. However, this observation is simply
i
a statistical percentage indicating that if any
irregularity (e.g. prolonged cycle, spotting) was
observed even in one menstrual, cycle during one
year period of observation it was calculated as
menstrual irregularity. When one compares the simil ftr figures for general population who are n: t
using any contraceptive, it has been reported that
‘ variation in so called "normal" cucle lenght was
tremendous i.e. ranging from 10-105 days (Amnr.
Journal OBGYN, Vo.20c 320-323, (2) Journal OBGYIJ
of British Qnpiro, Vol.44: 339-879, (3) Journal /jn.
Med.Association, 2031 89-92). Therefore, this
particular observation of 90% "abnormal mcnstrul cyclo"
is in no way an indOK of adverse effects of this
injectable method. This is supporter' by the obsorvation that the reasons of discontinuations due
to menstrual cycle disturbance wore small as indicated
below:
1.
The discontinuations duo to (^prolonged j
bleedingjWcro 15.6 per 100 users at 24
months. The break up of these discontinu
ations by period of use is 3.5, 75., 11.1,
contd./-
-17-
15.6 at 6^12,18,24 Genths of use respec
tively i.e. one can say that there was
an uniform increase,_in Jjhe_jdiscpntdnua —
tion due to this reason_in_the jtune of
4 per 100 users at an interval of fi months*
2.
The same is true for the discontinuations
due to^irregular bleeding.
3.
The sudden increase in discontinuation
due to iamenorrhoea ] towards 2-1 months,
was due to the_protocol guidelines
which necessiated women to discontinue
the method if the amenorrhoea persisted,
for one year even if there were willing to
continue in the trial with the amenorr
hoea.
4.
(
29.7 per 100 women dropped due to personal,
^reasons, clearly indicates that their
participation in the trial was purely
(voluntary and were free to discontinue
; trial for any reason at any time.
4.9 per 100 users of discontinuation of the
method duo to ‘late for follow-up' and 11.7 per 100
users due in 'lost to
at 24 months has been approc^kQ^-^y-VJ-rious .researchors including
indicating
a close monitoring of the subjects during clinical
|
-
trial.
contd./-
-.18In the light of the above comments, the
statement that 70% of the women did not find this
method suitable is incorrect as there were many
other compelling forces for the women not to resort
to any other family planning method such as desi-T
re for another child or objection from mother in J
law. Spacing methods are primarily used for a.3
years.
The published data., on the pharmacokinetics
of NET OEN does not seem to indicate a faster
clearance of thisdrug in under-nourished women
as compared to well-nourished women.
The ICMR
is also currently engaged in conduct-?ng the phar— C
macokinetic studies in under-nourished population
to collect
information. ' —The available
publis...
• more
-- - ... ----------------
hod data do not seemjbo indicate finy higher incldciicc '
cQnSen^tal malformation Recurring in the childrop
who were exposed to hormonal contraceptives incV
uding NET OEN in utcro< Since pregnancies with
long acting injectablos arc uncommon and any poteru /
/
V. .
.
...r'—•
-------------
»
tial teratogenic risk is small, this is nt likelyO
f!-to be major public health problem. Furthermore
f
f........
in l'
i ;
our present phase II study.!MTI is recommended for ;
***■■•• ■•*'■ •-**■■*'*•**
'*
•.
.all method failures. /
Avaliablc evidence d.cs net seen to indicate that
the hepatic function is adversely affected bt MM 02/ ?
preparation. The storoidal drugs are secreted through
hepato-bilidry system* Therefore, the diseases like viral
contd./-
-19-
hepatitis and amoebic hepatitis which primarily
affect the parenchyama do not seem to have ery adverse
association with the use of steroidal contracept
ion • At the present
all the study volunteers
are screened by the qualified gynaecologists for
all the conditions including the syspectcd pregnancy*
Furthermore, the present injectable drug is recomm
r
ended for use in first five days of menstrual cycle*
Therefore, the question of suspected pregnancy docs
not arise in the present trial. Ono of the
contraindications, for the use of NET OEN by the
Drugs Controller of India is the cancer of breast
and all genital cancer.
I
Para 1S - The present study of the JOffi has been—-------------- --- -------- -----------
a
under-taken with'.the
he necessary permission form Drugs,'
India as well as.„the Ministry of
Health and Family Welfare*
Lara 19 - An ideal contraceptive which would lac acco-
ptabie to an populations of different typos does n t
exist at present. Therefore, there is a need for the
wide variety of methods which cane be utilised by the
potential users living in the different socio-cultural
mileau and which can be operationalised in the different
health care delivery systems. The available clinical
trials^ data of net OEN indicate that (i) this drug
i
given as 200 mg at an interval of go
5 days provides
contd./-
adequate contraceptive protection, (11) there is
no adverse effect on the return of fertility and
______________________________ _____ _______________________________________________________________________________________________ ----------------------------------------------------------------------------------------------
■■
----------------------------- "
(ill) no serious health hazards has been noticed.
•--- -—
_____ _
____ Al-——------- ----------- ------
<
We do not recommend the drug at the present tine
to lactating women for six months* ^No published^
'evidence is avilable that NET OEN causeslong term
irreversible damage to the health of the woemn or
to their progeny.
Cn the basis of the published
evidence^ it can be concluded that the NET OEN can
be concluded that the NET OEN can be utilized as
--- ------------------------------------------------- ’
'■
■'
----------------------------------------------------------------------------------------------------- ...
!
I'
spacing method of potential users*
para a) - ^s indicated in the above paras , the present study of the ICMR is being conducted with the
full knowledge and approval of the Ministry of
Health and Family Welfare and the Drugs Controller
of India*
Is per ICMR protocol guideline, the
prior informed consent is obtained from the volunteers
of this injectable contraceptive*
Para, 21 - As per the information available now this
drug (the NET OEN) is approved for marketing in=3n'
•----- UK
countries .including/(not 45 as stated earlier). All
the information regarding the long term risks associ
ated with any drug can only.be...obtained provided that
particular product is in general use for a long period
contd*A
-21-
'if
of time, which includes the present drug - NET OEN. '
IIf
In India, Medical Termination of Pregnancy (MTP)
is legalized.
There are at present various methods
which can be offered to women desiring a particular
contraceptive for pregnancy protection after an
MTP. This includes IUDs and Oral Pills. In a se/ parate study conducted by the ICHR as well as by
i
the WHO
it is clearly evident that NET OEN can be
■>
t
j
utilized to provide contraceptive protection to the
women after undergoing MTP without any health hazard.
As indicated in the preceding paragraphs, the informed consent was obtained from the prospective users
Jilso we have indicated in the preceding paragraphs
that provided the proper screening and informed
consent is obtained, there is no scientific evidence
to indicate that NET OEN cannot be used in the
camp conditions which seems to have been done in
Hyderabad,
regards to the statement of petit
ioners that the ICMR is only serving
the interest
I of_the west Germany firm Schering ZG Berlin, this
can be considered as an arbitrary statement without
fo^idation and can be considered defamatory
. in nature. Furthermore, tho^^for^he preset study 1
was obtained through the Ministry of Health and Family
Wo.lfa'rc
the Special Programme for Research in Human
Roproduc tioh, World. Health ^Organisation, Geneva. fSierefore^)
there was no direct involvement with or sponsorship of ~f
contd./-
f
of German Drug firm Schering AG Berlin.
'
..............■
■
- ......................................................... ..............j
I
para 22- We have already given comments on the various
points raised in this paragraph. No additional comm
ents aro required to be made.
S3 - We have already given reply to various points
in this paragraph. At the present time, the use of the
i
drug requires the informed consent and screening by
qualified gynaecologists. Therefore, the potential for
abuse docs not arise. Furthermore, the pro! i rd nary
observations of the ICMR Phase IV study in B & C Typo
of Post-partun Contres quoted by the Petitioners, were
the very information which wore the objective of the
present study i.e. to find out the logistic and actual
pregranne performance of this injectable method in the
field conditions.
Para 24 - The various
methods of contraceptive tech-
nologies indicated by the petitioners such as hormonal
implants, prostaglandins and anti-pregnancy vaccines j
arc the newer potential methods which arc being investi
gated for their possible utilization by th 3 women and,
af the studios on safety and accoptabHit;," are oncoura- #
"gijig, those can bo considcred._for-thoir possible use in
thc National Family Planning Programme. Jlil the necessary
pro-clinical animal toxicology evaluation by Toxicology
Review Panel, ethical considerations to obtain the approval
contd./-
-
-23-
of the ethical committes of participating institutions
from phase I to phase III clinical trials, are being
followed by the IC IR. In addition the IOMR has its own ,
Ethical Committee (its constitution is appended) rwhich
includes the former Chief Justice of India, Mr.H.R.Khanna
as one the Member and all clinical evaluation of cont-
raceptives carried out by ICMR are cleared by the Ethi
cal Committee of the Council. The informed consent of
the women volunteers is also being obtained after getti
ing the approval of the studies by the Drugs Controller I
-W.-- -
_ _
.
of India. Furthermore, MTP is routinely recommended to
women in the cases of the methods failures
We have no
further comments on the other points raised in this
paragraph*
para 25 - Qurs is a voluntary National Family Planning
Programme, therefore it is actually the user who dccides which method she or he would opt for
At the present
time, there is no single ideal method for contraception
which will suit all ages, both sexes and all socio-cjlh.
turaily different population groups. Therefore, it isessential to have a variety of methods in the National
Family Planning Programmes which would include various
.barrier method also as indicated by the Petitioner.
para 26
The ICMR has already prepared the guidelinesfor
jgthical consideration involved in research on human
subjects and the copy is enclosed herewith.
contd*/-
-24-
.Para 2.7. - No fur ther comments.
GROUNDS
Ground. 1- The present study insists on an infomred
consent by the potential user. Therefore this Is
not unconstitutional as indicated by the petitioner.
Ground, 2- There is no scientific evidence to indicate
i
that NET OEN injectable causes any serious health
hazard based on the published reports of NET OEN
both from ICMR as well as from WHO and other scientific ‘
investigators*
ur..jUn.d 2~ At the present time, the basic objective
of the study is to find out the logistic requirement
before a product can be recommended for general use in
the National Family Planning Programme. No decision
has yet been undertaken by the Government of India to
introduce this injectable preparation in the National
I
I
Family Planning Programme. Thereis no published evidence/j
to indicate that the NET OEN poses a definite risk
to the health of potential user nor it is o potential
risk to the progeny. Furthermore, the
ilable data
on the return of fertility Ah ex-NET OEN users indicate
that this method can be utilised for spacing.
Ground
<Ail the published information of NET OEN
cqntd*/-
-25is available with the Ministry of Health and Drugs
Controller of India and with the ICMR.
Ground 5 - As in -iicated in the preceding paragraph.
the study was undertaken only after both medical and
paramedical staff were trained for the use of this
in j c c t ab le pro p ar at io n •
Ground 6- ^e have no evidence to indicate that the
use of NET OEN preparation violates the article 21 of
the Constitution.
Ground 7* As indicated in the proceeding paragraphs, •
the present study has been undertaken with the full
knowledge and permission of the Ministry of Health
and Family Welfare and Drugs Controller of India.
Furthermore, it was an essential requirement that
informed consent will be obtained and screening of
women would be conducted by the gynaecologists. Thero
fore the present trial does not indicate any arbitranes
on the part of the ICMR or Ministry of Health to conduct
this study.
Ground 8 - It is not a fact that women are treated as
chattel and their consent taken for granted. The very
nature of National Family Planning Programme is volu
ntary. Furthermore, the present study also obtains the
informed consent of the volunteers. It is obvious
cont da/.
-26that nona of th
fundamental rights guaranteed under
the Constitution are curtailed or infringed. As
such, there is .^o cause of action to file this
writ petition, for alleged violation of article
51<A of the Constitution,
\ 1
i
Ground 9 - Since the informed consent was obtained, ) !
it does not seem to violate' either the Helsinki
declaration nor the article 21.
Ground IQ - The respondent have not violated human
dignity or right to a healthy life.
as necessary
precautions are taken while implementirtg a project
in public interest. Furthermore, it is submitted
that the respondents have not violated the directive
principles of State Policy, in any manner. The case
referred by the petitioner does not apply to the
facts of this case.
In the premises the Deponent most humbly and
respectfully submits that the writ petition is
devoid of any merit and deserves to bo dismissed.
DEPONENT
VERIFICATION
I, the deponent above named do hereby
ccontd./-
-27-
verity that the facts mentioned in the above
paras of the affidavit except the legal submi-
ssions made th. re in are true and correct to
my knowledge based on information derived from
the official record relating to this case,
which I believe to be correct.
Legal submissions are based on legal advice.
Verified and attested at
on this thot
of 1986 •
DEit)NENT
cl ay
incorrect to state that Norethisterone Qenanthate (NET OEN>
Item 1
is not a safe drug.
The available clinical trial data from the multicentre
Phase ill clinical trial
v.
y
of Indian Council of Medical Research (ICMR) (copy
is well as studies conducted by the World Health Organization indica-ft
enclosed)
that NET OEN in the dose of 200 mg given 2-monthly is safe and provides adequate
contraceptive protection.
. that this
There appears to be no published evidence to indicate
associated with any adverse effects in terms of metabolic or
;rp
biochemica: parameters.
There are certain side effects e.g. menstrual
irregulari■
which are assoicated with any progestogen only preparations -
whemer ir
< t ah 1e or oral mini pills-which are more of an inconvenience rather 1
than posinc any health risk to tl
users.
This method is primarily being used
at a t me.
.1:: spacing meih'' >d which would be for an optimal duration of 2-3 years
fhere art u.' Io; g term studies which arc either published or ongoing at the
which would indicate that this durg is associated with health
present ti
haza ids, So,'h typ ?
of information can only be obtained from epidemiological
studies provided the drug is in long term use (more than 5 years of regular use)
1 ’i
uu adt ;uate number of user population.
Item. 2 Par-i.
- In the ICMR ongoing programme introduction studies of NET Ohib
attached to Medical Colleges, the informed
in selected Primary Health Centres
the use of NET OEN, therefore,
consent of the wemen is always obtained prior to
t uoc-s no i •... Late the article quoted by the petitioners.
1 tern b
such as Intrauterine Devices (IUDs)
All the available con :raceptives
or oral pills
do provide conr.rac ;:.xve protection by altering body physiology
5
2
/
in one way or the other.
Therefore, the injectable contraceptive is no
exception to this rule.
Ltec^c - The major beaefrt to the women with this injectable
that it provides adequate contraceptive
unwanted child birth.
contraceptive is
protection and thereby prevents
The injectable contraceptive is
not associated with any
potential risk to the health of women as compared to the risk of child bearing
*
is unacceptability higher (maternal
mortality 3 7 per1Q00 birth) in our country
These injectable contraceptives are not associated with any potential risks to
progeny and this conclusion is based on the available published data on hormona:
contraceptives - oral pills and an another injectable drug-Depo Provera.
The
available data from the ICMR studies indicate
that this method can be used for i
ing since the return of fertility m ex NET users does not appear to be adverse]
affected
.is
compared to IUDs (copy of manuscript ’’in press ii enclosed) which
supports the other published studies.
Item d
in
he National Family Planning Programme various methods are offered
on a voluntary basis.
To meet the need of diverse
group of our population.
specially the young married couples. it will be essential to have a variety
of spacin.. nutaods which may complement the available spacing methods in the
’’at i ona I : ii.Jly Planning Programme.
Therefore, with all the safeguards of
inf o rmcd consents and voluntary nature of our Programme, it
is not a fact
that the introduction of newer methods of contraception specially for spacing,
.ire
f article 21.
Control lei of
India, require that this injectable contraceptive is only
The present guidelines issued by the Drugs
available on the prescription by a Gynaecologist.
abuse of this drug does not arise.
Therefore, the question of
3
Itea e -
The published data from the
ICMR study phase III multicentre
clinical
trial indicate that under similar clinical trial conditions
the method failure
rate (1.4 per 100 user at 24 months) was
comparable to that of CuT 200 (IUD)
which is already
an accepted method in our National
Family Welfare Progranme.
The continuation rates were similar
to that of CuT 200 at 12 months period,
however, they were lower
at 24 months period. The
The answer to the long-term
progeny has
health hazards and effect on
theMlready been given in the preceding paras.
Item f
The findings of ICMR phase III clinical trial
carried out by WHO etc. in terms of
efficacy ,
as well as studies
acceptability and side effects
assocaited with drug, do not discourage
one to proceed with phase IV stud y#
Correctly speaking, the phase IV
monitoring and post-marketing
study
actually consist of long-term
surveillance of any drug-contraceptive
or
otherwise-when a product is in actual use.
However, the present study
with NET OEN has & very limited objective
to work out the logistical aspect
of this method of contraception in existing health
care delivery conditions.
This data is essential for
any programme administrator before the drug can
be recommended for wide scale use in National Family Planning
Programme.
Therefore the objective of present
study is to clearly work out the logistical
this study
aspects and / should be correctly termed as
pre programme introduction study
which
7
AS! '
is quit
different from the phase HI trials and
classically defined
phase IV studies.
The copy of the phase IV study protocol is enclosed
herewith giving the details of the objectives and design
of the study.
We are not aware of any
scientific evidence which would indicate that
the NET OEN cannot be used in aarip conditions provided the subjects
are properly
screened by trained personal for the use of this contraceptive
as per the
guidelines provided an informed consent is obtained from ethical
view point.
4
additipn
for medical and para-medical
In / the present study design, and training programme
staff emphasis on adequate
counselling to the prospective user which would
provide her information on the potential benefits and side-effects of this
contraceptive.
currently involved in this study have gynaecologist
Item g - The centres which are
as well as to deal with the complications
to screen the women for eligibility
that may arise from the use of this drug.
Item h - The drug is not yet
Family Welfare Programme.
introduced for general use in the National
The question of approving the drug for general
would be considered only after
use in the National Family Planning Programme
are made
results of present ongoing studies being conducted by the ICMK
available to the Government of India.
Item 3
was conducted at the Human
- The phase 111 clinical trial of the ICMR
Reproduction Research Centres
parts of the country.
and
located in the Medical Colleges in the different
The major objective was to find out the safety, efficacy
acceptability in a well controlled conditions.
Whereas the present
essentially being conducted in
phase IV study trial is
in the different parts
larger population
of the country, in order to fine out the logistical
the regular health care
requirements for the actual use of this drug in
£i) the training of medical and
delivery programme in the country in terms of
para-medical who would be providers
of this contraceptive, (ii) the acceptability
with . the available back-up counselling
of this contraceptive by the women users
the health care delivery system, (iii> back-up system support
facilities in
and (iv) the problem of the
of supply, storage and distribution of drugs
due to the distances involved
regular contacts of both the users and providers
in terms of outreach of health services.
In fact, the study in designed to help in driving our servicee to
5
Injectable as a route of drug delivery is preferred in our society
Item 4
and culture.
As indicated in above paras, the present ongoing phase IV study,
require the utiliteation of trained medical and paramedical manpower who were
the providers of these drugs after adequate counselling and obtaining the
informed consent of the volunteer.
Item 5 - No comments.
Item 6 - As per the report of the Toxicology Review Panel from the WHO page 202
jS- (coPy enclosed) both the rodents as well as beagle dogs are considered to be
unsuitable models for studying the toxicology of progestogens.
The scientific
principles behind this^hypothesis is given elsewhere in the affidavit.
Item 7 - At the present time, it is not recommended to use NET OEN in la. fat ing
women for first six months after delivery.
We do agree that long term monitoring
and surveillance is necessary for any drug including thi s injectable contraceptive.
As recommended in the XII Annual Report of WHO 1983 quoted by the Petitioners, the
performance of these injectables in the normal service situations iis already one
of the limited objective of the present study.
Item 8
No comments
Item 9 - Regarding the question of optimal time and dose regimes the 1CMR
conducted a Phase III mu.’ticentric clinical trial to compare the efficacy of
200 mg NET—OEN given at '? or 3 months.
groups i.e.
60 + 5
The subjects were enrolled in two
0roup I - The women who were given 200 mg of NET-OEN every
days through out the trial period and Group II “the subjects we r. ■
given 200 mg
of NET OEN for the first 6 months at 60
switched over to 90 day regimen.
5 day interval and then
About 1300 women in each study group were
recruited and observed Lor 28,500 women months.
The method failure rati- were
significantly higher in Group II as comoared to subjects in Group I (6.6 +1.2
per 100 women A
100 women at 24 months respectively).
.4 + 0.4 per / Most of the pregnancies occurred during the
6
r3rd monch
Of the injection interval in subjects
recruited for Group II.
This is further supported by the Pharmacokinetic data that the
level of Noretis terone is
circulating
non-existant around that time.
The incidence of amenorrhoea was
comparable in both the groups at
6,12,24 months of use.
The incidence of amenorrhoea, excessive
or irregular
bleeding were similar in both the
group during the entire period of observation.
The discontinuation due to amenorrhoea
during 2nd year of use was high
as compared
to 1st year mainly because of the
project guidelines to discontinue the
subj ects
from the trial if amenorrhoea persisted for more than 1
year. We agree that
NET-OEN 200 mgs. causes disruption in the
menstrual cycle in the form of
irregular bleeding.
spotting and amenorrhoea.
However, these menstrual
disturbanced did not cause
any health hazards.
Item 10 -
The other side effects due to its effect
on hypothalamus and pituitary
glands like headache, weight gain.
abdominal distention. anxiety,
nervousness
have beep rarely regarded as a problem.
The cardivascular effects
associated with the use of oestrogens
containing preparations of oral
contraceptives have not been found with
rhe use
of contraceptive <ontaining progesterone only.
There appears to be no
significant change i ii blood coagulation, or the incidence of thromboembolic
disease which is related to the
oestrogens.
Sclentists/medical professional
even recommends that progesterone only methods are the
women suffering with these complications.
is
The effect
contraceptive of choice in
on the blood pressure
minimal.
Item 11 - Posflibiliity of irreversible damage and
atrophy is not seen among users
of this contraceptive as shown by the fact that fertility
months after discontinuation of this
method.
returns within 6 to 8
/
Item 12 r 'Although animal data has raised concern about the
safety and long
i
term side effects of NET-OEN but certain animal models and
the doses used
appear
does not/to be appropriate for studying human effects of these steroids.
Extensive clinical and epidemiological studies
among women using these drugs
have thus
a
demonstrated no life threatening side effects, including increased
of Neoplasiay
The major controversy has been associated
with the interpretation of
animal toxicology.
The first problem in interpretation
arose with the use of
beagle bitches as a possible predictive model for human
breast cancer.
These
anima Is were treated with doses equivalent
upto 50 times the human dosage and
followed for a period upto 7 years.
Since that time a large amount of scientific
data from animals and humans has accumulated
indicating that beagle
bitch is
probably a poor model for the study of progesterone for predicting risk
f the
breast cancer in humane.
There is also evidence that healthy beagle breast
contain reservoii of microscopic neoplasm which may grow and occasionally
become malignant.
The second concern from animal toxicology came with the
appearance
of a small number of endomptrial malignant and premalignant
lesions in Rhesus
monkeys treated
fth NET-OEN with a doae of 50 times that of humans.
EndometriaI
carcinoma has not been reported among women using NET-OEN,
in fact progestrogen
are given for t rte treatment of endometrial carcinoma
in considerably higher
dot-es than those used for contraception.
There is a reason to anticipate that
treatment with these progestrogens will actually reduce the long term risk of
these cancers in women.
Lt is also been observed that
( 1 )
in monkeys
/ occurs in atrophic endometrium whereas in humans it occurs i n
endometrium and progestrogens suppresses this hyperplasia.
carcinoma in monkeys is of a different cell type.
endometrial cancer
hypertrophic
(2) Endometrial
The cell make up of these
anima1 a is quite different from that of humans (3) Tumors in
monkeys originate
from epithelial plaques which arc not present in human uterus.
8
Studies on rodents have been carried out and a drug related increase in the
incidence of tumors has been observed but it is due to the oestrogenic
activity of NET-OEN in rodents, which is not seen in humans.
In view of the
and
above findings in the monkeys, beagle bitches /rodents, the toxicology review
panel of WHO (convened in 1978) together with the expert scientists and
representatives of six drug regulatory agencies recommended
current and planned clinical trials of NET-OEN should conr■nue
that
since Clinical evidence from more than 15 years of use as contraceptive agent
shows no additional adverse effects. than those found with other hormonal
methods of contraception.
highly effective.
The particular advantages of NET-OEN is that
ts
i t
long lasting and reversible contraceptive, make an important
option that should be available for women desiring a method of fertility
regular i on.
There is no similarity between NET OEN and Diethyl
s r i 1 bos t ero 1 hor-.u ••
preparation because latter is oestrogen and NET OEN is a progesrrogen.
No studies have systematically followed the health and development of
Item 13
infants exposed in utero to NET OEN as a result of contraceptive failure or the
inadvertent
initiation of contraception in a women with undiagnosed pregnancy.
This form of Contraceptive exposure i s quite infrequent and it
d i fii< i j 11
identify sufficien tl y large number of infants for proper investigation.1
rt
observed that any teratogenic hazard associated
progestogen is negligible.
to
Howevc’
m utero expo
in the present study the injection is being giving
5 days of menstrual cycle and in case of method failure the MTP was adviced.
Item 14 - Effects of
j actat ion
E t f e c t of progesterogens on the production of milk in women appears to
be prociot ive.
NET OEN in particular has no adverse effect on lactation.
9
A recent study has shown chat the level of NET OEN 200 mg in the breast
milk is in the order of 3 microgram/1itre one week after injection whil e by
8 weeks it is usually undetectable.
This would give an estimate of total
exposure of the infant of approximately .05 per cent of the total intake.
The ratio of NET-OEN in breast milk to plasma is 1; 10. In human subjects the
measurement of NET OEN was undertaken on plasma samples from 4 breast fed infants
2 to 5 days after the injection of NET OEN.
The drug could not be detected in
the plasma using an assay system which has a limit of detectability of 0.05
microgram/litre.
Since there is no information on the possible effects ot
progestogens on maturation of hypothalamus and liver function in the neonate,
it has been recommended that infants should not be exposed to these steroids
during; the first b weeks post partum (WHO).
In the 1CMR study subjects who were
lactating for less than b months were not included in the study to exclude a 11
the possible risks of hormones on the foetus.
Effect on Lipid Metabolism:
The effect of NET-OEN 200 mgs on lipid metabolism
i-s very minimal and published and unpublished data indicate that it leads to a
small de crease in HDL-cho1e stero1.
Most investigations have found little or no
\effect on liver functions.
Item 15, 16 & 17
The phase III clinical trial of the 1CMR which showed
comparatively higher method failures in first six months of drug use as compared
to the later period,were within the acceptable clinical trial criteria of the
study.
Although the reason for this observation is not completely understood
one possible explanation could be that it may take some time for the adaptation
of the body physiology to the pharmacological effect oi
this injectable preparatioi-
■jifU
c
10
regards to 90% of the menstrual cycle being abnorml, this particular statement
was not reported in our publication^ phase III clinical trial.
However,
this
observation is SJ.:ply a statistical percentage indicating that if any irregularity
(e.g^j>rolonged cycle, spotting) was observed even in one menstrual cycle during
of observatioi it was calculated as menstrual irregularity.
When
one cogjares the similar^figures for general population who are not using any
ocntrace^ye^.itjtas beOTjre^rted ttat^variation in so called "nonral"
V,
U7
>' ‘
-length was tremendous i.e
i.e. ranging from 10-105 days (Aner.
cycle
Journal OBGYN, Vol.20:
320-323, (2) Journal OBGYN of British
fhpire. Vol.44: 839-879, (3) Journal Am.
Mjd.Association, 203: 89-92). Therefore, this particular observation of 90%
"abnormal menstrual cycle" is in no way an index of adverse effects
table method.
This is supported by the obser^zat ion. that the reasons of disoonti-
nuations due to menstrual cycle disturbance
1.
of this injec
were small as .indicated below:
The discontinuations due to prolonged bleeding were 15.6 per 100 users
; ' • ' J-1;1/ 15.6 at 6,12,18,24 months of use respectively i.e.
one ..an say tnat there was an uniform increase in the discontinuatico
due to this reason in the tune of 4 per 100 uers at an in2rS“f T
44k>; 1 LJ lo •
h
2.
The same is true for the discontinuations due to irregular bleeding.
3.
Itie suddc i increase in discontinuation due to amenorrhoea towards
24 months i-S
tO ^b92^0001
which necessiated wcnen
to discontinuefe the method if the amenorrhoea persisted for one year
even if there were willing to continue in the trial with the amenorrhoea.
4.
2‘. .7 per 100 women dropped due to personal reasons, clearly indicates
that their i^articipation in the trial was purely voluntary and were
free to discontinue trial for any reason at any time.
br3°0 Us.CrS
<tso°Ptir’uation °f the method due to 'late for follow-up'
has been appreciated by various researchers including WHO, indicating a close'monitoring of the subjects during clinical trial.
In the light of the above conments, the statement that 70% of the women did not
this method suitable is incorrect as there were many other compelling forces
for the wnnun not to resort to any other family planning method
another child or objection fron mother in law.
used for 2 - 3 years.
The published date on
such as desire for
Spacing methods are primarily
the
phannacaakinetics of
11
NET OEN does not seem to j dicate a faster clearance of r '
this drug ip under-nourished
women as compared to well-nourished women. The ICMR is also
conducting the pharmacokinetic studies in under-nourished -o currently engaged in
population to collect more
information. The available published data
do not seeni to indicate any higher incidence
congenital malformation occurring in the children who
contraceptives including NET OEN in utero.
injectables are uncommon and
Since pregnancies with long acting
any potential teratogenic risk is small, this is
not likely to be major public health problem.
studyw
were exposed to hormonal
Furthermore, in our present phase I\
MTP is recommended for all method failures.
Available evidence does not seem to indicate that the hepatic
function
is adversely affected by NET OEN
preparation.
through hepato_bi1iary system.
The steroidal drugs are secreted
Therefore, the diseases like viral hepatitis and
amoebic hepatitis which primarily affect the parenchyma
do not seem to have any
adverse association with the use of steroidal
contracept ion/
all the study volunteers
At the present time
are screened by the qualified gynaecologists for all the
conditions including the syspected pregnancy.
Furthermore, the present injectable
drug is recommended for use in first five days of menstrual cycle.
Therefore,
the question of suspected pregnancy does not arise in the
present trial.
the contraindications,for the
use of NET OEN by the Drugs Controller
One of
of India
is the cancer of breast and all genital
cancer.
Item 18 -
The present study of the ICMR has been
undertaken with the necessary
permission form Drugs Controller of India as well
as the Ministry of Health and
Family Welfare.
Item 19
An ideal contraceptive which would be acceptable
to all populations
of different types doe s not exist at present.
Therefore , there is a need to:
the wide variety oi methods which can be utilized by the potential
users living
in the different socio cultural mileau and whi'ch can
be operationalised in the
different health
delivery systems.
The available clinical trials data of
NET OEN indicate that (i) this drug given as 200
mg at an interval of 60 + 5 days
provides adequate contraceptive protection. (ii) there is
no adverse effect on the
return of fertility and (iii) no serious health hazards has been
noticed.
We do
nor recommend the drug at the present time to lactating women for six months.
No published evidence is available that NET OEN causes long term irreversible
co
damage to the health of the woman or/their progeny.
On the basis of the
Wife
published evidence, it can be concluded that the NET OEN can be utilized as
spacing method by potential users.
Item 20 -
As indicated in the above paras, the present study of the ICMP is
being conducted with the full knoweldge and approval of the Ministry of Health
and Family Welfare and the Drugs Controller of India.
As per ICMR protocol
guideline, the prior informed consent is obtained from the volunteers of this
injectable contraceptive.
Item 21
in
t this drug (the NET OEN) is approved for marketing
far
U^Z
Countries including —Ifilltf
All the information
regarding the long term risks associated with any drug can only be obtained
provided that particular product is in general use for a long period of time.
which includes the present durg - NET OEN.
Pregnancy (MTP) is legalized.
In India, Medical Termination of
There are at present various methods which can be
offered to women desiring a particular contraceptive for pregnancy protection
after an MTP.
This includes IUDs and Oral Pills.
In a separate study conducted
by the ICMR as well as by the WHO, it is clearly evident that NET OEN can be
utilized to provide contraceptive protection to the women after undergoing MT£
without any health hazard.
As indicated in the preceding paragraphs, the
informed consent w;m nbtainod I rom
Al . . •
pronporiivn
in the preceding paragraphs that provided the proper screening and inf«)i sued
consent is obtained. there is no scientific evidence to indicate that NE'i OEN
cannot be used in the camp conditions which seems to have been done in Hyderabad
As regards to the statement of petitioners that the ICMR is only serving
the interest of the
West German Drugs firm Schering AG Berlin, this can be considered as an arbitrary
statement without any valid foundation and can be considered defamatory in nature'.
■
7
Furthermore, the drugs for the present study was obtained through the Ministry
of Health and Family Welfare from the Special
Programme for Research in Human
Reproduction, World Health Organisation, Geneva.
Therefore, there was no
direct involvement with or sponsorship of German Drug firm Schering AG Berlin.
Item 22
We have already given comments on the various points raised iin this
paragraph .
No additional comments are required to be made.
Item 23 -
We have already given reply to various points in this paragraph.
At the present time. the use of the drug requires the informed consent and
screening by qualified gynaecologists.
not arise.
Therefore, the potential for abuse does
Furthermore, the preliminary observations of the ICMR Phase IV study
in B & C Type of Pest partuin Centres quoted by the Petitioners, were the
very
information which were the objective of the present study i.e. to find out the
logistic and actual programme performance of this injectable method in the
field conditions.
Item 24
The various
methods of contraceptive technologies indicated by
the petitioners such as hormonal implants, prostaglandins and anti-pregnancy
vaccines , are the newer potential methods which are being investigated for their
possible utilization by the women and, if the studies on safety and acceptability
these can be considered
are encouraging,/for their possible use in the National Family Planning Programme.
All the necessary pre-clinical animal toxicology evaluation oy Toxicology Revi ew
Panel, ethical considerations to obtain the approval of the ethical comm]ttees
of participating institutions from phase I to phase III clinical trials,
to 1lowed by the ICMR.
ire beiny
In addition the ICMR has its own Ethical Committee (its
constitution is appended) which includes the former Chief Justice of India,
Mr.H:R: Khanna as one the Member and all clinical evaluation of contraceptives
carried out by ICMR are cleared by the Ethical Committee of the Council.
'flic
informed consent of the women volunteers is also being obtained after getting
the approval of the studies by the Drugs Controller of India.
Furthermore, MTP
is routinely recommended to women in the cases of the methods failures.
We have
14
no further comments on the other points raised in this
paragraph.
Item. - 25
Ours is a voluntary National Family Planning Programme, therefore.
it is actually the user who decides which method she or he would opt for.
At the present time. there is no single ideal method for contraception which will
suit all ages.
groups.
both sexes and all
socio-culturally different population
Therefore, it is essential to have a variety of methods in the National
Family Planning Programmes which would include various barrier method also as
indicated by the Petitioner.
Item 26 -
The ICMR has already prepared the guidelines for ethical consideration
involved in research on human subjects and the copy is enclosed herewith.
Item 27
Item 1
No further comments.
GROUNDS
an
The present study insists on /informed consent by the potential user.
Therefore this is not unconstitutional as indicated by the petitioner.
Item 2
There is no scientific evidence to indicate that NET OEN injectable
causes any serious health hazard based on the published reports of NET OEN
both from ICMR as well as from WHO and other scientific investigators.
Item 3
At the present time. the basic objective of the study is to find out
the logistic requirement before a product can be recommended for general use in
the National Family Planning Programme.
No decision has yet been undertaken
by the Government of India to introduce this injectable preparation in the
National Family
Planning Programme.
There is no published evidence to indicate
that the NET OEN poses a definite risk to the health of potential user nor it is
a potential risk to the progeny.
Furthermore, the available data on the return
of fertility in ex-NET OEN users indicate that, this method can be utilised for
spacing.
Item 4
All the published information of NET OEN is available with the
Ministry of Health and Drugs Controller of India and with the ICMR.
i
15
Item
- As indicated in tbc preceding paragraph, the study was
undertaken only after both laedical and paramedical staff were
trained for the use of this injectable preparation
Item 6 - '.e have no evidence to indicate that the use of NET GEN
preparation violates the article 21 of the Constitution.
Item 7 - As indicated in the proceeding paragraphs, the present
study has been undertaken with the full knowledge and permission
of the Ministry of Health and Family Welfare and Drugs Controller
Furthermore, it was an essential requirement that
of India.
informed consent will be obtained and screening of women would be
conducted by tl ie gynaecologists .
Therefore the present trial
does not indic-'to any arhitranes on tlic part of the ICMli or
.’Ministry of health to conduct this study.
Item 8 - It is not a fact that women are treated as chattel and
their consent taken for granted.
The very nature of National
lamily ilanninj’ 1‘rogramnie is voluntary.
Furthermore, the present
study also obtains the informed consent of- the volunteers.
It is
obvious that none of the fundamental rights guaranteed
under the
Constitution are curtailed or infringed.
A s sue h, t lie re is no
of action to file this writ petit!on, for alleged violation of
article 51A of the Constitution.
Ite-i 9
Jiure tl <* informed consent was obtained, it does not seem
to violate either the Helsinki declaration
nor
t**y
txe »slbwared bJT
the article 21.
t^e
Item 10 - The respondent have not violated human dignity or rigM
a healthy 1i1c, a s necessary precautions are taken whil
e irapl^me
ing a project in public interest.
Furthermore, it is submitted
that the res oiHicnts have not violator?
the directive principles Of
State Policy,
in any manner.
The case referred by the petitioner
dors not apply to the facts of this case.
CONTRACEPTION
INDIAN
COUNCIL
Task Force
OF
MEDICAL
RESEARCH
on Hormonal Contraception
NATIONAL PROGRAMME of RESFAPrw
IN HUMAN RLT"
DIVISION OF REPRODUCTm
Reproduction
I fro IAN COUNCIL OF biolocy A fertility( CONTROL
medical research
ANSARI NAGAR, NEW
DELHI,INDIA
^VESTICATORS:
B*nerjee, S.K.1, Baweja, Raj2,
Bhatt, R.v. 3
, Chatterjee, a\
Engineer, A.D. 6 » Gogoi,
M-p- . Hingorani, v.8,. K>«turilal9, Kochhar.M,10
Mis". P-'2. Phillip.,’ F.S.
» Krishna,u’1,
Cboudhury, S.D.\ Coyaji> ,^’5
' -
Zavsri, K.18
L?
|°ORDINATING UNIT:
f«OJECT COORDINATOR;
• Rajan, R.
» Sengupta,P,c.15
Datey, S. 17
» Dey Biswas, s.K 17
1
, Dahiya, R.k. 17
17
> Kumar,
S.
. Mehta, $. 17
» Muthuswami,» V.
, Saxena, N.C. 17
Saxena, B.N,17
1.
P-C.Kar Medic.! College, C.lcutt.
2.
M-L.N. Medical College, Allah.bad
3.
Baroda Medical College, Baroda
4.
Institute for Research in
5.
K.E.M. Hospital, Pune
6.
X-C. Medical College, Lucknow
7.
8.
Reproduction, Bombay
M^ical College, Gauhati
AH India Institute
10.
Of Medical Scienc es ,
New Delhi
J ammu
Kasturba Hospital, Delhi
11.
K.E.M. Hospital, Bombay
Q
<
•
’
Medical College,
d
).
’mitted for publicatiion February 15, 1984
epted for publicat
|
ion
c.i November 15 1984
December 1984 vol. 30 no. 6
561
CONTRACEPTION
ti
12.
S.P. Medical College, Bikaner
U.
Institute of Obstetrics &
14.
Medical College, Alleppy
15.
R-M.s.p. Hospital, Calcutta
16.
J.J. Hospital, Bombay
1 7.
Indian Council of Medicil Research,
Gynaecology, Madras
New Delhi.
abstract
A total of 2388
Lrue^nt re’lmen ....
WUh
y--------
^:c:^c:r:^"ved
e
™
' for 9O-»5-day
' “ere observed for 24 montha0*"4"'^8 <NET 0EN) '200 mg
-1 triai represents t^ .hS' COn>tit«ln?
woajan-nsontha.'l
net oen.
The observations indicated thatund,r'“'«n °n J
intervals Provides adequate contraceptive ^Itec^
" “ 60t5-^y
the published ^eseise,here. ^ber^Sli^^-^
l! '^irJL^63^?'aroOnthS °f NET °®N > r.as;nshfor“thirds Wer8
at 6j45-day intervals
Intervals. The
.in W
• present study can^t bS-exoiilnaa —
S0-5-^ ^-n v£ » d-
th. /
*1 .i-9 -he injection, sU„estln, reduce* .ln
c-'ra^pt^^eJX^^^on^ :
t
during this
efficacy of
.period. Thin built women
risk of ;i"v° untary pregn.ncy. Disruptod
(body weight <40 kg) were „
kg) were
reason for
-J -nstrual pattern
pattern was th.
- discontinuation ranglng between
w«s the r
sf 2a months. ^h«t thuse, amenorrhoea wL the per 100
users at the
—end
dlsc< ntinuation.
commonest- reason for
No cnan.. m blood pressure
captive usage, The
was
observed
major hv of net OEN users
body weight. The
did not show during contra- I
^rali continuation
dny change in I
thus- observed in
rates with net 2OEN were lou>er thAfl
similar . editions
with Cu-t 200 mm I CCD.
I
!
Z-.
