ICMR BULLETIN VOL. 28-No.-1-JANUARY-1998
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- ICMR BULLETIN VOL. 28-No.-1-JANUARY-1998
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ISSN 0377-4910
icmr
January, 1998
Vol. 28, No. 1
MENOPAUSE AND HRT
All women who live beyond the age of 55 to 60 yr and
many of a younger age, experience a period of transition
from the reproductive to the nonreproductive stage of life,
of which the most striking feature is the cessation of
menstruation ie the menopause. Menopause is defined as
the permanent cessation of menstruation resulting from
loss of ovarian follicular activity.1 The mean age at
menopause has remained constant at 50, despite increase
in longevity. In developed countries,where women have a
life span of more than 75 yr the postmenopausal years
comprise one-third of a woman’s life. By the year 2000,
the average life expectancy for women in developing
countries is expected to be 65 to 70 yr1. The worldwide
population of postmenopausal women is expected to be
1.2 billion by the year 2030, of which 76 per cent will be
living in developing countries2. This sharp increase requires
serious consideration of the health needs of this age group
in developing countries. Although the term menopause and
climacteric have generally been used interchangeably,
menopause refers to a woman's last physiologic bleeding
episode and is only part of the climacteric. The climacteric
(or perimenopause) is the period of transition from the
reproductive to the nonreproductive stage of life and thus,
usually begins several years before (premenopause)
and extends for a number of years (postmenopause) after
the menopause. The climacteric is characterised
endocrinologically by evidence of decreasing ovarian
activity, biologically by decreasing fertility and clinically
by alterations in menstrual pattern and by a variety of
symptoms.1
Demography
The median menopausal age is 50-51 yr with a range
of 39 to 59 yr3. Undernourished women appear to have
menopause 4 yr earlier compared with those who are not.
Of all the known possible risk factors associated with
menopause, cigarette smoking is perhaps the most well
documented. Smokers have menopause on an average one
to two years'earlier than non-smokers. No other factors
have been consistently related to menopausal age. Repro
ductive history, including early menarche, parity, upper
socio-economic class, higher educational status and oral
contraceptive use have been suggested to be associated
with later menopause, but the associations have not been
consistent.4
The menopause is defined to be premature if follicu
lar regression occurs before the age of 40 yr.5 Women who
experience premature menopause, either spontaneously
or following surgery or radiotherapy are more prone to
the distressing symptoms and. long-term sequelae of the
menopause.
Endocrine Changes during Climacteric
Menopause occurs due to ovarian senescence which
occurs due to exhaustion of ovarian follicles. Oogenesis
starts as early as the third week of gestation, reaches a
maximum at twentieth week and subsequently declines till
menopause. The foetal ovary contains approximately
7 million primordial follicles which reduces to 2 million
n of Publication & Information^ l( MR, New Delhi - 1 10 029
at birth and approximately 3,00,000 at puberty. Ninety per
cent of primordial follicles undergo atresia and only 10
per cent ovulate ie approximately 400 ovulations in a
woman's reproductive life.6 The ageing ovary reflects the
decreasing capacity of the residual follicles to secrete
estradiol which decreases from 300-500 pg/m 1 to less than
25 pg/ml.5 In postmenopausal women estradiol is derived
primarily from the peripheral aromatization of
androstenedione to estrone to estradiol, which increases
from 1 per cent in premenopausal to 1.5-4 per cent in
postmenopausal women.7 This androstenedione is also
converted to testosterone. Decreasing estradiol levels and
increase in ovarian testosterone increase the androgen/
estradiol ratio8. The decreasing levels of estradiol result in
10-20 fold (ie 75-200U/1) increase in FSH, and 2-3 fold
(ie 60-90U/1) increase in LH.7,9 Excessive increase in FSH
is also due to lack of inhibin secretion by the ovary which
has a FSH suppressive action.10 The periodic pulsative
releases of FSH and LH are due to increased responsiveness
of pituitary to gonadotrophic releasing hormones. Later in
menopause the FSH and LH levels decrease but still remain
above the fertile cycle levels. Progesterone levels also
decrease. A decline in serum prolactin levels consistent
with decreasing estrogen is also seen.8
Menstrual Pattern during Climacteric
The falling levels of estrogen result in menstrual
changes. As women come closer to the menopause, men
strual periods ofren become irregular and are usually less
frequent. In some women there is transient polymenorrhoea, mainly due to a reduction in the follicular phase.
The menopausal transition-ze the time from the onset of
irregularity of the menstrual cycle to the final menstrual
period-lasts for an average of 3.8 yr.”