»
t
r
562
DECEMBER 1’84 VOL. 30 NO. 6
.<■
xd.' ’
j
s:
CONTRACEPTION
:'h
INTRODUCTION
The National Family Welfare Programme c'
" is being supported
of ~India
and strengthened through research and development i
: in contraceptive
technology by the Indian Council of Medical Research (ICMR)
-- . Newer and
better methods of fertility control are being evaluated by ICMR t ” ’
through
s network of Human Reproduction Research Centres (HRRCs) located in
ed in
m LreWelfare
wLrtSp°
f the C0Untry- prior t0 lheir
in the National
ramily
Programme.
Contraceptive research in recent years has demonstrated increasing
interest in the use of injectables,
as they offer long-term protection and
a more acceptable mode of delivery, Two injectable contraceptives that
are currently available are ^r
edr°XyprOgeSte— acetate (DMPA) and
norethisterone oenanthate (NET OEN)
. They share the advantages of being
—
a very effective method of <contraception, 4 ’
and require administration only ./
every
two, or
. .
. three months (l,2,3,4).
■ .
Available
data
-- a on previously under--- contr.ce^ive'giCen
in
kthr7
1CiC^tre-trial
CIial with !^
taken
multxcentre
—T’0EN
-- " ‘
three months,. indicated that i.a substantial number of involuntary once
.
pregnancies have occurred during the third month f ’* *
following injection (1).
WH0-8ponsored multinational trial with^injectable
LtL ? «lven at two or three monthly intervals showed that the NET OEN
two monthly
schedule considerably lowered the method failures as
compared to the three
monthly schedule(3,4) .
The ICMR through its network
network of
HRRCs initiated
of HRRCs
initiated a randomized Ph.se III
n cal trxal, tn March 1981,, to
to evaluate
evaluate the
the contraceptive efficacy and
\ 7,
lnJCCt 16 NET °EN (20° n,8) given in two different treatment
schedules of 60+5 days and 90*5 days.
METHODOLOGY
Subjects seeking family planning advice from clinics of 16 HRRCs
and fulfilling the eligibility criteria were enrolled for the study.
They were allocated to either of the treatment
treatment schedule
schedule (60*5
(60*5 or 90*5 days)
y random allocation. All subjects received the first injection within
days of the menstrual cycle. The first four injections were given at an
.°f 6°-5 d,,y’ t0 011 scudy objects and thereafter, either at 60.5
or 90.5 day, depending on their allocation to either of the treatment
'
schedule for two years.
At each follow-up visit, a medical history was recorded and
relevant examinations were performed, The subjects were required to
complete a menstrual diary card, The initial and follow-up information
was recorded on uniform pro forma©. The data were analysed at the
Central Co-ordinating Unit in the 1CMR Headquarters, New Delhi.
DLCliMBER 1984 VOL. 30 NO. 6
563
i
CONTRACEPTION
f
,
This communication focuses on the discontinuation
> rates due 'to
various reasons and side effects up to 24 months of use ,
of injectable
^t 2o°f n8)'-fThe data
analy-d * L°*
eehniG^'
t
freedom",6)
Ce
chi-square
0" Chi
7quare with
^St.e of
RESULTS
A total of 2602 subjects, ^29?,f- °r Che 60+5-day schedule and 13li]
for the 9
90+5-day
schedule,
t--^L'^O
?-5^ 6Cn
:dule’ ^re'enrolled
between’March 1981
1982.• Out of them, 2
21144 subjects were excluded from the — 1 to Septesb«n
protocol
violatron.
Thus,aubjecte,
2388 .ubject.,
1181 for the study because ot$
, --------- Thus, 2388
60+5-day schaawM
tutine
9°-5’day •chedule.considered for ,analysis consti-^
luting
toting 28,513 voman-months of use. The cut-off date for this
. —j analysis <S
was June 30, 1983. Number
r •
of subjects reportedI to be continuing in the ®
trial at 24 months of drugJ use on cut-off date >
were 73 and 72 for 60*5-<W
and 90*5-day schedules, respectively.
Table I give 6 some of the demographic characteristics and anthrrvJl
pometric ^o-re^ents
--of the 2388 subjects recruited for the study
□'(
study.
average age
25.3 years
j---- and parity vas 2.7. The mean weigh
- was---.3
c of'th.
acceptors vas 44,5 kji'flnd heigh'
there was no difference betw^Th!0'5^”’ At
““ °£ "Sistration.^
thcry was no difference
treatment schedule with
th* "
with respect to
TABLE I;
DEMOGRAPHIC AND ANTHROPOMETRIC
60+5-day schedule
Mean + S.D.
No. of Acceptors
Age (Yr)
Parity
Weight (k.
Height t.
564
VALUES
90+5-day schedule
Mean ♦ S.D.
1181
1207
25.3 <■ 3.83
25.2 > 3.74
2.7 + 1.35
2.7 ♦ 1.38
-A.3 + 7.66
^A.8 * 7.57
150.4 ♦ 5.79
’50.6 ♦ 5.98
DECEMBER 1984 VOL. 30 NO. 6
-
I•
Method tailure
A- :A''
i::. ysxOTS
21
schedule and 0 7 per 100 users for the 90+5-day schedule (Table II).
This difference in method failure rate at 6 months was not statistically
I
significant.
riiS.’X"
,■55.5.
The
treatment.
larmingly high method failures were seen with the 90-o-day
whereas, a
treatment schedule.
■ • was
-s reconstructed, assuming day one trom the
The daily life-table
started
receiving injections at an altered
pc* int when the subjects s*—--The method failure rates were 0.1.
I
(i.e.
after
4th
injection).
; c: t p r v i
the bO + S-day scln-duH «md 1.1, 2.i,
iv.d 0.
per 100 users tor t...
months ol
■,.v ... I 100 users for the 90+'>-day schedule ,,t 12. IE,’ .md 24i'.-.mt
(!’<<' U
•,tal drug use, respectively, which was st .it i si i -1 1 v
The 19 cases of method failures which had .ccurr.-d in the J0*S-
schedule after the 4th injection, with respect .• the einadf
onccption (calculated by uterine size) were turner analvsed. I
..
observed chat the majority of these (13 pregnaner • s) baduccurrec
..
cllt third month following
the injection.
inject ion. Thes.following the
These a.servat ions .1
indicate’thac the 90+5-day treatment schedule n
me. mure than ? 3 u: *
efficacy as compared to the b0*5-day schedule,
c- third m’'nth tollowi".
have
occurred
in
t.ht
pregnancies were estimated to
■njection, further supports rhe hypothesis that the rontraceptive effe<
of the drug does not last beyond 65 days.
Bodyweight VS method faUures
41 involuntary pregnancies were reported in
As stated earlier ,
had occurred during the first six months. Th.>
this trial; of these, 21
1 failures during the first six months o
gave unexpectedly high method
with other published studies (1,3,4). Keeping
treatment when compared
body weight ot Indi.m women is lower fh.u
in view the fact that average
countries, it is likely that the body
their counterparts in western
— causative factor responsible for higher
weight may be an important
For this purpose the association between initial body
method failures,
and method failures occurring within the first six months was
—
weight
failures
(Table III). U was observed that more method fa.
h.res wore
were repor
It was
CX2-^.'- ‘t
.^ng-.r women with body weieht of 40 kg and bc!ow (X
with body
December i9S4 vol. .w no o
505
j
.y*.
•
•’t-.’fe-
2 1........
^Jup* •
CONTRACH’TIOrs
i
TABLE F1
Rates
Ti e.Anxjnt
i’easoiu
z-'
CUMULATIVE DISCONTINUATION RATES PER 100
/K)Mh:N BY REASONS FOR DISCONTINUATIONS
t SE
18 Mths
24 Mthi
6 Mths
12 Mths
1 .2*0.3
1 . 2-U.3
1 . 4*U . 4
1.4*0.4
0.7+0. J
1.8*0.4
z.8*0 . t
6.b*l .2
i 1 .0'..t
43.5*1.9
Schedule
Pregnancy
11
’.vristru-i 1
-J
:> •
He<ivy & Pro
Bleedinu
1 r reqi) 1 a i
t? >
'1I
• ■
H lee ! inq
Ajne no rr hoed
• her Medical Reason-
'I
7.4*0.8 21.z*l
01 !»Lurr>.«n<.■ •
t -rsona:
P
i.jve for Fol low-up
11
8.8*0.9
19.5*1.4
•• I .♦ 1 . •-
42.2*1.9
I
3 .5*0.6
?.St0.9
11.1*1.5
15.6*1.5
11
3.2*0.5
6.5*0.c
’0.u* I . i
13 .5*1.3
J
2.5*0.5
7.8*0.9
10.b*l . 1
12.1*1.2
11
4.0*0.6
7.5*0.9
<1.8+1 .2
16.4*1.5
I
1.b+0.4
7.6*0.9
13.2* 1.3
23.8*1.9
II
1 .8*0.4
6.9*0.8
12.7*1.2
20.1*1.7
I
0.9+0.3
1.5+0.4
2.7*0.6
3.2*0.7
II
1.2+0.3
2.3+0.>
J .7+0.7
4.4*0.6
I
5.1+0.7 ll.o+l.l
22.0*1.5
29.7+1.9
II
3.5+0.6
9.2 + 0.9
16.9+1.4
23.1*1.7
1
1.7+0.4
3.3+0.6
4.9+0.8
4.9+0.8
2.3+0.5
4.7+0.7
5.9+u.e
5.9*0.8
I
7.6+0.9 10.3+0.9
11.2*1.0
11.7*1.0
II
7.3+0.8 10.0+0.9
11 .0+ 1 A>
11.5*1.0
I
21.8+1.2 41.5*1.4
56.9*1.5
J?8.6*1.5
II
22.0*1.2 40.2+1.4
S5.5*l.c
07.4*1.5
II
'•
{-ol Low-isp
otal Discontinuation Hate
f is
ft
at
11'
Ne. , <_• f
Mi'Cupt .JL S tf
'■’■’<11 nn i n>; • ■!
ntet '■
I
78,2
58.5
43 . 1
11.4
11
78.1)
59.8
44 . q
Jz . o
1
1 181
32)
• 4
II
1 20 f
? <9
'■pr
S!
II
- 1K7
! JZr. ■
o304
: :44 •
60+5-day Schedule.
•7
' ’• n
<
>•
IT: 9O*5-day Sene,duie
DECEMBER
I 9X4 VOL. 30 NO 6
___ _ ___ _
( ONTRACLTHON
< .
TABLE III:
Weight
■T*V,
KA.' ■
V-i'
INITIAL BODY WEIGHT VS METHOD FAILURES
(kg)
All Subjects
-
Method Failures during
first six months
Net Rate per
100 Users
Rate ♦ SE
832
12
-1.6 ♦ 3.S-
u’-O kg and below
1556
9
.,.6 * 0.2
41 kg and above
Total
238b
2)
(•p <.05, Chi-square = 4.5 at
(
■
I I
I d.f)
■-
I
Menstrual disturbances
constituted 7.4
Discontinuations due to menstrual disturbance r 100 users for the
schedule
and
8.8
p<pu.r 3 00 users for the 60+5-day
tr' atment. Thereafter,
90.5-.iay schedule at 6 mSnths of contraceptive
ion to 21.2, 3 I . 0
thJse figures rose almost in geometrical P«9r®S!.Hid
19.5, 31.2 and
..nd 4 3.5 per 100 users for the 60.5-day “hedule
18 and 24 months
42.2 per 100 users for the 90 + 5
^nstrual disturbances which
Of NET OEN use. DiscontinUa
,
x
ed bieeding and irregular
consisted of amenorrhoea, excessive/prolonged
9
cyeies/spotting were the major reasons for drop
I
I
g
i I
K
I
I
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f
r f•
567
DECEMBER 1984 VOL. 30 NO. 6
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-4.- v,
•C'J
CONTRACEPTION
<
I
s
Amenorrhoea
Discontinuations due to r--•
amenorrhoea were 1.6 and ,,8 per |00
respee’eively, at six
•8 and ?/. ’ 2’7 and 20 • ’ Per ,0° per 100 users for the 6O»5-d«T •
- • 12,
and 24 month; of NET OEN use “The” f°r 9°-5'd*y
-ha- to
°£ di’«Miou.£i
amenorrhoea was almost twice durinl eV0
wb.»n compared wi th the c,during the second year of r»’
first year for both trear™>nt
f treatB«ot <
Ki significant diffe
r>-re in discontinuations du7to SChCdules <T«bl. !«
•‘rvp ■ hetwp,,.. ,hp f
-P- of rreatcent schedufe?raenOrrhOe3 ““
,;r’r6-?,3,;2 “
P
SSi ve prolonged b1-eding
di.scont inuat ions
J Ur ' o jxcess.ve/prolonged
(----'
bleeding was 15 6
users for the 60
per
schedule
“
ule and 13.5 per I00 users for the
^•’_»5-da.y schedule at ?<,
n.»t ^sticaily sig'/f^3 °'NET 0EN
use and the difference .
was
‘T i .$ reason ranged betcen 6-7 peThe ,0*7“ rate of
'
per 100 users fQr bo(discontinuation
.h
due to
treatment schedules.
i!regular vc 1 e s / 5 po 11
'5
discontinuations due
’ co irregular c7.
Per 100 users for the <
cycles/spotting “as 7.8 and
60+5-day schedule
100 users
(• *■ — for the 90>5-d
-la and 7.5 and 16.4
per
thft drug1 use. No s .- . av treatment sch
schedule, at 12 and 24
^goificant difference
months
of
Ourttiori due to this
di’‘ontireason between the tvoatreOarerVed
Wo treatment groups.
Haemoglobin
0J
Haemoglobin (Hb) e
:evels in each f ’;
Cn»
subject were
,,,dv
the time . ,
monitored throughout
Kb
nrolment, 13,3^-■J per cent of the
ha l Hb" S 1 ‘ntiin8 becwee:.■ b
subjects had
to
9
gntf,
and
che
naf Hb more chan 9 gmX .
‘ remaining 86.7
•)f these, 48.7 per cent
iOgi-i# (normal
per cent had Hb levels over^
for Indiar ’Wn) .
Though a large
1 nuii’ijcr of ^bjects discontinued t —- .
bec nise of
enro7C£SS‘Ve menstr
^l bleeding
trom the trial
menstrual
I
time of enrolment showed
.8Bs*, e
etc..
nc, < ’
tc.. , the Hb levels
at the
the ■ ime
significant diffe
rence with the levels at
-f f
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DECEMBER l9*» VOL. 30 no. (,
K- i
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KALCl’l'lW
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Similar observations were seen in the subjects who had dis.'onl mued
1
i torn the trial because of amenorrhoea.
since in this trial the method of Hb estimation was not uniformly standar-,..4ized nor was any external quality control procedu^^j^||g^
---
Ocher side effects
Discontinuations due to other medical reasons amounted to 3.2 and
4.4 per 100 users for the 60+5-day and the 90+5-day treatment schedule,
respectively (Table II). The list of the reasons is given in Table IV and
none of these symptoms were found to be associated with the use of drug.
The decision for discontinuation from the trial was made either by the
subject herself or by the investigator as a precautionary measure. Some
of the rare occurring symptoms detected in a small sample from this study
could be due to the fact that the subjects were being routinely examined
c.s a part of the clinical trial protocol.
T'ABLE IV:
LIST OF THE REASONS FOR DISCONTINUATION (MEDICAL)
Reasons
No .
Heart operation for mital stenosis
Hypertension
Palpitation
Pain in chest
Indigestion/Breathlessness
Peptic ulcer
Jaundice/Infective hepatitis
Allergy
Diminished vision
Tuberculosis
Fever
Measles
Psychiatric problem
Epileptic fits
Decreased libido
Weight gain
f '
?
r
j I subject*.
I
I
3
3 .
1
10
1
2
3
1
2
1
1
1
Prolapse uterus
Ovarian cyst
Breast tenderness
1
1
1
Oedema
Weakness/Headache
10
Total
52
9.
DECEMBER 19K4 VOL 30 NO. 6
■'
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569
.
.f
■i
CONTRACEPTION
5
•
Xrensure
B I (,Qd
(
pressure (Bp) Was
subsequeni'
«very six months ! < recorded at the time of
enrolment. , *9.7
°r earlier xf indicated. enrolment and
per cent
ft 90 (.n:i j’i .
Oniof -he Subjeccs had
At the time of
,r below, fOnIy
a diastolic blood pressure
subject- (2
3 subjects ..r
rhe 90+5-diay treatment
subjects
the 60+5-day and
between 9i-iqq
schedule) had
oniy
one
bjascolic BP rangi
the trial
. th‘;
only
subject was
drug use.
biscontmued froo
because of |
!;1 rhis e K■ 8
hypertension
from the • • r j a ’00subject, her
hCr dias^Ii
ac
18 months of
— nm
mm Hg
Hg rose
rose to IOC r-c BP which had regressed to 90
tior..
hone of
mm
Hg
at
f
remaining
ftUd.y SubJects
the time of discontinuainv id ver < -IfLct. on°Bp
nH.n?J
s in the
on BP during the
-* period <of
Wei ;hc of ‘
ne accepcors
the
subsequent lv
vas recorded
•
on
every
folio,
subject was
,w~up visit, The ac the time of enrolment ancj
'umpared with
initial weight
the highest
>n the bod>
of the study
weight during
observation
use .
noted for
a single reference
any changes
Period of b
non'hS of drug
Cha ni?es in i
b°dy weight of
si8nifiCant;
Cain -I
in Ibody weight
tha" 5 kg
13.3 and 22.6
“as considered
kg) was c_
w
to be
per
cent
of
°bserved
in 3.
reference
subjects
! Periods■ of six
respectively
i
n
i
t
7.0,
r
months
of dru« use indie
as$ociaci<on betwei
II> HI and
-J IV
en
gain
in
i
However,
-•> weight and the period ating a direct
no signifi
-leant diffe
rhe two
fence in “ei8ht gain of dru
•ug use (Table V).
of freatDlenc
schedule UP to 24
.
—” — *•«; il
observation.
Weight loss (^5
subjects (Table V). kg) was also observed in
2-’ to 3.6
per cent of
rOLE vCHANGE IN BODY
W-IGHT DURING
CONTRACEPTIVE
EXPOSURE
per foir—
Wt
than 5 kg
Wt i<>ss more
than 5
No u>. nge
2
111
--------- —z~~___ 73.1
7.0
2.1
2.5
94.8
90.5
UZCEMBER 1984
13.3
~IV
Z
2?.6
2.8
3.6
83-?
73.8
1261
557
V'OL. 30 NO. 6
i
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• 1IF
CONTRACEPTION
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i
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*
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pi
I
another study (1). The effect of the body weight on hormone metabollsais incompletely understood. However, in a small study, no effect of the
body weight was seen in Thai women either on the metabolism of NET OEN
,o|r the return of ovulation (14). The available evidence in the litera
ture also suggests that women in different population groups may metabo
lize the injectable progestational steroids at different rates (13,15).
whereas, the Indian women ovulated within 10 weeks after an injection
of 150 mg DMPA, the Swedish women did not ovulate for at least 20 weeks
(13) . In contrast, after an injection of 200 mg NET OEN, Indian and Thai
women took twice as long as Brazilian women to resume ovulation (15).
Most women experienced disruptions in menstrual cycle while using
NET OEN. The major reasons for discontinuations due to menstrual dis
turbances consisted of amenorrhoea, excessive/prolonged bleeding and
irregular cycles/spotting. The discontinuations due to menstrual distur
bances almost increased in geometrical progression with continued drug
use and amenorrhoea was the most common reason associated with it. How
ever, no statistically significant difference in this regard was not
in
women using either the’60+5- or 90+5-day schedules at any time up to 24
months of NET OEN treatment. These observations are similar to those
reported in a recent study (3,4).
i
Discontinuations due to other medical reasons were small and not
related to the drug use. The total discontinuation rates for all reasons
were similar for the two treatment schedules at all points of observation.
No significant effect of NET OEN treatment was seen on the BP. The gain
in weight of more than 5 kg was seen with either of the two treatment,
schedules in a higher percentage of women, as compared to the loss of
weight which was seen in a smaller percentage.
percentage, However, no significant
differencein weight gain was noted in women using either the 60+5- or
imen. These observations are similar to those reported m a
*0+5-day regimen.
WHO study (3,4) .
Surprisingly, the method failures within the first six months, when
al) the study subjects received 200 mg NET OEN at 60+5-day intervals^
were
higher in the present trial as compared to the WHO study (3,4) . Cer* n
difficulties in administering the drug, such as the leakage of NET OE.. ’
solution from the syringes, was reported in general and specifically freife
the centres where maximum pregnancies were reported. However, no concre®
•vidence could be obtained after repeated enquiries which would implicat*
this factor of the leakage of the drug as the major factor responsible for
nigher pregnancy rates. This is an important observation which suggests
that in order to avoid any possibility of leakage of the drug for its
administration under programme conditions especially at peripheral centres,
.ttSeful«“W(,ie*lpaL.k—the drug tn-sreri 1 ized disposable syringes."
I
■y
DECEMBER 1984 VOL. 30 NO. 6
.3
,' I
Other ,reasons tor
I
diSCUidJJ^'L1
-
■
4
deluded persona aaue to persona! reasons for
discontinuations
reasons f°r
-
The other
, were B-6
.ntinuations C—
Discoi
'90.5-day, respectively
,-00
^00 U3erf~
traerflate tor follow-up60+5- and ‘
tceat-nent schedules of at -nnr year■ an**
this
the reasons under
100 users
and objection
Some of
and 9.2. P“r
for pregnancy
second year.
^re desire
.ntinuation rates
end
of
the
at th? t.
the subjects ’
the ditcon*
by
of discontij made to keep
category given Every
annual rate
attempt was
from (amily• follow-up to a minimum and the
100 usersdid not exceed 2 per
for Late for
this factor
nuation due to
i were 58.1
at the end ot one year
ntinuation rates <for the 60.!-day and 90+S-day
The overall co:
respectively. : marginally lower tha those
anu .9.6 P- 100 users,These rates were
in our
intrauterine
, conti"
treatment schedules,
sxmilar conditions for
and
observed under
100 users. At
the
country,69.9 per
31.4 and 32.6 per
nuatron rates were schedules , which are
users.. at
for cut-200 IUD U2-^pe
the second
g(,.5-day treatmen observed
continuation rates
i„ the continua
due lo pelrsona1
The» decline due to ^-ortxnuat on.^t^^t.on» due to
24 months (7> •
ase was mainly
■ - rates of*
laid down in
year of drug amenorrhoea. The higher
hovin9 a^norrhu'-a
lalned by
reasons and
intinuation
^.-enorrhoea could probably
uired discor
’tocol. which req’
the pro'
, than one year.
of more
.o SB
^<3
I
be;xctr-<"-^- °f “-men
■I
NET OEN
Clearly indicates that
protection,
yesuits of - present^tudy
adequate contraceptive
represents the
The
This clinical trial
, are
6O-5'd^e1go"-day regimen.
observations
•jjven at
NET OEN. These
a3 compared' tO
v.,
.7 rundertaken on
10,11). The
lir.ical trxai
trial unde.
IS
(1,2.J.
.Aroest clinical
treatment sclhedule
oth
fllr to those teportedrn
reported
90+S-day
I NET levels
1
irculating
similar to
,_ilure rates
contraceptive efficacy of c
have
higher r: to th reduced of the pregnancies were estimated to study with
failure rates in this
13) since t-o-third.
84«b-day treatThe method
n2' u,
- -- third month.
.( ds compared to the - • - ”j the evxdenc*rred m the
supporting
also higher,
(3,4). fur^vr
month.
*)04 5-day
WHO study
raring the third
t...sGhcdult
used
of
the
drug
«•d”1- ::lce^ e efficacy
the thin
f t.e<duced
4.1("od conttacepu
contr
indicate that
pregnancy
study
furthei
present
reased risk of
The results of the weight) are at an in*
increased risk ot
association ot
reported in
( 4 40 kg body
been
built women
treatment. Similar
vcht has a 1 so
OEN
with lower body we
while on NET
1
OEN users
• '• pregnancy• in NET
DISCUSSION
I
...........--
■
571
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DLCEMBER
19b4 VOL. 30 NO. t>
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i:
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CONTRACEPTION
t
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In conclusion, the results of the present study indicate that
200 mg NET OEN given at 60+5-day intervals provides adequate contra
ceptive protection and offers an additional spacing method for
possible use in the National Family Planning Programme.
K M
’MTNOWEEDGEMENTS
The study was supported in part by Special Programme of
Research, Development and Research Training in Human Reproduction,
WF’O, Geneva.
r
ii
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iE
REFERENCES
1.
2.
World Health Organization Expanded Programme ot Research,
Development and Research Training in Human Reproduction.
Task Force on Long-Acting Systemic Agents for the Regulation
of Fertility. Multinational comparative clinical evaluation
of two Icig-acting injectable contraceptive steroids:
norethisterone oenanthate and medroxyprogesterone acetate:
1. Use-effectiveness. Contraception 15:513-533, 1977.
World Health Organization Expanded Programme of Research,
Development and Research Training in Human Reproduction.
Task Force on Long-Acting Systemic Agents for the Regulation
of Fertility. Multinational comparative clinical evaluation
of two long-acting injectable contraceptive steroids: nore
thisterone oenanthate and medroxyprogesterone acetate: 2.
Bleeding patterns and side effects. Contraception
17:395-406, 1978.
1 r*' II
J
I
■ d
■
3.
j
*
‘
World Health Organization Special Programme of Research,
Development and Research Training in Human Reproduction.
Task Force on Long.-acting Systemic Agents for the Regulation
of Fertility. Multinational comparative clinical trial of
long-acting injectable\contraceptives: norethisterone oenanthate
given in two
two dosage regimens and depot-medroxyprogesterone
acetate: A preliminary report. Contraception 25: 1-11, 1982.
WHO Special Programme of Research, Development and Research
Training in Human Reproduction. Multinational comparative
clinical trial of long-acting injectable contraceptives:
Norethisterone oenanthate given in two dosage regimens and
depot-medroxyprogesterone acetate. Final report.
Contraception 28: 1-20, 1983.
DECEMBER 1 9X4 VOL. 30 NO. 6
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i
i
r ''
. . ' J
■
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CONTRACEPTION
5.
Azen, S.P., P. Roy, M.C. Pike, J. Casagrande and D.R.Mishell,Jr.
A new procedure for the statistical evaluation of intrauterine
contraception. Am. J. Obstet. Gynaacol. Vol. 329-335, 1977.
b.
Azen, S.P., S. Roy, M.C. Pike and J.Casagrande. Some suggested
improvements to current statistical methods of analysing
contraceptive efficacy. J.
Chron. Dis 29: 649-666, 1976.
7.
j e j uj a , S . , N.C. Saxena, U. MaIhotra, S.D. Choudhary and
G. Bhinder. Two years experience with Copper T-200 in
India. Contraception 10:337-350, 1974.
■
,
t
I
8.
El Mahgoub, S. and M. Karim, The long-term use of injectable
norethisterone oenanthate as a contraceptive. Contraception
5: 21-29, 1972.
9.
Kesseru-Koos, E., A. Larranaga-Leguia, H. F
Hurtadokoos, and
H.J. Scharff . Fertility control with norethindrone
------ .j oenanthate,
a long-acting parenteral
--- 1 Pr°gestogen. Acta Europea Fertilitatis
203-221, 1973.
10.
Chinnatamby, S. A <comparison of the long-acting contraceptive
agents norethisterone oenanthate and
J medroxyprogesterone acetate,
Australian and New Zealand Journal of Obst. and Gynaecology 11:
233-236, 1971.
U.
Swenson, I., A.R. Khan, and F.A. Jahan,
A randomized, single
blind comparative trial of norethindrone
oenanthate and depomedroxyprogesterone acetate in Bangladesh
. Contraception 21:
207-215, 1980.
12.
Saxena, B.N., K. Shrimankar, and K. Fotherby.
Radioimmunoassay
of serum norethisterone oenanthate levels in
women after intramuscular administration. J. Steroid Biochemistry, 8:
117, 1977.
13.
Fotlwirby, K . , B .N . fSaxena, K. Shrimanker, V. Hingorani, D. Takker,
E. Oiczfalusy and B.M.
ILandgren. A preliminary pharmacokinetic^M
pharmacodynamic evaluation
--- 1 of depot-medroxyprogesterone acetate anl?
norethisterone oenanthate. Fertility and Sterility 34: 131-139, 19$
14
Fotherby, K. and S. Koetsawang. r
•
Metabolism
of injectable formulaCions of contraceptive steroids in obese and
-- thin
--- 1 women.
Contraception 26: 51-58, 1982.
15.
Benngiano, G., K. FFotherby,
■’
E. Coutinho, J.C. de Souza, V. Hingorani,
0. lakker, S. Koetsawang, and S.. Shrisupandit.
Return of ovarian
function and endometrial moirphology
'
in women treated with norethisterone oenanchatr: A pilot study
Fertility and Sterility 34456-460, '1980
—.
»»
>74
DECEMBER 1 984 VOL. 30 NO. 6
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ICMR TASK FORCE ON HORMONAL CONTRACEPTION
Return of Fertility Following Discontinuation of An Injectable
Contraceptive - Norethisterone Oenanthate (NET EN) 200mg dose.
<
NATTONAI
-'KOGRAMME OF RESEARCH
!)i vi s 1
• of Reproductive Biology
IN HUMAN REPRODUCTION
Fertiliu.
.out ro ■
INDIAN COUNCIL OF MEDICAL RESEARCH
ANSARI NAGAR, NEW DELHI-1 I 0029.INDIA
INVESTIGATORS:
, Bhatt,R.V., Chatterjee,
1 . Choudhury, S.D. 4 , Coyaji, B.
, Engineer, A.D. , Gogoi,
(
. P. ' . Hi ngorani,, V.H. Lal K.
11 sra. P.
<: ver 1, K.
;OOKr>I NAT 1N(. IP. >T:
PROdrST COORDINATOR:
j.
!i
j
ianeriee, S.K.(late)1, Baveja.R.
Philips, F.S.
1 <
6
. Kochhar, M.
Ra j a r i, H..
1
!6
, Krishna,!.’.
I’atey, S.
1 'I
.
17
i /
, Gupta, S.
. Mehta, S.
, Saxena.N.C.
*Saxena, B.N.
17
R.G. Kar Medical College, Calcutta
M.L.... Medical College, Allahabad
Baroda Medical College, Baroda
Ins'-r.ute for Research in Reproaucr i onV B^nibav
K.E.’-i. Hospital, Pune
K.(j. Medical College, Lucknow
Med: <n College, Guwahati
.Ail
ndia Institute of Medicaj Sciences, New Delhi
Med:.a 1 College, Jammu
Kasturba Hospital, Delhi
K.E.M. Hospitai. Bomba y
S P. Medical College, Bikaner
Medical College, Alleppy
R.M.s.P. Hospital, Calcutta
Hospital, Bombay
Indian Council of Medical Research, New Delhi.
*To whom reprint requests may be sent
11
, Sen Gupta, P.O.
16
!nst:tute of Obst. & Gynaecology, Madras
17.
10
15
I
ABSTRACT
The return of fertility following .discontinuation
<’ ’
of Norethisterone Oenanthate (NET EN) 200 mg injectable
c
—
• •
'
contraceptive
after using
aiO.rcoa„^“Srl?th^ sfot”T±" oore
"ho
copper intra-uterine device (cLt 2onf pre8nancy.
The former users of
Another 161 women who had discontinued OT? EN^ne T
COntro1 grouP’
amenorrhoea, excessive
^Ue t0 ot^er reasons (e.g.
for return o' fertility aft^
TeaSOns) were alao etudiJi
fertility after <
of ccontraceptlon and
were exposed to the risk of pregnancy.
The c^nulati
b°th groups were followed
----------- 1 for a period of one year,
lhe cumulative conception rates at c~
one year were 72.5 arri 83.6 per 105
eX-NET EN arxJ ex-CuT 200 users who had discontinued rhn
method..for planning.^.,
.pregnancy
thls dIfference „„ nol
significant (P> 0.05).
The median time for i
conception for ex-NET EN
users was 7.8 months as compared
to 3.7 months■ in ex-CuT 200 users but
cumulative
cumul^r4Ve conception rates
future return of fertility in NET EN at the end of one year show that
users does not appear to be adversely effected.
the return o'
fertilir
discontinued I”"
NET EN due to amenorrhoea
of fertility r .
7 T predictab]>' slower
• - / a nd less.
The return
subjects who discontinued mft pm r
excessive bleeding arri
&concinued NET EN for other reasons(e.g.
EN and ex-CuT 200 users.
Personal reasons) was similar in ex-NET
introduction
Injectable
are
by over three
as a spacing method
women in
evidence
countries
(1). Available
once the effect
former users
worn off, the
at the same rate
the
former
methods (1).
users of other
Injectable
c
do
-u not harm women's future •
fertility nor the children theycontraceptives
bear
—• (1).
The most widely available
togen only Preparations - frv*n rPrMLaratiOriS are two synthetic progesAcetate (DMFA)
given as 150 mgm every three Depot-Mttiroxy-Progesterone
months
—J injection and Norethisterone Oenan
thate (NET EN) given as 200 r*'”“
mgm every 60±5 or 90±5 days Injection
Various studies indicate that within
one year
after the discontinuation,
over 60 per cent Of former DMPA users
become
Become pregnant (1,2,3,4,5),
In contrast to DMPA, NET EN is metabolised
more ]rapidly and return
of ovulation is earlier (6,7,8,9).
Therefore
there is
inhibition of >vulatlon, and in many women,
-J no long term
the ovulation occurs even
before the etd of the injection Interval
In one study, 31 (77.5
Per cent) out of 40 former users of NET (6,10).
EN
conceived within 12 months
of discontinuation
-1 of the method (10).
In view of the p*" ■ *
the
^ograX'
as 3a SpaClng method
the National
National Family
Family Planning
Planning Sogra^e;'
. Th
;’ r J*
Research (ICMR) decided to study the ’return of f
°f Medlcal
- - of
-- this contraceotivfl
discontinuation
contraceptive method °f fertility following the
)
MATERIALS AND METHODS
The present study was carried out at ICMR's network of 16 Human
Reproduction Research Centres (HRRCs) who had participated in Phase
UI clinical tr^l of NET EN as an injectable contraceptive (11). Women
who had discontinued NET EN for planning pregnancy after a minimum period
of six months of use (ex-NET EN users) formed the clinical material
or the present study.
In addition, data on return of fertility wasa so collected for women who had discontinued the use of NET EN for
other reasons (e.g. amenorrhoea, excessive bleeding or personal reasons)
nd were exposed to the risk of pregnancy since they were not using
any alternative methods of contraception.
The study design involved
enrolment of age and parity matched women who had discontinued the use
forCrnPer
12?ra‘uterlne device (ex-CuT 200 users) as control group
for comparison. The number of study subjects who discontinued for plan
ning pregnancy consisted of 69 ex-NET EN users arri 110 ex-CuT 200 users.
Both the groups were followed for a period of one year. The zero Mint
of observation of ex-NET EN users
excluded tthe
contraceptive effScy
users excluded
‘
^th^one deg^ee o^-freX?
6
^
- chi-square
The test of significance
OBSERVATIONS
Profile of study subjects
The study subjects were <
comparable with regard to age, age of
husband, age rat marriage and parity
(Table I).
The average duration
of contraceptive use
wasj 11.9 and 28.2 months
— -in
ex~NET
EN and ex-CuT
200 users, respectively.
TABLE I:
Age of Subject (yrs)
Age of Husband (yrs)
Age at Marriage (yrs)
Parity
Duration of Contraceptive
use in months
Total No. of Subjects
DEMOGRAPHIC PROFILE
Ex-NET EN Users
Mean ± S.D.
Ex-CuT 200 Users
Mean ± S.D.
24.8 ± 3.3
25.0 ± 3.1
29.9 i 3.9
29.6 ± 3.9
19.4 ± 3.1
18.8 ± 3.1
2.2 ± 1.3
1.8 ± 0.9
11.9 ± 4.9
28.2 ±14.7
69
110
6
Sa?.
>6 •
i
I
Return of Fertility
I
Amongst women who had discontinued the method for planning preg-- .
nancy, 50 ex-NET EN users and 92 ex-CuT 200 users had conceived during
the one year of .study period giving cumulative conception rates of 72.5
and 83.6 per 100 subjects respectively (Table III).
This difference
was not statistically significant (P>0.05). The median time for concep
tion in ex-NET EN users was7.8 months as compared to 3.7 months in exCuT 200 users (Fig.l). This is mainly because the peak in monthly concep
tion rate was observed within first four months in ex-CuT 200 users
as compared to that observed at 4-9 months in ex-NET EN users (Fig.2).
1
f
Besides planning pregnancy, ex-NET EN users and ex-CuT 200 users
who had discontinued the contraceptive method for other reasons were
also enrolled and followed up for a period of one year (Table II).
Regular follow up of these subjects during the 12 months study period
ensured that they were not using any other method of contraception,
and that they were exposed to the risk of pregnancy.
■
TABLE II:
REASONS FOR DISCONTINUATION OF CONTRACEPTIVE METHOD
Reasons
(
Ex-NET EN Users
No.
Percent
Sx-CuT 200 Users
No. Percent
no
69.6
29.5
24
15.2
42
18.3
24
15.2
230
100.0
158
100.0
Planning Pregnancy
69
30.0
Amenorrhoea
51
22.2
Excessive Bleeding
68
Other Personal Reasons
Total; ’•
Out of 51 subjects who had discontinued NET EN due to amenorrhoea,
only 26 had conceived within one year indicating that return of fertility
was relatively slow in this category (Table III & Fig.3). However the
conception rates at the end of one year were comparable for ex-NET EN
and ex-CuT 200 users for other categories of discontinuations (e.g.
excessive bleeding and other personal reasons) as shown in Table III
and Fig. 4 & 5.
—
EX- NET EN USERS
.^EX -CuT 200 USERS
tO
do
8
V)
70
§
2
.-zH
Q.
Ui
s
S
a
50
u.
40-
£ :
jo
’t
i
20-
(J
10'
0
1
2
J
4
7
6
5
9
6
10
11
12
MONTHS
Fig.l: Cumulative conception rates in subjects who discontinued
the method for planning pregnancy
EX-NET EN USERS
• EX CuT 200 USERS
2 J-I
I
i
i
fu
JO
5
Q>
C>
Cr
u,
a.
5
''
6
8
•)
io n 12
MONTHS
Fig.2: Monthly conception rates In subjects who discontinued
the method for planning pregnancy
■
■
- - ■
’
Sft.
.
■
1
1
1
90
• -------- • EX- NET EN USERS
EX -NET EN USERS
* --------- • EX-CuT 200 USERS
90
EX-CuT 200 USERS
dO
EX-NET EN
USERS
El
so
£
70
§
ya
60
§
i
•v
J
40
§
•4-
5
5
1
£
c>
$
50
50
I
CO
5
**
30
1
60
0
50
40
&
g
20
do
o
20
30
ki
I
jo.
s
§
20
o
io
n-
12
months
6
7
P
0
r
o
12
MONT HZ
^r. THS
Fig.3. Cumulative f-*'-*
—* •
conception
rates in
subjects who discontinued
- — — - -—the
method due to amenorrhoea
!
Fig.4: Cumulative <conception
----rates
in subjects who discontinued
the method due to excessive
bleeding
Fig.5: Cumulative (conception
--------rates
in subjects who
-..a cdiscontinued
the meth'd due
—- toc other
persona: ;caso:^
»
<■
TABLE III: RETURN OF FERTILITY AMONGST Ex-NET EN AND Ex-CuT-200 USERS
Reason for Discon
tinuation of the.
contraceptive
method
______ RETURN OF FERTILITY_______________
ex-NET EN USERS
ex-CuT-200 USERS
No.of women Conceived in No. of women Conceived in
at risk
12 months
at risk
12 .months
No. Percent
No. Percent
Planning Pregnancy
69
50
72.5
Amenorrhoea
51
26
51.0
Excessive Bleeding
68
50
Other Personal
Reasons
42
26
110
92
83.6
73.5
24
15
62.5
61.9
24
19
79.2
DISCUSSION
Adequate information about the return of fertility following
discontinuation of a method is crucial for promoting a particular contra
ceptive as a spacing method.
There are more published reports on this
aspect on DMPA, as the drug has been in use for a longer period of time
in a larger number of women (1,2,3,4,5), as compared to NET EN (6,10,
11,12).
The available evidence suggests that the injectable contracep
tives do not adversely effect either the women’s' future fertility or
their subsequent progeny (1).
The results of the pp^sent study
. indicated'that.
. ..
return of fertility
in women who discontinued NET EN for planningJ pregnancy (72.5 per 100
subjects ) Jis comparable to that in women who discontinued CuT 200 ( 83.6
per 100 subjects )at the end of one year of observation (P>0.05).
There is a considerable delay in return of fertility in women
who discontinued the use of NET EN due to amenorrhoea (51 per cent) as
compared to that observed in women who discontinued the method due to
other reasons.
The CuT-200 users do not form a valid control group to compare
the return of fertility, since NET EN is a jprogesterone
~
onlyj contraceptive
having a totally different pharmacokinetic and pharmaco-dynamic profile.
Therefore, ideally one should have enrolled hormonal contraceptive users,
preferably injectables as a control group in the present study. However,
since no other injectable preparation such as DMPA is available in India
nor we could find sufficient number of oral hormonal contraceptive users,
we could enrol only the CuT-200 users as a control group in our study.
The wide variation in time of conception of ex-NET EN users could be
due to wide variability in uptake and metabolism of NET EN reported
amongst subjects, (10,13).
It has also been reported that even though
ovulation may return in NET EN users, the antifertility effect of the
drug may continue by its action on other vulnerable points such as corpus
luteum, endometrium or cervical mucus (14).
Furthermore, the role of
j
extraneous factors such as reliability of study subjects in reporting
true reasons for discontinuation of method, frequency and timing of
coitus, have also to be kept in mind while evaluating the return of
fertility following discontinuation of a contraceptive method due to
other reasons except in those for planning pregnancies.
I
In summary, though there is a difference of
4 months in rhe
median time for conception in ex-NET EN users as compared to ex-CuT
200 users, the net cumulative conception rates at the end of one year
show that there is no long term inhibition of ovulation, In many women.
ovulation and pregnancy has been reported to occur before the next injec
tion period of 90 days in NET EN users (6,10,11).
In other words, the
results of the present study supports earlier observations (1,6,10)
that NET EN as 200 mg dose regimen (two monthly or three monthly) does
not adversely effect the return of fertility in the users, of this injec
table contraceptive preparation.
ACKNOWLEDGEMENT
The authors are grateful to Special Programme for Research in
Human Reproduction, World Health Organization, Geneva for the supply
of NET EN drug and technical advice for planning of study.
REFERENCES
1.
Family Planning Programme - Population Reports J. Series No.28,1984.
2.
Pardthaisong,T.» Gray, R.H. and McDaniel, E.B.: Return of fertility after discontinuation of depot medroxy progesterone acetate *
and intra uterine devices in Northern Thailand. Lancet 1 (8167): 509-512, 1980.
3.
Dodds, G.H.:
The use of sterile medroxy-progesterone
as a contraceptive during a three year period.
Contraception 11
: 15-23, 1975.
4.
McDaniel, E.B. and Pardthaisong , T.
Depot medroxy-progesterone
T. :
acetate as a contraceptive agent: Return of fertility after discon
tinuation of use. Contraception 8 ■ : 407-415, 1973.
5.
SchWallie, P.O. and Assenzo, J.R. •. The effect of depotmedroxyprogesterone acetate on pituitary and ovarian function, and the
return of fertility following its discontinuation: A review. J
Contraception 10
: 181-202, 1974.
6.
Fotherby, K. , HoWard, G., Shrimanker, K. , Elder, M. , and Bye,
P.G.T.; Occurence of ovulation in women receiving the injectable
contraceptive norethisterone oenamhate.
Contraception 18
: 535-542, 1978.
acetate
-
■
(
.7.
Fotherby, K., Saxena, B.N., Shrimanker, K., Hingorani, V., Takker,
D., Diczfalusy, E., and Landgren, B.M.| A preliminary pharmarnkinetic and pharmacodyanamic evaluation of depot medroxy-progeste
rone acetate and norethisterone oenanthate. Fertility and Steri
lity 34
; 131-139, 1980.
8.
Dhall, K., Dash, R.J., Chadha, V
v
‘
r__
V., “Rastogi,
G.K.,
and1 Devi, P.K.:
Effect of three Injections of norethisterone oenanthate on ovarian
function.* Indian Journal of Medical Research 69
: 93-98, 1979.
9.
Garza-flores, J., Cardenas, S. , Rodriguez, V., Cravioto, M.C.,
DiazSanchez, V., and Perez-Palacios, G.:
Return of ovulation
following the use of long-acting injectable contraceptives; A
comparative study. Contraception 31 : 361-366, 1985.
10.
Fotherby, K., Yong-En, S., Howard, G., Elder, M.G. and Muggeridge,
J. • Return of Ovulation and Fertility in women using norethis
terone oenanthate. Contraception 29
: 447-455, 1984.
11.
ICMR National Programme of Research in Human Reproduction..: Task
Force on Hormonal Contraception. Comparative Evaluation of’Contra
ceptive efficacy of norethisterone oenanthate (200 mg) injectable
contraceptive given every two or three monthly.
Contraception 30: 561-574, 1984.
12.
Howard G., Blair, M. , Chen, J.K., Fotherby, K., Muggeridge, J.,
Elder. M.G. and Bye, P.G.: A clinical trial of norethisterone
oenantnate injected every two months.
--- Contraception 25:
333-345, 1982.
13.
Fotherby, K.: Variability of pharmacokinetic parameters for contra
ceptive steroids. J. Steroid Biochemistry 19: 817-820, 1983.
14.
Fotherby, K., Howard, G. : Return of fertility in women discontinu
ing injectable contraceptives.
Journal of Obstet. Gynaecol
6. (Suppl.2) 110-115.
•X
No
&
^INTRODUCTION OF INJECTABLE CONTRACEPTIVE (NET-OEN 200 mg)
IN SELECTED PRIMARY HEALTH CENTRES ATTACHED' TO MEDICAL
COLLEGES (ROME
SCHEME)
A PILOT■ STUDI
.
------y - ■ r
.
t-i
1.
RATIONALE:
I he strategy of the Ifetional Ifamily planning programme
is to offer a wide variety of contraceptives to eligible
couples to assure a® far as possible that each couple will
be able to find a method that meets their particular needs.
j
i
&
Currently the fictional family planning programme offers
sterilizations, IUD, 6ral gills and conventional methods.
Injectable contraceptives still do not form a part of the
programme.
However, injections as a delivery'systern is
popular among Indian women.
(a )
The Indian Council of Medical Research has recently
completed Phase III Clinical trial with injectable NET-OEN
200 mg, on 2600 subjects.
The data of this study has indicat ..i
that the method has no life threatening side effects. has low 1
failure rate and is an acceptable,route of drug delivery
sys tern.
Based on this experience, the ICMR is now engaged in
the Programme Introduction Study to assess the -acceptability
of injectable contraceptive under existing programme conditions
with a focus to Identify the operational requirements and
logistics of such) a contraceptive in Postpartum Centres in
H •’tJtes since August 1983 and so far have accumulated one
year experience in this contraception in Urban/settings.
(B)
In the light of these findings of a ingoing Phase IV
studyz it is quite appropriate to.look into the problems of
logistics and back up facilities which may be required in
,.u.
2
rural areas when the method is included into National Family
Ua^ss?wig Programme.
Hence what is being proposed at this stage
is to generate comprehensive information ±>n operational aspects
and logistics both for rural and urban clinic settings,
s j thut
an appropriate strategy could be implemented when it is desired
to introduce injectable contraceptive with the irMin sstxeagrth
of the National Family Welfare Programme.
1.2
OBJECTIVES:
Overall Objectives:
Introduction of NET-OEN injectable into the Family
Planning Programme under existing operational conditions
at
PH3S. Specifically following
aspects will be studied:—
A.
Logistics requirements for this method of
Fertility Regulations^
This has following
components
draining of Medical and Para-medical staff
II.
Education and motivation potential for the
clients.
III.
Follow up needs and mechanisms.
IV.
Management of side effects including
referrals and back up facilities.
V.
1.3
Data recording requirements.
SIMILAR STUDIESi
WHO, which undertook a Phase III Multinational
comparative clinical trial with the injectable contraceptive
Norethisterone enanthate (NET-GEN), given at 60 day interval
for the entire period (NET-OEN 60 day), and NET—GEN given at
3
60-day intervals for six months and thereafter at 84-day
. 1
intervals (NBT^OENQHdttay) . After two years, the pregnancy
rate with NEI'-OEN (84 days) was 1.4 (+ 0.6 SE) per 100 women
compared with the two years rates of
0.4 (+ 0.2 SE) with NET-OEN (60 days),
z —
The 12 month pregnancy
rates with injectable method (0.1 - 0.7 per 100 women) are
generally lower: than with oral contraceptives (1.0 - 6.0 per
100 women)
.
Thus injectable preparations appear to provide
an effective alternative to oral methods of interval contra—
ception.
i
The choice of the most appropriate injectable regimen
for a given context will depend upon a variety .of medical c .d
family planning programme, considerations . Although the prt-.,nancy
rates with NET-..OEN (84 days) regimen is slightly higher. th is
schedule has the logistic and economic advantage of ’less air .norrhea and may be more appropriate in these societies with i
low culrural tolerance of amenerrhefectvid may be more approp *iate
in these societies with a low cultural tolerance of amenori ea.
ICMR initiated in early 1981, through its network of
Human Reproduction Research Centres (HRRCs) a randomized
t
clinical trial to evaluate the contraceptive efficacy and:
safety of NET-OEN 200 mg given in two different treatment
.
• . _ . _ ,
3
schedules of 60 days + 5 days and 90 t 5 days . The obser-
vations indicated that NET-OEN given at 60 + 5 days intervals
provides adequate contraceptive protection .-—Thin built women
(body weight / 40 kg.) were at higher risk of -involuntary
pregnancy.
i
Amenorrhoea was the commonest reason for dis-
In conclusion, the result of this study sh .- >d
continuation.
*fewer injections and less pregnent re-visits compared to -a .
NET-OEN (60 days). NET-OEN who has another advantage of
that 200 mg NET-OEN given
at 60^5 days intervals provides
adequate contraceptive protection and offers an additional
Spacing method for its possible use in the National Family
Programme.
In the light of thase findings of this Phase III Study,
ICMR is now engaged in the' programme introduction study4 at
the request of Ministry of Health and Family Welfare, to
assess the acceptability of NET-DEN injectable?tas a spacing
method under existing post-partum; condition (urban'clinics)
with a focus to identify the requirements for the operational
aspects including the logistics. .During a period of one
a total of 1553 subjects were enrolled.
Majority of the
discontinuetionsoccured after first or second injection,
indicating lack of counselling or educational material given
to the subject and every casual behaviour of’ the clinical.
staff dii^ocixsag^s the enrolment of subjects.
The lack of
active involvement of the providers and insufficient
information provided about this method to clients may have
influenced ^to discontinue from -the study.
Now, the study
is ongoing in 27 post-partum Centres and it is hoped that
future progress of the work yieldsuseful scientific inform-:.ti n
with regards to this method.
1.4
Outline of Design and Methodology;
1.4.1 Overall Design;
(A)
The study will be conducted in Primary Health Centra
attached to 15 Medical Colleges under ROME Scheme,
Each v
the selected Medical Colleges would implement the study in
5
<•
i
1 3 Primary Health Centres.
The coordination and supervision
of the work at three PHCg' would be carried out by Prof,
g
P.S. 1.
and Obst./Gynae.
1 he Medical Colleges have been selected jointly
by ICMP and Ministry of Health and Family Welfare.
------ — ' .
X
Each Primary Health Centre will enroll 50 subjects f.
the study and thus a total of 2250 subjects (50X3X15 =
2250 s
subjects) will be enrolled and followed up for a period of
>r
year.
(B)
The first injection of NEl’-OEN 200 mg will be give\
within 5 days of the menses and subsequently -at an intervcj
60 days for a period of one year.
4
also be given within an interval of
The subsequent inject! >n n.
5^’79
days for the previ
injectlonsa
1.4.2
Description of the drug;
.
NET-OEN 17-ethinyl-4-Oestren-3-One 1713 heptanoate J.-,
the c.rug t© be used f.ir. this study.
The product is manufactured
The product is manufactur
by Schering ag Berlin and is presented as onljf solution (Benzeil
benzoate: Caster Oil in the ration of 6:4) with 200 mj. of
(
nor ethisterone <?eaanthate in 1 ml.
The route of administration
will be intramuscular.
The initial dose will be administered within
the first
five days of the menses or immediately af ter MT? (■>
e. on the
/Cases of
same day), ^actational amenorrhoea cun be enrolled after rul.in
out pregnancy by both clinical and urine test.
1.4.3
Recruitment:
total of 2250 women will be’ enrolled into
the study
during a 6 months period.
Women
come to
seeking
advice for family planning will be recruited.
■..•cKjer
4
6
1.4.4
Follow-up
Continuing subjects will be followed up for 12 months
period from recruitment.
1.4.5
Duration of the study;
Recruitment
6 months
Follow-up period
12 months
Data analysis
3 months
Total
21 months
2.
SUBJECT SELECTION riND ^LLOCnTION
2.1
Criteria for subject selection:
Healthyt informed women who seek family planning
services in the Primary Health Centres will be selected if
they fulfill the following criteria;
1.
Age between 18—40 j^eurs
2.
Proven fertility
3.
Exposed to the risk of pregnancy
4.
Willing to rely only bn NET-OEN as a method of
fertility regulation
5.
Willing to return at prescribed interval for
follow up
6.
Previous Injection NET—OEN user can be re—enrolls
in the study if last injection was given more than
4 months ago or it can be given after she had 6ne
manias. Only 5% of cases must be enrolled.
The following will be the contrai-ndications for the use
NET-UEN;-
f
1.
Breast feeding in the initial 6 months since
del ive.ry
2.
Liver disease, including a history of jaundice
pregnancy or jaundice in last 6 months
7
-
3. ■Known or suspected breast malginancy
■
■
4.
Uudiagnosed vaginal bleeding
5.
Known or suspected genital malignancy or uterine
myoma
6.
Suspected pregnancy
7.
Cardiovascular disease including
Hypertension thromboembolism,thrombosis zmyocardial
infarction and diabetes are not a contraindications
such women need to be monitored closely.
8.
2.2
Previous IUD/OC user immediately Switching over
^dmis r-?on Procedure
Each potential subject will be screened for admission
criteria and for contraindications .
If the subject is eligible for the study/ she will
informed of all aspects of the study including that at the
old
of 12 months of NET. use, she may have to stop the Inject!
and advised another method of contraception.
She will be
specifically explained about possible menstrual alterations
return of menses, facilities provided for undesirable side
effects including for pregnancy termination.
All questions
asked will be answered.
A medical and gynaecological examination prior to
admission must be carried out.
Pregnancy will be ruled out
by history apd
/^ny abnormal condition not
examination.
excluding the patient from the trial will be recorded in t. .e
admission form.
2.3
J
Follow-ups
/*t each scheduled follow up visit. information will
be recorded.
«...
&
Each subject will be asked far symptoms/camplaints )>y
non-specific questioning e.g. “How h<ive you been since lest
visit”.
Details of menstrual changes will be recorded on the
foilow-up f orm.
Efforts will be made to reduce the discontinuations due
to “Late for Follow-up”.
follow-ux) appointment will be
given at a appropriate time. informing the subject that she
can make a visit
days of this date.
Unscheduled visit
will be accepted at any time and details recorded.
If the women fails to return for follow -up, a clinical
staff will go to her home to determine the reason for disc.,
tinuation.
This will be between 1 week to 4 weeks
after the scheduled visit date.
2.4
Treatment of Bleeding Problems:•
^ny woman complaining of heavy and/or prolonged bleed!• g
will be first examined for possible causes of bleeding uth<l-.'
than NET-ubN;
1.
She will also be evaluated for anemia and given
supplement Iron if indicated.
2.
^fter ensuring the absence of other, pathology the
women will be given 2 tablets of oral contracepti
every night for 7 days.
3.
If after having taken oral contraceptives the
bleeding is still unabated, subject will be
administered Inj. bstradiol Cypionate 5 mgm. IK
The injection will oe repeated only once again
if bleeding^not stopped within 24 hours./is
4.
faC will be performed if bleeding does not st
with above managements.
*
, r :•
. ; .u ‘
!i ' >
9
l
'
Manaqercent of Am^noyrhoe^ Cases:
of amenorrhoea of atleast 8 weeks confirmed
In the
clinical examination and urine pregnancy
due to pregnancy by
test the subject will be asked to discontinue from the study
2.5
)
and advised to undergo MTP.
the
However, if amenorrhoea is not due to pregnancy,
may continue in the study but examined periodically.
2.6
(
2.7
Criterla for Discontinuationi
1.
Foj;- the Subject -
Pregnancy/Bleeding/any other
reasons.
2.
For the Centre
Loss to follow up in more than
25% cases after enrolling 50 or
more subjects.
3.
the ?tudy
If 40% or more don't turn up fc?
2nd Inj. then terminating the
study may be considered
Data Collection and Analysis;.
The objectives of the study listed earlier will be met
in the following waysMECHANISM
OBJECTIVE
Pre & Post Training
Assessment
Training
Nos. enrolled
Wcsnpr turning up for
subsequent injection
Data from proformae
Site visit
Education and Motivation
F.U. needs and mechanisms
Management of side effects
Local operational problems
J
Amount of rectifications
required
Data Recording
By administering short
questionnaire at the
end of the study
Providers acceptability
Continuation Rates
Client’s acceptability
10
The training of the
medical and PHC. paramedical
staff will be given by medical colleges staff.
The protocol
proformae. will be discussed in
detail including manogem^nt
side effects. Educational and. motivational material win
developed by the specific cont^es.
n-
The training will be
undertaken by both Ubst. + <Gynaecology and Social
and
Preventive Medicine^ tTe Medics! College
which is involved
in the study.
For Monitoring of the study 2 teams (2 members each)
will be appointed who will be site visiting .the centres
periodically to resolve the technical, operational and
administrative problems. They will keep record of the staff
-1
position, supply position and quality of data recording.
In
problem centres team of senior persons from ICMK and Ministr
of Health will make visits.
Clients acceptability will be fudged by the
continuatior
rates at the end of 1 year of method use.
For assessing the acceptability of the Providers
a short
questionnaire will be administered to them at the end of the
study.
A
simple and easy to fill in data recording card has 1
developed and will be pretested.
Its suitability will be
judged by the amount r'jf rectifications including
"blanks”
required for the completion of the curd;
The ('Uta generated in the study will be helpful in
tmding out the data follow up needs and mechanisms.
A data summary will be sent
every 3 months to the ICbip
Hqrs, in a prescribed form given by ICMP.
.■'re
11
•H.
Data analysis utilizing computer facilities will be
undertaken in the ICMk Headquarter. -- ' "
3.
ETHICAL itSPECTS:
The p ssible risks are th^&e already known for the
combined steroid contraceptive in actual worldwide use.
w. unwritten consent frem-tbe patient win be obtained.
It is als-; understcod that the
treatment whenever she wants,
patient is free to discontinue
Howeverz she will be immcrii Italy
withdrawn fr .■m the study for any unpredictable high risk .x>ssi~
bility that endangers her health.
• —
No incentives j<re given to patients
or the paramedical
'>*■
staff.
All int.’ividual personal data recorded in this study will
remain confidential botween the subject, the
investigator and
others who need to have access to such information.- Subjects
will- not Le identifier: by name or initial*: in any publicati- rP
the t may result from this study unless
written consent for sue!
identifications is obtained from
each indivieual subject.
F'aCILIT ies .1 g
The existing staff of the
centres will be working i\ r
this project -’.Iso. The professors of ubst. and Gynaecology
and SPM will do the supervision
and monitoring of the study.
5.
DEF1NI1luNS:
For the purpose of the study use the foil,wing
d.ef ± nit ions
do
... . .
• *>r;<**y*-' •
17
1.
M e ns trua1 Cycles
a.
b.
Begularecycles
1,
Normals Cycle length - 22-35 days
ii.
Short ; Cycle length - 15-21 days
iii.
Long
: Cycle length - 36-45 days
Intermenstrue1 bleeding/spotting
Bleeding or spotting
;
' ' ’
occurring in between
two well defined cycles
c.
Irregular cycles
Complete disruption of normal menstrual pattern
such that it is not possible to differentiate
between regular cycles and intermenstrua1 bleeding
d.
'■MTienorrhoea
No bleeding for more than 45 cays
2<
3.
Amount ■.,£ bleedinc;
a.
Excessive bleeding;
I"
Bleeding is profuse and/or
prolonged as compared to
‘j pretrea-tment cycles.
b.
Scanty- bleeding i
The amount of bleeding is less
than pretreatment cycle.
c.
Spotting;
Blood staining not requiring any protection.
Scheduled visi t
.i?3g:iOTs •
interval
days. This means subject's clinic
visit tor t)fe injection between day 5^and $7^|Will be
treated as scheduled visit.
4.
Unscheduled visit
Subjects will be encouraged to visit the clinic
2£pny tlay in case they have any complaints or side
effects, rSuch visits which don't fall on scheduled
date will be considered
-d as ’unscheduled visit' and
the information will be recorded as in the case jf
scheduled visits.
.13
INS^KUK'IU^S FJX FILLING-UP THE FukMS
6.
j<EG I LTx-OsTIkJN kECUi^D
Enter the name of the subject, •name of her husband
and her complete address on the space provided.
suggested
a 1s
It is
het th^ name of the motivator. if any, should
le rec., rd o’. which might be helpful in treeing the sub
sul ject f >r subsequent enquiry.
-t-^TT; N ■ .
Titl:.e
Instructions
1.
Centre
Write the comijlete name of Centro
and leave the boxes flanks.
2.
9
Subject No.
AH the subjects enrol led for the
trial should be assigned the
‘Subject Number' consecutively ir.
the order they are admitted t •
trial.
For example. the first
subject enrolled^for the trial
will be assigned subject Noa/O/C/T/
second subject will be assigned
siibijuct N •)./0/^72/ift
enrolled will b<. assigned, sul jc'
No.7071757 inc. s j on
Age <of thc sul ject in complet
years sh >uld be recorded in thboxes pr >vi<.od
For
xampl*-;, i
age of the sulject is 35 years
as /37B7.
■
14
4.
No. of living
children
i<ecord the number of living children
in the boxes xirovided.
i-
i /
For examole.
.
r
x
a
if the subject has two living children,
enter as /C727.
Also mention the sex
of living children.
5.
Age of last
child (Mths.)
Knter age of the last living child
in months.
for example/ if age of
the child is 2 yeers enter as Z2ZI7.
In case the aj
of the youngest chill
is more than or equal to eight years.
enter as 797^7«
6.
Is woman
lactating
Encircle the appropriate answer giv-^n
and enter the code in the box.
7
Hite of LMP/MT?
Enter the date of the
first day of
the m^st menstrual’ period.
For ox-rnjle,
if the last period starred on 15.4.1985
•A--
1
enter as/^757^7^757^7• in subjects
continuing with lactational ^menorrhoeuz
write L.A.
outside the boxes.
For
m.)St MTp subjects. enter the ;.l^te of
LMP and write ?n*P outside the Lox.
8.
Menstrual cycle
Encircle ^PPF'vriate answer and enter
the cor res;; mding code in the box.
»
ic
-. -
15
9—10
Blood Pressure
Blood pressure should be record
in sitting position and with Sphyg
momanometer pressure cuff applied
to the upper arm.
Record systolic and
^nd diastolic blood pressure in the
boxes provided.
For example, B.P.
120/90 enter Sys. /Wo/ and Dia
i
/U797Q7.
11.
Height <3m.)
The height of’ the subject should be
measured in centimeters by standard
scale and recorded tc the nearest
centimeter in the boxes provided.
For example, if the height is
151.8 cm., enter as
11.
Weight (Kg.)
Each subject should be weight with
minimal clothing and without she. US .
Record weight in nearest kilogram
in.the boxes provided.
13.
Systemic
Examination
If the systemic examination is
normal enter 70>I7 in the boxes
provided and if any abnormality is
detected specify the abnormality
on the line provided and leave the
boxes blank.
14 .
Rel vic
Record the findings of pelvic
examination.
as /C7T7.
If
‘Normol1,
J
enter
If any abnormality is
detected,specify the abnormality on
the line provided.
Leave thu boxes
■
blank.
■; Bl
• i.
■
■<
16
15.
IXite of
injection
Enter the date on which the first
injection of ImET-OEN W’.is given.
For excimple t if
|
th
first injection
is 'given on 15.1.65 enter as
/175707178757.
16.
Date of follow
up visit
Enter the elute on which the follow
up, visit is due.
the
For example, if
subject is given the first
injection on 15.5.65, next fallow-
up Appointment should 1be on 1(5.7.85
(ufter two months).
The subject
should be told to visit the clinic
on eny day between 6.7.85
to 22.7.85.
FuLL.uW.-Uv UECukD
Each subject will receive .200
nij. of NET—uEN at admissi -n
to-the trial and thereafter at the interval
nu y^ar.
>f
days for
Each appointment will be given at an appropriate
cate- (2 months)
informing
..,i
,t she Cin vis“^
'•nninj the
the subject
th^t
days .jf this date.
This will reduce th,
to late fur follow
up injection.
disejntinuations due
In case the subject furls tr> return n scheduledvisit,
the clinic stuff will make a h >me visit
tu find out the reas <n
for disc mtinuuti jn. The home visit m^y, be mode
<_>n any day
between 2 to 3 weeks after the scheduled visit.
■
-Flqcia^
17
At each clinic visit, record the following information
in the space provided*
Visit No.
Enter the visit number (scheduled/
unscheduled)
in the space provided.
Date of Visit
Enter the date of follow-up visit.
•L.M.P.
Enter the date of LMP.
Complaints
On Non-specific questions:- Record
the complaints/side-effects experience
by the subject since her last visit
to the clinic.Non-specific questioning
should be made in the following manner.
“How have you been since your last
visit0.
This also includes abnor
malities in menstruation (Ref.
Definition)*
Bl<‘C>cl Pressure
Record systolic and diastolic
pressure on every scheduled visit.
Wt.(kg)
Record weight in kg on every visit.
oystunic d Pelvia
Ex- mi net ion
Systemic and Pelvic examination
s hou1d be do ne
n fevery visit.
Enter th^ findings of the systemic
nd pelvic
T r e e tinent, i f a i ;y
xamination.
If any treatment is given to th^
subject for her complaint or
?■ nv
abnormal systemic or pelvic fincinos, '
the same should b.
recorded.
If t.he injection
given at this visit
Self explanatory.
is sh^ c nntinuin j
in tie- trial
In case the subject is not continuing
in the trial, complete the details
under the heading “IF DISCONTINUED” ,
18
Date of next
follow-up visit
Enter the clete
n which the next
follow up visit is due.
For example,
if the subject is given the inject!,n
on 10.1.85 next follow-up appointment
should he . n 1U..3.85.
should be told
The subject
visit the clinic
between 3.3.85 to 17.3.85.
IHE^FOnSwiS HHS DISCObfi'INUEDimi 1HE TaIaL COMPLETE
, of I nJ octi..) ns q i yen :
2.
Date of _discontinuution;
1.
3elf explan .t,jry .
Date .f disc-ontinu-tien
sh.juld be determined as
follows
In cose of method failure.
date on which the
prejn^ncy is detected.
at.
2.
*lsp enter the uterine size
time pregnancy is .Jetected.
Eor other CeseSt enter th
c'-ita of last cont.ict
with the subject either at cj inic
r at h^mu
•r t
through informaMt menot by letter.
Peas >ns for i'j-.8Centiiiuation •
These Could be bro&dly
categorized as follows, specify th
reason in details
on the line pr >vided.
i.
Menstrual -abnormalities ■-
Such as (1) excessive
bleeding (2) irregular bleeding of spotting
(3) pr.l.mje! bleedilig ttbvi (-J
ii.
amen.',-rrh3eo
tc.
aadljlLtllOJO (Jnv duntary ^vjnuncy) : ? ,r the
c^se
>£ meth .kJ f ailures.
^ls.
specify the meth• .d
and < late of termination
jf pregnancy at the Lett >m
of the pa j
For example, if pregnancy was terminated
‘■m 6.5.83 by
19
buctijn £v.’.luatiun. Entcri^ss—
- Method failure
r
- Pregnancy terminated on €.5.83
— S/E vj< s d .jne
iii.Other Mv.dical Reasons: Ouches chest pein, palpitation.
nausea, vomiting, excessive weight gain. oe i: ema, hy^) e rtension,, liver disease, joint
?uin, etc.
iv.Pers mul Koos >ns: Like desire f or further pre_n<ncyz
nv need £ ;r further contract>tion. opted f >r permanent
methjd o£ contraception, otjecti m from family members.
left the place.
for Follow—uq; In case the subject reports to the
clinic after
of the last injection.
vi.Lost to i ,1low-up: In case the subject does not report
for follow-up • .;r address not traceable on home visits.
In Guise trie subject c.,uld not bo contacted during home
visit, an other h >mu visit may be made to ol tain tho
informat
;n before labelling her us “LOSl1 1c FOLLCW~:V‘
LHV must make a h jinu. visit and meet the client -n : must
(
>ut the reus ./D f r disc mtinuati-.n
r ,'t' th.- :.-
vii.End of the study
Qjg the su 1 j.jCt c .m^ t.) tile clinic t > inform
oledoNT INU xT IuN ; -
elf exjlanat'jry.
ut
■
*
20
5.
If no, H av v;--s th
inf -rrndti n ;Lt^ ine I: Specify th
source fr>ra which trie inf<-rm-ti n about th
f inject! ,n w^s
disc.ntinueti ,n
'Ltuinec f r uXJznjle through relatives.
hnme visit. letter, etc.
IE THE bUBJECl H
’ho Nut REa/uRT to the clinic
lXjE
uN SCHEDULED
TIME CumrLETE THE EuLLUWING;1.
Nu.
2.
tote .jf last visit to the clinic
3.
Specify whether any clinic staff visited the
.'f injucti' 'ns given; Eclf cXplen^i t jry
subject's hame.
4•
The reason for n>t c..’ming t.> the clinic
m^y be ohtain^H
f r >m the subject through h ;mc visit ♦
5.
In case the clinic staff elf;
n >t meke h
the reason fur n >t cluing so.
f'rB1 should signed by the
Officer Inchir.;e
the PHC/
Prjf. utst-Gynae/b^/ —------------------- ■
visit state
I a
-
Ife _
I ■■
KEFEKENCES
1.
Multinational comparative clinical trial of longacting injectdEle contraceptive: Norethisterone
enanthate given in two dosage regimens and l£4j?A4
{
Final keport.
Wriu op<_;Ci.al Programme Research^ Development and
i
Research Training in Human Reprouuctijn, Cuntracepti>n
26: l-20y 1983.
i;
2.
(
v
WHO
W
kly Epidemiologic Rec.: Magnitude of
Tuberculosis Problem in the World (1981) Geneva.
V
Compa rat iv-
1
of NET—OEN (200 mg) injectable contraceptive given
/three
every tv; ■ or/manthly.
ICM<Z Task Force on Hormun-l
evaluation .;f contraceptive efficacy
Contraception (submitted for .publication) .
4.
Introduction
2Ou mg)
Injectable Contraception (NET-OEN
jn National Family Welfare^ Rrogramm.
through
L
Rost-par turn Centres.
.-•'•■I,;.
Progress r epo rt ^ug us t 1964.
»
fj
vr.
S'';
1‘itttrh
M' ?.
- i**UV*2i
Facts about injectable contraceptives:
Memorandum from a WHO meeting*
-
.
I
I
I
I
i
fi
8
Jj
J
Injeciublc hormonal contraception with the two loni^-uciin^ steroid preparations,
depot'medroxyprogesterone acetate (DMPA) and norethisterone enuntute (NET-EN),
provides an effective means offertility regulation and is becoming widely used in family
planning programmes. However, there is still much debate and uncertainty about the sajety
of these preparations. The present Memorandum from a meeting organized bv the World
Health Organization attempts to clarify the issues by summarizing the results of recent
research on anmuds and human subjects, h identifies areas where continued research is
needed and pr-merits the conclusions 0/ the meeting regarding the saletv of use of injectable
hormonal con '' :< eptives.
\hhough ./la from some animal studies have raised concern about the possible
■ (//cint’^c'iK u. ' >/ 7M77< I and \ET-7:.\, cerium animal mt)deT\ used appear /<T^TVTmTppi-TTpi~iuiejoi studying the effects of these sterouls in human sub/ei tc Studies in women given im
injeiTablc cant.' uceptiVehuve not \o Jar shown anv serious \ide-ef/ecb. However, since both
DMP.‘\ and V / / A have been used tor only about If wars the potential longer-term
effects are not A town
More rcsem .7/1\ needed on theeffeits and physiological consequences oj long-term use
of these drugs on carbohydrate and lipid metabolism. In addition, well controlled studies
me needed to e smninc the risk of neoplasia among women using the compounds and to
assess the later development of infants who are exposed to DMPA or NET-EN in ulero or
through breast mid
Eased on the extensive epidemiological, biochemical, and clinical data available to
date, DMPA am!
- EN appear to be acceptable methods of fertility regulation. Clinical
evidence from more than 15 years of use shows no additional and possibly fewci adverse
\ide-eflects than are found with other hormonal methods of contraception. The particular
advantages of DMPA and NET-EN as highly effective, long-lasting, and reversible
< onlraceptives make them important options for women desiring a method of fertility
regulation.
since ns mcepimn in 1971. the W I IO Special I’roiiainnu ul Research, Development and Research
I rammi ml hi man Reproduction has addressed itself
to as'cs■ancm ci the safety am) effvehvenessof inject
anie hormonal contraceptives In iespouse to issues
raised h\ t’cscininenis and the scientific coininunilv,
a has ..rnd kicd numeioiis clinic •’ trials, including
oliow n;' ‘indies if women who bad ivceived inject• ibh .■ 11.itcplisi'•. case coii(K‘! indies ol neomasi.i, ■■ I mvcsiigation ol cfiildim born to women
'ho i-.'d (Isct| muciables; data fr mi oilier clinical,
■ ’\ico!
.-nd animal studio- have also been
Because of the long actin’naf tire of inject *
al’ic ciii-.i•jccptiscs, and because they have been
studied ess extc.’isivciv than oral toniraceptivcSi
I •• ■ S1vJI!Of;lf<illi>ii u,i\ dtnlicd »»v
. •, luipi ««•% l|MC(l <’fl
'’•'I •" 1
.'US' al ,i iicciinp held in < ki • ... m i >■
’•ild
;i<ldii' i-il li.
ci«•<?.
»h I iiM-hipniciii. .ind Hvicat.h I ruining in
I h<ii'.i:i h ■ "i
‘.i, v or kl 11c;di li i u g.iii! i t.’ii, 1211 (iriivva 27,
.hi .!•. J.i! i. •!. . 'i , '•, m -i -.Hiitinn Mill appi'iii
;i 1.1!' i ■•
more research is needed in order to identify possible
adverse effects.
Injectable hormonal contraception with the two
long-acting steroid prcpaiations, dcpot-incdroxy
progesterone acetate (DMPA) and norethisterone
cnantalr (NI T-I N), piovidcs an effective means of
fertility regulation, which has become an important
method of family planning. DMPA and NFT-l N
have several advantages which make them partial
larly suitable for some women and acceptable in
family planning programmes. /\ single injection can
provide highly effective contraception for 2 or more
months; delivery is simple, independent of coitus, and
ensures periodic contact with medical oi trained ancil
lary personnel. Furthermore, progestogens, unlike
estrogens, do odt suppress lactation, which is an
important considefmjon where there is a need for
postpartum contraception and where infant health is
dependent upon breast-feeding.
At a special meeting convened in 1978, the loxicology Review Panel oi the WHO Special Pro-
— 199-
i
f
I
2(X)
MEMORANDUM
gramme, together with other scientists, and represen(e.g., for hygienic purposes in mentally retarded
tatives of six national drug regulatory agencies, persons).
reviewed the result* of animal and human experi
— Whether, in the event of contraceptive failure,
ments with DMPA and NET-EN, and concluded use of DMPA might increase the risk of teratogenic
that, for DMPA:0
effects more than other systemic contraceptives.
«•
— Whether, in view of DMPA’s adverse side
" Hie available evidence does not indicate a risk of adverse
effects associated with Dcpo-Provera (DMPAJ which would effects or pharmacological effect, estrogen therapy is
preclude the use of this drug as a contraceptive
However, as ,ike,y 10 be prescribed in addition to DMPA in a
----- ----- .---------shown by the experience with combined oral contraceptives, significant number of patients.
relatively uncommon complications mas not be dJtecicd
-- Whether there are labelling and distribution
until a drug has been used on a large scale lor prolonged controls that would permit marketing of DMPA as a
penods of tunc. There is, therefore, a need to monitor the
safety .»! Depo-Provera on an ongoing basis, and the Special safe and effective drug on a limited basis. (There may
•'•rog.-a.ninc will continue to place high priority on such be patients in the United States for whom the benefits
research.”
of DMPA for conn aception outweigh the potential
risks. This population may be very small and may not
Subsequently, for NET-EN:"
warrant general marketing of DMPA for contra
“In ihc light of the findings in the niunkcv, beagle and rat ception.)
; he Panel ecommendcd that the cuneni and planned clinical
Pressure has also been generated by certain
• riah. .u norcthisicrone enaniaie should continue"
consumer and women’s groups. In particular, in the
V ■ :»thcless, since ilwn, consKlerable pressure has summer of 1980. an article entitled “Depo-Provera
heen mn on government offivials throughout the —a critical analysis” appeared in H'umen and Health
(2)' a jou’na,
by the National Women’s
'.nrld to ban the use of injectable contraceptives
parncuiarly DMPA. This is partly because neither Hcallh Nc,work
the USA. This largely inaccurate
DMPA nor NET-EN has been approved lor use as a arl,de was di^ributed world-wide, and the resulting
contraceptive in the USA. DMPA was reviewed by alarm has causcd sevcral governments to withdraw or
the Food and Drug Administration (FDA) in 1978/ con5lder withdrawing DMPA from both nationa*
• nd tithough approval was recommended by the fanii,y Panning programmes and private outlets, and
l-DA’s Obstetrics and Gynecology Advisory Commit- !?as made niany wonie» reluctant
reluctant to
to consider
consider the
the drug
drug
ice, a group of specialists who advise the FDA on for contraception.
Particular concern has also been expressed regard
technical matteis, the FDA did not grant approval for
us use as a contraceptive agent (/). Rather, a Public’ ing the potential for abuse by persons or agencies
Board of Inquiry, which has not yet met, was providing jnjectablc contraceptives, including their
administration without the woman’s consent or
convened to review the following issues:
knowledge. While the topic was not discussed in detail
- ■ Whether, in comparison with other drugs
at the meeting, it was acknowledged as an area that
ipproved for contraception, the benefits of DMP/X
should be addressed both by international agencies
outweigh its risks under conditions ol general marketand by the countries using the drugs.
mp in -.he United States of Arneiica. '
Thus, although there have been many reports
Whether data from beagle bitch and monkey
studies on DMPA submitted by the Upjohn Company recently on the safety and effectiveness of injectable
■ndica.-c .i potential risk of breast or endometrial contraceptives (3), there is still much confusion and
uncertainty. This Memorandum attempts to clarify
<ancer m human subjects.
the issues by Outlining the results ol recent research in
- Whether the data submitted by Upjohn from
studies in women can refute the risk of human cancer animals and human subjects, and summarizing the
current state of knowledge on injectable hormonal
suggested by fhe animal data.
contraceptives
- Whether approved useof DMPA for contracep
tion under general marketing conditions is lik-eiy to
• ncrcase use of the drug as a contraceptive under
Vonditions not stipulated in the approved labelling or
iNjfcl fAHLh PREPARATIONS
io mcic.ise its use for unrelated indications for which
AV Al LABI E FOR CONTRACEPTION
safety md effectiveness have not been established
S'/
,h<‘
injectable con irocenTive Deno
'otc-.. WHO unpublished document, 1978. pp. 1-7.
•
..j■ ,hf lonx-aaing injectable contraceptive norethi;
■
- 'n.ha/c (\ onstera, or Norigest,: un a^sment of recent
r
ir ■ 'iT™!/ Ivitn" ’ Tr'-
. ... .
dotl"
The only injectable contraceptive drugs currently
available are depot-medroxyprogesterone acetate and
norethisterone enantate. By October 1981, DMPA
had been approved for contraceptive use in 84
countries, and NET-EN in 40 countries. They are
201
1 Alli I ( < IN 1 H A« I »' tiV 1 ■■
. ,iv Kdes am! the incident o' IKO
^„s-re untUar in ah three groups,, and no deaths
... ht.i belong to diHcrcnt groups 01
could be attributed to the drug.
/^'<'s/-/-.A7-years.ud> of DMPA in beagle
aeetme nas
has ikvi
been; used
u-v. since
lieuKIC ........... - - .
A comr0l group of »<’
variciy ol conditions bilcjK.s was coinpleUi
.onmared with a group
the I95'b I...... ’'•■'"■'""'''threatened
... abortion,
..u..,.»,n prenre- biubes receiving no drug
p nan contracep{hc
mcludmr ''Rl"’nuru'r;„nt.l,;,|v. endometrial carcm- ot 4 receiving the cqmvakn t
V' ' Jet hreaM cancer, anti premature
onia, renal <.mu. .
b;iVC bccn
human dose. All inc g
uterus) within 31
labour; dose‘.-ol u|
■.(iveixcc’'cels. In the metra (an accumulation olf
lcs givcn any
years. >’yomc"“X''not develop inovariectomized
progestogen butI d
u, (hat estrogen has a
<
--a
106 ' sm'e'hen. an esnmated 10 mtllion women
SvS.Sw-i.lS”””-1”....
among women given DMI A.
d in aH bl|chcs
Mammary gland nodilies
for ? from
that lived beyond the ir•
nodules seen in the
—
the control group. The i <
•
r wbjjc those
.slctcj Iv. .mramusculat m tv
-lsco„lra.
controls tended to appeal e
high-dose
.nmr<.crv^,Utne suspensor
in the treated bitches, csptuaI y
.^..t ettetprumu
\ndometrium. the
group. uppcYCd. |C?ro|Cthe animal. Mammary gland
IXZHd-atKHheptodtKttontdtetv^lmuuts throughout the lilt
‘
(6 bigh-dosc
adenocarcinomas occurru
A j asl some
bitches and metastasized
the control
—”
DMPaJ"Administered^ as an
” f’c
J. '-cer-a!.......... . ^d hutenon.
^ontr.Kci .ist .<
±h may
ov" -
malignant, especially m fcs| o
colUraM, such a
'''''’’'‘''''Hn^mheen'^
liea'"’y *0'"C'’ ''"Ul ""d
reservoir has not i
shown no increased
among women who receive
.‘icclive in preventing preg-
inonths and every 60-84 days, .hc.ealier.
u».3,,i<.< However, admin-
from high levels c b
‘'“'"SXw'S
™»*“”d "»"h h"”“” '■
\NlMAl s I I'DO S
SO.du on the toxicology ol the two drugs have
x....
lon«-lcrn\USCed^n?hrsutceptibility of the beagle to
rSS
current
studies have been
t„ch meets twice yearly to review and
Rex icv. I’anvl, xvl.
sion was based on
_
I development of aero-
from those found m women (4).