Short Term Symptoms
At climacteric, ovarian estrogen and progesterone
production fall to low levels which in some women is
associated with a series of signs and symptoms due to the
physiological consequences of sex steroid deficiency.
Deficiency of estrogens may result in atrophic changes in
the genital tract leading to vaginal dryness, atrophic
vaginitis, dyspareunia and the development of vasomotor
manifestations such as hot flushes, excessive perspiration,
palpitations, headache and vertigo. The women may also
suffer from psychological symptoms such as increasing
nervousness, apprehension, lack of concentration,
irritability, depression and insomnia. These symptoms
comprise the menopausal syndrome. The prevalence of
menopausal syndrome varies widely not only between
individuals in the same population, but also between
different populations.Also, it has been difficult to
distinguish between symptoms that result from loss of
ovarian function and those from the ageing process or from
socio-environmental stresses of the mid-life years. Some
of the more common symptoms are described below.
Vasomotor symptoms
Hot flushes, night sweats, insomnia, palpitation and
headaches are usually attributed to vasomotor instability.
Of these, the hot flush is the specific symptom of the meno
pause. The hot flush is described as a sudden reddening of
the skin over the head, neck and chest and is experienced
as an explosion of heat followed by profuse sweating. The
flushes usually last from a few seconds to several min
utes. They occur at varying intervals from every 10-30
minutes to once a week or more.12 They occur more fre
quently at night. Insomnia usually occurs as a secondary
effect of sleep disruption caused by night sweats.11
The prevalence of hot flushes associated with
menopause varies in different cultures. For example, the
prevalence has been reported to be nil in Mayan women,
10-22 per cent in Hong'Kong women, around 17 per cent
in Japanese women, 23 per cent in Thai women, 45 per
cent in North American women and up to 80 per cent in
Dutch women. Although some studies have shown
inconsistencies in the reported prevalence of these
symptoms, in general, flushes and sweats are more
common in European and North American women than in
other populations. A high intake of dietary phytoestrogens
(estrogen like compounds found in plants) has been
suggested as a possible explanation of the lower frequency
of menopausal symptoms in Japanese as compared with
Caucasian women.11
Recent studies 13 suggest that menopausal symp
toms occur due to an imbalance of the endogenous opioid
system. Endogenous B-endorphin and other opioids regu
late nuclei in the brain stem which in turn may influence
not only the temperature regulating centre but also vessel
wall functions. The endogenous opioid system is regulated
by several factors and after some time a new equilibrium
is achieved and symptoms subside.
Urogenital atrophy
The epithelium of the vagina and of the urethra
and bladder respond to estrogens. If estrogen
concentrations are insufficient, these tissues atrophy. The
vaginal epithelium loses its normal rugose appearance and
becomes attenuated, pale and transparent. The depth of
the vaginal vault is shortened and the upper third begins to
constrict. Atrophic vaginitis can result from marked
atrophy of the lining of the vagina. Vaginal atrophy can
cause vaginal dryness, burning, pruritis, dyspareunia and
prolapse.The pH ofthe vagina increases, thereby promoting
the growth of bacteria which may result in vaginal
infection. Atrophy of the mucosa of the lower urethera
and bladder may lead to urinary symptoms such as urgency,
frequency, dysuria, nocturia, incontinence, as well as the
development of urinary tract infections.
A Swedish study14 that interviewed 900 menopausal
women found that 29.2 per cent complained of urinary
incontinence, 13 per cent gave history of repeated urinary
tract infections, 15 per cent complained of pruritis and
vaginal discharge and 38 per cent had vaginal dryness and
dyspareunia. Loss of interest in sexual relations was found
in 32.7 per cent of women. There is marked variability in
the onset and severity of atrophy of the urogenital tissues.
This is in part due to variations in the rate of decline of
estrogen production, which may be acutely or chronically
muted by factors that increase either prehormone
production or efficiency of conversion of prehormone to
estrone. Some women may become symptomatic in
months, others may take years to develop symptoms or
urogenital atrophy, and some may never develop such
symptoms.
Welfare Clinics ofIRR were interviewed with the help of
a precoded questionnaire. Data collection included age at
menopause, menstrual history during the transition pe
riod, vasomotor and genitourinary symptoms, history of
sexual activity and frequency and their attitude towards
HRT.. Preliminary analysis of responces of 100
perimenopausal women revealed that the mean age at
menopause was 45.08 yr. The age of the women inter
viewed ranged from 40 to 60 yr. Hot flushes, sweating
and insomnia were complained of by about 25 per cent of
women. The most frequent complaints in this age group
were fatigue and muscle-joint pain (48%); 84 per cent of
women interviewed were not aware about HRT. When
asked whether they would be willing to take long-term
HRT, only 16 per cent of women agreed . The common
reason for refusal to take treatment was on account of vagi
nal bleeding (34%), while 15 per cent felt that menopause
is a normal phenomenon and hence no treatment should
betaken.
Management of the Menopause
During the current decade, the management of meno
pause will become a national health concern as millions
of baby boomers reach, this stage of life. Medical inter
vention at menopause should be regarded as a programme
of preventive health care in the same category as family
planning. In this context HRT has found its place in the
treatment of symptoms and some harmful effects of meno
pause.
Other complaints
Some frequently mentioned symptoms ofmenopausal
syndrome are depression, irritability, nervous tension,
palpitations, headaches and fatigue. Changes in Bendorphins and other opioids that occur during this period
lead to an influence in the nervous transmitters of the
GABA - system and serotonin system J3 These changes
may explain in part why many women experience psychic
and psychologic symptoms around the menopause. Thining
of skin, loss, of hair and brittle nails are also some of the
changes evident during this period. However, it is unclear
to what degree each of these symptoms is related to
estrogen withdrawal, ageing and or environmental stress.
Studies are ongoing at the Institute for Research in
Reproduction (IRR), Mumbai, to evaluate the prevalence
of menopausal symptoms in women in an urban setup and
to determine their attitude towards hormone replacement
therapy.(HRT). Climacteric women attending the Family
In general, there are three indications for which HRT
is used . These are (i) vasomotor and genitourinary
symptoms related to estrogen deficiency, (ii) prevention
of osteoporosis eg estrogen therapy reduces the rate of
bone mass loss in postmenopausal women to the
premenopausal rate thus reducing the number of fractures,
and (iii) prevention of cardiovascular morbidity and
mortality. To.derive maximum benefits of HRT for
prevention of osteoporosis and cardiovascular disease,
treatment should be started at menopause and continued
for at least 5 to 7 yr.
There are many controversial issues surrounding this
therapy due to conflicting data from epidemiological
studies viz. (i) what hormonal agent or route of
administration is best? (ii) what is the best regimen,
sequential or continuous? (iii) how long to continue the
therapy? (iv) should very old women be started with HRT?
(jv) does HRT increase the risk of cancer? etc.
3
Hormone Replacement Therapy
Estrogen can be given in a variety of routes. In prac
tice, the oral, transdermal, subcutaneous and vaginal routes
are commonly employed. Each has benefits and disadvan
tages. Selecting the appropriate drug and route and also
duration of therapy would depend on whether the woman
desires long-term systemic treatment for the premature or
sequelae of menopause or wishes to merely have relief of
climacteric symptoms, whether she is willing to experi
ence bleeding, the presence or absence of uterus, the pres
ence or absence of risk factors or osteoporosis, cardiovas
cular disease, the availability and cost of the preparation.
Oral HRT
Synthetic estrogens (ethinyl estradiol) are not used for
HRT because of their enhanced thrombogenic effect.
Natural estrogens are used. Oral estrogen preparations are
relatively inexpensive, easy to administer and easy to
discontinue. The disadvantages are that some women
experience nausea and compliance cannot be guaranteed.
Oral ingestion produces a first pass hepatic effect. Although
no increased risk of venous thrombotic disease has been
documented it may be prudent to use transdermal estrogen
in women who have experienced deep vein thrombosis.
The commonly used oral natural estrogens are estradiol
valerate, conjugated equine estrogen (maifi component is
estrone sulphate) and piperazine estrone sulphate. (Table I).
Progestogen supplementation for about 12 days in each
month restricts endometrial proliferation and ensures pe
riodic transformation of a proliferative endometrium into
a secretory one. The progestogen commonly used sequen
tially for 12 days each month with the protective doses for
endometrium per day are listed in Table II.
Table II. Protective doses of progestogen for HRT
Progestogen
Protective dose
Dydrogesterone (Duphaston)
20 mg
Medroxy progesterone acetate (Provera, Farlutal)
10 mg
Norethisterone (Micronor)
1.05 mg
Levonorgestrel (Neogest)
150 pg
Conjugated equine estrogen,
0.625 mg, 1.25 mg (Premarin)
Unfortunately the addition of cyclical progestogen
leads to withdrawal bleeding and premenstrual syndrome
like fluid retention, breast tenderness, irritability, headaches
and depression. The androgenic progestogen?