,fl>rlkey su^es. A lO-year Mudy
regulatini
5-
mOnkey7aae:nXoup of monkeys who recetved
DMPA
studies. The lost toxicological studies m
animals vverecarried out1 on several hundred mice and
100 or 200 times the human dose
rats. Animals given I ■
spared with animals receiving no
cl DM PA were
Rodi■hi
I
fe-:■
-
-
-
»
v.
•
■
?<)?
Ml Moraniium
months of the study, there were 2 deaths in thecontrol
^r^eplaced'Viprotel^
each group dted during the study; an outbreak of
of the deaths, but many werl^rotablv'din. to'agmT
since lhe monkeys» were wild-caught and of indetcrminable age.
Autopsies Of the monkeys that dted spontaneously
hl d
hal Were sai;rilit':d during the study
n? ATh?'"’r nOdUleS' no"eof which was malig
nant. A though mammary nodules developed in
animals trom the control group and the low-dose
oXl\XX~
t,OU'KlU’;.."a,'l"lh'mCd*
Endometrial carcinomas were found in two of the
replacement monkeys in the high-dose group Endo
metrial carcinomas observed in women not receiving
I'm'"one treatment generally arise Iron, a hyper
pluMK endometrium, whereas the carcinomas in the
two monkeys were found in an atrophic endoH-irium. H appears ihai (he tumours in the monkeys
m
'ypvnoi found in women. Funhere^sX?^.
S USed in relH,ively high doses with
considerable success to treat some forms of endomeiital carcinoma in women.
Rodeni sfudiej,. As pan of routine toxicoloKical
Nl T LNCVCr|al hundred mice and rats were g^cn
' ' .'N ‘Ind examined at autopsy for any drue
the
A"h0Ugh lhere was '’0 difference hi
a
'he human dose
Although NET-EN has not been shown to cause dia
betes mellnus tn women, the development of the disof NET
OfJ-he animalS reteivin8[hc hi8l,er d°^
o/nct FN*'’1 S toh*"
ot NLT-EN indicates a need for further
olisrn
ET EN on carbohydrate metab-
Among the 20 beagles that dted spontaneously and
an additional 31 that were sacrificed at scheduled
intervals, all other findings at autopsy were typical of
h shm
ad,n'nislralio" o''any progestogen,
hv tt r d bc.rc'":raIcd ,ha' 'he beagle is considered
by the roxtcology Renew J*aw|
ai, Ulls„llilb|c
loxtcologtcal model for the study of progestogens.
fet^e‘rh"“- ? ,l)->ears'lldVH’xually mature
lent, k rhesus monkeys was also begun in 1975 In
add'"0'> to a control group of 24 monkeys who
and hieh'd U8’ 'hCrClow-dose’ medium-dose,
and high-dose
htgh-dose groups, each containing 24 animals
w
'ftictl received
wh'ch
received dosages
dosages of
of N
NET-EN equivalent to
those used in lhc beagle study
in During
^h'/''!,8 the
l,he|first
r'rS' 5 years
y'arS of
Of the
,be sl,,dy- ,T’ore monkeys
' control group died than in any of the treated
tn the
S grn0"31^;3^5
Similar in each of the
able m 8 T S’ ar nOne Of lhC dea,hs *ere a»nbutab e to effects of the drug. Since the monkeys were
d caught and of indeterminable age. many of the
agi*M$ iTd.r1’ a"ribu,cd ,0 P'e-existing disease or
nfnni'
add’hon lo ‘hese spontaneous deaths 31
monkeys were sacrificed at scheduled intervals
all nndin0'
end<’n’c|rial carcinoma in one monkey;
»■ e wasdrug-relaud increase in the inci“r '0,,nd
a ™'tkcy in the high-dose
rZp
w,.!
2'L'?c 'ungs. It did not resemble histo-
where rodents
mm r r’WS ^''“^"'C^^'^iitrode'i
-------- to this were
bcen rcporled
3“ g s. ■jx S“S±i
!'“effects
*rc fnr "?JTn°'
”°"g
ogestogenic
"!’.Pr^?.U>gen'“"
^Biventutreatmem
;
h
t
rt
„„,
£
r;x
“
Z
”
.S;
?
"t"
”
'™'
carcinoma in cxmsidcrably^hi
higher
were considered to have toxicological significance
d°SeS lhan ,hosc l,scd for contraception. Hosvev,
’h<H
i care,...
’,H>'4or
a
„a,
|nneon
.....in .....
.. ’.6c development
......-...of
neophsta rn monkeys and other animals given
I9n. wtth 4 groups of 24 animals: a control group
nft
whKh tecctved no drug, a group receiving the equiv
a em ot the human dose, a group receiving |o Xes
XX’«''-a"da8roupteceivmg 50 times the
A*
years, more bitches in :hc medium- and hiuharcHHA0 MAW*0 d'eJ‘han 1,1 lf’vcontrol and low-dose
XL
H<>wcver. the only deaths attributable to
-Heits of the drug were due to complications of nrn
A requested that insulin treatment be gXn ^o
" g'S C10^ 10 lhe human dose, and to continue
ma NET FN
P°SSible nc°P|asia m women recciv
•ng NET-EN or any other progestogen
( onc/HMOfis from animal siiahes
I he JFoxicology Review
Panel saw 110 ^^on io
nirrrT.
KVV,ew ranel
k
op«mon that DM Pa is safe for use in human
enama
m “ P,an”ed S!,,dies 01 "Prethisterone
tand ln ihi dxxass?' “
201
IN ;i < I AB1 I (ON I K AC'I I’HVl V
DMPA and Nb.T-EN the continuation
For both I
rates have been found 1 °/f5^1^ neM^^ at I
ent populations, ranging
.mc hod failures) have
year (13). Pregnant j 1)MpA__|essthan 1 pregbeen consistently low with
pregnancy
......
ever, daia .»c just bcsonti k
*
*x X^^“=XjZS,=»S“!
and studies are
p-'“; ■'
•
effects ol NE.T-EN.
........... -...........
was discontinued (13).
u rtf om me every 8
centre clinical trial tested a schedu'
mg
weeks for the first 4 mjecnons, andevery
»!“““ ‘"i
SX'
“■
XSStSX'Sy^fcfiBtSC 5
u.. . ■«“ '“o1*;
"currently
m ™PPorl'n..
™°.»
* ',C
[ p^ppines. Tunisia)
In contrast,
iclTvc st ci oid iKMCthj2!££SiOc
fTKTrTG'sT.KinulatcdasamicrocrystalL- c suspension
nd the medroxyprogesterone
>f known particle size and
mecroxy, _
a'Jt'ue (SW) released into the cireulat.on ts ..sell
biologically active.
The differences in foimujahoii art rellccted in the
(Bangladesh. India I aki.t,
P
NET-EN
for the further evaluation of DM! A ana i
•
-y
clinic
conditions.
family planning
■■'The most frequent reason for discontinuation of
quentiy
P
( ....( u { occurs in the majority of
■ :==«'¥;.. :
siSKtfjgg
•
'" <JdySo|Asi'l;t in the blood declines rapidly and is
IS ^^^eby^JQdays^rur^
liyor^HTrnpHidd-n^y K-«eetT^d^
.lavs (7) I evels of MPA decline me. e -osUv. and can
be measured throughout the -m ....
—It " ",SOmfliT<^'/0b Thue\s^X^ari-
at'o'n among *omcn°in the rate of metabolism ol the
amcnorrhoea. With
a
similar
discohlmuaiioni^atc
for
Die
b
wSSfaniww
>■■"
~feau:
rate..
'Binding problems
r
Se
a inhtb.t.on of ovular,on can ^achieved with
dX;'0f PMPA ot less than 150 mg - 'C, and WHOis
embarking on a use- effectiveness s c y
dose The more rapid
abd’>«
ovulated (II, 12 )•
,.wk
...
The maiority ol women who receive DMPA or
NET-EN experience some disruption °f
duration in which
days. Fewer than
EN W th approximately half of the users reporung a.
least one normal cycle during the first year (/< 75).
204
MEMORANDUM
Although there me no known adverse health effects
of either irregular bleeding (if not heavy or pro
longed) or amenorrhoca. unpredictable bleeding or
spotting can be inconvenient and of concern to (he
woman, and heavy or prolonged bleeding may lead to
depletion of iron stored
Severe bleeding is uncommo_n.among users of both
DMPA and NEPIEN^IcssthanJ m lOOd users_rcguire
dilatation anTcurettag£ f6Y^re,iirnent.(/6, 17). ry
A .
satisracfdry'^pfO^TrfbnHF'managenicnt of pro|
longed or heavy bleeding dug fo injeelahle contracep
tives has not yet been developed? Although estrogen
therapy has occasionally'been used to attempt to stop
heavy bleeding and to nnrmali/c irregular bleeding
Icsscflcct on HDL cholcslciul ihan do lhe twoollici
synthetic progestogens, levonorgestrel and noreth
isterone acetate (3/, 32).
..
Carbohydrate metabolism is also affected by syn
thetic progestogens. DMPA has been shown by some
workers to raise fasting blood glucose and ,nsu,,n
levels and to cause an increased response of both
glucose and insulin to a glucose load in comparison
with pre-treatincni levels (33, 34). Several other
studies, however, have failed to show these changes
(Js - 37). There is also little evidence of substanuve
changes in carbohydrate metabolism after NLT-L.N
administration (25. 38) (K. Fotherby, personal com
munication. 1W).
|
Although iHlicnal MippusMOit has been observed
uscfulmHtfc treaty bleeding problems associated
the treatment of cance ( )) or precocious puberty
(40), adrenal insufficiency has not been reported
with piogeMOgen-only contraception.
iB during contraceptive usage. One study, in which the
Little is known about the basic mechanisms of
bleedmg disturbances, especially those related to£ two steroids were compared at contraceptive dosages,
showed no change in the circadian rhythm of plasma
steroidal comraccption (/9)< Neither the blood level
cortisol or in its reponse to synthetic ACTH with
of the progestogen nor the endometrial morphology
either preparation (41). These findings have recently
appear to be related ip the bleeding patterns. Further
been confirmed for DMPA; although some sup
study of bleeding mechanisms, on a cellular and
molecular level, is necessary in order to develop effec pression of circulating levels of cortisol was observed,
there was no change in circadian rhythm or in the
tive approaches to the prevention and management of
functional capacity of the adrenal glands (42, 43).
bleeding disturbances and amenorrhoca,*
Most investigators have found little or no effect of
DMPA or NET-LN on liver funciipnU2.35.44 45),
MciuIhiHc effci i\
but the cvidctice from the various studies is conflict
Oral hormonal contraceptives have been associated ing. In one study. DMPA produced no significant
with a variety of metabolic effects
as evidenced by change in aspartate aminotransferase, alkaline phos•bilirubin,
••• »-— or bromochanges in coagulation and fibrinolytic factors, plate- phatase, lactic dehydrogenase,
while
another
let function,
». k(BSP)
™; retention (45), '*'
v"
funetion. carbohydrate and lipid metabolism, and sulphthalein
liver, tcnal, and thyroid function. In most instances sludy
showed
some
increase
m the in^m^raZ
a,T]‘un0’ra^,^iJ'es
(idYaniTa
third
found
no change
these effects have been considered to be a conse
fcrases but increased BSP retention (24). It appears
quence of the estrogen component. This has been
that hepatic function is not adversely affected ^ihe
borne out by observations that DMPA has little or no
two injectable contraceptives, and in fact^ primary
effect, on these functions (2,0 - 24) except in the case
of carbohydrate and lipid metabolism. Fewer data- biliary cirrhosis and chronic active hepatitis have been
shown to respond' to therapy withpimp
DMPA
(47). . More
cfkcuxd nora <d7\
ore-
have been published on the me|abQlic
metabolic cfkcLS-of
over. in subjects with an active parasitic infestation
ethisterone enantate but it appears not to affecupost
with the liver fluke (Opislhorchis viverrini), DMPA
biocheirncajLfjmim (2372oj7
(BT^T ~
Voncern has recently been expressed regarding lhe does not give rise to any deleterious eflects on liver
effect of progestogens on lipid metabolism and trans function (48).
port (2'7, 28). AH ctirrchily used synthetic proges
togens decrease circulating jew Is of _hjg_hj.de n bit y
lipoprotein (HDL) cholesterp], which is one of .the
As already mentioned, results from animal studies
few metabolic changes that can be linked, to.an
have
raised concern regarding the possible carcino
increase iTTTfi’e incidence and sever it y_o(_£aidiovasc. lar disease,’particularly i^ hacmic heart disease genic effects of DMPA. However, the beagle studies
(29). Both published and unpublished data (30) suffered from two major problems; the species is not
(M. H. Briggs and K. Fotherbs, personal communi an appropriate animal model, and massive doses, Up
to 200 limes the human dose, were used. THisnas led
cations, 1981) indicate that_boih DMPA and NETto the conclusion that the findings in these animals are
EN lead to a dccre^ie_jn_HpL-cholesterol. However,
DMPA. given al the higher dosages used in post not applicable to women. Although epidemiological
studies in women receiving DMPA have thus far
menopausal replacement therapy, has considerably
I
•I
IN JI ( I AHI I CONTRACI I'll VIS
(A
(
• . <;<•
lumonstrated no increase in the risx of developing
ar.v type of cancer, a WHO Scientific Group con
vened in I97"7 to review nepplasia anc steroid contrai / on concluded that •‘that arc uo adequate data
»Tom ‘Jbdiex in women to assess whether proges.ogehs e^d as contraceptives in the form of proges
togen-only pilh or as injections have Any effect on the
nsk of neoplasia4’ (<9)
At least five studies in human sub;et(s have exam
ined the rel.itionship be ween DMPA and~breast
cancer (50)' In the two studies that included a com
parison group of women who did not receive the drug,
ihere was no evidence of an increase in breast cancer
imong womqii using DMPA.
Studies conducted to examine the risk of cervical
coplasia among DMPA users have suffered from a
.iiicty of tnchodological problems: however, they
.re not demonstrated an increased risk of invasive
ficinoma ol the ccrsi.s (49). In mans countries,
v hiding tin ; SA. endometrial carcinoma is one of
few indie; : ions for which DMPZ is approved for
Howevei, because of the findmgs in monkey
indies, a studs was conducted in Clu ing Mai, Thai.md, in which women admitted to the hospital for
idometrial carcinoma were questioned regarding
i .evious DMPA use. Although 16 of the 27 women
ame from areas where DMPA wa's wic ely used, none
reported previous use of DMPA (51). Two series of
•ndometrial biopsies among women who had used
DMPA lor at least 3 years failed to rev cal any malig.'.mcy (52, 53 ).
.
of ,k
the" lack ''f
of wch controlled
However, because cf
mt fyeriod
iwrind of some cancers, it is
trials and the long~ latent
important to c_
'
‘
‘ ,possible
;
continue
to monitor
the
devclopment of neoplasms
women who
•Anincmc among whmm
^hn have used
DMPA or NET-EN. especially those who used them
many years ago. Therefore, WH>. .is.-xuMewtly
inducting a muliination»rca.w^nH<MjiOldX-lo
"nminc ^he. re.latjon^OfiwKn steroid contra-
205
>
permanent infemlity (54. 55) As yet. on'., one study
has examined the return of ftrCiHty following discon
tinuation of NET-E.N (55), Although (he results of
this study are difficult to interpret, il showed that of
55 women who were followed for 6 months after dis
continuing NET-EN, and not using any other contraceptive method, 14 became pregnane
In utero exposure. No studies have systematically
followed the health and development of a large
number of infants exposed in utero to DMPA or
NET-EN as a result of contraceptive failure or the
inadvertent initiation of contraception in a woman
with undiagnosed pregnancy. Because this form of
contraceptive exposure is infrequent and me potenti
ally hazardous outcomes, such as congenital abnor
malities, are uncommon, it is difficult to identify a
sufficiently large sample of infants for proper inves
tigation. Most information on the effects of proges
togen.s on fetal development and infant health is
derived from studies of oral contraceptive failures or
of progestogens used as hormonal pregnancy tests or
as treatment for threatened abortion and premature
labour. These studies have major methodological
problems and can only, at best, provide indirect
evidence on in utero exposure associated with longacting injectable contraceptives. There have been 3
reported cases of chloral enlargement among
daughters of women who received MPA during the
first trimcslcr (j7).
A |arge numbcr ol studics have been extensively
reviewed and the results appear to be inconsistent
^7-59). However, it is clear that any teratogenic
hazard associated with in utero exposure to progestogens is smalL and the more reliable in vest igat ions
v risk or an approximately, .2-foki
..
suggest either ..no
increi?e~iH~ttie~risk oTsome ibnonnal^I tyeb.
urcinoma-oT
flic breast. cervix,
ovary,
....
.^rviv .minnirtrm.n
nvarv, endornefrium.
CQim?g5rfvc
’and'^non-contraccptivc jSDQMxres.
tnd hepatobiliary system.
. ThtiCsmce' pregna nciefwit h long-acting injectables
] arc uncommon, the disorders infrequent and any
. potential teratogenic risk small, this is not l.kely to be
a major public health problem. Moreover, if proper
following cessation of DMPA administration,
precautions are observed and drug treatment is
MPA appears io remain in the circulation and to I initiated during the first five days of the menstrual
lehibn ovul.Hion for several months. A large study Icyclc or before the return of postpartum fertility,
conducted m I h.iiland showed that ‘.omen discon- Inadvertent exposures of pregnant women and
. 'iiiiiH its
had a median delay ol 5.5 months knethod failures should be rare.
’ . lore hvco’i
pregnant flic delay aus somewhat
Exposure of breast-fed infants. DMPA does not
ass lor bor H'l) and oral contracup ’•-c users (4.5
and 3.5 months, respectively;. However, after two appear to have any deleterious effects on the quantity
\uars, more than 90°/c of previous DMPA users had or nutritive value of breast milk. In fact, some studics
become pregnant, and no significant di!ferences were ■have suggested an increase in the quantity of breast
observed in comparison with IUD or oral contracep milk with use of DMPA (58), and a well controlled
study currently being conducted by WHO has inditive users, suggesting (hat DMPA does not cause
i
?l)6
Ml Morandum
Hiat there is no decease in volume of breast
Medroxyprogesterone acetate (MPA) is present in
hreas milk m approximately the same concentration
, 7.7 /Ig/ihre,
■ ,
• decreasing to u
Hg/Iii
rc al
a. 8X
"i.ndy
0.8o M
g/|ilrc
\Vi’«’Lc
•»«/! ■>• ..t.ll ................
> ■
. .
' "
Z^nal1i,2?lT,SUr?b,eJ^
**•
»*
unlikely (o give rise io adverse effects on the child’s
devclopmein (69).
Injectable comracepHves —both DMPA and NETl N ol I er ses eral advantages as a method of contraccP!,on- and I»‘‘VC been shown in a number of clinical
g|ve_a»r£^.i.L»ate of total exposure ol thf’mf^r
apPi^fflBteWWof the maternal dos™ ofDMPA
.KXCl./.nh
,n
picgmincy and
h?1
’ C"■"1> uo,lu;l1- Although animal data
X' r?
c?'^er" abuu' "’e safety and long.1£tm
o.er the 1-month mjcqion interval and 0.05% of ,|1P
N£iI-JN oyeM^J^^
“'V’L l>S,PA and Nt-r-EN. certain animal
X ror't‘V "“r u'^J*2LJ!OUpS^
£f Ih*** •steroids,
no lifc-thre.itemng sidc-cffe< K
side^fied .s (he d.sjurbance of
nx ng characteristics of these three steroids to progrst.tone receptors and circulating binding proteins
ate quite dillereitt but it,is unlikely that jh>- small
a,!12UW^|2^rbed_!^r^17a^lentiai7inrm!ihe
s?-^
ld bc no'ed 'hal ,he Quantity of
steroid received by the infant is considerably less than
«
O|f.eSlrOgen 10 which children bottle-fed
UXSSSKSSfcBSK•'I
Since there ls no informatmn on the possible effects
I h.rrrTnXninO"hn’a,Ura,'OnOfhyP°’halaniicand
wI^‘h occurs in the majorii>
nrima'”" US,"» injc‘;lab^ contraception, and is the
„ . ,
~ - ------- •'* contraception, and is the
p
P in ary reason
rea“n for its discontinuation.
"
■■■
Women fre
quently report irregular bleeding, spotting and
uXmom8' bU'
0' Pr°l0n8ed bleed'"« is
Studies thus far have not shown any serious short
or long-term effects ol DMPA or NET-EN How
ever both DMPA and NET-EN have been usedior a
iffer,VC/y Sh°rl "me’ a"d Ihe Polc"l>al long-term
With °Ver ,,|H'fC ’,an 15 >ears> ar,: not yel knowncomin . m? l'1’
e'lccts. research should
u X >
■
*S a"d Pb^OBical consequemes
|01,g.Ierin use of DMpA and N£
arbohydrate and hpid metabolism. In addition
t'"'I “•'“ is '"-eded regarding the long term
NEkEnSi'v a",0SJf Won«:n usil>« DMPA or
I "’S j-:;'=”' -.TS; "n”
I mended (hat infants should „o, u.,
b
? rctom-
">ent of infants who ar,-
I
1‘<- on i(.productive development ■ (65), children
rixbed to MPA Via breast milk have not yet been
- owed through puberty. A recent review of (he
e d'"‘‘ bas su88cs<ed that (he small amount o|
"‘I mgested by the infant through breast milk ,s
v
is
'
I
C'!tfc,s ,han
found with other hormonal
^f DMPa^'"''!''^01’"0'1' Tbe articular advantages
°slm
r" NKT EN 8S hlshl* effective, longmnmf, u" 'CVC[s'bll‘ contraceptives make them
IcI^ity ^.lamm"'dC'iri"S “ ,"C'l,od
>
'N 0 ’ I AHI I I ONI K,\( I HI IVi s
207
■\nia a /
■.
(
'>11)1 RM IONS iOR ADMINISTERING DMPA OR NET-EN AS A CONTRACEPTIVE
Each Ionian, preterably with h- partner, should
<•'. j!ii<-o:,,d oi the various conn eptivc methods
<oa larr.
(hc ,i>ks and bvnefus of each method
snouid !\ clearly explained. I he final choice of
method yhould be hers. Both DMPA and NET-EN
arc effective methods of contraception and if she
should choose either of these, the common sidc11 frets should be explained to her. These are:
trrv.ilar
Pfolrtngvd
bleeding
and
spoiimp.
I
. ' c.imon sidc-ellects include headache and
g.m,
••• '.i.i’h:
u < '•ju. ■
.
'•Mlh pifin’ems that i epivs'.nt coniraindicilhe' DMPA or M: I i N should be
■nc'liftls o| voniraceplion. Women in
f'-il present special problems loi ihe use
HMR - or NE I-EN should
T counsel from
’' .i.'l'Cd !))■
■ii' al personnel.
; o.licalioBs lor use are .is odious;
'•'ItJd’hH
• am
'uin;•
i |! ( ,||lK
oeatment
for
und.' •nosed abnormal uterine bleeding
suspe. ted prey nancy
'special problems that requirc medical assistance
•Hid ads in.' from a physician
or other trained
medical supervisor areas follows:
abnormal liver function or
iccuil hiMory ol
loci discus,
■ histors or evidence of cardios u-cular disease
dial < :
mellitus or history o!
eestational dia-
<
•U"
c: 40 scars
women who wish to have children at a later time might
be advised to use other methods.
The woman should be given her first injection of
DMPA or NET-EN within the first 5 days of menses,
’IYUlLlcuii ayeek s post-pa rt u m.
At the time of each injection, the woman should be
asked about medical problems occurring since the lasr
injection. Women with heavy or prolonged bleeding
should be evaluated for anaemia and for other patho
logical causes of bleeding, and should receive the
tit the breast or an und-agnosed breast
•’ll -1 filial cancels (except
‘Hilt i|t1C|
As subsequent fertility has not been studied follow
ing the use of either DMPA or NET-EN, nulliparous
to ensure that she is not pregnant when r ceiving the
drug, and to maximize the contraceptive efficacy
during the first month. Subsequent injections of
DMPA (150 mg) should be given at 3-monthly inter
vals. NETEN should be administered in 2(K) mg
doses at S-weekly intervals for the first p months ol
use, then at intervals ol between 8 and 12 weeks. A
slightly lower pregnancy rale has been observed with
8-weekly intervals, but this is accompanied by a
slightly higher rate of discontinuation because ol
bleeding abnormalities.
Women who do not propose to breast-feed their
infant can receive either DMPA or NET-EN immedi
ately post-partum. whereas women who are breast
feeding should not receive either of these con(racep-
sometimes
arn-.n irrhoca
dH.o m becoming preynam
ter discontmui>MP \ <d approximately h mon'hs aftei the last
"
— congenital hyperlipidaemia
appropriate
therapy.
Women with
prolonged
amenorrhoca, especially during the first year of use.
should be tested lor possible pregnancy.
Ideally, annual pelvic and breast examinations
should be undertaken. A woman who develops any of
the contraindications listed above should not t c given
further injections of DMPAt or NIH I N, but another
method of non-hormonal <
contraception should be
offered.
More detailed guidelines lor the use of DMPA and
NET-EN, including recommended treat mem for sideeffects, have been published b\ WHO (66).
I IS I Ol PAR IK IRAN IS
•’<
Heakin luuursus. Belnioi:!. Victoria.
\u'!. .Hi
Rt'f ! \ .
pit |l \|;
‘’C-anmem ol Pathologv. London Hos
d ( ollc.ee. I ondoii. I nj’l.ind
I.. Dixon. I aboratorv oi Rep oductivc and Devel
opmental Toxicology. National Institute of En
vironmental Health Soenecs. Research frianglc
Park, NC. USA
b
I. E. Jirasek, Institute lor Care of Mother and Child
Pragiie-Podoli. (Vcchoslos.ikia
M -Ur— -
20N
Ml MnRANDUM
A. ( oxia c I tun, Endocrinolop
if e Diabetes, l oriaRva. Ceara. Bia/il
Schering AG. Beilin (West)
M|(
G. Schuppler, Dcp.inniciii ol I
h‘
nvpi,rh'ncnl ot Bhannacology.
\pcninciif;il lo\j.
cology
B Miihe, Depart mem ol I ndocnnolopv
I.achnii-l i\M>n. Department ol (. linicul I ndocn nolog y
I acuity ol Medicine, University of Singapore
Singapore
G- lyncro'e, Department of Biochemistry, University
ol Ibadan, Ibadan, Nigeria
M. ten Ham, College Ter Beoordcling
van Gcnecsmiddelen HV Rijswijk (ZH). Nethelhinds
It. Kloss. Apariado 18, Merida. Venezuela
K
von Ftckdedl. Bundesgc.tmdbeitsami
Berlin
< V\ cm )
Representatives oj the Si centiff Comminee of the
HO /ask / uree
on LonfrActmx Aherns for
lertihiv RckuIuiuhi and other invited experts
1 .,?1,1"':,'U'5'-1Kcr’ro‘1''<-'‘« P-ndocrfnology Research
Umt. Karoluiska Institute. SisKkholm, Sweden
(C hairman)
Suporn Koetsawang, Family Planning Research
Kepreseniutive.s of dru^ reKitlaiory authorities
I* Gupi.i, Drug Condolki’s
Ollicc (India),
Diiecioratc Cieneral ol Heahh Services, Nirnian
, Hhavan, New Delhi, India
I-.. I.ypez Amor, Dircccion Cieneral de Conirol de
de Control de
A Iinenios Hebidas y Mcdiainenios, Secrctaria de
S.ilubndad y Asisicncia. Mexico
K. Strandbcrg. Department ol Drugs National
A
!lea"h and Wdl:,ri-- Upp^uku Sweden
■ikdee I oihisin. Food and Drug Administration
Mtmstry of Public Heahh, Bangkok, Thailand
’
R. Corcoran. Department of Health and Social
Security, London, UK
«• <
Bennett, Division of Metabolism and Endo
vrine Drug Products. Bureau of Drugs Food
and Drug Administration. Rockville MD USA
l)"it. I epanment ol ObvlretricvandGynaecology
Sinraj Hospital. Bangkok, Thailand
K. Foiherby. Department of Steroid Biochemistry
Royal Postgraduate Medical School. Hammersmith Hospital. London. England
R Gray Department of Population Dynamics
Puh'| S I I°P| T 1l,J,,"VCrM'y- Sch001 ol Hygiene and
ygicne and
public Heahh, Baltimore, MD USA
s. Fraser. Department of Obstetrics and Gynaeco-
W«Ua'°l SydnCy- Sydney- New Soulh
wales, Australia
B. N. Saxena. -Deputy
Director
General,
Indian
Srh?CIndiaMed,Ca' RCSearCh’ AnSari Nagar’ Ncw
M Toppozada Department olObstetrics and GynaeM«EV'|Sh:,'si M;,lc,nil>' Hospital. University of
Ak.xandria, Alexandria, Egypt
lr</m lhl.
j
I lie Upjohn Cpmp.my, Kaiatnu/oo. Michigan USA^
I* //() Sei retat tul
I-. Hall. Sciem 1st, Special Programme of Research
<;.W. Duncan, Scigntiik l.iaison Unh
I (
l eriihty Research Un,i
K. G, < arisen, Toxicology Unit
J. R^. Assenzo, Bios(a(i5lic5 and hl|orlll;1|jon ScieiK.e
in Human Reproduction (Secretarv)
S'k'"'!*:hMcd;cal Or[icer- Sl*™l Programme ol
Research m Human Reproduction
Resch' MNdiCal °fl‘Cer’ Spetial Programme ol
Research in Human Reproduction
KF-I I RI-NCES
I. <
,mem ..f the itniicd Stale.
'I America, I'l’derul
/•.
Waoimgio,,. |)< |.)7S p|. ,s
2K 556.
‘
’"'' a7 V""’'P"'vtr'r
danuF.,.
u 1
69(l9X(n
I''
I. S. UViAiOb, I..
■ "i:pi\ l.t. nsix c rc\ K.u
• let.fable ■ tinr,iei'pii,H| Wu|
fc.i.il emphasis tin
'vj i i iicJiv-wpiogcsicroiie
"
* Iran a! louruul
d \uorulm, | (|) ..upp| I|
I >(I9X|)
roue s|0!!CHs .(Dll 11111111 ij | \ ItlJIHHII S III
4
'
M H II ’rogcMoce
the beagle bit h Research m
2lf
IW 202(19X01
5 I’l hi / |» \| AC !(» . <». I I Al
On the ii.ccli.iiii',11) ol UCIlOli
<»l piOitCMitls
l( Kt vndtH'rinoltnf i\ a, 97:
120 UH
(I9X|)
6. hit III Rin. K. f ;K|
7
oik aliccnni! (he duiaiion ol action
ol
the injectable
Cnntr..
,■
i conn.i
,
*,ccl’ii'e mHclhiMeronccnaiiiaie.
sCv
i 7 «■"
■■
HWD
'
! 1 Xl Dh.nniacokincites ot norcilu
......... ..................
X. Klklox', K I (5. ( nKM J |( J c
Return ol <nul;itoi v
cyclicity rolkuviim .m
1 "inamiiscul.ir injection (>i
mcdrocypt ugcsieronc ;
acetate. Conlraccinion, |i)
19 45 (1974)
VA'.h i' " '' Sv,
‘
""
'A «>''eenuamlns ,uul
Scrum MI
MPA
i)cm P r"
i "’"""'"ir iniranmwular injectio,, u|
Xp< I rovera. Journal .,/ <■/„„<.„/
,m/
nietalKthsiu, 44: 12 IX
IK (1977)
(1977)
209
|NJI <
•
table CONTRACEPTIVES
10
Fothirhv.K .El Al Apharntacokinviicsiudy of differ
ent doses of Depo-Provera. Coniracepaon. 1
!!
1K et al. A preliminary phannacokmdic
and plnrmacodvnamic evaluation of depot medroxyX-"ne acetate and norcthisierone enantate.
•■endo .- ;md sterility. 34: 131 - 139 (I >8().
Btnm.. snu. G. ft At Return of osanan ^ncl,on^d
e^ontctrtal^rp^yinw^.r.^d^n-
•2
OA CAirtr F M A A»i>-Ei.-Ha.. M. M. Liver function
24 ^^.htuseofiong^rngp^—eontraceptives. Con^pnon
”
6; 409-
fttuse-js
^urnul of obsidnes and ^naecology. 84. 618
26. & MaHGOUB. S. & Kakim, M. The
norethisterone oenamhaic as a contracepli
621
.
27 E.^^^^vesintech^ntsinthrontb.
Hv. 34 456-460 (1980).
WHO Expanded Programme of Research. Devel p13. meni and Research Training in Human Rcr,r^d“cn _
Muliin.itional comparative clinical evaluation o
long acting,injectable contracepuys steroids: norelhimedroxyprt evsteronc acetate.
'stcrom enantate and
m«.»
Contraception. IS- 513 — 533
1. Use-effectiveness.
(19-71.
14 WHO Special Pi.•gramme of Research Dcvclopmeni
and R< carchTraimngin Human Reproduction. Multi
national comparai..c clinical trial of long-acting mjec able contraceptives: norethisterone enantate and depo medroxyprogesterone acetate. A preliminary report.
28 ^"’B.To'n'coi^
d^ase
612-618.672-677 (1981).
29 Miller N. E. et ai Relation of angiographicalh
29' denned’eoronary artery disease to phsrnahp=
Hr ifish medKill
subfractions and apolipoproteins llnnih
,0 ^TE^'sel-h'-nsi.yhpoprotemcho).
esterol levels in women using a contraceptive injection
Of depot-medroxyprogesierone acetate. Contraceplion.
22:359-367 (>980).
Lipid n)Clabolic studlc.
Sii.verstoi.pe. G. e. M Lipid n.e.aoonc »«.«> .»
oopho.ec.on.aed women. Effects of three different
progestogen*. Ada obsleincia cl gynecolonica Scan-
Contraception. 25: 1- 11(1982).
WHO Special Programme of Research. Devclopmem and Research Training in Human Reproduction^
Muhmafional comparative clinical evaluation of two
long-acting injectable contraceptive steroids noretbtsierone enantate and medroxyprogesterone acetate.
2. Bleeding patterns and side effects. Contraception.
31
17:395-407 (1978).
.
16. Parvfen. L. et Al Injectable contraception medroxy
progesterone acetate) in rural Bangladesh. Lancet, 2.
33
(
946-948(1977).
Present management oi abnormal
17. KOEfSAWANC., S
bleedmg associated with steroid contraceptives. In:
Diwfalusv. L et al., ed.. Knd.m.ctnal bleeding and
steroidal contraception.
Bath.
Pitman.
1980.
IX
23
no S() 64.
.
MOHH.
N. R. A. Grunsean. A.
evovennu^ estrogen at the (oady 'demnruil famil)
Planning Clime. Kalamazoo. USA. Epiohn < ompany.
li
1980. pp. I
I7 (Technical report).
iHAs’i-. i S A
\l css
i:ss.. II
A p’-ispccuve ol
A Dic.'i
r>i< .'I Al
..•io« !.«' contraieption
v viiira- < ption and
and abimri
abnori ■>> bleedmg: whal
Dic/laluKy. I*
; . >spr is for improvement ’ •I
3|
. /■ tidoi' Ciriai bleeding a> iteroidid contraccptif’ . Bath. Piiman, 1980. pp 3k4 4i'9
A s 11. , B. t < ai jI ibrinolytic
— acti'-is ol 'tins during
UM- 0! depot-medroxyprogesterone icctate as a contra■; 492 (1971).
ccpto Fcrtiluv and sterility. 23 4XM
el feci ol an injectable proWin. - ai, K. A i ,. ai
.. The
•
....... r ise on blood coagulation and fibringcsiocvv Iti xOlHl.Kk
Hnii'.h piuinalo] obstelncs and gynaecology.^
dlssi >
X(k> x )9 U979)
,A < K A
M 1 XL H. I •. I
I ocr function
Niudn- and prcvoiogcu conttacepiiofi. lertility and
McriliH . 19 172 185 (I96K)
iLHkiM.toN. V W. it al Effect ot a long-acting ster
oid cont racepl is c (medroxyprogesterone acetate).
New England journal of medicine. 305
dinavica. Suppl. 88: 89 - 95 (1979).
Hirvoran, E Et al Effects of different progestogens
on lipoproteins during post-menopausal rcP,accnJ!"1.
therapy. New England journal of medicine. 304.
32
Sp^llacV W. N. et al. The effects of medroxyproges-
’ terone acetate on carbohydrate metabolism: Measurenrent of glucose, insulin and growth hormone af.et
twelve months' use. /eM./.r.' andstenlity. 13 239-244
34. v'Seien. A. & Thierv. M. normona! contraeep-
lives and carbohydrate tolerance. II. influence of
medroxyprogesterone ’cetate and chrome or«. contraceplives. Diahetalogia. 10: 253 - 259 (1976).
3< AmaiavaKUI . K. Oral contraceptives and ’’uinbon
The effects of Depo-Provcra on carbohydrate lipids and
Barnin metabolL. Journal of deroid hiochenustry.
11:475 481(1979).
ai A study ol glucose tolerance,
Tankeyoun. M. Lt
and lipids in women using depotstrurn iiansamina.se
medroxyprogesterone acetate and a combination-type
Contraception. 14: 119-214
oral cont i accpt ivr.
(1976).
Bick P 1 1 ai Ll
Lileci
leei of contraceptive steroids on
37
arginine-stimulatcd glucagon and insulin secretion m
women III Medroxyprogesterone acetate. Meta»
36
oltstn. 26: 1193 - 1198 (1977).
IJIIAII.. K. l l AI Shon-ierm cffwis ol norcthislcronc
' enamau- and medroxyp.ogesierone acciale on glucost
insulin, growth hormone and lipids. Ferlillly onii sler
39
My 2» 156 158 (1977).
Heli man. 1.. 1T ai fhe effect of medroxyprogesieu.ne
aceiaie on the piiuhary-adrenal axis. J°ur^ °{c^a
endocrinology and metabolism. 42: 912-917 (1976).
Clinical chemistry. 17: 667 (1971).
■
■
. .......... -
w
...
...y.
'-.WK-.-
*
210
MEMORANDUM
.'4
haisom.. T. i i aj Return of fenda> alter div
$4
40. Saim-Gih Ntjad, A t T ai I hc effect of mcdroxyprocontinuation of depoi-ntcdroxyprogcMerone acetate
gestcrone acetale on adrenocortical function tn children
and inira-uicrincdevices in Northern Thailand. Lance!<
with precocious puberty Journal of pediatrics, 7g;
616 624 (1971).
1:509 51! (IMO).
41 HoRowxkt, R. fj ai . Influence of depot-progestogens
55. Pardiiiaimini,, T. & Ghas, R. H. The return of
on anterior pituitary and adrenocortical hormones.
fertility
following
discontinuation
of
oral
Ada endocrinologica,
(suppl. 215): 98 (1978).
coni racepl ncs in Thailand. Icrtility and sterility. 35:
?32- 534 (I9KJ).
42. Ahx», A. R tr At. Studies on ovarian and adrenal
steroids at different phases of the menstrual cycle. Ill
56. Kesm kii-K<m»s, I., i t \i Fertility control with norethisSteroid and hjiroptn levels before and after the adminis
teronc enaniatc, a long acting parenteral progestogen.
tration of a single contraceptive dose of depot-medroxy.'Ic/t/ Eitropaea fenilitatis. 4: 203 -- 221 (1973).
progesterone acetate (DMPA). Contraception. 24:
57. Schardfin, L. Congenital abnormalities and hormones
117 -135 (1981).
during pregnancy: A clinical review. Teratology, 22:
43. Aedo, A. R. et-ai. Studies on ovarian and adrenal ster
251- 270(19X0).
oids at different phases of the menstrual cycle. IV. The
58. WHO Technical Report Series, No. 657, 1981 (The
iffcci ol dexamethasone suppression and subsequent.
effect oj female sex hormones onfetal development and
ACTH stimulation at different phases of the menstrual
infant health: report of a WHO Scientific Group).
cycle and following the administration of 150 mg of
59. Gray. R. H. Progestins in therapy: risks of teratodepot-medroxyprogesterone acetate (DMPA). Contra
gencsis. In: Proceedings ofan International Symposium
ception, 24: 543 558 (1981)
on Progestins in Therapy. University of Chieti. Italy.
-14
Bi Ki.sTEix. N. A. M. A. M1 •-’I Zt st-na\R. II. l iver
(In press).
Gtociicti dci /ock hij viouwv 1 mei incdroxyprogcstcron
60. Saxi na, B. N. t t At Levels of contraceptive steroids in
ci.iai l:0mg (Depot-Pros via). Gcnceskundige gids
breast milk and plasma of lactating women. Contra
.New set a s). 8: 289- 291 (I’ -TO).
ception. 16: 605 - 613 (1977).