(norethisterone and levonorgestrel) will lower the
concentration of HDL cholesterol. Ifthe daily progestogen
dose is reduced to norethisterone 1 mg and levonorgestrel
150 pg, the changes in lipid profile are minimal. Estrogen
and progestogen may be prescribed separately or as a
combined preparation (Table III). In a woman with an
intact uterus if a combined preparation is not available a
natural estrogen should be prescribed daily together with
dydrogesterone or medroxy progesterone for 12 days of
each* calendar month. The compliance among
postmenopausal HRT users may be poor because of heavy
or prolonged withdrawal bleeding but the problem can be
overcome. Progestogen therapy can be avoided in
hysterectomised women.5
Transdermal
Estradiol (Estraderm TTs 50,100 pg)
Table III. The commonly used combined preparation for HRT
Subcutaneous
Estradiol (25, 50,100 mg.)
Nuvelle
• *
Estradiol valerate 2 mg
Levonorgestrel 75 pg
Vaginal
Conjugated equine estrogen 0.625 mg in 1 g
base (Premarin)
Prempak C 0.625 .
Conjugated equine estrogen0.625 mg
Levonorgestrel 75'pg
PrempakC 1.25
Conjugated equine estrogen 1.25 mg
Levonorgestrel 75 pg
Table I. The commonly used estrogen preparations for HRT
Oral
Estriol succinate 2 mg (Evalon)
Estradiol valerate 2 mg (Progynon)
Estriol 0.1 per cent (Ovestin)
HRT - hormone replacement therapy
Progestogens
Continuous combined regimen
When estrogen alone is taken for a long time, there is
risk of endometrial hyperplasia and endometrial carcinoma.
The risk is related to both the duration and dose used.
The aim is to give continuous combined estrogen and
low dose progestogen to render endometrium atrophic
4
ultimately inducing amenorrhoea. However, many women
discontinue the use of this combination within first 6
months because of irregular bleeding. Continuous
combined therapy is currently a subject of extensive
research.
vaginal dryness, atrophic vaginitis, urethritis or
dyspareunia. The commonly available vaginal creams are
conjugated equine estrogens (0.625 mg in 1 g of base and
estriol 0.1%).
Non Hormonal Therapy
Tibolone
Tibolone has weak estrogenic, androgenic and
progestogenic actions and may be used in postmenopaus
al women. The dose is 2.5 pg daily and is used mainly for
the relief of vasomotor and psychological symptoms.
However, 15 per cent of postmenopausal women have ir
regular bleeding. It is also expensive.
Non-oral HRT
There is no first pass hepatic effect and nausea is
avoided. The transdermal estradiol patch is self adhesive
and delivers estradiol over a period of 3-4 days at a con
stant rate of 50 pg per 24 h . One patch is applied twice a
week on a dry hairless area of the skin, below the waist
line. A new area should be selected for each application.
The patch is easy to apply, easy to remove and has a short
half life. The drop out rate on account of local skin reac
tion is around 5 per cent. It is relatively expensive.
Subcutaneous estradiol implant
Subcutaneous pellets of crystalline estradiol release
the hormone over a period of more than 6 months. The
commonly used dose is 50 mg every 6 months which is
adequate for bone conservation.
The disadvantages are that implantation requires a
surgical procedure under local anaesthesia every 6 months
and in case the woman wants to discontinue, it is difficult
to remove the implant. A small number of women may
have recurrence of menopausal symptoms despite adequate
levels of serum estradiol. The anterior abdominal wall,
about 5 cm above and parallel to the inguinal ligament is
the common site for the insertion of pellets.
In the presence of an intact uterus the patient needs
to take oral progestogen for 12 days in a month along with
non-oral HRT.
Vaginal estrogen
The therapy is useful in women who have been post
menopausal for some years and wish to have relief of
In the last decade, efforts have been directed to find
non-hormonal alternatives to prevent postmenopausal os
teoporosis for women who prefer not to use hormones or
where estrogen is contraindicated. These include:
(i) A moderate level of physical activity especially weight
bearing exercise appears to have a beneficial influence on
peak adult bone mass although it does not prevent os
teoporosis.
(ii) Calcium is an essential element for normal bone health.
A life long supplementation with calcium in a dose of 800
mg/day is recommended as complementary therapy. Cal
cium intake in childhood and adolescence may be a deter
minant of peak bone mass. Calcium does not substitute
for estrogen in preventive therapy in postmenopausal
women. Vitamin D helps calcium absorption in the gut
and reduces the rate of bone loss .’5
Certain vitamins (B1, B2, B6, B12, Vit.A, Vit C, Vit-E)
along with minerals have been shown to be effective in
alleviating the menopausal symptoms eg hot flushes, pal
pitation, depression, anxiety, etc.