4.« Amai as aki'i . K tt st Fleets of medroxyproges61. Commentary on Dcpo-Provera. Kalamazoo. Upjohn
.crone acetate on scrum lipids, protein, glucose
Company. 1980 pp. I - 55. (Submitted to the US House
tolerance and liver function in Thai women. Contracepof Representatives Subcommittee on International
^.i-inn, 21: ?83 297 f 1980).
Economic Policy and Trade).
46 \.)i i hi Kt i I/, H. <V Tt shim x. R. Some aspects of the i62. Mtl is, G. B. i t At Norcthistcrone cnantaic as an injec
micraction between natural and synthetic female sex .
table contraceptive in puerperal and non-pucrperal
hormones and the liver. American journal of medicine.
women. Contraception, 23: 77 - 88 (1981).
49: 630-648 (1970).
63. Karim, M. ei ai Injected progestogen and lactation.
47. SoTaniemi. E A. n ai Effects of medroxyproges
British medical journal, 1: 200 - 203 (1971).
terone on ihe liver function and drug metabolism of
64. Huber, D. A. t tai Oral and injectable contraceptives:
patients with primary biliary cirrhosis and chronic
Effects on breast milk and child growth in Bangladesh.
active hepatitis. Journal oj medicine, 9: 117-128
In: Zatuchni. G. et al., ed.. Research frontiers in
(1978).
fertility regulation, Hagerstown, Harper Rowe, 1980,
48. Grossman, R A. tj ai. Effects of the injectable
pp. 127- 135.
contraceptive depot-medroxyprogesterone acetate in
65. Satayasuit, N. tt ai The effccl of medroxy
Thai women with liver fluke infestation: final results.
progesterone acetate, administered to the lactating rat,
Bulletin of the World Health Organization, 57:
on the subsequent growth, maturation, and reproduc
829- 837 (1979).
tive function of the litter. Journal of reproduction and
49. WHO Technical Report Series. No. 619, 1978 (Steroid
fertility. 46: 411 - 412(1976).
contraception and the risk of neoplasia: report of a
66. Injectable hormonal contraceptives: technical and
WHO Scientific Group).
safety aspects. Geneva, World Health Organization.
50. Greenspan, A. R. etai . The association of depot-med1982 (Offset Publication, No 65).
roxyprogesterone acetate and breast cancer. Contracep 67. Cameron. A. M. & Faui kin. L. J. Hyperplastic and
tion. 21: 563 - 569 (1980).
inflammatory nodules in the canine mammary gland.
51. Me Dank i . L. B Endometrial carcinoma survey in
Journal of the National Cancer Institute, 47:
1 ha.land. IPPF medical bulletin, 13: 3 (1979).
1277 - 1287 (|97|).
'2 Pi ns-Dek.six), J. tr ai Uso prolongado del acclato 68. Koetsawang, S. i t ai Transfer of contraceptive
jc rnedroxiprogestcrona cm la anticonccpcion. Semana
steroids in milk of women using long-acting gestagens.
medico de Mexico, 98 331 - 350 (1981).
Contraception, (in press) (1982).
53 t i i<vantes. A. ET ai Effect of medroxyprogesterone
69. Sc kwai t n . P. C. The effect of depot-medroxyacet ate on human endometrium after five or more vears
progesterone acetate on the fetus and nursing infant.
ice as a contraceptive. Kalamazoo, USA. Upjohn
Contraception, 23: 375 - 386 (1981).
Company. 1981, pp I - 23 (Technical report).
I
ii
I
I:
i
I
■............................. •
...
'J';/:"
...
. ..-’ry:-uj'‘
. ..
.
4/?./'i//(/'z£j< (Jf< L
4
1
J
i
THE VARIABILITY OF MENSTRUAL RHYTHM AND
CHARACTER
By Samuel H. Geist, A.B., M.L)., F.A.C.S., New York, N. Y.
\.
IT HAS been more or less accepted that the normal menstrual rhythm
1 is a monthly cyylc with verj’ little variation in time interval, dila
tion, and amount. Alterations from the set cycle have been accepted
as indicating a pathologic condition. The careful histologic studies of .
Hitschmann and Adler have shown that the uterine mucous membrane i
undergoes definite cyclic .changes, and in more recent times Schroeder,;^
Meyer and others have correlated these uterine stages with correspond^
ing cyclic processes m the ovary. More recently Frank and his cowort-'
ers have showm that in the blood there is a definite cycle paralleling tin J
ovarian and uterine one. All of these correlated cycles, ovarian, blood, /
and uterine, may show variations that are classified as normal, ’it hu'
been demonstrated that approximately between 8 and 14 days after the
last period the mature follicle ruptures, to be followed in a certain '
specific time by the appearance of the menses, provided the ovum haa i
not been fertilized. While we have realized that individual variation!
in the menstrual per iods take place, and that periods with a time in
terval of 24 to 32 days have been considered normal, we have accepted
the fact that the type for each individual was more or less fixed. Sana a
(Am. ,1. Obst. Diseases of Women and Children, 1916, Vol. 73, p. S3)
has studied this problem of periodicity and states that 77 per’cent of ?
women have regular ocriods. If there was an irregularity noticed, it j
was of one or two days cither way. Ho has also notiood that en*
if patients have menstruated as long as 4 days regularly, a temporaty j
period of amenorrhea may supervene. He has also noted some iireg-.i
ularity in duration, but finds 3 days the most common type. He mentions the fact that during a period, one or two days may occur with- 3
out any bloody discharge followed by one or two additional menstnul |
days. The common type he finds is the 28 day period with a duration I
of 3 days. When there is an irregularity the tendency is for the period *
to be prolonged, and he concludes that 75 per cent of women menstruate, ■
ms he terms it, regularly.
■!
I have made a careful study of 200 cases, ascertaining with great J
detail the exact days of each menstrual period for the entire year. These i
cases were not actual.y ill, nor were they suffering from uterine or
ovarian neoplasms or disease. They represented women who were under 'observation for such conditions as cystorcctocele or retroversion; women »’
without gynecologic disease, who simply reported for a check-up on the
menstrual type; a group of postoperative cases whose clinical historifg,^j
S20
$1
.
■
I
OfilST:
VariabtlitY OF MENSTRUAL RHYtjIm
before operation were
321
apparently normal as far as
^ concerned; and a small
gynecologic disease
Rtoup of female workers
auturbance.
without any phys-
£
variations in interval
The most striking find
was the fact that the
^or regularly on any
dW"?,
menstrual P^iod did
any
»ho stated that her ncriod specific day. 1 °thcr words. ‘he patient
. > occurs
on t"
’hen closely questioned and w'hen
'retmfred
the month'
'’Port, was noted to be in error 1„
6
“ aCCUrate wr'tten
^WTed on the twenty-eighth day for
lnStances the Periods
‘^ees, however, there were vtr °0 s °V C 12 m°nths- In m-t
months.
Menstrual disehare-o tl.m
, 1 1 °”s 111 the cppc„
lul
appearance
of the first
10 10 days after and tl '
°'n 5 daVS bcfore ‘he
accepted time
frequently as
f°r an entire month win
>' ■
’“Ranees periods were skipped
cases where
“"We accident, may Imv,. f .'.I'" ' “
‘
' ____
contributed The foil .ano^lor' an auto■wniul in character and duration 'T
Tlhe
1I'C following
followille periods were
"
>» obtain tissue or -•
exam In neither of
°f these
theS° two
,w» cases was
-ammation so that the
th' possibility
Polity o,ff
: “ U.dC<i' bul ‘J* his'»X mate
U
monthly periods were
™t n-kbothof these cases the return
d of amenorrhea, was normal
group gave a history, and their
■' onset was every 18 to 23 days
In other cases for 6 or 7
“sularity, racing iXl^'toWd
2« to 40 daws- andT.
by CXtrCrnc ir‘
He year a so-called rnormal 28
- day cycle.
“n<i «*«•
'" S" dcni-v for tbe^rest
VARIATIONS in duration-
lu addition to the marked variations in tl
‘^noticed that there was a dis^t t ‘ ‘j menStn,ul i,ltervai- “ was
“,.“ie duratiou of ‘he flow. In 115 of the 200
lmarkcd’ variatio“
«>t<re year lasted exactly 4 days in 50 f r
6 Periods for ^e
"> 9
7 day8; in 3 for 8 dayss and1 i. 4 7
in 18 for 6
^es where the period lasted 4 days a sind
In * nUmber of
' ou,d last but for 3 days or oecnsinr ii
& 6 peri-od during the year
that normally lasted 5 days there' were seXr
In th° Cases
-on was only 4 days for one, two or even thr
WherC the dura’
•o oeeamonal period that lasted 6 days
th° year- and
m those cases where 6 days was thr
T?j
variation was noted
in addition that 00^ .,' did th" d ”<,mal
™
™. one-half day to 8 day, t|*
,
“U™t,0,‘ “f
Period vary
""I 'hal in lhe aanm
™ ds" n H 8r°UPed “
1 PCri0ds miSht present slightly dif-
^22
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
t I
ferent aspects not only as previously mentioned as to interval hut 1
as to duration. In several
n
interval, but al*
a half day for nine periods w mid
♦
Wh° menstruated bm
ZXdiaPPr0XimateIy Of.the same
-d
i
way or the other occasionally being obseXS Tosethlt wTre^
in the normal group of 4 to 5 days likewise showed only slight
tiona either in onset, duration, or character, usually 24 hours’ prolong,.
tion or curtailment being the
3 greatest variation.
6
VARIATIONS IN MODE OF ONSET AND INTENSITY
The mode of onset and intensity of a period also presented differences,
In those women whose periods were 4 days, the usual history obtained
was.that the ]period began with slight spotting for 24 hours, and then
becameThe
moderately
"tr ' prc use for 24 t0 36 hours with a gradual cessa
tion. r" spotting stage necessitated only one napkin for 24 ho^X
and that merely
.' as a precautionary measure; during the more profuse
stage 4 to 8 napkins per day were
(
of
£
j
«
patient.
(.uose periods fasting over 4 day,
with a slight staining for 24 hours, the secpenod being more profuse, with a gradual
tapering off for the m ;t few days. ’
In those women whose periods
were of longer duration than 4 days the flow
’ was usually described as
ven,
lor ..
3 (,f thc daJS 0(
be ng confined to home or
for 24
24 or
or 48
48 hours,
hours.
or bed
bed for
allvInrtthWaS
1"
This period of con
’ '
SeC0”d or
°r 1third
twenty-four hours of the period Usu’
ally n those women whose periods were of long duration the n,
------ 1 as a brownish discharge for 2 or 3 days with
wou< e described
profuse and often painful flow for the next 2 or 3 days The nai
“
at tm.es was sufficient t(, confine
rhX»XTa' ,i°"'72 iM"rs °i
The character of the onset also varied irrespective of the interval or
duration. In imost instances the onset of the period was described as
dark brownish stains,- In a small number of cases it was noted to be
light blood-streaked mucus, and in another group a bright red spotting
The character then changed t_
to the dark unclotted thick blood which'
persisted for the duration of the heavy
’ flow and eradually subsided
’ Xtf'd
disappearance- 111 a few instances where this
the
< accepted character of the flow, it was noted that the period waa
stonned
« n,p I, ,„stead of being
6radual cessatb„ w„c„Pth“d
occurred
ho,
!
01 u'« period was observed lo be from
ours less than the accepted normal for that individual. 24 to 48
In many
i
GEIST:
VARIABILITY OF MENSTRUAL RHYTHM
323
instances the onset was described as a moderate staining for 2 days
with complete, cessation for one day, then the sudden appearance of
more or less profuse bleeding persisting for 2 or 3 days, and a grad
ual disappearance. Again in a number of women the mode of cessa
tion varied. In some’there was a gradual diminution of the flow to
complete disappearance, in others an abrupt stoppage at what seemed
the height of the flow, and in a third group the flow would apparently
cease, to reappear after 24 or 48 hours. In this latter type the re
appearance of the discharge, which was usually slight, added a day
or two to what the women considered their normal duration. This lat
ter type was often accounted for by the patient as due to some physical
exertion or to the taking of a bath. The character of the flow we have
wen varies somewhat in individuals and in individual periods for the
fiune woman.
Clots were described as being passed in 28 cases, in 20 of them with
out pain, in 4 with slight pain, and in 4 with great pain. The histologic
examination of these clots showed blood leucocytes, desquamated vaginal
epithelium, and varied sized fragments of uterine mucosa. The size of
these fragments bore no relation to the degree of pain.
It would seem from these observations that there is a wide range of
rariahility in the actual concept of the normal menstrual function.
These variations may be dependent on different factors. The following
deductions are, however, purely hypothetical.
1- A difference in the rate of production of the ovarian hormone, or
hormones.
2. A difference in the concentration of the hormones.
3. A variation in the rate of excretion of the hormones.
4. The variable susceptibility of the individual to the hormones; or
5. A variation in the synergistic or antagonistic activity of the hormones.
( 100 East Seventy-Fourth Street.
lUtrain. E.: Huptute of Ovariah Tumors.
€
■
Wien. klin. Wchnschr. 42: 1350, 1929.
ease report of rupture of & dermoid ovarian cyat following a fall in a
women. The cyst contents localized not in the pelvis but about. the
The literature on the subject is reviewed.
Frank Spielman.
fKj^CAC^
Menstrual Periodicity:
•*
t
Statistical Obse vations on a Large Sample
of Normal Cases.
rU'
BY
Donald L. Gunn. B.Sc. (Wales), Ph.D. (Birm.),
Lecturer in Zoology, University of Birmingham.
I
Penelope M. Jenkin, M.A. (tit. Cantab.),
Lecturer in Zoology, University of Bristol,
O*';-
AND
Si : .
Alistair L. Gunn, B.Sc., M.D., B.Ch. (Wales),
F.R.C.S. (Edin), M.C.O.G.,
Zi’’ Obstetrician and Gynaecologist, London County Council.
B7, -
jpiAX k <
I. Introduction.
g’-ttas investigation was Lndertaken to obtain a series of accurate
Wenstrual records from a large number of normal women. In
when we first became interested in the periodicity of men£.•. rtruation, we were able to find only one paper containing satis& factory scientific evidence on the subject, namely an account of
V lieries of 56 cases by Foster.1
«’
At that time, one of us was interested in reproductive
L rhythms bearing a definite relation to the phases of the moon,
fe ®ch as are found in certain invertebrates, and another of us in
•cdkal aspects of the subject. Since then, additional interest
been given to our investigations by the recent work on sex
fkl/«onnones and by the writings of certain other authors. One-of
is Jolly's3 theory of the duration of pregnancy in terms of
tr •^pressed menstrual periods; another is the theory of Knaus3
periodic fertility and sterility.
■■ ■
II. Previous Work.
Duration and Uniformity of the Interval Between
Menstruations.
Evidence on menstrual periodicity falls into two parts, def^chag on the method of obtaining data. The first section
histories, in which women describe to* the
^eir menstrual intervals of the preceding years. This
ST011?, and it is almost valueless as scientific evidence.
to estimate any interval exceeding 14 days in weeks
an(3 it is, therefore, not surprising that the majority
839
St
I
r.
*/
JOURNAL OF OBSTETRICS AND GYNAECOLOGY
JSS
of women, m answer to questions about their periods sav
the usual interval is 3 weeks, or 4 weeks, or a month
may be variously recorded as 28, 30, or 31 days), or 5 wSl
I his kind of evidence has led to statements to the effectttoJ^
commonest menstmal type 1S a 28-day one, but thaTa
ypt occurs, and that 21-day and 35-day types are less co™®;An inquiry was conducted by a committee of the London^W"
c ation of the Medical Women's Federation/ the date Sil
0 tamed from over 6000 schoolgirls by the historv blkSWl
method. One of the findings of this committee was thaUbe^S
tribufion of types was of the kind mentioned ab^e^^SB
a predilection for whole weeks. The number of girls rSSw
21 days was considerably higher than the numbe^X^W
and similarly for 35 and 34 days. Other workSTiS®
used this method on young girls obtained similar results
lolentino, Kosakad and others/ Yang and Gear1)
Histones obtained from hospital or private patients of rJ
eulogists show the same preponderance of 21 day, 2^da^^W
< ay, and 35-day cases, with an implicit assumption of regukJTOB
his is seen m the figures of Nakagawa’ and Haiek,••
write;; In some of the 31-day type the mJnst^al
feared mostly on the same date (of the month) mdepends/rfM
the number.of days in the month." This fact eithef^SlfO
mental mliuence on the date of onset of flow, or itXSJjli
on the value of such records. Kennedy11 also used hcSO
case records depending on histories. The best contribtS?LS
this class of evidence was made by Geist.13 He collected hkfcJtrom 200 hospital patients not suffering from S
W
ob aining with the greatest detail the exact days of each^ W
trual period for the entire year". He concluded thSt^X W
individuals there were deviations from the expected dlte
Jfa
mg trom 5 days early to io days late.
In view of the large amount of evidence of the kind
phfied above, it is not surprising that the idea thatXS^Sfa
periodicity is a matter of exact multiples of 7 days is^uSS^^
lnMma^ teXtbOOks (Youn^14 Whiteh^
_tune ). Novak” stated that in. 80 per cent of normal
the interval between periods is 28 days, and that in the SlK
mg 20 per cent it is commonly some multiple of 7 davtZSW^
h‘Z s,ame (1933) omitted the
siven
but referred to the 21-day type, and the less
cascs of intervals 01 25 or 26 days, 35 days, and so on
the textbook writers imply that there has not been any
s4°
''i
e^.
MENSTRUAL PERIODIC11 Y
pWiicace on variations in menstrual periodicity by stating baldly
the cycle lasts about four weeks (Blair-Bell,la Berkeley,1’
Evans30).
■ErTne other section of the evidence is derived partly from
who made a note of the beginning of each period in a
MPuy or on a calendar, and partly from observers who interjl|hewed the patients frequently or received communications from
llgaem regularly. The published evidence of this kind is
meagre. It embraces \56 cases recorded by Foster,1
King,31* 131 by Allen,22 76 by Fluhmann,23 100 by Engle
Otad Shelesnyak,34 51 by Scipiades,25 and 4 cases recorded by
g^Khards/’ a total of 472 cases. Even the diary’ method of ob• i mi
data may be inaccurate, because the subject may neglect
O>D0i0 the date at the time, and may then fill it in wrongly some
eitlier from an imperfect memory or on the assumpIgSfoa of regularity. Indeed, we have evidence that this methc d
||¬ so reliable as one in which any delay in recording is plan
^^) tbe observer. We did not depend on diaries in our investigaWon; and we include in our primary analysis only those women
Mpo recorded each menstrual period within a few days of its
Epccurrence.
Foster's publication in 1889 appears to have been ignored
recent years. In his 56 cases the women kept records for
1K5 to 18 months, and only one of them had a regular cycle.
gS>e had a 26-day interval. All the others varied, and Foster
astomshed at the amount of irregularity. When he read
paper, his medical brethren were sceptical and suggested that
subjects were abnormal. King's subjects were machinists,
gderks, and college students; she concluded that in normal
|*ocnen the menstrual period did not occur regularly. Fluhmann
gfamd a marked variation in the menstrual cycle. He divided
^^76 cases into two main groups. The first included 28 women
I™0 showed a certain degree of regularity, and the second
^jnxip included the remaining 48 women, who showed marked
■MItgukrity.
hnq^darity.
Scipiades, who was principally concerned witi
marier, came to the conclusion that varia|wU in the intervals of one individual is the rule rather than the
dCtteption.
work °f Allen is one of the most satisfactory so far pubHe obtained his data from nurses in training, who
•-aaude-J to the school nurse a note containing the menstrual data
ouset of each period. He found that although 87 women
of 131 cases thought they menstruated absolutely regu0.^
841
£/•
' '■'. V'^dB5r»ri
•
ladv. th J0UKNAL °F °BS" AND GYNAECOLOGY
case histories. Actoally X "
data otaXS
regular, and 30 of thenf wen° these w°men wai S
notceably large numbers of 2
He
ngle and Shelesnyak used
,d 35^aV cases. .3
of the menstrual data of wo ad , 1 hcal methods in thea^ij
age m New York. They found
regularity of the cycle was dre '
Other th^
decreased whh increasing menstrua
that the
finally, Holt,:’ in a criZi
exPenence.
unpublished data, writes
tZ6* baSed PartIy uponhiji
cegu arly as a
woman whose
whose' peri^Sl
It IS thus clear that the results n/nncess outof a fairyjSS
Periodicity published dunn/l i ?
fashio
ZgttThlt'Zcontradictory
01111^^^ fash
-re.. ThTfe:" 50
-c current view of the
Our resu]ts should assist in
contradictions.
r assist in resolving some of ^'1
("lfi the jnoon goes through a cycdeV h10^ ^We*s«. mn^ll
ever, there nre many cases i
y sexual behaviour-—is unH
?e^avi0lIr’^and
moon's phases. Most of h Undoubtedly connect
rhe additional light of thekTV16 apparently caused
-sects (Hora...
M -o
and neap tides, as in thn '
d thers bY
cycle
(Hemplemann.,,e ™™e '’orm.
- wMcb a satisfactory exnliX
how'™r 72*33^
«at'nCV""i‘rrhyfh“^ sXin/Y
“•
spaXnX ft“aX’“‘5
«w moon; another’as?™//^/'00" and « a
**®™
!*n 11
(cUamysj „p„c,/p™''i<«rby >h
;' f
' PaP"
* — “< ^tea, XX
842
WCi-"
; ^ITziy****
xne o:nns examined were tatnn f
^“**3 10 about.*
■‘--40 metres of water wh k
|E
the bottom of
gPWetrate. Thediff.
U*«, when less
rwasa,^ifs?v"——
gjaaB?-- Um " • 7” “i 111
BwaK. ,. ^en is borne i
^.'•yQ^CtlOj
I
■ rwhaps due to similar causes r„d /"‘m '"
l;om devils of about 12 o,,„’ ndeed’ "rrhemus” con1 ’ rtythu. His wort; is d,scu”ed hne!'rUa”OnS ,hat there -=
—r«“"a As recently as m^D t
co””“ion with
fiaS °‘ W°men rae"struate9durin/ th'' S,a‘Cd thal ,l,e
took the view that "trad.rtn^ "e'' In<>0''' whiJe
|aK?‘,°nS ’ llaw fed too strons a h it e7fS and lunar
worth while
knowledge
ko„„.W or 10
“—
■SSXSI?'"...
ffisravwiu l
--------- ‘■“rti uie samnlo < xu
P°pulation as a
iPwhslv
” n?
as nearl-v representative
nr
°
po
P
uiati°n studied
rePnot
resederiv
ntative>
^^iJngly our data are
H f ran<^orn as possible Ac
aretrim
not derived
i&J? our databut
ti Xfrom
m'TfcnlS “ hosPital-r
buf from volunteers
KJ®® volunteers
was
send to n
i
1 le meti]od of obtainwas to
to
th^ ^rs
to help
bysend
se^mP us th'6
3 Pn'nted letter<
to help by
the inames
and^addm^6’1 T" ,nenstruai data
[S us
tis the
—
^e. In addition to thV.nd f ? °therS who mi^t
■In addition
IS
bached. UnfortunatZ
organizaapproached.
helpful,
~x~ * M1 / with the result tint y' CmpJo-vep- o{ labour
Pfydenved
derived from
froi the profession. , °Ur SamPle 15 almost eng-^part from this, there is T /Z? Y565’
&^°rds were obtained from volun Z6"1 rlSelection in that
Rabons which would influence a wZ
personal con^njords are impossible to assess ‘ The Z
conseritmg to
tne Question of whethpr th
j6 auth°rs are not agreed
tend to bias the resets L
of recordG£ »« consider, howevir /hr7?™" 1°f Or “f’™« nor,
Kg’from a truly random 'm>fet <fe sample does „o< deviate
KZboutc|^^ut
95o Women consented ?
?• h S respect^•allotted
R allotted to each of these so that InAn index’nilmber
r' ^3t her na^ was never asso>’
br
f-
JOURNAL OF
°BSTETRICS AND GYNAECOLOt
I
>■-
,-. •<.
was sealed and forwarded
f (L°nd°n). and corre
t0
key, who th"t
1 <.
eventually renumbered so th n > • ?
data ,hemsei3|
I he investigation was ohnn .
W1S ronaplet^«
Irom each individual. To h
S0 aS to o}:,tain °neyifiS
some stamped, addressed and'
3 que'stion*^ !&''•"
Person was asked to post' a r nUmbered record canfcffl
inning of each menstruation gitiSl
onset of flow and an indication of th g
me and
Further cards were sent out ag
th S1evcnty of the synwafey.
a second questionnaire was drcXed" '
tamed information about the age and n
the symptoms associated with "the d C^patlon of the^B
the menarche, and a numbed of oH,
Cyc!e'
'
wth in this publication. The second XT Wh'Ch arC
'’
other things, for details of any nartin/l^ 1
the preceding year Thus if ti ‘ '
y IonS 1[1b-rvahSSfe
card record which was „ot' reportKi'inttc s"/ ‘"T’’
there was reason to believe that
T second
tion had been missed and 'he'
rather 111317 a nSSlI
(see below).
’ and lhe case was classified
The Classification and General Treatment nf a
tosetho” «“h ^he'po^martd ,^,r''“rd
«m
estimate of the promptness o?n<
e °f ,postlnS' »
of .he data coild 5" PW
j
onsets of snccessive menstruation, ™d he 7v *35
intervals were worked ntv f,
’> na the average'WCB
were classified.
'
eac 1 case< and then t&|||
fonLta“:"thT baS.Cd T" M a' extent .Ji
S£F^S
sX S Z deS
sXTrdpo;s;?mi
period recorded. Grade b
one discrepancy of a nm I ™
7
the
-s a stightiy greater degree -of deJay in
844
<MiKiro
g
life
<
i
MENSTRUAL PERIODICITY
-1
for Grade a. Such cases are satisfactory for working ■
bB%aVerage *ntervaJs> provided there is no doubt about the first
l^^ujast dates of the series or about the number of intervals
;|Saui comparisons as could be made showed that this process
did not reduce the random character of the data
for the fullest treatment—namely Group ia.
all, 852 people sent information of some kind. Of these,
classified ss ia, apparently quite reliable, while a
returned at least the first questionnaire and sufficient
records to provide some evidence about periodicity.
f
Distribution of Average Intervals Between
Menstruations.
• of women into “menstrual types” is a
■^W*cuous feature of the literature which we have reviewed. (
■gmjustifiable character of such classifications is clearly seen
6,1 and F1,!< 1’ which show 1110 frequency of each
interval. It will be seen that not one of the women in
‘
°Ur groups h, d an average interval below 22 days; if,
^y*er> averages of 22, 23, and 24 days are counted as 3
jHBos, as we believe many previous workers have counted them
Ut 7 per cerc of 311 the cases fal1 Into this class, a
■ion not differing greatly from those mentioned in the
r »»h oe.
PMIbc top four groups gave consistent results. Only about
cent of women lad an average interval of less "than 24
3 prr cent of 37 days or more; 97 per cent had
’
•j
°.
f° 36 days, and 78 per cent of 25 days to 31 days.
PT
Meal classification should be as natural as possible. There
- either be no cases intermediate between classes, or, if
not possible, the number of intermediates should be
■M. rt.mPyed Wldl the nuinber of cases undoubtedly falling
class limits. These requirements are by no means
a
y tbe usuaf classification. An examination of Fig. i
^.Ulat a natural classification is impossible. The com»^_.aVe.rage jntei vals are 26, 27, and 28 days. Women with
a?1
^ong'r than 28 days become progressively
difference between them and the 26 to 28-day group
Ihus there are in Group ia 21 women with an
29 daysA19. v'ith 3° days, 14 with 31 days,'8 with 32
k0 ^nnilarly, the numbers become progressively
te S. °rt£r interval cases. The only possible classificao be that implicit in the figure, namely to describe '
i|
845
i
JOURNAL ()1- UBSTETKICS AND GYNAECdinii!
r"
Mated with her data. A key list was kept in one place J
ham) and the data in another (London), and u,.„_ ,
was sealed and forwarded under the number tn
the key, who then addressed it. The
The data
data themjdn$£>
eventually renumbered, so that secrecy was completetyju^
I he investigation was planned so as to obtain one
""in each individual. Io each were sent a
?
some stamped, addressed, and
and numbered
numbered record
record canfoiafr
person was asked to post a record card immediately
beginning of each menstruation, giving the time and
onset oi flow and an indication of the severity of the
I nrther cards were sent out as required. At the end of
a second <iuestu)?inaire. was circulated. The
tamed information about the age and occupation of the'iQMiZuflKi
ihe symptoms associated with the menstrual cycle,
the »ienarche, and a number of other items which are
with in this publication. The second questionnaire
'ither things, tor details of any particularly Ighg-ititervahSSwro
the preceding year. Thus, if there was a long interval
card record which was not reported in the second
iheie w.k reason to believe that a record rather than a
tmn had been missed, and the case was classified
ISCC brhiw).
(^) 1 he Classification and General Treatment Of the
In due course, the data from the record cards were
together with the post-marked date of -posting, so thitrfcasr^^S
estimate, of the promptness of posting, and thus of the
ol the data could be made. The time intervals
oikcIs ot successive menstruations and the average
intervals were worked out for each case, and then
were classified.
•.
The classification was based upon (a) the extent
tormation sent, e.g. the number of questionnaires .fiUoRgS
(bl the apparent reliability of the data Thus Class i
women who returned both questionnaires and at leaW
year's records; Class II defaulted only with the secondz^O
nairc Grade a contained records with no apparent <jbS«
cii s between postcards and questionnaires, and with t&j
than two cards posted more than io days after the
period recorded. Grade u included cases in which
one discrepancy of a not very serious kind, or in m/toQ
■■
■,> A’**
*
Number of cases
■rt
V|
o
o
O
Ulf.:
I
I
T
T
T
T
T
T
T
T
Fn
HK
M
0
-L
1» f,
t-
>!
“1
i!
i •
?
7 5-
ii
.
_
■
* ,
rr
—
J
I ?
US
.i
B
O
ET
t
Hri
I
- -t
o
r J
f
r
K
5 =
n
a*
‘
;
•«
9
\ •
.;
0
h
•f
7II
I 4 •
4
* 7 *
1
1
1
I
1
1
1
9
•Sc?
< in Hips
•up
da ys
1A
U roups
; B, 2A, 2B
Other
groups
17
ia, IB, 2A, /b
All
I
i
21
.V.
1
5
I
3
5
2Z
4
■u
J5
-’5
40
48
74
3-
43
75
4i
39
49
114
21
62
111
3J
3('
53
<>7
120
3«
5”
81
4 ’
6b
17
^5
12
31
43
15
io
23
4
8
7
33
«4
5
»5
20
i
5
>
6
14
3-’
.>3
3
>4
<5
39
5
1
2
37
2
3«
4°
3
I
v
I
2
43
4b
4*
I
54
5«
2
4
4
4
1
I
1
3
I
1
1
I
I
1
2
I
I
!
291
479
<7<>
28.9 days
28.3 days
29.0
28.7
3 4-31 days
’ 3-7 ‘
• 3-^7
± 4 -^9
t 3 -74
+ 0.30 days
T °—’ X
2(Xj
27<»
29.0 days
‘ Standard
* Standard
mor
4
1
3
7
3
1
2
4I
deviation
12
26
19
cabe
7
22
21
T*xjJ4
4
26
?
.’X
3
16
<5
’
3
±0.19
* <’13
each indiv)duu|( t.h< aver.u»< interval between the
onsets ot sun essive
n»feUuot;0ns dlirinp
yeai
year w.i>
u,i> worked out
The
table shows tht
^Urrx’<■* °l these average intervals
Sec St at hi i< al. Appendix I
«I7
£
:
£
........... .......................................................
■
'•
Tw'i'. ’ •
3
I
JOUKNAL Ol<’
obstetrics AND
A ECOLOGY
*
i
/
J
I
f
’
t 1i
4
O
C4
sasBo jo joqiun/Q
848
I
i
ft
MENSTRUAL PERIODICIT \
'.is- of Woman whose ;average is iiuin 22 days inclusive up
r- but not including 23 day
as a 22-day case. I he classes so
• ad sa 11 sfv the rrequirement
— •-- of being mutually exclusive.
j'j-gh they are not naJHrai Ciasscs‘
*vth( rr - - 1101 such a classification Il still remains a question
is ol value, for if a given
•^vidual belongs to the 22-’-day class in
one year and the 33-day
m the next, it would
stun useless to classify individuals at
u This question is dealt
with later under the heading of
’vi^then^hf interVaI
Z CaSe is treated as °ne obser-
• (kiv ’ ph Zaget 0 the 209 observatlons in Table I is
menstrualCctclln8 13S the average duration of
^•-d- i of hl 7 '
Se(‘ that K differs from the average
uZs t gT ClaSS<'S Ot cases- whlch are 26 days, f7
■
idme 2o daZ Th' k<''n 26 dayS lnc!usive UP 'o but not
< v, I where th A 1S 1S rellccted 111 the asymmetrical form
hwh 'iv
H
aiP scatteri‘d cases in which the women
C nt L
gCS UP t0 54 da>'s' but no sat.sfactorv cases a
Z
' 10W aVTgfS bdow 22 davs. It 1S ■mpoZk to
ihan Se'av
than the average as 54 days is
-r uuired for th^V !)IcsllinaWV> also, there is a minimal
I and tor the structural and physiological chants of
J
I
■ h'^ot
b'\a rx‘n,al ,imc ■ "ot
sU>iy
■■ It IS not known whether these women with verv lone
-’^vais have
... <i; ma(,'™dsC‘'rr"1,"n'',n,! 10 ,he Mt«trous P'nort
v. Variability in the Individual
'nonth^peXd fs^ts lack'"^ I'eglllarith,ing,;lbout the reguv’i''"inzig Regelina—i
ot regularity.
("An der Regel
‘‘kt does "reeula ’™ ,dlt;bnrAegeln^ssigke't"-FraenkePs).
•^uon. we see^that "absolute! AS T0” aS
examine this
imp rivalling a
*
1
(' reSu^r can only mean someo^Res wiThT
31
Wha* we -ZTable II gives a' list
1S the d^ree of ’^regularity.
■ «™rrence of selected / H i SUCCtVsslve 'Nervals, in order of
• * -i
fe'r K'fdays *
"n-No-2875
"th variations of less than ±7d y’. The’ *
Is
« so -e aTtoVa'
^Jcal
<849
JOURNAL OF OBSTETRICS AND GYNAECOLOGY
Table II.
Duiahon of successive intervals m order in cases selected from Group n
Case No
Cns< Ng.
2875
ir.1)
I»kvs Hrs
Drivs Hrs
6
23
2?
28
12
22
27
16
22
2b
28
4
12
23
23
^7
17
28
5
13
25
26
27
27
28
o
(.'ns* No
2O.'»9
l)ny 8
Caso N<>.
2048
Days
Cnso No.
2036
Ln.vs
Cnsc No.
2041
Davs
Ca»e No.
^5
2b
3°
3°
26
4i
26
9
*4
Days
14
23
^5
26
24
27
35
32
26
27
12
29
26
20
29
37
34
29
32
39
8
29
25
24
34
26
22
8
24
28
35
16
24
23
20
26
25
19
20
23
35
28
36
19
25
29
31
25
7
16
24
12
24
29
29
28
39
36
29
3i
13
14
12
23
22
27
27
30
27
32
17
19
27
32
3°
24
23
22
5
27
25
14
8
25
23
25
19
22
17
25
23
24
2s
Cw. V
M
25
<■
39
26
27
Average interval:
25 '2
I T
25.9
31.4
30-7
28.2
±3-9
+ 4.6
Mean deviation :
o O days
.0 days
vi.5
Ti.y
±2.9
In the light of this conclusion an examination of the (Lu
cn
Oil which Table I and Fig. 1 are based indicated that many a
the averages ot the 2QI cases in Other Groups are of bt
value. Thus the woman m the solitary 17-day case returned oca
two record card:,. If the woman of case No. 2159 (TaUe I!
had also recorded only one interval and that one the ninth cr.
our list, she would have been entered as a 19-day case, instrs
of a 23-day one. That is to say, averages based on a snul
number of intervals are unreliable, owing to the variability, u.f
for that reason we do not attach much importance to
inferior groups. Their results are set out here, however, v
show that they do not differ greatly from the more rtlubfc
* See Statistical Appendix I
850
*
ru'
KVOQ
VU4
A<4.OOH Jk>U ll\Jl I
unu
Uldl
11
lldb
11UI
twax-d our conclusions.
It must be accepted, then, that there is a considerable variaklhy in the interval between the onsets of successive menstruatwns m each individual. A convenient measure of variation
uj an individual is the mean deviation from the average per
period.* This has been worked out for Group ia, and the results
rre shown in Fig. 2. This figure shows that only two women
had mean deviations of less than rO.74 days, and both of these
'-iried by more than +0.50 days per interval. The women in
'be largest class of cases, 27 in number, varied by ri.25 to
I 49 days per interval, and the average mean deviation for
[ "hole gioup was ±2.59 days. What these figures mean in
■mns of a single series of intervals can be seen in Table II,
•n which the examples have been chosen for this purpose. Most
the very variable cases, though not all of them, had high
i'trage intervals. The central value was about ±2 days, so
that about half the cases had a mean deviation lying between
J-5 and 2 days, and half a higher one. Altogether 78 per cent
the 209 cases had aa mean deviation below +3 days, and 87
prT < ent below 4 days. Mean deviations greater than +4 days
xcurred in the remaining 13 per cent of the total, and in 5
recent (10 cases) the mean deviation was greater than a weelc
Between the ages of 20 and 40 the mean deviation was found
W to vary much.
Th1',19 married women in Group ia gave an average value
: 1.8,8 days to +0.28. In comparing this with the average
w spinsters, allowance was made for the correlation of mean
Ovation with average interval in the long interval cases, and
expected average was calculated for spinsters of the same
‘nrage intervals ±2.40 days. The difference in variability
aw thus not significant, though it might easily prove to be so
*itn a larger number of married women.
A more vivid picture of the variability of the interval is
9
P5 . Prov'ded by th< difference in length between the
modest interval and the longest one (D.S.L.). Only 9 per cent
tne 209 Group ia cases had a D S L. of less than 5 days, and
,CSS than 6 days’ whlle 30 ^cr cent (62 women)
a " L' °t r3 days or over. In all the 12 women with a
devmtion of 16 days or over, the D.S.L. was over 30 davs
these had an average interval of 25 days, r of 31 days.
.» v. <2 days, and the rcM longer ones. Of "the 45 women
I
* Sec Statistical Appendix 1
4
*
!
i
*
i1
JOURNAL OF
obstetrics and
i
»«
««, »as ,2.6 dav
Coi.s,denng only ,6e
Gy NA ECOLOq y
”rn d=™«on or ., dav
y days- The
Tco®cr
T-t
D1^ *
“Sys*
’■
'■}
' 6 CeMral Wine u^s n .
*■’ *
niosi cases
Jhus in the "'oiniin ,n Case No
™ "d «» average (F"T
days, with 1 exception of t9 days a’9d ,h' "lCT''als
o<l ,
diey vary from y to J7 days. ,( 100^’;° ( a S So
between those two
J women, as expressed hv th •
‘C diflFfrfSi»
r
(see Statist.cal1Append x II
T untamed from year to year
U Such 3
VJew, namely that cerfam 'inJ J'0 m,Sht
Sorter intervals than certain othV
s d°
^4-clay cases andCe«™ “then. and „
^mber Of Women responded^a T
I
'ben the average mterwil f
t-> the sources of X
is question .A
— rc reque^k
fncse dates ~
’ntcrvaIs ^ere worked out
year
P00.10||S|y;„e„tiiaJy«da,a
'be .tv<-.'gc intCIA,a]
-< K ntgnirH ,hf.v
|-'llI p< )S(- ( s< >(•
I <s44)In 10 C.lSes,
(-..... NJOS
yy, 2500. and 200(j
difference bctwe(.
•<‘H a * yvt'fs average, and thfnunEuj;
average is 0.75 da\
"’'P'hayomaninCase.Vo 2“ . _
frnn> ■’■7.7 djvs to
29.0 days, lh,a* ,s 'o say. „, one T ,1?
""'s
27-ckv < ‘’se, and in
a""llm a 49-lav *
fcrtainlv <!<>< I:
Hu‘ look like beconn
d Js, therefoK
'
a 24-day or a ?1 u
to ssneak
nt .
a .34-<by <*»
v case f ' nOT ucorrect
Orrect t0
Pc-ak Of
•?'s"dav
'
■ CdSt
" bci.mse she
is Kkdyto
likelv m t.n
in
--fa!, in.o'a
’d'y;;:!^
into a diffe
'
W-
yearly a ver age nitcrva'.s 11/ cr.r■::/!; ca.’iiS
I. [ruin /liary records
Case No.
C.isc No.
Case No
Case No.
Case No
2083
2500
2O2 7
281 u
2908
^9 3
20.7
3
-0 8
26. i
25 5
(<>1
28. 5
20 (
!
1
*vh < < ssi ve
V'-.irs
2?. <
~7<
*
28.2
2(.)aj
25.8
26.0
28.5
A\ (•lag.
uitit vals
27.7
28.2
!
<5 ’
28.2
24.o
2<). 4
28 7
24 o
•■5 2
29 o
26.0
25.0
28.2
25.6
2 <8.4
-1-2
28.4
27 1
-•I '
27.0
2 7. (»
-’4 i
27 2
26.6
27-3
26.1
27.!
26.4
26.2
26.6
I
2.5-7
i
26 2
a vt-raj>e
.’fl .4
<5 45
<5^
27.4
26.8
the following year.
1
1
i
She
This term ..,V4C may properly
be termed a 27-29must on1 no account be
supposed to
that all the intervals» are
27
to
29
days
long,
but that
-v intervals cluster round these
hgmes as the yearly averages,
as the individual heights in a
population cluster round the
<'crage (Fig. ?).
Cast No.'
is not fundamentally different from the three
Hist me TT '
N°
Sll(,ws 11 differencc from
others which
i
-•> is dealt with later, under the heading of average
^‘*1 m relation Io age.
^7 case.
data (Table Uli
1 ■lC' nnforiiinaiely not suitable- tor ,1
of c onstancy of varia biht v
no < heck on the .iccuiac\- "i
of < a< h individual, since we
<
I
i'" ording of the .separate
VI. Some Posshh.e Causes or V.AtUATtoN.
*1 (icncral.
h has been
pointed out above that the- frequency curve of
®tervalb of ’various lengths (Fig
o) is similar to manv curves
'hich show (he
the frequency distribution of
............. sizes of a measured
V
s5.f
J
I
I
•l
I
c
JOURNAL OF OBSTETRICS AND GYNAECOb
■ r
2o
1
25
T"
30
“T"
(00-
■1
*1
73
u
ii
■*-'
WM
:
I
50
u.
X>
E
3
X
'ti
1
o
17
a<?
13
Hg. 3
Distribution of separate intervals in twenty-four Gi
whose
average interval was 25- days, including 394 interval. Uij
854
&
M-':
MENSTKUAI. PERIODICITY
>■*— charactenst^^^^^pulatiqi^. and in tact tb/s curve approxi
mates to the so-called normal distribiili^^lt^iT'theTand^ *~***-«**^-*^-^
of curve which is obtained when many factors, none of which
H predominant, tend to alter the character (mm its essential
,iz< It is not unreasonable to suppose, therefore, that there
ts a certain essential length of menstrual cycle in nhe human
r.K e The average length differs in different indinduals (Fig. i);
ihis is perhaps due partly to the influence of a large number of
genetical factors, which alone would produce a normal distribu
tion even in a uniform environment, and partly to environmental
t ((tors In the same way, the variation of the separate intervals
m an individual may be attributed to the influence of a large
number of environmental factors. This section, VIb, will h
devoted to the question of whether or not the duration of one
uitvival influences the duration of its successor. The following
;. lions will test for (VII) correlations of average intervals with
i upation, age, and season of the year, and <VHI) correlations
<.i Hie date of each occurrence with certain external cycles.
ii.huJv the days of the week and the lunar evdes.
»
I
I
J
(h) Correlation of One Interval with its Predecessor.
( orrclation of a particular interval with its neighbours might
!«• cither positive or negative. If positive, the tendency would
lx- for long intervals to occur in runs, each followed by a run of
-hurt intervals; if negative, it would mean that each short inter* J tended to be followed by a long one, and vice versa, so h.ii there would be a quick return to the general average A
•>: !nl examination of Tabic II shows that both of these pheno
:i'-1 occur Thus the woman in the very exceptional cast-,
\’o 2040, there are 9 successive intervals of 20-27 days,
“‘Unwed by a run of 4 of over 30 days. Here the intervals
•m |>ositively correlated with their neighbours. Case No. 204-8
'hows the same kind of correlation, though a much smaller one'
h' < -ise No. 2041, on the other hand, an interval longer than
1 ’» average tends to be followed by one shorter than the aver
's’- Ihis case shows a negative correlation of successive inter' ' though only a small one
Mere inspection of the data does not tell us if thes< corrclaare general or accidental. A statistical analysis is mvessary.
1 !1’- analysis used on the first >0 cases in Group i.\ is summarized
*“ >i<itistical Appendix IV. It gives a correlation of - 0.012 da\ ;.
"“I •' significance so low that we can be sure that therv is
r'"'Ht.int correlation worth bothering about. In short, the lengir.
*55
I
>
J
i £!>
___________
1
‘■1
1‘i
f
i
1
JOURNAL OF OBSTETRICS AND GYNA^jj
>i each interval is independent of the length of itsj
ft
so that we can legitimately use the methods outline?
» *• *
1
■
•
<1*
“■ \
cal Appendix HI.
Average Interval in Relation to Gm
Possible Factors.
a) Occupation.
.-$3
The information available under this heading
;n Table IV The occupation of each subject was
hrst questxonnaxre. The average given in the table#
dividing the sum of the individual averages in
the numlxr of women in the group. Thus the suT
,verages was 22.106.9. which gives the general avgg
..1;1V, then divided by 7?O- Incidentally the table^
another way, in that it show.s how far we have M
'■
getting a random sample of the population, ini?;•
L?' ’
occupation.
]V
J
VII
I
I
1
L5.' i
I
I
h
1
Average interval i»» relation to occvpafc***
Oth^
Groups
I
( >1 < up.ition
Group 1 a
No Av
IB. 2A. 2B
No. Av.
btudeut
(physical training)
13
32-1
»7
29 7
4>
30.1
63
296
res< arch, eti .
1 c. <. h«-r (physi< al training)
«4
47
29 7
28 2
32
•9
?t/.2
215.5
29.8
28.2
45 «
39 1
. .-arhei (general)
.8
41
4S
28 8
23
28.7
27
27.H
'5
29 o
n-1
27.)
28.2
27 b
*5
32
27-4
41Jif/’
2<).<j
270
28.9
29 l J
btudent (mostly s< irnev
or medical)
I •mvrrsity l‘ ‘ turrl.
I {ousrwork
> brk. tvpict,
1 I
p
J
< )thrrs
I
I
|< (.tl averages
2(X)
■
■
»
53 4
10 A
a
first the end coiunyi'i
In Tabb IV consider .........
?
from the two student categories and me v
f
A careful examination of the constituent groupl$
form categoncs does not reveal any large or -
f. I Sil'
7
I
F
1:
W)
No. aS
J
V
!
M
Groupik
j!
L
■:
1.
)
t
-
____________________________________ ■
-!
■I
■I
MENSTRUAL periodicity
*?3S
[Mdonal effect It must be borne m mind th .t . ,1 ’
. nough » make . s,n,||
u| ,v'erJ"''
> 1 Hv-rs
"“■I.*.m.-r.... Z"“!, '
are consistent.
■
and
nn category except the ■ Others" ,s the average below 2S
all 4 columns. Similarly .,nl- m the -/(8 1
“
>■ the average higher than z<( d nx m all a c ? Ut tnl ':atc
■.r.
g..m.
44;^J*-.
^e obvi^
,s (hili students
t »u’.t in>
u< t<
’^aching but hoidim' .ml
On'milnyo('vhom
' n,. r6 medical practitioners tnd Mh*15 T th'' subject'
facts suggest that there •, colml?.
?0,t' ,nan'r<'
•• '< interval, a suggestion whu-h L o'‘ bet"c' ri age
" ””s paper and found to be eorro -t
d
neX'
'f
average ln„.rv;il.
'i;
Jr..
to say that tl e
Thu 1
• •I ,i\
"•
i).
. /I
J
'
V* ■>”’<’there a.entrL. 'hZZ^nr4^''''1"^
gi'ilndr as the age differences
*“"* order
'
h
I
‘Ltt.i
“-'''/
“t.onu,.?••
VTc”""1 '" arri‘,at,on
““ to age art <uin’ hi Table V.
un(i
Mllh
'aW' V- In Group IA t|le
- ‘ige of one woinaji was
•h I i»o
bT she T5 o'nltted’ 0thenMs“e the
* nia ferial is the
ll” Tables I and IV
Table V
r.. .
iB
'« n luliun I(j a^e
'ntervuls art tor th '■ periU(f _XOV I92S (t
'
17i</
11
»
<la \-s
4
.•/a.
*
u
d<l \ .-
4 0 47
rb.?..
.’b
4«
*<9
r ° 50
u. 1
Av
Nb.E
* 'days
S.E.-
55
*7 4
.’8 4
■ ‘i 26
’ 0 39
».5-
0 .•)«
•3’
29.^
30 1
• 0 j6
3' 5
' ' 3
-■
t o 4b
-99
jo. I
Av
..
sE '
•’7 4
14
•I
i f>
f
A%
J.
• U.42
41 '
-'7 .»
: o 37
• 0 47
28 8
jo. j
_i ;• 1
jo b
54
' 11 (’J
0 35
0 57
V} t.
•
Six SlutibUc.il
Append
a.
I
1
857
'!
fe '
<:•
2
■
-------
Days
35
oo
(
1
.2 3o
f
Noo
18^0
'05
figure, aw . \ of jd- days and over arc entered as numbers, and fee
i>ori! befon 1SS4 (i) and after 1910 (3) arc omitted. The line joim
five-year a. tagc-. of the points, except that the females born from 1M4I
18<K’ •‘rr p> mtu one class to give a seven-year average because these caa
1 hi;*- tin long interval < ascs are omitted from the averages, ki
are few
the-,- 1- an evident decline in average interval with increasing age.
858
I
menstrual, periodicity
IA ^ere *s,a continuous fall in average interval with
hi age of subject (big. 4). In Groups ib, 2a, 2B the
te true except for the years 1896-1900. For these years
W* - cnce between Group ia and the other groups is rather
’4 *
’ and 1S unllkely t(J happen by chance (3 chances
* SC',ithat./t 10°ks aS lf there is some important cause of
E^colum?61 than age‘ Apart from that> tht averages in the
|^_coluinns agree remarkably well. It is, therefore, best to
EuLn)6 m°re dCtailed teStS °n a1’ f°Ur gr0Ups c°™bined
“ ;ase is ‘he
between adjacent age-gronps
1 v“ornPared w‘th its standard error) to be important'
StaS,
exCeptlnS the smal1 group of the youngest
FBark/n.™ dlfferc‘lccs between alternate age-groups are large;
theCCdiffre at e<St 3°q0 tO 1 against their being accidental.
» dlTT Or(tl896719°io and rgoG-rgro is r.7 days
the betting is about 1,600 to 1 against tlie
‘ng accidental (see Statistical Appendices I and II).
tab
Wlth increasing age occurs in every ageJnch makes accidental occurrence even more unlikely.
ta «X7KmyfTied woinen also showed the age effect, though
P"etUn,iabl-v because ^ey are few. Their rerrom Table V had no material effect.
tberefore saV that the average interval in 1929 be1929 be-
i^SitW’’’ S
? 7and IaStfr°groups
m the yfor°Unger
Wonien t0
*
the sake of homojCnin'
11 10 average has a mean value of 0.18 days per
?
|h k impo.abk for the whole of this fall to be due to the
w w! 1^’prort.r“lfe""“
“geS 7hen t‘Ufent life ls
Past-
•Ik-bv'tltek
n
? expla,n the h'e1' average for stu/
e1^ age' and not to explain the high average for
'S SamPlft 67 thC
that
°f them are
gMUfte cannot infer, from these observations on a single samole
ISlh
°f Cachof Ta
individual
fallsto-?thsuchgL3n
* intCrVal
e*aniinatlon
blc HI lead
a simplfg
ofk-*^ N°’ 28 T° ^able In) shows the fall clearly,
d° n?r' In °thcr less comPlcte and extensive
■BfeinchaS^tSh"w a fa!1' °;hers a
a
and still others
! a ' Though the general tendency seems to
a aU' these additional records arc not good enough
a lnorc sweeping generalization
859
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JOURNAL OF OBSTETRICS AND GYNAECOi
;
z
■ne ’ks' Sge iSXP<nX “ ’ "h* *•» beef
Thus s„(;ial hahiis, Warsa'lndeilt'nrfidU^l
wancnt effects nn thn r ■ /•
rS/ ‘ n “lc
tnayfa®
selection may be weedingUhc °h T y°Ung girl; 4
possible that our .•uses g, , A short Interval cases.
purpose. We do not sav'tli r'
“ ni"tIo,n sample W
possibilities which re not
^bilities, bit J
would fit them Th I t? eXCluded by ™r data aJ!
for an evolutionary1 chanT be}Ween a8e"&roups arg|
the average interval of th S
WC incllne to
viO
advancing years
he Indlvidual tends to get
i »
Of effect- < i||
reason comparisons between our6 ‘fn,emkage
authors who do not give th
Ur a^erages and those 3
are useless. A comoLison
dlstnbuti<>n in a suifaSj
able method. The average taerateofTh a*'1
-I
of spinsters was then I (
women in the same group and thet. fth,efnumber of nS
married women was divided by theiTumhl
expected average interval of th/
• jUrnber- This 53^
differ from spinsters^ davS
marned women in the 4 groups of Table
of H
Tins difference of 0.9 divs fe leJth „X
t0-5«
one average (±0.54) so that th. I
tWlce
S.E"®
cantly different from the sp.JsterTin ?hi WOmen WeK'10t^
Appendix II).
P
rs ln thls respect (see StaWi
(C) Season oj the Year.
longer or shorter thin^L^cragc^onheWaS
intervals differing from the average XT3''
shorter and 1,393 /zg p
n J’ *
(54 per cent)^^
The divergence Ln the so
than
intervals were often much longe Tan
faCt ^<11
ones were not often so much shorter M
While W "
t‘h°eT
rch
nnd 54.2 respectively. There is
thu^Xeneral^d^^S
860
• :
4
4
f
E*
MENSTRUAL PERIODICITY
•I
*:
J change in the proportion of intervals longer than the
;e during the year. There may be cyclical changes of this
Sbft in individuals, but if there are they work in one direction
St some cases and in the opposite direction to an equivalent ex
Bent in others.
B^There is a good deal of recent work showing that the annual
EMe of natural light intensity has controlling effect on the sexual
Of some mammals and birds (Marshall).3* Even if this
Influence was effective on primitive man, the above results show
wat it has no great effect on the interval between the menstrua«fchcns of adult women under civilized conditions.
I
cT ■
K-VIII. The Date of Menstruation in Relation to certain *
g.
External Cycles.
j
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j
I
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I
?
(
I
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Periodicity.
!
SgAn examination cf the data was carried out to see if there
■hrany general tendency for menstruation to start, say, at the
Mek-ends, or on Wednesdays. The number of women (lA)
Wting to menstruate on each day from November 3rd, 1928,
p-August 31st, 1930, was first tabulated. The numbers thus
gwamed were then written down in order in horizontal rows of
Wren, so that the numbers for Sundays, for example, came in
gc vertical column. Each of the seven vertical columns was
Stt added up, so that the number of onsets was known for
Bch day of the week for the 22-month period. The data for
fe other groups were treated in the same way, and the results
«summarized in Table VI.
f. Considering all the records together (last column, Table VI),
« average number of onsets per day is 1,488. For every day
he actual number of onsets differs from this average. The y/
(Fisher37) guides us in deciding whether the differences
tan the average are fortuitous or not. For all the data together,
Bp test gives a probability of 0.025 (25 chances in 1,000) that
divergences are accidental.
B.Careful examination of all the columns shows that nearly all
numbers below average occur during the first three days
■the week, and most of the higher numbers on Thursdays,
jklays, and Saturdays.. The first two columns are fairly
psistent, and the inconsistencies of the third column of less
[Sable data are not sufficient to eliminate their effect on the
tai. Accordingly the data were grouped so as to show up the
t
j
<
ferences (Table VII).
861
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JOURNAL OF OBSTET1UCS AND OTw.MM
^nber of menstruations starHng on each
Of ^28,
the to III
November
Day
—--------- —
Group
IA
Others
*
422
417
448
472
U4
436
457
4078
3066
io^
43«
■ . i 2
Average per day 467
5S3
7.86
0-25
736
0.29
6.61
°-37
z’ = I2.53
p
=
OthA^
■
z.’hJMfi II
55 *
57o
572
612
582
628
563
• •• 3272
*xa
P
■'x
'
IB, 2A, 2B
Mondays
... 456
Tuesdays
440
Wednesdays
■ 443
Thursdays
... 508
Fridays
• •• 483
Saturdays
•• 476
Sundays
... 466
Totals
1930..
•M
0.03
4
^5«
Table VII.
of menstruation over ,1. .
Data from Table VI. tne parts of the m
D'-'ubution of onsets
Days
*
i
Mondays to
Wednesdays
1 hursdays to
Saturdays
S u. i days
Totals
7-
P
Group
IA
IB, 2A, 2B
Othe^
I^93
1287
J339
1467
466
1822
563
3272
4078
5-84
0-05
0.06
5.55
= 10.97
= less than 0.01
* See Fisher37 (1933).
862
<»
♦
4*
'-^5^12^. .
1322
457
4
3066
1-43
0.48
less than
MENSTRUAL PERIODICITY
test applied to the first two columns
whole of the data gives a probability of
than 0.01, This is sufficiently small (less than i in 100)
to say that the divergences are probably not due- to ranerrors. Sundays' values are substantially average, so that
^iere *s a slight but real tendency to start to
^^struate on Thursday, Friday, or Saturday, rather than
the earlier part of the working week. The average proof onsets for a thrce-day period is about 43 per cent,
41 per cent of onsets occurred during Monday to
gcdnesday, and 45 per cent during Thursday to Saturday,
effect is more evident in the two more reliable groups,
MMess evident in the least reliable group, it is hardly likely
t0 sys^ema^c error in the recording of the data.
■gOCw married women (19) in Group ia gave 132 onsets on
||S^ys to Wednesdays, and 125 on Thursdays to Saturdays,
the weekly periodicity cannot possibly be due to them.
g^wintcrpreting this result, it must not be forgotten that the
are not wholly independent. Thus each woman supplied
^g^hber of dates, and a woman who had a 28.0-day average
tenci to start to menstruate on the same day of
The fact that three separate batches of women show
is evidence against this being the whole cause of the
"EJa ^le eftect *s 80 smah' however, that little importance
to it in the absence of confirmation from quite
ffi^pe^dent sources.
Tnble VII, the
ig) -rlMnar Periodicity.
fUere are several kinds of lunar month. The most familiar
!unar month- during which the moon goes
t e phases of new to full and back to newj this month
gcs^in length by about 12 hours, and it averages approxi^7 29-53 days. The other kinds of lunar month are unguar to those not having any special astronomical knowledge,
&i^C0Uld nOt haVC a 6eneral psychological effect. Indeed^
KlVerage town-dweller is hardly even aware of the phases of
p.moon. Some of the other cycles are the tropical lunar month
F-^days). the sidereal lunar month (27.32 days), the nodical
gar month 27.21 days), and the anomalistic lunar month
V-55 days). The data were examined in relation to each of
pe.and the methods used can be indicated sufficiently in the
e synodical lunar month. The average duration in
Pose can be taken as 29! days, for at the end of the 22
i
8^3
1
$
5
3oc —
250
200
I
Other groups
u>
tn
C
o
E
if
c
IS
tn
F
i
LAST
<j| I AH IK It
■’I
01
u-
X
ezs
Z
too —
Group ia
o-
i
Fl... 5. Lunar periodicity (syno
rhythm in Group i* cases is not con
,b no statistically significant synodic
■?DO1
5P-
MENSTRUAL PERIODICITY
■r
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of the investigation this causes an error of only about
a day. Two such months will, therefore, last 59 days. The
women starting to menstruate on successive days
wntten down in horizontal rows of 59, just as they were
wldown in rows of 7 in the investigation of weekly periodicity,
women starting a period at full moon, for example,
nearly into the same vertical column. There are two
the 59 days, and one was fitted below the other so as
^^Wjyyntuate any effect which might be present. The vertical
were then added, and the numbers plotted into a figure,
any considerable periodicity could be seen at a glance
I
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gives the results of these operations. In both parts
there are considerable irregularities; but for the ia
]0°hs as if there is a trough lasting about a week just
fed moon, and a series of frequencies above the average
|tbuut a week after new moon. The two other groups do
|pmfirm this suggestion. Nevertheless, the x’ test was applied
jKe data. 1 he deviations from the average daily frequency
Poot greater than would often occur by chance.
further, when the days are grouped together in threes, fives,
^sevens, so as to show up the slightest rhythm, the deviaM-iare still not significant. Such grouping gives a minimal
pe of p of 0.07 for Group ia, but much higher values for
pother batches, and for all the data together. Consequently,
“ere is a synodical lunar rhythm, it is so small as to be
«n by the random variations, even with over 10,000 dates.
tropical lunar month was tested in the same way, with
t.«ven less significant result, the lowest value of p obtained
Rgo.io. Since Arrhenius” found a tropical lunar rhythm, it
^^^•wcssaiy' to examine his data to see if there is any reason for
l^^'~ClieP:incy between his conclusion and ours,
^■^rrhenius’- used the case-records of 11,807 women who had
l^^patients in two lying-in hospitals in Stockholm, Sweden,
1848 and 1897. On entry, each woman was asked the
her
Periocf, which had taken place some
or more earlier. The reply given must often have been
w!v1^:urate' and ,in thc form " early *n June ”, ” the middle
HKg?™ > an(f the like; so that for the loth; 15th, and 20th
calendar month the frequencies were 420, 723, and 528
H^iectively, while for the nth, iGth, and 21st they were 114,
HPR1 &od I1[8 respectively. Arrhenius was aware of this (his
on P- 379) ■ but he considered that he could overcome the
|B
865
X-x
!»
4
9
L
4
3
4
1
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JOURNAL OF OBSTETRICS AND GYNAECOLOGY
*
■
dchcK ncics of the data by a statistical smoothing proce^
data and the smooth curve fitted to them by a Fourier mi
arc .sb )wn in Fig. 6, together with our data. On the cum
maxi rial and minimal values are only about 7 days apaif^
it will be seen from what has been said above that mauyJ
dates are likely to be in error by at least a week. Flirting
error- are not random but systematic, for there are vS
maxim.r on certain days in the calendar month. Cons*Q^
Arihmius's curve can be regarded as showing the Irani
with which these days (10th, 15th, 20th) coincided'«sl
passage of the moon through Aries, and so on', ratMjl
showing an}' relation between menstruation and thtyfrn|
lunar month.
*•
Arrhenius's data are thus gravely deficient in reliabilW
the lor.ri in which they were collected could be responrila
the rhythmical appearance. Our data are about the^ttg
number (10,416) : they are far more reliable than his, aiyffi
do not show any tropical or any other lunar rhythm?
Ano her conclusion arrived at by Arrhenius was I
v>
average interval between menstruations is about the !
the h ng-h of the tropical lunar month. His average was
from data collected by Hannover,1" in which the interval
usually given in whole weeks (compare Section Ila), so that®
of verv iittle value. Moreover, even if one collection
weic 1 > ive an average of exactly 27.32 days, another
h'lvim 1 different age distribution would probably
fi'ieni average (see Section VII6).
' "
' cannot, therefore, find any justification whatev^^
tssot rating the date of menstruation or its rhythm withafcSs
plit iK ..'iima.
IX. Discussion.
A
.rc unable to support many of our concl
conclusiorii®5^W
letviciii-' to the literature, because none of
of the
data
the data so
so fat
fat tw^S
fished ha been analysed as ours have been. Indeed,
the accur itely described groups of cases are too small to
of sueh analyses. Hartmann,'1” in an accurate scientific asEfW
of meiHi. mtion in the rhesus monkey, correctly states that'^^Ol
know almost nothing about the physiological variations
iiiciisii ii.-il phenomena of women. ’ The analysis of
data is difficult and requires exact statistical handlingT-^E^g
may hav< deterred other investigators, and we have,
866
SO
»
I •<«
,■
MENS! JvLaL PERIODICITY
■1 *
BbjpoPM"—
I#-**—
R
HE
1
i
a
Average
►iWi
Arrhenius
IS
0
z
K
C
||k
is*
o
</)w
2
2
£
n
3
as
u
u
z
o
>
Average
.■7
/•
IS
IS
w
'CWjj
5
>
0
Gunn, Jenkin,iGuNN
*
. oJB
Fk. 6.
U. 'Lunar periodicity (tropical month).
S-
The upper part of the
"presents the data of Arrhenius'” and the smooth curve which he
^lemj the lower part shows our data. Arrhenius’s curve certainly
not fit our data. There is no statistically significant tropical lunar
£ ^riodicity.
a
y;
867
Lr-.-
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JOURNAL OF OBSTETRICS AND GYNAECOLOGY^
J
V
{
given in appendices, examples of’our methods of des
the figures.
The large variations’ in the menstrual intervals
noi.mal women have been indicated by all the rec
accurate data. The information about these variatiem^
several applications in cuiTcnt practice. It is evident
< (dogists should abandon the use of the word “type*-^^3H
presumption of a regularly recurring interval. In its
gynaecological history should make such statements
tru'd records show an interval of 24-29 days,
days " or “ thd patient states that menstruation occura1©^
weeks". Unless the patient has kept records for at
mo/ ths, any attempt to describe the interval in days fa
misleading. The fallibility of menstrual histories pmff
explains some of the inconsistencies which have been faraij
thr past between the appearances of endometrial curetting®
the 1 icnstrual history.
Knaus's1 experimental work seems to show that
worm n ovulation occurs exactly 14 days before the iwl
menstruation. .According to this author, the ovum
fertilized only during the 24 hours after ovulation,
spor natozoa become inert within 2 days of emission. Tlrifa®
cept/>n can occur only during 3 days in any one
interval. He advises a woman who wishes to know whHM
her fertile days and which her sterile to keep an exact mer^™
calendar for a year; she will then have some knowledge
variations and will be able to make some prediction of
of ovulation. If, for example, she finds that her intervifa^
from 26 to 28 days, then ovulation may occur in future nyfchff 3jO|
on any days from the twelfth (26 minus 14) to the fomaS
(2^ minus 14). The spermatozoa may live for 2
ovuhtion and the ovum for one day after; and so, wwl
................ day before and after as a margin for error,' Mer,
additional
sible fertile days would be the ninth to the sixteenth <&j
her intervals.
Our results show that a variability so low as that pca&j
in the example above (26 to 28 days) is rare indeed;^
per ct nt of our cases had a range of at least 6 days. The tn
range was 8 or 9 days. Taking a fairly typical example, ^
menstrual intervals varying from 25 to 33 days, the poat
ovulai on time would vary from the eleventh day to thr w
teenth, and the sterile days would fall before the eighfi’il
Siv-••iaM
and after the twenty-first. Allowing 6 days for menstnnt^Jrf^
it";
868
fulfill**
V>
* » T-» Z'l
4 T1
Z'X % » 1
T
T-
Z'k
Z-l *■> f T
** — J
!aH
v-l
I
Mi
>1 Kl/AL PERIODICITY
P055^^ fertile days would be 13 in number, and the sterile
•^8SCS wou^ be the seventh and from the twenty-first to the
of the next menstruation.
An increase in the length of Knaus’s possible fertile period
bet?n suggested by Latz40 and by Holt,27* on the basis of a
number of records of sexual intercourse-. Holt, using interBenstrual pain as an indication, concluded that the time from
to the beginning of the following menstruation varies
fey 2 days on either side of Knaus’s 14 days, but he agrees with
and Knaus in saying that it is this time rather than the
from menstruation to ovulation which is relatively constant
whatever the length of cycle. Holt takes the view that a single
exceptionally short or long interval ("anticipated” or
delayed ” menstruations) may be due to external factors
'.eperating after ovulation has taken place, and that such an
exceptional interval ('an be neglected in estimating the fertile
KwS..He nets out rrrtmn principles for the. guidance of medical
advigrrx, and lie stales that they have beem found satisfactory
ilc ti()es not make Knaus’s allowance of a day
afU'r <)vulat,on as a margin for error, but allows 2
!°n\and a?Cr f°r variation in
time from ovulation
Wfa « d ? T' InJhC «* Given above, he would allow
HE
to b°e JT e
lit!; inS,ead of IJ' 80 that whM we
$ ftfavr*
f
airly typical case, the safe period would be
"'u'^o^H bC,°7 to”^onT “sole Xd
occur at nnv
Wlt'’ OVU,afion'
?SEE?‘ia
j
1 k‘< sin n <hvurrencr mav remJt
i
P’vgmmn. On thc o(ner
Iesuit
W^rnlwnh thenunuumu,! ^,nl i
>
’ ■ PreKnancy >s
, o,lt t use 1 n>'\ , H 1O'
r 1,1 ,h'“ '’^g
’‘nimal
1
tiiwutmonrl.s
ovulntH.n
('VS°S,lrro,llld
the
.. ...... .. vas... .uedlctoXX,? ac“-"'>&h'ne this
|-*rurate senes of menstrua] recmH.
mac,e without an
t
,and
results show t nF-o"! 7 COvcrinK at ,east
should ^amended from t.n e n n ,0'1S f,om •'’"'’uai
,"n’
"na as th,. agv of (1)c
P
individual OmF' ^'"rth mcasJlres ul the
variability
'•
is (he difference
between
the
shortest
86g
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JOURNAL OF OBSTETRICS AND GYNAECOLOGY
interval and the longest (D.S.L.). and the other is the J
(Icvi-’Hiom rivr
n \ . rh,. n q T •
uro xo
deviation
(M.D.)
'• 1Irl
is normally determined
usual ccircumstances, the occasional very short and veryl
intervals, and it does not gi
give any direct indication of the
variation. In a few cases, ifc a single exceptional interval
counted, the D.S.L. falls to a quarter of its previous valued
further year' s records would be likely to yield another exca
tional interval, so raising the D.S.L.; no amount of subseM
regularity
reducev .u.
it. Nevertheless, this measmS
“■ , , / will ever —
variability has its value, tor example, in connexion with Kndl
method of contraception, when the exceptional interval
very important. On the other hand, the M.D is
corrected both upwards and downwards as the time covmtS
the records increases. Consequently, the longer the tinv-rflK
records, the larger the D.S.L. will be, both absolutely ^3
pared with the M.D. It is, therefore, the M.D which shonSS
used as a measure of variability in comparing reunite nfaSSl
workers whose records cover different periods of hme^lS
Jolly cites evidence to show that some of the cycTcal lS
changes, o which menstruation is one, go on during
He takes the view that birth tends to occur at a defiXSI
cases1* th fK C0?cea!e.d cycles’ nHmeIy, in the short-intfS
ases, he time when the eleventh missed menctnuHn^SS
have occurred. The predict,on of th“ d™*™ 3
foie, a matter of some interest.
1
If there were women who menstruated regularlv
days, we could predict the dates of their'future me^^^H
™th ease; but Jolly's assumption that such wo^Si
a most eer ainly incorrect. Nevertheless, if we
about (.■<. last dozen or so menstrual cycles we can SSSI
piobabmtv that a future menstruation will start between^S
a rly (lose dates on the assumption that there is no
factor affecting the periodicity (StatisticyA^X
not improbable that pregnancy itself is suchTfacSf1 ^‘5
dur itim'inf>ar!SOn betWeen, Past menstrual intervals «
dotation of pregnancy could verify Jolly's theorv nnhi
assumption happens to be correct. WhaUs cS SL
is some test to reveal the sexual cycle during
investtgation using such a test in connexion with
d m-ert penod.city and length of gestation would exS
lolly s theory and its basic assumption, and might
other ('(^-relations.
6
By establishing the fact that the length of each
dyo
'"S
Cd
•J
VENSTRUAL PERIODICITY
I
interval is independent of the length of its predecessor, we have
an addition to the knowledge of the cycle which is a
g-necessary prelimin? y to any study of the causes of variations.
B'.
We did not find any variation in average-menstrual interva
B in relation to occupation. Had our cases included substantial
£ groups of factory workers, waitresses, chorus girls, leisured
women, and so on, the result might well have been different, it
Kwould certainly have been more valuable.
w
Our results make it probable that as a woman grows c er
her menstrual interval tends to shorten. This is a new observafe^tion for which we can find little support in the literature, uc a
iBririation with age nullifies comparisons between our cases and
^ther cases for whic i the age-distribution is not suitably stated.
F Engle and Shelesnyr k24 found an average cycle of 33.9 days in
E^loo adolescent girls. Had they worked out the average y our
i^Dethod, their figure would have been still higher, for it would
have been weigl ted by the larger number of sh orter cycles.
Oar youngest women (aged about 20, cf. Table V) gave a mean
W cf the individual average intervals of 30.1 days, so that the work
Engle and Shelesnyak suggests that the decrease in interval
' rts early in life, and is greatest at that period.
Marriage appear- to have little or no effect on the periodicity.
periodicitj .
Many women state that their menstrual intervals are. longer
during the
weather. Our
results show that such an effect
£ anring
the cold
cold weather.
(
icertainly not the rule.
C':. This
in discussions between Dr. C. Amir'
This work
work originated
originated in
t ■fiulingam and one cf us (D. L. G.); Dr. Amirthalingam would
^iave
^';have continued to take part in it had he not left the country
fjbefore the collection of the data was completed. We have availed
Womsclves
people and we wish to
F^otnselves freely of assistance from many people^
JixBeord
Harold Beckwith
^lecord our thanks to them. Professor
T--------- Sir
.
Whitehouse has been interested and helpful from the beginning,
sponsored the work and obtained from the Research Com
Com-
mittee of the University of Birmingham the considerable grants
iSasary.” \Vc
thank especially
especially Professor
Professor R.
R. A. Insher,
Necessary
We "also
also thank
|£R.S. (statistics),
(Statistics), Dr.
LT. A.
/X. M.
1V1. Bidder,
uiuua, Dr. - ---------- - - _•
#Dr. L. R. Bishop (analysis), Professor H. Munro Fox, FT<.S.
‘ periodicity in animals), and James Toung,
q»
KR.A.S. (astronomical data).
•
We hope that the results presented here will m part discharge
indebtedness tc those many people who sent us address^
records, and we wish to thank them, particularly the 209
information was placed in the first class.
fl
JOURNAL OF OBSTETRICS AND GYNAECOLOGY
I
V
X. Summary.
1. Menstrual data have been collected from normal wora^^
a postal rn thod in which tests of reliability were possible. 'W
2. The 770 women providing*periodicity data were dM®
into (a) 209 reliable cases, (d) 270 fairly reliable, and
unreliable. Many of the best 472 cases recorded in thelito^'
would fall into (/?), so that wc have probably doubled thema^®
of first-class records available.
'flfl
3. Wc find that 90 per cent of cases had an average
between the onsets of successive menstruations lying hgSfl
25 days and 36 days inclusive, 3 per cent had an averamfflB
days or ov lt, and 7 per cent of less than 25 days.
2 per cent had an average of less than 24 days. The
interval d;d not show any predilection for whole
The average for all cases in section (a) and (b) (479
29.0 to.19 days; the commonest averages lay betweejOfl
and 29.0 days.
4. No cases were found which did not vary by at
days between the shortest interval and the longest. Thenfl
difference between the shortest interval and the longest
was 8 or 9 days; the difference was 6 days or more in*Sfl
cent of the women, and over 13 days in 30 per cent of
?
5. The lowest mean deviation of the separate intervab^flH
the individ’. il average was ±0.6 days. About half tbe.ifl|
had mean c viations of ±2 days or less, and the other
2 days or more. In 5 per cent of women the meandaS^^ ywas over a week. The term Mregular" has no precise nwOfl
in connexion with menstruation.
6. The duration of one interval is not influenced
duration of its predecessor.
7. Among the professional classes which we sampled
relation between occupation and ayerage interval was
Marriage did not appear to affect the periodicity.
r-flH
d. There was a progressive decrease in the average onflfl
with increasing age amounting to one day in 5 or 6 yea®:
• q. There was no tendency for the interval to vary
Mi
seasons of th? year.
10. There appeared to be a slight tendency for
to start in the latter part of the working week*.
'OM
11. No connexion whatsoever could be detected
menstruation and the moon in the data of over 10,000
tions. The a ^proximate coincidences, which are so weJI mSTdc
appear to b1 fortuitous.
-l^^fl
8/2
'
.'
.
■
.
'■
.•. a&
'
' ■
■■Zj. :■■ '■. z\ '< '
\
i
MENSTRUAL PERIODICITY
The bearings of our results on a method of control ot
B^'-ffMxxption and on prediction of birth date are discussed.
XII. Statistical Appendix I.
^Cfxeral Statistical Methods.
*«^Many
attributes
of the individuals in a popula' measurable
------------------- - —
gfa^are
normally
distributed.
wn are normally distributed An
An approximately
approximately normal'
normal disdisTOJUtion is shown in Fig. 3. This figure summarizes the available
Sjformation
gynPation about the frequencies of the various lengths of
al in
*n the
^le 2525~ day cases. It is often convenient to have still
--T summaries. ""
fJMrter
The shortest of these is the average, the
of all the separate intervals iin days divided by the number
- __ Sx \
intervals
t
V
tzh / '
J116 average alone does not tell us anything about the scatter
rT~eitems (>-e. the separate intervals)—that is, whether most
R pern are very near the average, or many of them far from
je average. This is represented in the figure by the width of
I he simplest measure of scatter is the arithmetic
deviation (M.D.). The difference between thc average and
individual item is worked out, all these differences are
together irrespective of whether positive or negative, and
'
-J
pt sum is divided by the number of items (m.D.fes measure of scatter has been used in our estimate of the
parity of menstruation because it is short to work-out and
to understand.
pother measure ol scatter is the standard deviation (S D )
»root mean square deviation. The differences as found for the
«iLar^.SJvared; f,he 5(B>nres added together and then divided
wy the inumber of degrees of freedom (n
1, i.e. one less than
the number of items), ano the square
root of the result is
p«md fs.D, = ± y -r
The S.D. is usually about 50
0ft.
n-i /
tfercent larger than the
D. The S.D. is more valuable than
■ M
-----because it can be used in tests of the reliability of the
f’fcrage and so on.
7
'SfJ,1tlarger thc sailTle we take the more nearly is our average
Wo approximate to the real average of the whole poputhe more reliable the average found is likely to be
gra sample consists of few individuals, the average will be un-
H
8/3
J ( a?!Ill iMUMiiii inmiwi iiWEBi^ailiaWiEK^
___ -
1
■
■S*: fl
JOURNAL OF OBSTETRICS AND GYNAECOLOGY
reliab’e. Another sample
then likely to give a very
aven /e. A convenient measure of the reliability of the
is the standard error (S.E.). This is the S.D, divided
C V S.D.,\
S^i , Ji
square root of the number of items S.E.= —J. It B®
Vn
S.E. which usually follows an ;average—e.g. 2^7±^
If the distribution is approximately normal, the
can be used to tell us the probability that the average
error by certain specifiable amounts. Tables have bcea tit
strue -d for this purpose. If a reasonably large n±i»»
items (over 30) is used to find the average, it can be'eMO
in 31/ per cent of samples, similar to the one in questioi^B
average will differ from 23.47 by ±0.34 days or mat; mH
per cent of samples the average will differ by -^ig
days or more ( = 2S.E.) from 23.47 days (Ezekial)"
natively, from a similar table in another form (tabteW
Fisher3’), we can say that 20 per cent of samples from thcsH
population are expected to yield an average differing
by ±. .28x0.34, i.e. by ±0.44 days or more, and sow,'fl
remai Jng 80 per cent of similar samples are expected
averages differing by less than ±0.44 days from 2347. ' JgJj
With the aid of such figures as these, the S.E. dm be'lM
to compare two averages/ to see if the difference behrera
is likely to occur by chance even if they ^re derived frooitmi
samples from a homogeneous population. If the diSereKrE
unlikely to occur by chance, it suggests that our sampfiag’^
not random, or that we have really sampled two distinct paar
lations, instead of one, or something ot that kind (seeStwliang
.Appendix II).
Statistical Appendix II.
'
■
w
gL-;'#.;
■
■
B-
'^1
( onipanson oj 7ivo Averages.
<^a
Supjxjse we want to compare two averages, to see KW
difference between them is likely to be due to chance,
difference can be ascribed to chance, we have no iiidkatisfcii
a real difference between the two populations which haw
assess! d bv the averages of the two samples. Thus fnmt'ltt
II, tl woman in case No. 2875 has an average'intend
27.fX> days ±0.22, and case No. 2159 of 23.47 days ±0.34^
The difference between the two averages is thus 4.19 'dg
The S.E. of this difference is less than the sum of the ts
separate standard errors, and is found by taking the square
of the sum of their squares,
squares.
874
•^|
I"
w®f
i
ssJi
“Jr
■g-:
-,VA
E^-
MENSTRUAL PERIODICITY
F
A
S.E. of difference -
!
+ v/0/227 + 0.343 = +0.40.
ten times its S.E.
) at « = 29 (the
standard devia-
* The difference (. .
■U0.40 days). Entering the
(Suni of the degrees of 1- pVmt) we see that a difference• that it is not in the table at a .
L, unlikely to occur by chaI^e ■
women as having signifimay, therefore, regard these
Indeed, a difference of one day
feantly different periodicities, showing this degree of variability,
iwould be significant with casesin line with our general conclusions
febe result of this test, then, is in
Eni the data of Table III.
t ,XS\»„..sS,E. r
Mjt ’
Statistical Appendix Hl.
0/ Ihr. Date of a
M“Sd”to“ onset ot some
Suppose that »e ».sh to «™»te
e
itoe"menstruation in the woman >n cast.
its interest in connexion w
J y
that there will not
lliBenstniation in the future. We m
further assumpK^iyttriking change in the Per’0^C1^eiSive intervals is
g&Mi that there is no correlation between^^t0 recur
I^Bhfied in Statistical Appendix I •
tb,\.ieventh one would
(K regularly at the average valu^ the
days
Kirt II times 23-47 ^vs after
^ry probable, in fact,
Ullfter it. Owing to the variabil y
Wc can
ilhut it will fall a certain time before 01 alter
Estimate the value of the probabilities.
1 variability
W' If the periods go on much as before,
g
.
• th<‘ s.n. of thc ir futurc
UllaWtlw cum’ n'maiuing much the sanuUs‘ the S.l). for Ibe past I?
W&wvab. will be 1 l..|>. the same
HffihbKV«U. Consequently the S.l'.. ol the uwiagc - of the future
npl tntvrvnlM will be • 1..|I divided by vn i 0.42 clays. We
not know what die .ivemge ol the 1 1 tutuu? intervals will be..
the S.E. ol this .ixelage should be • 0.42. Now we know
lOiat the S.E. of the average (23.47 days) ol the past 17 intervals
±0.34 days. Consequently, whatever the average of the II
-fflBtervals, the difference between it and the known average will
tekave an S.E. ol ± v0.42s + 6.34*= ±°-54 days. Entering the
®probability table (Eezkial") at >1 = 16, the number of degrees ol
®
of the actual observations, we find that
0.333 for a
jifierencc equal to 01 greater than the S.E. That is to say,
pScre are 33.3 chances in too that the past and future averages
fwil differ by ±0.54 days. Similarly, there are about
ebeut 66 chances
L '
875
1
:<•
JOURNAL OF OBSTETRICS AND GYNAECOLOGY
m 100 (h
) that they will ditlvr by twice' the SJG or nxM>.
I.ikniv the I.Hhi u> .1 fan l\ Miiall | Um biht.\\
(o |
il the .1 veiages dilh‘|- by 2 x i 0.54 days
1 l .06 days, then the
Z
sum ol 11 intervals will differ by 11 times as much. There is,
<
theret(H(‘, betting of 15 to 1 against the total of II interval* t
differing by 11 * 1 1.08 days or more (i.c. about ±12 days) from
the 258 days originally reckoned.
•
It is clear, then, that we cannot estimate the date of the
eleventh future period with any great accuracy, even in such a
regulai case as this one (M.D.= ±1.0 days). The chances air s_.
about 15 to 1 against the period starting outside the limits o( $
240 to 270 days after the recent one, and about 2 to 1 for the
limits 252 to 264 days. This is of no value in fixing the date ol
a holiday, but the method is of interest in connexion with JpDys
theory. The proper tests for that theory are indicated in the
body ol this paper.
V
Statistical Appendix IV.
/
7 <-'■/ Jar Correlation Between Successive Intervals.
It is not intended that this appendix should be understood
by the general reader. It is necessary, however, to place on
record the methods used.
If there are n intervals in a particular case, the first
intervals are put down as a column of x, and the last n-iasa
column 01 y. .x and y are the averages of x and y resj)ective|y.
, J
■ v.
1 he sum of (x x)y and the sum of (x - x) ' are worked
oat for • #
each case, and for the first 30> cases of Group 1 a the follows^
irral n
nn b.
K
expression is evaluated, giving the correlation
4
6-
I
i
rS(x-x)y
L'S(x
x)'
For the first 30 cases in Group ia, b = - 0.0123. The correhtioi o
is ver}' small indeed.
Significance is tested by the expression
bNS (x - x) v
Vi
y) ' •- 6NS(x - x)y
”0.22
\
n
I he correlation found would be very likely indeed to
accident.
876
NS(y
x.
•
MENS'! RUAL PERIODICITY
Way1
Vi
References.
F. P.
“ The periodicity and duration of the menstrual flow.”
Med. Journ.' ’^89, xlix, 610-611.
“ On the cried of human gestation.” Journ. Obstet.
Gynaecol. Ffnt. Ernp. 1928, xxxv, 258-270.
Knaus, H. " Periodic fertility and sterility in women.” Authorised
English translation by D. H. and K. JKitchen. Vienna, 1934.
55x2? ‘4- Loodon Association of the Women's Medical Federation. “Menstrua-
y
JoBy. XV. A.
tioo
t>oc in schoolgirls: a survey based on replies to questionnaire.”
L/tncet. 1930, CCX1X, 2, 5; <)2.
5^5. Sb, K. “ Menstruation of Japanese schoolgirls.” Jap. journ. Obstet.
rf
Gynecol.' 1927, x, No 2, 42-43.
S'-.- ♦» Tolentino,
M
------ .1.
“ A study T menstruation in young girls.” J.P.l. Med.
Auoc.. 1927, vii, 372-378
Kosakae. J., and others
Beitragr zur Statistik liber die MenstruagVx
lion der Japanischen Studintm.'
](ip lourn. of Obstet. and Gynec.,
K',; tyJJ. *vi. 141-162.
1 Ying, S-H., and H. S. Gea
” Menstrual cycle in Chinese of East Cen-
tn] China.” Chin. Med. iourn , 1934. xtviii, 641-650.
Nakagawa, J.
' Relation ictween menstrual periodicity and duration
if.,-
pregnancy menstrual j -.nodicity of Japanese women
Jap Journ.
•/ Obstei and Gynecol., J<)3l, xiv, 154-163
O
Cher Variabiiitat des Menstruationszyklus.” Zen tr alb. j
Gptdkol., 1933. Ivii, 257 . SaiKs, K. I. " Menstrual ntistics; a study Ixised upon 4,500 menstrual
; kiftones ‘
Amer Journ Abstet. Dis. Worn., njib. Ixxiii, 93-112.
Kennedy, W. " The menai< he and menstrual type.” Journ Obstet.
y,
Gynaecol. Bril. Emp.. 1933, xl, 792-804.
XI- Cwt, S. H
“ Variability
menstrual rhvthin and char«4£t< r
A tr.t r.
»'
Jovr* of Obstet. and Gyn-col., 1930, xx, 320-323
M* Yocng, J. "Textbook of Gynaecology
Third edition, p. 29, Londoli.
B ’v
3
Young, J. "Birth Contro' ” Brit Med. Journ., iq^b, 1, 1092-1095.
Whitehouse. H. B.
Eden a.id Lockyers Gynaecology.
Ht: p. 113. l>?ndon, 1935.
Kt Johnstone, R. W
“Tcxtl • -ok of Midwifery. "
Fourth edition,
Eighth edition, p. 37.
London. 1930.
i
Novak, E. Kelly's ”('»vne< ^dogv ‘ Nh
u York and London, 1928, p. 118
Neu
Novak, I'
"Obstetrics and C/ynecology ' /edited by A. H. Curtis),
f . Philadelphia and London, . /33, 1, pp. 28(>-7
Bkir-BelJ, W.
"The Pruciplcs of Gynaecology.”
Fourth edition,
17 P- 169
London, 1934.
Berkeley, C
“Diseases of Women, by Ten Teachers.” Fifth edition,
53- London. 1934.
Evans. C. Lovatt.
“Stai ing s Principle^ of Human Physiology.”
Seventh edition, p 1042
London. 1936
f'lL KiAg, J L
“MeiiMlrmil records and vaginal sinvaix Hi a select rd
877
a
-
•
'
■ ■
■
■
■
■
loUKNAI. <>l*' OHSli: IKK S AND G Y N A ECOLOGY
group> of normal women.'
ConlK Embryol. Car-neg. Inst*.,
No. 05. 79-94
T
2 ia. King, J. L
'‘Menstrual intervals.’
A mer. Journ.
of ObsUt
Gyn< 'oi., 1933, xxv, ^^-§87
22. Aller, E
“ The irregularity of the menstrual function.” Atier.
$
ObsteL. and Gynecol 1933, xxv, 705-709.
cyde.”
-3 Eluhmann, C. F. “ Length of the human menstrual cycle.
Journ of Obstcl. and Gynecol., 1934, xxvii,
xxvip 73-7hu
.4. Engl
E T., and M. C. Shclesnyak.
First menstruation 1*1
qucni
menstrual
cycles of
pubertal
girls.
J ' ”"
Hum.
43 1"45j
25. Scipiades, E.
“ Beobachtungun uber den Typus des humaneo M—.Tm.
tionszvl<lus ’
Arch. /. Gyndkol., 1935, clix, 360-3^.
Jdch. ds. O W
■Systematic variation in the human menstmlcjdt,*
Amer. Journ. of Med. Science, 1935, cxc> 641-69.
27- Holt, J. G. H. “ Die statistische Methode beim Fruchtbarkeibp^^
und • ei Mythos des .regelmassigen 28-tagigen Normalzyklus.”
<
I. Gv>akol., 1935, lix, 1161-1164.
-■7*1 Holt. J. (.; H
“Marriage and periodic abstinence,”
PP »
Loiich
New York and Toronto, 1937.
J* OX . H
Munro
‘Lunar periodicity in reproduction."
S(/r
Cad .
x< \ , 523 550
M U ID (J.
l ' x I111 Munro.
Selene, or Sox and the Mood.
I^ondoo,
Hoi.1 . > 1.
]
” Lunai periodicity in the ivproduction oi imo*
funni Proc. A sial u: .Sue. Bengal, N.S., 1927, xxiii, 339-541.
Williams, (
i i
33
B.
insects
1 he inlluence of moonlight on the activity of
Philos Irons B.,
ccxMvi, 357-3^
H1 • m | 1 11 m n 11,
1■
Zur Naturgvschichte von Nereis
/.oolor .1 Stuttgart, 1 •> 1 1. xxv, Heft 62, 1-135?
Amiri 1..diiigam. C
On lunar periodicity in reproductioo of
.ffa-r( uiaris near Plymouth m 1927-28.
Journ. Mur Biol. Aaot Ct
i«j28, x\ , (>05-041.
ihh tu1 i 1.11
Arrhenius, S.
Y'-rha1’mssr.'
“Die Einwirkung kosmischer Einflus^- auf
Shand. Arch. Physiol, 1898, viii, 367-416.
D» L< < ,
B.
Principles and Practice of Obstetrics. ’ Sixti
1 . i«. Philadelphia and London, 1933.
35. Frac-nl 1, L.
Zeit—und Llrsachlichkcitsverhaltnis zwachra
tion 110(1 Menstruation.” Handb. Norm. Path. Physiot.,
34
P- 454
36. Marshal', I-'. H. A. “Sexual periodicity and the causes whfci
mine it
Philos.
Trans. P., 1936. ccxxvi, 423-456.
Fisher,
K.
A.
“
Satistical
Methods for Research Work err’’
37
edition pp 104 and 151
Edinburgh and London, 1952.
•r, A
38. Hanno-T,
“ Undersugelser angaaende menstruationen.” p 0
set/. Kjdbenhavn., 1865.
3‘E
Hartmann, 0 G “ Studies in the reproduction of the monkey Jfaw*
(pithecus) rhesus, with special reference to mcnstruatxM]
’f
nancy " Contr. Emybrol. Carneg. Insln., 1932, xxiii No J34. |^|
878
'
’
4
!
•V
MENSTRUAL PERIODICITY
F- tab, L. J. " Natural conception control ” Jouru. Amer. Med. Assoc.,
1935. cv» 1241-1246.
Ogino. p. “Histological studies 011 corpora lutca, {Maiod ol ovulation
relation between corpora' lutea and c ychc changes in uternu mucous
membrane, and the period of fertilisation. Jap. Med. World, 1028. viii.
H7-X4&
4^ Exekial, M. “Methods of Correlation Analysis, ‘ p 20
New York
and London, 1930.
I;
<S7()
' <
>1
I.
ii
L*
I. ■
Nt.
/•zV/I/AA C -A 4-
12
AMEKK'/.N
OF OliSTETHiCR ANI> (IVNEl Ol.otn
ex iNt.cn i. <Ovul.d <hi ini rcf|iH:nl ly uccurs in patients who
are habitually
anicnorrhcic.
8. A brief review of the literature on anovulatory menstruation is
presented
KEFERENCES
]09U19nUn\'4 r' [htif k' r,: i n<l,
JUy
jy.i.),
J ^l7: ?^’„1W7' <3>
onoV-pn^
'l"
1>roc’
(jJj hvek, John, keboul, Jean, unrl iVioocrs
71
a il':
l')llh,>ck> J' ,,,,d
r/
ExWr-
1/ ('■
A'.;
* Mod. 33:
r
>
J. A. M. A
Med'^o:'
t 3 A
oiotrr
w
N
j
t
108-
j9^'
^erwe,(i<:nt :
M. Thesis, Utrecht, 1905.
(14) Comer G. IV :
J838-' ^21'
AUm, Edgar:
Contributions to Embry<^rwgic InMlitution of Washington, Tub. 3SU, 19: 1, 1V27.
kS8' 18: ^S992'
-2n- ■lka^!inannf
^™t“lbl
Zcntrnlbl. f. Gyniik. 56: 2058, 11)32.
(22) JVemer A A
and
A a^d'e^Ut
r
*' ’ ‘L
No’ 3bG3' Fcb' 23» lfl35« (2n) ^nd P. B.,
t Lf'Sr
Goldale\n, L.: J. A. M. A. 105: 1231, 1935. '(27) Mazer C brael
L., and Sacher, L.: Surg. Gynec. Obst. 65: 30, 1937.
. ’
*
THE DEGREE OE NORMAL MENSTRUAL IRREGULARITY*
An Analysis of 20,000 Calendar Records From 1,500 Individuals
Leslie 13. Arey, Ph.D., Sc.l)., Chicago, III.
(From the Department of Anatomy, Northwestern UmveMy Medical School)
I T IS a traditional, medical teaching that women usually exhibit a
1 regularly spaced menstrual rhythm. That this belief still reflects acurately the opinions of many obstetric and gynecologic authorities is
shown by their published statements. Representative lists of such textbook references have been given by Fluhmann (1934) and by Gunn and
othew (1937) ; it would be easy to extend these citations. Moreover, one
is sate in asserting that it is the custom, both in better hospitals and
pnvau practices, to assume 'the normality of menstrual regularity as
the basis of clinical questioning for case history purposes.
The commonest source of information from which judgments con
cerning menstrual periodicity haw been derived is the hospital case
record As typical examples may be cited the extensive compilations
by bane&
1U tlns country, Nakagawa (1931) in Japan, Kennedy
•Contribution’ No. 215. Acknowledgment Im due sevemi norar.no
i
i
idled information to further the completion of thia report
Dra F* a)1^V^SU^'
Fluhmann, J. L. King. L. J. Calx j n Pratt nnrt
n
,I)ra;
Allen, C. F.
by sending miscellaneous. supplem<-nta?v data to^Ur!?; Ind e$uiJd
.-.ccounta of group studlea.
viarny ana extend their published
&i
,
A. EY :
<
I
A
DFXJKEE OF NOHMAL MENSTRUAL IRREGULARITY
13
(1933) in s-otund, and Hajck (1933) in Czechoslovakia Character
istic of this kind of inquiry is the conclusion of Nakagawa that 97 per
cent of th s group of 2,080 selected women menstruated regularly, or that
of Kenne
who credits 75 per cent of 9,768 patients with having a
regular tv nty-cight-day cycle. The uncritical attitude customarily ex
hibited on these matters is well illustrated by Knaus (1934), who, bent on
doing a bit of special pleading for hi’s “safe period,” explains away
Kennedy’s high (sic!) pcrcenlngc of irregularly menstruating women
on the basis of the group being drawn from gynecologic patients and not
from a normal, healthy population. It is also Knaus who was irked
by Fraenkel’s well-known paradox concerning the irregularity of the
menstruati ng woman (“Das einzig Regelmassige an der Kegel ist ihre
Unregelmassigkeit’') into stating that he was “not prepared to settle
this very important question in quite such an airy fashion without any
foundation of fact”; whereupon he proceeded unquestioningly to
accept, as he foundation stone of his theory, tabulations from routine
hospital histories’
Ilistorica’ly fundamental to a popular belief in a regular twenty-eightday cycle ■ ; the world-wide tradition of lunar influence. This supcislition has been fostered through the influence of Arrhenius (1898) and
has been credited by De Lee (1934) and others. However, Gunn, Jenkin
and Gunn (1937), using reliable menstrual data, find no justification for
associating the date or rhythm of menstruation with lunar phenomena;
they are also able to show how Arrhenius reached his conclusions
through the use of wholly’ unreliable data. In addition, it is now
sufficiently established that an abetting factor that has done much to
confuse tl true picture ol iiiciisl.runl periodicity is the utter unicliability o. woman’s unaided memory in these matters. Her testimony
may not even be consistent on different occasions of questioning (Sancs.
1916). Moreover, even if woman’s memory concerning her own men
strual history were trustworthy, the mere method of approach by which
menstrual histories arc customarily obtained for clinical records would
still load the scales against, the truth: the questioner suggests by im
plication the “normal” reply.expected ; the patient senses that any other
answer wiP mark her ns atypical, and so reacts instinctively in a pro
tective manner ; the easiest way for her to avoid further discuss on of an
often embarrassing and seemingly inconsequential topic is to give the
answer su. gested, and especially so since “regularity” is entirely a
relative measure that depends upon personal standards of interpreta
tion.
For these reasons the analysis of accumulated hospital records is fruit
less, while the numerous published articles dealing with menstrual
periodicity, which have been based on these records, arc without value
Onlv data taken from actual calendar records of women who are mh.mxlrd mi.’ r^lH.nsil.lr (or otherwise i.re a.lequnlely s.ipervLsed) are
neceplnble lor .serious eonsideral ion.
Fori iinnlc.ly I here is a limited
number of studies, published mostly within recent years, which make
avnilnble th'1 lenglhs of eonsemilive menslriial cycles ns ivcordvd by
uelcc.ted women over different periods of time. The general trust-
14
AMERICAN JOURNAL (>E OBSTETRICS AND GYNECOLOGY
uoi.'hiness of these data has been reasonably safeguarded by various
i-u/ins and it is believed they are, on the whole, as accurate as may
"’(•11 be expected under such circumstances. It is the purpose of the
present article to select and assemble these data, to subject them to
statistical methods of analysis, and to reinterpret them both as individual
Indies and tis a composite group. In this way it seems possible to bring
: > a conclusion certain fundamental inquiries regarding menstrual
periodicity. This does not imply that the further collection of menstrual
d.ita is not badly needed On the contrary, it merely signifies that the
time has come to close certain of the simpler problems whose answers
arc sufficiently at hand and to direct future energies into resolving those
other features of the menstrual function on which exact information is
still lacking. For example, rather than to collect further quantities of
short records, it wilf be far more profitable to sock out long-term men
strual histories and subject them to analysis. Richards (1935) and
.Hartman (1936; 1937) have already made a start in this direction, while
the present writer will soon contribute also to this phase of the menstrual
problem.
Some of the published menstrual data present the detailed records of
the actual participants; other sets of data conceal this individual in
formation and, instead, combine the cycles of all participants into one
group, in a corresponding manner, the conclusions given sometimes
represent generalizations drawn from individual records and averages,
while in other instances the massed cycles of all individuals have been
treated as though emanating from a mythical “average woman.’' On
the whole, the former treatment is more, exact and instructive, although
certain valuable facts, as well, do come out of merged data. As a prac
tical matter it has been necessary, in every instance but two, to accept
the data as printed and to make the best of them in that form.
THE DISTRIBUTION FREQUENCY OF MENSTRUAL CYCLES
Some worth-while information can be gained by arranging the data
to show the distribution frequency of all the cycle lengths encountered.
In Table I this has been done for nine studies on adults and one on
pubertal girls. All these subjects were white inhabitants of the north
temperate zone; further details pertaining to the several sets of data
are listed in Tabic III. but here it is only necessary to state that the
participants were all supposedly-healthy, or at least without conflicting
pelvic disease. As may be seen, the modes for the several adult groups
are divided evenly over 27, 28, and 29 days; the grand mode, both for
adult women and for girls, is set at 28 days? In the adults this value
is clearly established, while for pubertal girls there is little supremacy of
-S days over 26, 27.
lentHhc
27, and 29 days. Although the recorded cvcle
cycle lengths
•tn conliaat to me Ucts vnwodled in Table I It is enllghteninK to com oar p the
i>..vnt conclusions of Hajek ( 1 933 ) who relied upon the verbal testimony of 1480
• ■ • n
recorded m case histories at the polyclinic at Prugue. He credits' 82
.r u'«I m being regular.” Of the whole number 56.7 per cent reported a >5 •>
c.. cle wRlle only 0.6 per cent and 0.06 per cent claimed 27- and 29-dav
’
tlvcl>. The neglect of 27 and 29 days In these histories
rtliance that can be placed on the details of hlstorl*-
I
F
I
4
«
*
i
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■< ?;. W<.
..
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KO. or
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■ :;;;1‘-7-..S
I JLCT3 |
1. I Miner, 1889 j ““j
120
2. L&u aad
j
102 • 1.113
Twiner, 1935 !
1,336
3. Lata and
100
Reiner, 1937
17! 523
4. KIhk. 1926
5. King, 1933
354
6. Scipiftxlfts, •
319
1935
7. AUen, 1933
511
8. Huh maim,
747
--,*1934 -,•••
5Q
P. Pratt and
299
o then,1929
10. Engle and
100 ! 3,140
;
•
•
Totals,;
. . adulta <>.
' *•>"'•■*,- IO. Totals, pn-
-'
1
1
.I
-t
21 1 22 » 23 1
—i“
2
1
?; ■ 22
18 I 46
4!
5’ •
i!
r
-ii n
?.| ii
I 144 1
16
10
133 175 eiS
‘66
X?3s • « >
’23J
•4i
aM
u
8
51 16a 102 135
—• ■
’
1OQ
5/122
■63
JM<0. 14 51 166 [L’^2diz’ • ■ .'4U
‘M ‘
■•__________________________________
. ■
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28 j 29
209
30
31
13 j
u
76
61 136
■ 18 • 25 - 36
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• 87 I 80
J?
158
114
<75
23
15
17
22
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11 . 6
20 15
32 24
50
47
20
3T
JLO
50
37
45 . 36
49 '36
6
36
I inio’j ’• 41•fa* j 51
!O< , a 56
50
;<j ■ sr
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h? 33 j
19
119
^■■
.46 . 37
r-36
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55 ,155
.72
,72
h
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1« Mt ---’L-
- - -
....^
■: 'iO
-’ 485
.J
I
3*1
25
161
25
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14
4
11
2
6 7
6 w5
9(11
5
7
16
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6
6
11
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3
5
13 1 5
24 J 17
201
50
29
18
3
665
61
7S
73
60
. 57
15
32
5 •” ’
193
rr^»fcJrt&4
7! 594
109 '-150
ira
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P< 105
— I - 8 6 69 224 199. <>78
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—
456 332
151 fipo' 65 139
a
E
q
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d io
13. £;
33’ 17’• 16
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..V j 33?
;__ '''.J ' •' ' •*
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[1011127 152 tot
,^2
- •'
iM-r______________
' .J '.i
UR
u^rv
!
11-
npi
. r*« ! -
i
- I
■
'
■ -, < Ta-bt * I. DiBraiBunoK Fixi5ut?tcT^Acct®M»a *o Lordri^'i^jT
u VaNST&VAL Crctaa ExpEutNczn SYV485 Adult Whitt Wumf.n, and
* ’’*.
: ~3,140 Cy'~les Expwxxctd bt 100v PVBat?Az n?»*D
2_
■
-•■,
-''.
- :T ■■:-'■
;r—•? ; TRJ M0D4XxVAtUl»'ABE IXMCATED BY ITALICS
;.
■
r
F
9
-■.^.
-
Ar4:y..
’7*'‘
v:-
'^7<
A
'
r5«
■
§
. rt-v.
Hi
,. ,1)(1 7
"f the-ndnlt WO(,„;„
and
^NEcolooy
1
K^citXsh.i',aif ,ri‘e«r^r^‘''^ii;ty.,;ho; ,"h"c
'
''"expected.
from $ h'structixe f0
fu"ct'on has been smoothly eStablXd
U?ertal
bv puberta]
. is not
eoinpare „„,le „mi|
•^pnnew WOrnpn t
(numlK.r of cycles
. F-’K^S^(j«;V'yc,ca)’Qn* «"
............
......
while
dnyn.
i allow
tyjwa Of cycle
e*en credited
7CO"I», m which ii,,.,,. '"J'.'
'llC vcrb“l
•' Kennedy '>
J«P«nese ,l„tn jt is .. « en day „ag(,s aro (
3^000 ho»pitn|
1 ,xali^XX'"
ot interest to find h
. » Rtron
42
<’ ’ -bcre nre
-^•
"--t
at v..^v• ■ "trca.scd. Yct ln X'
“7 ^h' elev„(i..... :
infer,,,), ‘ 2"C0"bine"
This i”
''""''■'
I”- eorr..'
’ 7. "l"• C’1 '''eturb
'•
“Ix-fli by
CQirtMnon,!;.
<,<,aurb th„
the Otherwise
*'8, 36’ an'1
Such "Murrenee,
(
reg
(
' P0"'<"‘K irreguiarin^injnOB -.-k'ulnr
diMrib“"on.
they rare T«-l feature,■ of -he
' .ne^,::^
,Ctl<lv
KG‘
” COUld -t
to bias
■■- rUf —
r on -he
T""
‘"--venen or the/;,4*^
know,,' f0 l)c\' '^' fyni’-nng the rtat.,."'
'or white
Hint the other
'I'"- t»-o .■on.pooe,,; j.;r * 'l,V O0"ected, ,|10w5 r- no fact that the curTC
su3piciOuft t|lnt
’Urh
u bui:,eOrVeS
Uck
They ...o.,!,!
resul, f “
“''S 'n """ in»<»n.
'"i"0
s•’ "■ -nos „f
' 'llc '“'-‘"ion of rschool ijirl, bv
*»•«• pri-diloet '.... 10,1 I Or whole wcoliji
’'•“dencics nppenr
Y’
H«iek (IMS) n,1(| Konno^'f^Y' "’
'"-i'.
T’„t
A„
the Medical v
fulling froni
',l‘0*n
‘XXf.
of Na^X
‘^-Uothcr wrde £thc ‘'hs- ibntion frequcncy js . (
(
of each pe^onXXr^h'r"1
X^..thc distrib^
^Iioution accordin.r ♦ • -.
Jn,s ilnfi
data in which inXid ,,?d,vidual Per^ntTf th" two0' p 3PPCtSni^ed
tb
^ten too Jin,iteJrta0C2;;-';
available for
characteristic
».d.
c«n be taken as> truly
j—
::"“»«■<.. •> S”;
for nurȣ wou?d 11uh,nann s"Vl 93^5 * nt'
be*ow 20 and
'»-3^ “
IBilfiilSfiSW
-V
ron^v^
■’v^r- ——s-.
4
!
Table (I ’
DtSTRlBI TIGN FkEQLEACY, ACCORDING TV AVERAGE LENGTH of Menstrual Cycle, of 1,165 Adult Women (14,512 Cycles)
100 ni rf.rtal Girls ;'3.1-*n vcles). The Modal Val’--., '
TNnir^-rv- nv Itu.icr
V'l'RCE OF
DATA
1. Issmer, 18S9
2. Latz and Heiner, 1935‘
3. 14itz and Reiner, 19371
4. King, 1926
5. King. 1933
6. Gunn, et al., 1937
7. Scipiadea, 1935
i
8.• Fluhmann,
r* luncuanu, 1934
i
9. Engle and Shelesnvak.
1934
18. Totals, adults
9. Totals, pubertal girls I
1-
KO. OF ; NO OF
’.BJECTS ’ CYCLES
120
. “TT ‘
102
100
17
37
770
51
76
100
IhNGTlt OF AVERAGE CYCLE IX DAYS
16- ! 21 ’ 22 | 23 ■ 24
25 * 26 ! 2
27“ j 28 : 29 I 30 ‘ 31
j 20 !
—-|--_
1 ‘
1
1,113
1,336
523
354
: io,ooo±
319
747
3,140
2
4
1
1
1
1
I
1,165
14,512
100 j___ 3,140
4.
,
;
.
5
8 ! 26
1 I
2 '■
I
2
1
2
“TF!
... 31
|
3 t
R ,
2
57
5'
1
5
9 I
17
17 '
f.5
15 ;
3
5
112 ' 116 100 1
• 6
2
7
5j
4
3
15 l
13';
J 2I
943 1
3
2
~7TiTT6 j 158
Il 21 4
10 I
1’1
14
5
8
74
11
8
9
2
5
54
1
11
W
32 I 33
34
35
9
2
2
1
i
2
13
1 I 2
5
8 ,
2i
90 * 62"
4
1
<•>
2
7
rnr
Q j S ! 9 i
9 i 10 i IV ! 9
17 ji j 164 * 133
I-
I
1
“i___ j'iir hswl'
9
41- | 5150 . 100
1
1 d Ji
2
24
• 38
4
’ 2 !
i• *; 6 I
., 10 ! 9 ,
I 3640
2
and
15
2
5
7 I
1 1
4 I
15
9i
3
1
4
3
“23~-13 ~1’
9
15
3
7,
2
3 I fii
2 I
•The exact number of cycles’collected is not given by these
thes* authors bevond
beyond the general statement that: "The investigation
investiga
was planned to
obtain one year’s data from each individual." Hou
However,
....k— -from
ever’ it is evident
text that
some ---subjects
furnished
more
...........the
- ------------- ------,.— -------------------- d;
Jata than this (their
Tables II and III). Since
considered
allI average cycle lengths of. for example, 23-0 to 28.9 days as being 28 days, their
” Gunn
----- and
- ■ his co-workers
— -----— •—.»*• —
distribution frequencies
f-?r------ ’
’ comparable to those used by the present uriter who has listed averages between 27.5 and 28.4 as 28 days,
are not entirely
To make Gunn
________
jnn ’s.. distribution
approximate the others in the present table, half of the individuals constituting each entrv have been droroed
©vf mtc
•
bark to the nav
day nr
previous.
J
• I
I
i
!
I
i
I
Y.
■
I
»■
3
I
I
Table III.
SOURCE OF PA TA
General Data Concern.no Mo« Than 15,500 Menstrual Cycles Furnished hy 1,189 Women and Girls
1 NATIONALITY
1. Foster, 1889
2. lasmer. ' 4.^9
■ S;
orri-pAHOJf
* American Selected patients
• German
Housewives
3. Lntz and Reiner, 1935 | J American Housewives
;} Canadian
? American Housewives
4. Latz and Reiner, 1937
Canadian
5. King, 1933
American Industrial workers
6. Gunn, et al., 1935
British
Professions
7. King, 1926; 1933
American College women
8. Scipiades, 1935
Hungarian University students
9. Pratt, et al., 1929
American Nurses and office
workers
10. Allen, 1933
American Student nurses
i
11. Fluhmann, 1934
I American
Student nurses
12. Engle and Shelesnyak,
JewishOrphanage inmxtes
1934
American
1-11« Totals, etc. (adult groups)
12. Totals, etc (pubertal girls)
NO. JN
GROUP
AGE RANGE|
MEAN
AT START
AGE
(YEARS)
( years')
56
RANGE IN
NO. OF
CYCLES
' REPORTED
330
18
10
44
ICO
10.9
49
13.4
j02
19- 39
20- 45
26.8
31.0
120
1.113*
100
21 49
31.7
1,330
21
479
33
50
■50
17-35
131-51
17t 35
18 34
12-36
23.3
27.31
23.8
24.5
-L-H
161
6,0001
716
339 §
299
18-27
11-15
20.4
13.1
1,291
747
3,140
no
76
100
MEAN
NO. OF
CYCLES
PER
PERSON
TOTAL
NO. OF
CYCLES
10;
6;
4;
13
3; 104
3;
20;
19
69
oo
SHORTEST
AND
LONGEST
CYCLE
(DAYS)
’16; 46
20; 40
15; 51
-
ISee p. 21, last paragraph.
■CBM
-
^aTnY^a^
sn
U4
4
O
C
x
19; 101
16; 57
Z
>
7.7
13.01
21.7
6.6
6.0
18;
20;
19;
53
91
36
o
11.7
9.8
31.4
13; 84
11; 144
7; 256
o
1,089
12-51
26.1
12,452
3; 104
10.7
11; 144
100
11-15
13.1
3,140
20; 69
31.4
7; 256
•Seven cycler, have been omitted Zs®
Gv.1?i.~F
the recorJ of~Subject 149 in the original report.
acTOmpanying notation that the individual
was surterag: tronT an ulcer of tte‘stomacw'
11 ■ Ththis
”C period.
Cycl“
during
atypIcally lo^
there is an
were under 18 "years of
The average age. total number
------u-fiKtoiar
of cycle
“s —
a"Jd mean number of cycles furnished by each
. tta "dlu
data as
furnished.
JThe record of c _
__ 1 I™,.™.
°r
e
J"
d
.L
v
.
ld
“
_
1
.A
nc
J'
,d
?
d
.
2<
cycles
MartUir
from
C._
yc
-•?.
-----‘
the
Ume
she
was
13%
rh>MbmSUrned These earlier cycles have been
—.. included
——J tn the computations, since, strangelv
rYYoS’/h. tAhfeVra?e ^r:t^nOc^nes\^nre:7ththheerrTa%d^
I Al though the total number of cycles Is istated
‘ ' ‘ to
* *be lt«, a smaller number
"«e“mor ^andtaUvel'y’'^"'"'’ an<1 ’uppres’ions iB
handiinedaU
>
detailed analysis given.
o
Is
>
Q
><
s
o
5
Q
■
i
arey •
DEGREE OF NORMAE MENSTRUAL IRREGULARITY
19
¥
Tho distribution according to the mean cycle length of ‘"dividuals is presented m
Table II This infonration was obtainable from eight groups o
a shifting of the group nwd'J values; yet tee d
s
o{ aU
sua. -....
form customarily considered normal.
DETAILED ANALYSIS OF GROUP DATA
t
>
The distribution curves, shown in Tables I and II, theoretically might
be produced either by closely spaced, individua :records which,a^igMy
regular or by overlapping records of considerable individual variability.
InOrder to ascertain which possibility is correct one must s^utimz^in
dividual records, accurately kept. Yet it is remarkable how few of these
have been collected until recently. Scientific curiosity was quick to
invade almost every aspect of human behavior, yet it long neglected thu
most obvious one. Menstrual regularity has been so thoroughly
that onlv a few persons have ever thought it worth while to gather
reHable ’information through the medium of actual calendar record.
All of the contributions of this sort which I have been able to dis«>ve
are reviewed in the paragraphs which follow In order to make t
several studies more easily compared, some of their genera! dat*
b-en assembled as Table III. This tabulation, like those which follow it
has been prepared by working over the raw data of the original .papers
and adding, where possible, other desirable information obtained throng
correspondence with the authors. In this way the data have been cor
rected and altered in some instances, while in others they have been
made more complete than the original publications show. Some apparent
disagreements with the original publications are due to errors which
exist in those communications but which have now been eliminated, lhe
following notes supplement Table III by presenting certain information,
mostly of a general nature, not amenable to tabulation.
The factual attack on the problem of menstrual regularity is not al
together new.
As long ago as 1889 Foster reported on 56 New York women 20 of whom had
at some time been pregnant, under his observation for various affections. Havmg
included only those whose ailments were not accompanied by disordered menstruamn he obtained calendar records of 5 to 18 per.ods from each participant The
cyclw ranged from 16 to 16 days in length. One patient reported perfect regularity
throughout her period of observation, but the length oi! this
™ "s from a
The cycles of the remainder showed a maximum variation of 1 to 18 days from a
2May norm although whether this departure was from the group mean or from an
a.
*
"‘^nteT Tam "year Issmcr (1889) in his ''otoworlliy ^contribution
“ ’ ion tho duration
of 12* Bavarian housewives for ten
of pregnancy included the menstrual records c- -
i
s
/
» 7
( *
i.
20
AMERICAN JOURNAL OE OBSTETRICS AND GYNECOLOGY
*
|
i 3
I
I
months preceding pregnancy. The shortest cycle was 20 days and the longest 40 days,
while no person was regular in the menstrual function. The maximal departures
from individual means ranged from 2 to 12 days.
These two reports should have opened the eyes of physicians to the desirability
of collecting additional information, but the/ were without appreciable effect and the
time-honored faith in normal menstrual ngularity continued to dominate clinical
thought. .Pence one must pass over an interval of some forty years before the next
serious contribution appeared. This study was made by King (1926; 1933), but
before considering her investigations in detail it may be simpler to continue with
some other reports made on women drawn from the general population.
.
1
I
-t
; i
?
’i
t
I s
5
•Somewhat comparable to Foster’s original material was a heterogeneous group
observed by Geist (1930). His brief report covers 200 women who kept records for
one year. Most of these were patients, who, though not actually ill or suffering from
pelvic disease, were under observation for various reasons. Those women who had
previously declared their periods occurred on a specific day found themselves in error.
"In most instances, however, there were variations . . . from five days before the
accepted time to ten days after, and this variation occurred almost os frequently
as would the so-called normal cycle.” In a few individuals 28-day periods were
experienced for nine of the twelve months and in some others there was extreme
irregularity for six to seven months and then suddenly a return to a 28-day cycle
for the rest of the year. No other details are given in this report, and, unfortunately,
attempts to supplement these meager facts through correspondence have been un
successful; for these reasons it is not possible to include Geist’s results in Table III
or to consider them further for detailed analysis.
Two other sets of data drawn from the general population have recently been
published by Latz and Reiner (1935; 1937). Included arc 2,449 cycles which 202
women from various parts of the United States and Canada had recorded on
calendars and sent these authors in the hope of establishing their ovulatory rhythm.
Although unsupervised, it would seem that the purpose (contraception by the
"natural method”) for which the data were collected should have been a sufficient
incentive to insure accuracy. Yet to a certain degree these records are selective and
show a greater regularity than the average; especially do women who are so irregular
that they feel they cannot use the method, fail to submit their records (private
communication). In any event, the cycle lengths given range from 15 to 101 days,
no record is regular, and the maximum departures from individual means vary
from 1 day* to 53 days. In numerous instances nolations of illness (including
colds), fright, abortion, mental stress, physical strain, change of climate, etc., are
record'd as accompanying unusually long or short cycles. If these cycles are re-,
moved as atypical, as Latz believes they should be (private communication), then the
regularity increases appreciably. Lntz and Reiner conclude that 90 per cent of
women show a range of variation not exceeding eight days and that 80 per cent of
all \ omen menstruate regularly enough to make safe use of the Ogino-Knaus
Hterile period. Burtelmcz (1937) has commented on the 1935 publication uh follows:
..." by excluding all relatively long or short cycles which could possibly bo at
tributed to external influences like emotional upsets, infections, etc., and by an in
genious method of grouping his cases, [Latz] endeavors to minimize the extensive
variability observed. ’ ’
Part of King’s (1933) study, already mentioned, was devoted to a report on 21
women engaged in industry at Rochester, N. Y., and Baltimore, Maryland. A total
of 161 recorded cycles was collected, but difficulty was encountered with these
women in maintaining a sustained interest in the keeping of proper records; this
is shown by the fact that 11 individuals supplied not more than five cycles each.
None was regular. The maximum departures from individual means ranged from
one Jay (only five cycles recorded) to 26 days. Considering the small number of
cycles per person, the variability shown is considerable.
•One exceptional record shows 9 out of 11 cycles as 28 days long and the other
two as 27 days. The
Tl subject had been mentally deranged some years before .hence
one wonders
wonders at
at the
the trustworthiness of this sequence even though it Is possible to
And segments of long-term menstrual records that approach this one in uniformity.
4
ARBY
DEGREE OF NORMAL MENSTRUAL IRREGULARITY’
21
J he other homogeneous group
of women
women studied
King (1926;
1933) consisted
consisted
group of
studied by
by King
(1926; 1933)
of 33 Baltimore college undergraduates, graduate students, and instructors who r—
plied information
’ range of’ cycle
’ ' 'lengths
Q,"UVVVI3
”n0 from
8UP
phed
information concerning
concerning 716
716 cycles/^
cycles. The
extended
tH to 53 days and no individual was regular in any true sense over her respective ob
nervation period.
'IThe
he maximum variations fnom individual means varied from
2 to 20 days,.
On the whole, the younger members (17
(17 to
to 19 years) listed in King’s tables
show definitely more erratic records than do the older women. A greater variability
m adolescents, before the rhythm is well established, has boon mentioned by various
writers, yet the exact degree of such variability remained unknown until Engle
and Hhelesnyak (1934) recently investigated this matter. They have published data
obtained from 100 pubertal girls of a Jewish orphanage under conditions which
should guarantee the accuracy of the records. At least 20 periods were obtained
from each girl. The range in length of all cycles varied from 7 to 25G days, and
the individual variability was high, as well. Although 28 days is the mode of all the
■•ycles as a group, it is actually modal for only eight of the hundred individuals.
Irregularity was found to decrease as menstrual experience increased. At the end
of the first 20-24 cycles (mean terminal age, 15.5 years) the average standard
deviation from the individual means was ±20 days. Thereafter, there was a progressive trend toward regularity; for example, when 40 to 44 cycles-had been experienced
average terminal age, 16.4 years) the standard deviation for the total period sin^e
menarehe was reduced to ±10 days. Ball (Hartman, 1936) also found a great ir■ngularity m a study ( f adolescent girls at a state school near Baltimore. Hartman
19.iG : Las emphasized this matter in an interesting and significant way by publish
ing beneath Ball’s distribution diagram a second diagram, based on adolescent
monkeys, which is strikingly similar.
Another study limited to college students (of philosophy and medicine), resident
in university buildings, has been made by Scipiades (1935) at Budapest. Fifty
women furnished data for eight months. No person was found to be regular; the
extreme conditions are shown by two individuals who maintained their means in 43
per cent of their recorded periods and 38 women who on no occasion experienced their
means.
It is possible that clinical patients, such as those previously mentioned,
‘Io not present ideal material for menstrual study, yet it must be ad
mitted that their variability is no greater than in the college type just
described. More pertinent are the objections which have been advanced
against the representative nature of certain menstrual data obtained
from nurses training schools. This is because it is held as a welliecognized fact that a nurse’s mode of life is. conducive to marked
menstrual irregularities and even to indefinite periods of amenorrhea.
Not admitting the validity of this criticism, Allen (1933) studied a group of
uoent nurses at ‘ hicago. The individuals were unsclectod, but detailed conaidcraOu.i
bu "Hiilvd L. 11(1 uhoso .1,291 cycles wpio kumI to have boon strictly con(rolled through u diligent, pcrtumul check-up prosecuted by the supervising' nurse
at the time of each expected monthly report. No subject proved to be actually
regular, uue in four was
absolutely irregular/’ while
while the
the extremes
extremes of
of cycle
cycle length
length
ranged from .13 to 84 days. The six detailed, individual records which Allen gives
-— give.s
as typical samples show great irregularity. It is of interest that 87 rurses, who
at the beginning belicv d in their perfect regularity, actually were marked irregular,
bifty-three recognized that they wcro somewhat irregular but were astonished by
tne degree of irregularity brought, to light.
More fully presented were the results furnished by Fluhmann (1934) on 76 Cali
fornia student nurses. It is possible that these subjects were better selected than
Allen s. inasmuch as an elimination was made of individuals who were adjudged to
’■‘how. signs of menstrual disturbances duo to the imluonco of their changed environ
ment
A total of 747 cycles was collected over a period ranging from 6 to 13
I
22
AMERICAN JOURNAL OF OBSTETRICS AND
GYNECOLOGY
months. The cycles varied from 11 to over
of them were between 18 and 42 days lone 144 days in length, but 97 per cent
divergent than the
five-day range between their shortest
i
6 •
..1..... y..,h s
•'»
?d»-
“a
----- j irregularity.
nurses conspired
with
this seemingly excessive
P
*
0ccupatl0naI ^fluence to produce
Less homogeneous is a group of 50 nurses and office i
'
workers
uraished 299 cycles, as described by Pratt and his associates
(ig-’g)nt Detroit
At’the who
all considered they had regular periodicity
V.t
.1
7 A the start
disclosed, each was astonished at finding herself to hav h '6 'Vere
unfortunately consists of a mixture of adolescents and ad^ih
T'0"’ T"3 gr°UP
record# were not preserved it
nnt ,
-ki
an<
Since the original
cording to age actually was. In a let’tcrM])r 'pr'att0)
Hhat
d‘8tribution ac’
J
ecter, Dr. Pratt has written as follows: "None
Table. IV. 7
Detajled Data Pertaining r
to^8,812 Menstrual Cycles Furnished i
644 Women ano
_ G
---irlsA. ll the Cycles —3 of Each Group Were Combined and BY
Treated as if Belonging to a Single Individual
I
i
I
co
co
w
o o
I
©
M
Q
Jr f-
° v-
(
■<
M
Q W
r« f?5 a*
O o
O o
o
u.
o
Di w
M
'w
►-
f
w Q
w A
K
co
55
o o
►M
< Q co
£
OS F
2
MOO
«tt
2 H
?r
*
S? 3 3
Jr 0.4(1
10.54
27.8
28.4
2.09
2.34
2.93
3.27
0.13
0.05
11.51
0.12
27.3
2.2]
3.05
0.05
13.37
0.17
29.1
27.7
3.13
2.59
5.46
3.68
0.21
0.07
18.77
13.29
0.71
0.23
I 29 I 30.2
3.42
7.17
0.19
23.74
0.63
27
27
27
I
28
| 26.6
2.22
2.81
0.08
10.50
0.29
29
29
! 28.2
30.4
2.89
5.83
3.77
11.58
0.08
0.20
13.37
38.09
0.28
0.66
28
33.9
10.48
11.80
0.10
34.83
0.30
0.12
17.03
0.39
i 33.9
10.48
I 11.80
0.10
34.83
I
I
*In calculating the average deviations, the mean cycle length of each
r^»ced to the r.c-r.
‘It’ is impossible
0.30
1934
Means for
adults
Means for pu__bertal girls
' ■
... v. ... o
• ■ i c i c iy
28.4
I-
I
2.97
i
I-
28
4.92
I
[ ________
i vi <
j^*nce the percentages
"”™. “‘J-S.""." “s,“™ “ if,7 "
I
£
oi
c_>
S• p
1
: ?f*
28.01 -
28
28
o P
p°
SE %
?
- •
2. Lanmtir, 1889
Latz and
Reiner, 1935
4. Latz and
Reiner, 1937
»• King, 1933
I
* King, 1926;
I
1933
T. Scipiades,
1935
> Pratt, et al., I
1929
I
* Allen, 1933t
I
Fluhmann,
1934
1: Engle and
Shelesnvak,
p s
w5 £ *
o o,
G to
K
’ 5 <
z
o
p
I-’
i:s
A,,ep?fWo'J<
Although 1.291 accurate periods were
TMU III
It
I g
f’?!”
lo
were actually summarized in his
a<^aily extended fH nUSi •< Uf
<?neM o,n,ttc<l fro’” the ends of hU aericy. which
7l« or.? < cxt< nc*c^ from 13 to 84 days, can account for but few of the missinu
may' never STav?"’';1 (c,’rn’;,unk:aV°n J<r. AIh:n
that many of the original
r.o'.n V have been i . corded on the permanent record and this loss was
VpVe^ntaVlve^anr^
H(- bHIcves from memory that the entries in his Table III
Tabhs iv ? v? of » L th e rt H
Aave becn U8e<1 for the details entered
Slf ev. h? w r .
Present report. One can calculate proportionately that
i
'vcrc drawn from about 44 nurses. On the other hand, the more
ral data of the present Table III pertain to the full group of 110.
A HEY :
P£,U «
first menstruat.ons. Most
the
of the records included i> But since marked irreg
^Talle VII), one would ex
9f 16 and 25."-uounced at the -e^year (^V
the ag63 t
adolescent and is still pron
pect part of the
which gives
en3trual perio^ty h 1J
regular.
recent publication on me
■ careful investigation ye
volunThe most
This is the fullest and mo t
(mostly of the pro ®“,‘°t(j o{ uacb mensis.
Gunn (193/).
v J^ge number of British women (
month,
showing
I »'■ 0<'\1q womcn provided in•\dults. huuil record curds, nmn h b
- ■- -onlinued for one year. a
A /,iotal
“''and'41'others furnished less
leered to
Of data continue(for onej^
-3 be considered reasonably .P7?t’lie slmrtest and longest cycle is
The collection
that can be const er •
between the
t' ; shortest
formation
data. The typ.ca
‘
3Q pcr cenl of the women
complete
(osidered to be eight or n> three (jaV!t. The authors
(01----
it is so
days; - »’ “-..T^h'/r un absolute myth, or
case
is
either
an
very regtimr
computed from these
which have been extracted and
““ •;» v,
VI. It should
The details
in the original pubi investigations are presented in several
Jed. that many of the hems listed
L- do not exist in
13,500 Menstrual Cycles
be
.■uriositv.
More Than 0; Each Individual in
, Data Bertainino to
anp girlnThe RMODE,
e<ori> MEAN AND DEmT.0Nh
D
etailed
Table V.
973 Women and Girls.
SEPARATELY q.ve M
; ean
. Values eor the
Fvrxished BY 973 s-- W
as
i
ik
^
t
'
avbka
oed
to
a Group
erenaverage
THEN '1HESE W
NXbKb
_np AS 0A' WHOLE
and
Group as a
I
i < 2
Sg
I
I
I
I
X
<
v-
0 <
■z c._______
■.
§■£
r-lT
I
0as
27.8”'
I
29
i
!
•
!
ce
a: H
-J.
>
g5 'i027'
h1 5
I
/. >
I
S 7. I “ £ <
o I
I t ; u55z 25 iI o5S
>. < J 5.6?
C z 1
o
5. /■
"T. iHM/ner, 1889 1 27 ; 28 ! :’,0.8 '
2. UUz. nn<i
1.39
Reiner, 1935
I 27.7
27
3. Latz nnd
2.64
Reiner, 1937
i 28.9
27
I. Kibg, 1933
26 • 28.5
5 Gunn, et uh. b
2.04
1937
*1 28.4 I
27
6. King, 1926;
1933
‘ 29.9 '
29
7. Scipiadets,
5.06
1935
I 27;; 29) 32.4 !
S. Flnhmunn,
1934
9. Engle Rud
I
i i ■CS !
<
a P 7"2.11
Ti'i
1.42
i
i' hs|
w
■.r.
I
-
® cc r;
2 >- w
^-1 ^-----co—-- —
0.35 • i
c
'5.81 ;
6.53
0.31
0.35 .
0.09
I 11.59 I
j 14.10 |
1.25
0.30
0.21
I
I
1.83
0.00
I
3.35
4.09
I
I
I
2.59
.
1.31
0.27
0.0*
r
ft. o
—
9.49 i
I
j '2.56
1.79
I
0.75
8.98 |
I
I
I
6.50
1 1.28
I
0.35
0.68
20.03
I
I
I J
j
42.50
1.08
2.03
Shelesnyah,
0.75
0.22' ’ 10'93
3.24
1934
27 ';"29.3 ( 2.44
2.03
Y.8'McanH for
! 42.50
I
14.28
j
°G8
adults
I 33.6 I ------29
9. Meant for
*- •» value ot
table, *the
- means in the
puberUl g^lfj
■with other
reduced by 0.5
C-- day. See
has
been
co-worKeis.
n
avaraee
.. ’-lo
ro n
aake
this
average
make u
Gunn
j___ 1
’ -/ Gunn and i'ls
this”9.0 days, gTable
ven vj for the reason for doing
footnote to Table 11
II I
AMFJitCAN JOI RNAU <’F OBSTETKtCS AND GYNIX'.ObOGY
¥
24
lications except as they lie concealed m the raw data, ^he gfand mean
at th-- foot of all tables represent the averages of the ndtvidual
these are simple means designed to show the average value of the
Xral lots of data and mtentionally do not attempt to wetg t he un
even populations of the component groups. It seems
J
specifically on the facts’
II
of
"TplX^haTtZnX a'pparont at first inaction shottldI become
i
"tein". b e after ft..- a„p».le.l s.-.fton .... slatiat.c.l .ntorpretotm.. (p.
the cor
28) has l»-™
ft ■« o’’""-'’ th“t ■"
in' Tables IV to VI one must also
responding data for different groups
general, but pertinent, information contained in
keep m mind the r
Table HI.
Menstrual Cycles With Respect to
TABI.y VI. . 1’ATA -N the Distribution of The Tabulation Involves 8,812
I
ndividual
M
eans
.
Group Means ani>
Cycles Furnished by 644 Women and Girls
(
\
►j
I
‘ if
IS
i r-
I>
> o S Eu:
g
]. Foster, 1889
2. Issiner, 1889
3. kittz and Rcin.-r.
1935
4. I .ntz and Roinci.
10'7
Kin,'. 1933
6 Kilk. 1926; 1933
7. Scipiados, 19.
8. Pratt. <-t. al.. 1929
B Allen. 193.“.
10. Fluhinann, 193l
11 Engl'1 and
Shcl«-.‘ nvak. 19.>4
tor
1-10. Men:
adults
11. Means,
Inr
pubertal girls _
z
Ig3-z
i i'11.9
- z
-PS
2
! C c-
i
c z
°w *• zx:
I ., c
c
u. S
at. at
i at W c2 0^
_ z o
o2 at
“
c
Is
Ci B C-
1
p
C o
~c O
£
£z
§ ^°g
a.
Z
■<J
«S
5e
S
E> H >
5£s
0
C/3
S
’- w
Cl —
2
i
o
z. c
t ..is £
i W O ■—
w
S o M ft- S
co
*7 .© * K
J > w
- P >• <
< c z.
z5
o
fi o
w E* w <
r z t- w tn iz
“ S 5? z
— tjj •—
<
S z° w >P £ c o u:
S
S
=
£
X w - C
59.2
41.7
4 0.5)
28.9
40.0
41.3
25.0
4.9
8.3
35.3
2;
1;
12
22
ir».:;
■18.9
.31.8
•1.0
38.0
1;
53
39.8
54.6
38.1
48.1
41.5
59.1
85.7
33.3
15.2
76.0
23.8
9.0
5.0
1;
2;
26
20
13.5
9.1
12.4
1 1.0
7.5
50.9
.>1.9
52.8
.'’.9.5
47.5
33.4
11 6
32.9
33.0
13.2
1.0
2; 69
6; 211
12.8
•14.6
•123)’
27.3
18.9
1;
11.6
85.7
33.0
1.0
6; 2-1
18.3
18.2
I
09
_J______ 1_____ _ _________
established clearly the degree of variabilityr CXNo pro.vious writer has
• Only Chinn, Jenkin and Gunn (1937)
hibitcd by different. a<ro groups,
, <)n mis .opm. Yet the results of these investi-'
this topic
have presented information
.... confidence since they show the lowest variability
gators do not inspire,
(13 to 22 years; standard deviation, ±2.01 days) and
among the young ■■h v at 23 to 27 years (standard deviation, ±7.01 days),
the highest, conclusions
variability with respect to young individuals are direct.y
But these Cw,------ 1 x-noricnce Especially
.
contrary to general < xpe.rienee. Especially are
are they at variance with the
l0Benei“
1
•; conducted by Engle and Shelesnyak
detailed study on pubertal girls c------
25
DEGREE OF NORMAL MENSTRUAL IRREGULARITY
A HEY .
(1934) who found the standard deviation for the first 22 cycles (mean
terminal age, 15.5 years) to be ±20 days and for the first 45 cycles
(mean terminal age, 16.4 years) to be ±10 days. However, the two sets
of studies are not directly comparable since Gunn had access to only
three records in the 13- to 17-year period.
In order to arrive at some firmer conclusion on the relation of varia
bility to age, all the'available data used in the present report were sorted
into age groups and analyzed. In the furtherance of this Shelesnyak
kindly supplied his original records on pubertal girls. It was desired to
obtain information on the early, middle, and later periods of adolescence
and on the definitely adult woman. Practically all the studies heretoTable VII.
source
The Degree of Menstrual Variability in Relation to Age.
Mean Standard Deviations in Each Group Represent the
Average of Individual Means
or DATA
Engle and
Shelesnyak
(1934)
Engle and
Shelesnyak
(1934)
Fluhmann (1934)
King (1926;
1933)
Fluhmann (1934)
King (1926;
1933)
Isomer (1889)
Latz and Reiner
(1935; 1937)
Gunn, et al.
(1937)
Gunn, et al.
(1937)*
I NO. OF
I SUBJECTS
AGE RANGE OR
CYCLE NO.
SINCE
MENARCHE
(ALL INC.)
mean no.
MEAN
OF CYCLES
AGE OF
PER
SUBJECT
PERSON
The
MEAN STANDARD
DEVIATION FROM
MEAN (DAYS)
22.0
20.0
15.0
10.36
ca. 18.5
ca. 18.5
10.3
S.9
ala lmean>4-33
22-27 yr.
22-35 yr.
23.1
26.6
10.4
18.4
2.67 >
2.24
10
200
22-39 yr.
22-49 yr.
28.1
31.4
10.0
12.2
2.37
1.8 V
j
336$
23-51 yr.
30.3
F3.0
4.57
i
146||
23-51 yr.
30.7
13.0
3.95
26
l-22nd cycle
14.5*
18
25-39th cycle
15.51
21
14
18-19 yr.
18-19 yr.
15t
33
I
I
I
I
-mean, 2.27
I
i____
•Age at the end of the eleventh cycle.
tAgc nt the end of the thfrty-KCcond cycle.
|One very irregular record of only four cycles (standard deviation, ±35.34 days)
was omitted.
{This constitutes Gunn’s full group of reasonably reliable cases.
by Gunn from the larger
3A selected group, with most iclliabic data, chosen V
group of 33G.
1
i
.1
■
fore have been based on mixed groups of young and adult women
(Table III), so that the conclusions given in Tables V and VI do not
fulfill the present need. The results of these new calculations on the
relation of variability to age are. summarized in Table VII where de
creasing variability with increasing age is shown clearly. Since Gunn’s
data are not in agreement with the general findings presented in this
table, his figures have not been used in obtaining an average value for
adults. If his larger value (±4.57 days) is included, then the mean
standard deviation rises from ±2.27 to ±2.79 days; including his smaller
select group, the average becomes ±2.61 days. It may be concluded that
fl
fi
( >
• I
AMERICAN
JOURNAL OF OBSTETRICS
and gynecology
fcxtx—1 r'i: s X"3?d^=dx
. I-
(her individual mean.
H Collateral evidence ae to the general
Xicenung the existence of considerab
Imes from Hartman's (1932) close o ^J0"8
Regularity is the rule
For exampl
‘
menstrual cycle
mOnkey colony; there, also,
22
fema]es the
m 392lcyc.es
27
ffistribution range extended from 14 to
? ’
bc
the wide distribution of
>28 days and the mode at 28 days^ s m l
nnfl not to differencea
/cycle lengths is due to thet .rregu 1 ^y
individunls
tietween regular individuals.
irrepularitv exhibited in the detailed menstrual
-Ranged from 24.G to 31 days; ye> *
evi(lenc0 i„ to be
Record of almost every animal v a.
cyclc of the
[Cnd in the recent study of E 1 Cr
normal alld mature animals the cycle
tfaximpanzee. For 164 cycles o
P
.IVnr-urc for till cycles was 36 days, the
Qength varied between 29 and
<^uys
»c <
shortcbt nn(1 iongcRt cycle of any
[kode 35 days. The smallest difTerence
human femaie,
*Cimal was 9 days; the largest differe
• 2^
understanding
I
I
; .both of these Pnma,eStrRri'cXuation one cou’ld scarcely expect it to be a wholly
; -of the factors governing menstruation one
Pperfect mechanism, either in monkey or m man.
SUMMARY AND CONCLUSIONS
I
down at the time of
set
1. Only the records; of consecutive menses,
duration and variability of
in studying the
occurrence, are of value
histories, oral testimony, and
Ordinary
p menstrual phenomena, orainary hospital •n" " cannot bc given serious
unaided memory
consideration since experience proves them to
2. Some 20,000 calendar records from
in 12 different t------ ,
‘
1 ’"X —w
kJ
—rCTh"’/kncth of all oyoios is 33 9 days for gM- »«
. <
i
CVclcs (the prand mode of the inU days for women
4. The
.“'ns1) 'is a.eided between 30 .nd 31 da.r. tor
divadual modes of 1:26^1SO /or flf]ult womCn. The mean length of
pubertal girls and is
yj | an(j 29.0 days
cycle, based on individual averages, is 33.6 days
I’
for women.
5. Statement*
unrepresentative of the
significance i
wide variability encountered.
6. The maximum departures
from 1 to S9 days in “dolt.
from combining all
---- r distribution,
7 The smooth frequency is r
»
result of overlapping innf a croup into one curve, is the result ;^ividnal
« „ ........... .
il
*
■
8. The exmeace of favored, subordinate types of cycle length (such
as 3, 5, 6 and 7 weeks), in addition to the modal type, do not appear
either in the massed cycles of groups or in the records of individual
performance. This is in sharp contrast to the conclusions based upon
oral testimony9. In the first few years of the menstrual function the cycle length
is extremely variable (7 to 256 days). It can be calculated that during
the period of observation employed (averaging 31 cycles per person) onethird of the 100 pubertal girls never had a cycle that corresponded
with their own means. Only one girl experienced her own mean as
often as once in three cycles. From menarche to the twenty or twenty
fourth cycle, only two-thirds of the total cycles of an average individual
kept within a 20-day range above and below her mean. Yet in middle
adolescence, occupied by cycles 25 to 39, the regularity improved to such
an extent that, on the average, two-thirds of all the cycles kept within a
10-day range.
10. At the end of adolescence, during the eighteenth and nineteenth
years, the variability is still further reduced. In the 35 individuals
studied, two-thirds of the cycles kept within a range of ±4.4 days with
respect to the mean.
11. In several hundred adults more than 21 years old, a fluctuation of
about ±2.5 days with respect to the mean expresses the limits of varia
bility which contain two-thirds of all cycles. Expressed differently, an
average adult woman must expect one-third of all her cycles to depart
more than two days from her mean cycle length.
12. The amount of variability shown by adults is greater than
ordinarily is credited. Cycles ranging from 2 or 3 weeks to 7 or more
weeks appear in all of the groups (17 to 49 years) from which data have
been collected. In the records of more than 500 women, 27 per cent
never showed their own means during the observation period which
averaged 11 cycles in length. Only 20 per cent experienced their own
mean in at least one-third of their recorded cycles.
13. The adults, reported in detail by 11 different investigators, repre
sent all ages from late adolescence to approaching menopause. They
include American, Canadian, British, German, and Hungarian subjects,
and they sample various grades of society. In no instance did an ex
ample of perfect menstrual regularity appear over any significant period
of time; this is all the more noteworthy since many individuals had
previously declared themselves to be the acme of invariability. The
most regular records are short ones. In a separate (unpublished) study
of menstrual records extending as long as 20 years, it will be shown that
temporary successions of atypical regularity (or irregularity) may occa
sionally interpose themselves in a rhythm of fundamentally different
characteristics. It is these unrepresentative fragments of the true record
that sometimes lead to erroneous conclusions concerning an individual
rhythm; even a record extending for over a year may prove to be un
representative.
14. In the face of all these facts it seems improbably that menstrual
regularity, in any true sense of the word, ever will be encountered over
I
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28
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
sigfi Scant periods of time. Certainly, not the slightest evidence pointin» jward perfect regularity has so far been produced for even a single
exqj tional individual. Should such a person be found at some future
ting she will constitute a true medical curiosity.
$1 Studies on the monkey and chimpanzee disclose menstrual irremlarity comparable to that of the human being.
STATISTICAL METHODS USED AND THEIR INTERPRETATIONS
I
►ta can be interpreted properly only through the uae of proper statistical
mei )dn. Since many arc unfamiliar with thcHC method*, and CHpecinlly with the
inti retations to be made from such numerical findings, it seems desirable to explain
thejprocedures used in the present study.
A. 5 ea^ures of the Central Tendency:
IfThe a ithmetic mean (M) is the sum (-) of the separate variates (v) divided
by^ e! number of variates (N).
~ v
M
i!
I
The n\ode is the class with the greatest frequency.
B.;^easures of Variability:
2 The range is the total spread of distribution from the lowest to the highest,
It tells nothing about the shape of the distribution or the degree of concentration
ab<Jut the central tendency.
21 The average deviation (AD) is the average of the individual deviations from
thejsnean (regardless of sign).
Qie individual departure of each variate from the mean (v - M) is found by subtra jtion. The sum of these is next obtained without regard to whether a deviation
liei Jabovc or below the mean. Finally, this sum fX) is divided by the number of
vai Jtes (Nj.
S (v - M)
AD
N
average deviation of a normal distribution marks the limits of the middle
Applied to the present study, the chances arc
57J per cent of the measures.
slii itly better than even that the length of a random menstrual cycle will lie within
thd limits of the average deviation from the mean.
| The stand deviation (<r) is the square root of the mean of the squares of the
de’ ations from the mean.
o find this value, each individual variation from the mean is squared ( v - M)2;
th* 0 are then summated (regardless of sign) and divided by the number of variates
(n: Finally the square root of this mean value is extracted.
™
/
a
V
(v - M)2”
N
TH? standard deviation of a normal distribution marks the limits of the middle <17
|>ertcent of the measures. Applied to the present study, it. may bo expected that
txviTgcycles out of three will lie within the limits bounded by the standard deviation,
i— thrice
-------- the
— standard deviation can be
Siglarlv, a variation equal to twice and
Lcted only once out of 22 and 370 cycles, respectively.
. The coefficient of variation (CV) is n value obtained by reducing a standard
dqj Fation to an abstract number which then allows this particular standard devia
ti<J to be compared directly with any other standard deviation similarly treated.
js obtained by multiplying the standard deviation by 100 and dividing by the
Xt?
mei n.
i
Hence it expresses relative variability in terms of per cent of the mean.
100 a
CV =
M
i
AREY :
DEGREE OF NORMAL MENSTRUA
IRREGULARITY
29
tested. The chances are even that the true value lies within the range of the probable
error. The chances that the true value lies within ±2 PE are 4.6:1; similarly the
chances that the true value lies within ±3 PE are 22:1.
1. The probable error of the standard deviation is obtained by multiplying the
standard deviation by 0.67 and dividing by the square root of twice the number of
variates
0.67 a
~ V2N
2. The probable error of the coefficient of variation is obtained by multiplying
the coefficient of variation by 0.67 and dividing by the square root of twice the
number of variates.
0.67 CV
PECV
V 2N
REFERENCES
Allen,
Am. J. Obst. & Gynec. 25: 705, 1933. Arrhenius, S.: Skand.
Arch. Physiol. 8: 367, 1898. Ball, J.: Cited by Hartman (1936); see his Fig. 28.
Bartelmez, G. W.: Physiol. Rev. 17: 28, 1937. Davenport, C. B.: Statistical
Methods, etc., New York, 1926, Wiley & Sons. De Lee, J. B.: The Principles and
Practice of Obstetrics, Philadelphia, 1934, W. B. Saunders Co. Elder, J. H., and
Yerkes, R. M.: Anat. Rec. 67: 119, 1936. Enqle. E. T., and Shelesnyak, M. C.:
Hum. Biol. 6: 431, 1934. Fluh-mann, C. F.: Am. J. Obst. & Gynec. 27: 73, 1934.
Foster, F. P.: New York M. J. 49: 610, 1889. Geist, S. H.: Am. J. Obst. &
Gynec. 20: 320, 1930. Gunn, D. L., Jenkin, P. M., and Gunn, A. L.: J. Obst. &
Gynaec. Brit. Emp. 44: 839, 1937. Hajek, O.: Zentralbl. f. Gynak. 57: 257, 1933.
Hartman, C. G.: Carnegie Contrib. Embryol. 23: 1, 1932; Time of Ovulation in
Women, Baltimore, 1936, Williams & Wilkins. Hartman, C. G., and Squier, R.:
Am. J. Obst. & Gynec. 33: 690, 1937. Issmer, E.: Arch. f. Gynak. 35: 310, 1889.
J. Fujin-Koron (Feminine Public Opinion); see Ogino (1934) for cited statistics.
Kennedy, W.: J. Obst. & Gynaec. Brit. Emp. 40: 792, 1933. King, J. L.: Carnegie
Contrib. Embryol. 18: 79, 1926; Am. J. Obst.
Gynec. 25: 583, 1933. Knaus, H.r
Periodic Fertility and Sterility in Woman, Maudrich, Vienna, 1934. Latz, L. J., and
Reiner, E.: J. A. M. A. 105: 1241, 1935; III. M. J. 71: 210, 1937. London Associa
tion of the Women’s Medical Federation, Lancet 219: 57, 1930. Nakagawa, J.: Jap.
J. Obst. & Gynec. 14: 154, 1931. Novak, E.: Menstruation and Its Disorders
New York, 1922, D. Appleton-Century & Co. Obata: See Ogino (1934) for cited
statistics. Ogino, K.: Zentralbl. f. Gyniik. 56: 721, 1932; Conception Period of
Women, Harrisburgh, 1934, Medical Arts Publishing Co. Papanicolaou, G N •
Am. J Anat. 52: (suppl.), 519, 1933. Pratt, J. P., Allen, E., Newell, D. E., and
Bland, L. J.: J. A. M. A. 93: 834, 1929. Richards, O.
6. W.: Am. J. M. Sc. 190; 641
1935. Stynes, K I.: Am. J. Obst. Dis. Worn. & Child. 73: 93, 1916. Scipiades E.'
Arch. f. Gynak. 159: 360, 1935.
Sasaki, S.; On the Effect of the Function of the Anterior Pituitary Lobe on
Narcosis, Jap. J. Obst. & Gynec. 20: 620-632, Nov., 1937.
i
The author studied rabbits which were subjected to general anesthesia by means
of, chloroform. He injected one group with anterior pituitary gonadotropic hormones
and found that the duration of anesthesia was decreased but the recovery time
showed no change. The effects of the injection of anterior pituitary hormone were
almost identical with thoso produced by entrin. When the pituitary gland was
irradiated with large doses of roentgen rays the duration of the anesthesia was
increased and the recovery time decreased. Prominent regressive degeneration was
observed in the pituitary gland and in the ovaries after strong irradiation of the
pituitary gland with x-ray.
J. P. Greenhill
zJ-Z''z/zEjf 0 /< c- -
German Remedies
c
Limitec
6E. Ram Jhansi Road. Jhandewalan Extension. New Delhi 110 055
Pharmaceuticals of
Boehringer Ingelheim
Homburg
Nordmark
"Schering A G
July 22, 1986
Wulfing-
Drugs Controller (India)
Directorate General of Health Services
Nirman Bhavan
New Delhi
Dear Sir:
As desired by you, we give below the latest
where NCRI5TERAT is registered/available:
^GER^ANY, [DENMARK, [FRANCE,
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list cf countries
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Bangladesh,
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•t
IVORY COAST,
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/
PORTUGAL, RHODESIA, SPAN* SPAIN, SOUTH AFRICA, TAlwAN,
We hope the above information given
Than king you,
Yours faithfully
for GERMAN^REMEDIES LIMITED
SRI LANKA.
will suffice the purc-o sc.
I
$
I
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9
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THE
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MEMBERS OF
ETHICAL ASPECTS
TO CONSIDER
HUMAN SUBJECTS
/
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S-368, PancXsheZl Park
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Chand iga rm 160 012
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I
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(Cha i rman)
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Dr.S.S.Gothoskar*
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!
.»r - V v. x i ill C a i A j . ; .
Jontracept iw
■ r r ■;: d a 1
.'•’ou r t .’i D r .j r t , 19 H.-b
1.
rrv mble
Ur.en the rirst steroidal contraceptives were developed, it appeared
logical to submit them to the same toxicological tests that were routinely
conducted with other arugs. This included a set of repeated-dose toxicity
studies in at least 2 species, lasting approximately 3 months (sub-chronic)
anc lx uonths (chronic), and standard reproductive toxicity experiment
in rats
and raboits with special emphasis on teratogenicity. As a general
requirement, all these experiments had to be performed with at last 3 doses
one of /hich was expected co cause demonstrable toxic effects.
Since contraceptive steroids are taken by a large number of healthy younv
w' ien tor a considerable length of time, the carcinogenic risk had to be
consiceieu carefully.
Therefore, a standard rodent life-time carcinogenicity
bloassay was requested and performed in mice and rats.
Fur the rmorc the U S
Food .nc. Drug Administration decided that all contraceptive steroids should be
evatuuu.a i!- long term studies in beagle dogs and rhesus monkeys, lasting 7
0 eurs respectively.
For these experiments, it was .imi turiiv decided
that they should be conduced with doses corresponding to 1-2, 10 and 25 times
Che anreipated human contraceptive dose in dogs and 1, 10 mid 50 times this
dose in monkeys, calculated on a mg/kg body weight basis.
Ext'nsive experimental and clinical experience has shown that these
toxic- 1 •gicai procedures do not provide the best possible Jat.i base on which
huipan r sk can be assessed,
The animal studies are buruened with an
unitee□ ably hign incidence of adverse
-- » effects which are either clinically
irrelevant or uninterpre table.
The costs are excessive for the limited
informa: ion that can be gained, and the overall
approach is too inflexible to
allow for an optimum design of the experiments.
The principal reasons for the unsatisfactory performance of
current
toxicologicl testing of contraceptive steroids are:
lack of concern for the special characteristics of reproductive
physiology in different species of laboratory animals and in man.
insufficient consideration of species differences in responsiveness
of primary and secondary f-*-'
sex organs to pharmacological concentrations
of steroid and pituitary hormones
- ; and steroidal contraceptives.
failure to take into account the species-specific peculiarities of
feedback mechanisms and responses of individual hormone-dependent
organs.
disregard of pharmacokinetic concept» in the design of the toxicity
tests.
is made to propose a more scientific approach
/ In
co safeiy testing of
tliat th«» Important speciespharmacokinetics preclude the uncritical
organ rssponsiveness and iP
*
Instead, studies in various laboratory
standard toxicological test models, and for all measureable pharmacodynamic an
animal ipecies should be performed
should be established. Whenever
toxicological responses dose-relationships
with measurements of blood
possible these data should be supplemented
^Srp^vi^ th:8:L"ct:n:X:"hr: mor^eaSgful^ta
concent rations and <--’ » clinicians with a
these investigations t_ of human risk than that obtained with tae current
risk than that <-----base fo\' the assessment
check-list approach.
* ■> differences in target organ
It is also recognized1 that the markedto species
predict the effects of steroidal
impossible
responsiveness make it often
c
animal data. For this reason, these
humans
from
laboratory
Contraceptives in
to the careful assessment of
importance
Recommendations attach great
in humans and to a diligent and prolonged monitoring
endocrinological effects
bf selected populations of contraceptive users.
(
2
Tes.ing Strategies
The safety test proposed in these guideline
Toe mos important ones are as follows:
J
have different objectives.
• (endocrinological) propertie1
• i of the pharmacodynamic
Characterization
frequently used laboratory animal
in the most 1
at effective doses
<—
species.
_j after single and
Detection and characterization of toxic properties
(toxicity “per se“>.
repeated administration over a broad dose range (
----- repeated administrations of effective dose,
Target organ response
animal species.
stnairmultlples thereof in selected laboratory
and s--- —
PM„.eokl«C1e. .nd ....folic 1... ol .1.0 .«•<
the
frequently used laboratory animal species.
teratogenic properties.
Detection of mutagenic and
(^endocrinological) propert:
Characterization of the pharmacodynamic
in humans at effective doses.
I
i
h
I]
III'
Binding characteristics
and androgen receptors.
of compounds toward progesterone, estrogen
administration of effectives
Target organ responses to prolonged
doses to humans.
the test compounds in huoar^.
Pharmacokinetics and metabolic fate of
li
Dose levels and mode of administration s.iouid be Justified, taken into
consideration the physiological characteristics or rhe laboratory animal
species used, and the pharmacokinetic peculiarities of the test compound.
Every effort should be made to avoid the induction of endocrine dysfuncitons
of a kind that are unlikely to occur in humans treated with effective doses.
3.
Test Procedures
(Note: awaiting additional material from Giinzel and Heywood on 3.2, 3.3,
3.4, 3.5.)
3.1 Central Concepts
All toxicolog lea; experiments must be conducted according to modern
standarcs of industrial toxicology and must comply with the objectives of good
laboratory. .practice,
—• Observance of guidelines for laboratory animal welfare
must be assured.
(
As , general rule, test compounds must be administered by the route
proposc< for human use in a suitable vehicle which need not necessarily be
identic..! with the one envisaged tor theiupeutic use in humans, unless test
procedures have to be adapted, taking into consideration the special
pharmacokinetic and physiological characteristics of the animal species used.
['
*'
p.2 Pharmacodynamic (Endocrinological) Investigations
*■
i
!*
. I|
A detailed analysis of the endocrinological profile should be performed
aping standard bioassays in a given species lor cstrogenlcity, gestagenicily,
lindrcgernicity, anabolic effects, and the corresponding ant i-effects .
In
addition, the central steering mechanisms ot endocrinological balance and the
influences on peripheral reproductive functions should be Investigated.
For
all pharmacodynamic investigations it is essential to establish dose-effect
■relationships and to consider the pharmacokinetic characteristics of the test
<subs t ances.
ii
3.3 Single- and Re pea ted-Dose Toxicity Studies
In order to assess the hazard of acute intoxication for new compounds, a
limit-tjst using3 one group of not more than 6 rodents of each sex should be
iperf or» »d. A single very high dose of the test substance, not exceeding 100
ijtimes t le antic i t pa t.rd human dose calculated on a body weight basis, should be ,
i Itdministered by the route anticipated to be used in humans.
I
Animals snoulo b# observed for at least one week or until signs have
disappeared and norma i feeding behaviour and weight gain are re-established,
/Clinical signs must
carefully monitored. All animals must be autopsied.
Organs exhibiting suspicious morphological changes after dosing should be
■: urgans
I examined histopatno logically.
I
I
kepeated-dose toxicity
:
experiments should
conducted in at xeast one
laboratory animal species, The preferred species is one in which the desired
phr .-macod ynamic effect can be demonstrated readily.
However, it is well known
t, < xhat this mignc be impossible because of fundamental species differences even
in pharmacodynamics,
In any case, the choice of the animal species should be
just i fled.
• east enree .jobc levels should be used t<? demonstrate dose dependency
unless it is not possible.
The top aose should be a multiple of the low (not
more :h.in 2 5 times ,i o f anticipated human dose, calculated on a mg/kg body
weigh t )asis provided the bioavailability of
the compound is sufficiently
high.
ihe
Lhe xow dose snould be
bp the
rho one ccausing the desired or another
pharmac Jdyr.amlc ef fee: , if possible but: at least sufficiently bioavailable.
1
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The duration of treatment should be a cinimuci of JU days and, in general
general,
not i
;er :han 6 months. C'
’ '
Clinical
and laboratory variables monitored during
and at ihe end of the experiments are the same as those studied in standard
toxic it / studies .
3.4 Pna.-macoKinetic and Metabolic Studies
Single dose pharmacokinetic experiments should optionally be performed
in
those species of laboratory animals which were used to establish the desired
pharmacodynamic effects (see 3.3) and regularly in those selected for the
repeated-dose toxicity and carcinogenicity (see 3.2: 3.7) studies,
In the
same animal species, the metabolism of the test compound should be
investigated.
The major routes of excretion and organs with preferential
accumulation after single and repeated administration should be identified.
The elimination kinetics in blood and organs of accumulation should be
determined.
If possible, the major metabolites of the test compounds should
be identified, at last in the species used to establish the desired
pharmacodynamic effect and those used for repeated-dose toxicity experiments.
!i
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3.5 Reproductive Toxicity
Considering the marked species differences with regard to steroid
petabolr.sm we propose to continue using the rat and rabbit for assessments of
embryocoxiclty/teratogenicity.
Three phases must be considered preimplantation, organogenesis and the period of perinatal development - with
tagard »:o the compound studied. The perinatal phase is of importance wnen
dealing with androgens, antiandrogens, estrogens and antiestrogens.
|
I
Three dose levels might be used. /.Il
All main studies have to be prephased by
preliminary dose-range finding studies to acertify appropriate high dose
(levels. The ’high
’ _‘ dose Level for the preimplancation study must not interfere
$ith inplantacion.
For the teratogenicity study the high dose must not induce
•'•ore than 10 per cent embryolethality or significantly interfere with body
weight gain. The studv design might be one which might allow dams to litter
spontaneous!;, and tn.- pups should be examined for malformations, particularly
In the ,iex organs by studying the next generation.
Stardard fertility segment 1 studies
pos t-nat al studies of development might _might not be appropriate. Perl- and
take into account that sone compounds
might
delay partition and the study might
Th.
: be designed for normal delivery
This could be achieved by withdrawal of
dosing during the delivery phase, 11th
sopic of the depo-agents it is impossible
to study this aspect of performance.
ihe low dose selected
should be the effective pharmacologic dose in that
species.
3.6 Hute.genicity Studies
(
Genotoxicity should be
examined in
in
be examined
a system which measures
— specific locus
mutation and evidence of ’clastogenicity
should also be sought. Tile use of in
dependirg°on th recon™ende‘?• Appropriate methods
------ j are left to the sponsor aepenuir.g on the outcome of rodent
carcinogenicity
studies for example,
covalent binding to DNA in selected
target organs might be desirable.
3.7 Carcinogenicity Study
A standard lif e-time bioassay should be
The choice of the species should be justifiedconducted in one rodent species.
At least 2 dose levels should
ne used .
The highest dose should be a small
multiple
(2 to .) times) of that
causing significant
| '
- ----- pharmacodynamic
effects
in
the
species
selected for t he
test. 7he lowest dose should be a small multipl
e
provided
me bioavailability
is sufficiently high, The dosage regimen should
be
patterned
that ant icipated for use in humans.
according to
i
t.
I
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c
■ff
Z
07
3.
First Evaluation in Human Subjects
Tnc following qualities of the test dtugs toiiould be established in human
v> unteers:
i
Human tolerance (single and repeated doses)
Dose titration
Endocrine system monitoring
■
3^9 Pharmacokinetic and Metabolic Investigations in Human Subjects
Single dose pharmacokinetics should be studied in at least female
volunteers.
The following parameters should be measured:
Bioavailabili ty
C max
t max
Terminal half-life
AUC (ug/ml x h)
Major routes of excretion and major metabolites should be investigated.
4.
Sequence of Clinical Investigations
r
} v
In order to perform Phase I (tolerance, single dose pharmacokinetic) and
Phase I', (efficacy trials lasting not more than 3 months) clinical trials, the
u. single-oose and repeated-dose toxicity studies (3.3), and the essential parts
i; of the pharmacodynamic analysis of the test compounds (3.2) must be
fl*completed. No teratogenicity studies are necessary at this stage, provided
that pregnancies are excluded.
»
For the initiation of Phase III clinical trials involving treatments
lasting more than 3 months, the reproductive toxicology (3.5), the
mutagenicity experiments (3.6), the pharmacodynamic analysis in laboratory
animals (3.3) and in humans (3.8), and the essential parts of the
pharmacokinetic and metabolic studies in animals (3.4 must be completed, and
the lif<-time carcinogenicity bioassay in a rodent species (3.7) must be
underwa).
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