(iii) Calcitonin is effective in prevention of bone loss, but
it is expensive and is only available as nasal spray and in
injectable form.
6
(iv) Sodium fluoride has been known to increase bone
density but studies are limited due to its adverse effects.
Osteoporosis and Estrogen Replacement
Osteoporosis is characterised by decreased bone mass
and increased susceptibility to fracture most commonly of
the wrist, the spine and the hip. Estrogen replacement
therapy is very effective in preventing osteoporosis and
reducing the risk of the associated fractures.
For conservation of bone in a well built, menopausal
woman with no risk factors, the minimal effecitve dose of
estradiol valerate is 2 mg and of conjugated equine estro
gen is 0.625 mg daily. The minimal effective daily dose
for bone preservation in a small built, thin, sedentary regu
lar alcohol/tobacco user who has undergone bilateral
oopherectomy is likely to be higher and these factors must
be borne in mind while prescribing HRT.
The greatest benefit is obtained if HRT is given shortly
after the menopause prior to significant bone loss. How
ever, there is clear evidence that in all stages of the pos*
menopausal life HRT prevents bone loss. Five years of
appropriate HRT reduces the lifetime incidence of the frac
ture femur neck by 50 per cent and ofvertebrae to a greater
extent16
Cardiovascular System and HRT
Mortality from coronary heart disease (CHD) like
myocardial infarction among women increases with
advancing age. Changes in serum lipids after the
menopause suggest a relationship with estrogen
deprivation. Total serum cholesterol decreases. Several
epidemiological studies have demonstrated that with 4 or
more years of oral estrogen therapy in both normotensive
and controlled hypertensive women, the risk of CHD is
reduced by more than 50 per cent as compared to " never
users". There are no data available on CHD and HRT
from developing countries.
Mechanisms of action of estrogen for cardioprotection
A 35 per cent reduction of LDL cholesterol results in
a 50 per cent reduction in cardiovascular disease. How
ever, estrogen reduces LDL cholesterol by only 10 per cent.
This may explain about a third of the cardioprotective
effect of, estrogens. It also increases HDL which is be
lieved to be protective against arteriosclerosis. Estrogen
also increases the coronary blood flow as demonstrated
by many angiographic studies. It also acts as an antioxi
dant and there is a favourable effect on haemostasis. Un
like synthetic estrogens, natural estrogens do not have any
significant effect on the blood pressure. In only 2 or 3 per
cent of HRT users there is an increase in blood pressure.17
When Should Treatment With HRT Begin ?
In the past women over the age of 60 yr have been
denied HRT in the belief that they are too old and their
skeleton is too osteoporotic to benefit from estrogen re
placement therapy. Recent studies18 using conjugated
equine estrogen 0.625 mg daily plus calcium showed an
increased bone density in both the spine and the femur
neck after two years of treatment. Garnett et al19 re
ported similar benefits with 75 mg estradiol implants in
women over 60 yr of age after one year of treatment. The
increase in bone density was greater in women who had
more severe disease and it was concluded that implants
are more effective in the treatment of established os
teoporotic disease. In the elderly woman with osteoporotic
fracture, hormone therapy is advocated as it decreases, the
risk of further fracture.
In fact Black20 has convincingly argued for delaying
the start of HRT for prevention of osteoporotic fractures.
Reasons given for waiting until a later age include (i) the
possibility that hip fracture risk can be more precisely
estimated at 65 or 70 yr than at 50 yr of age; (ii) that
treatment duration will be shorter and therefore, more cost
effective if begun later, and (iii) the uncertainty associated
with long-term treatment can be eliminated.
HRT and the Risk of Cancers
Breast carcinoma
Epidemiological studies on the risk of breast carci
noma are to some extent contradictory. The overall mes
sage is that extended use of estrogen therapy entails an
increased risk being 1.3-1.6. The risk increases with the
duration of therapy. Patients who develop breast carcinoma
after estrogen therapy are Usally detected with early stage
tumours probably due to the close monitoring which they
undergo during therapy. Women with a strong family his
tory of the disease may be at a higher risk for developing
breast carcinoma after estrogen therapy. Progestogens do
not appear to have any protective effect. Breast cancer
surveillance is recommended for women taking hormones
at the same frequency as women not taking hormones. They
should have regular breast examination and regular threeyearly mammography from the age of 50 years.21
Endometrial hyperplasia and carcinoma
Estrogen use of 10-15 yr may have increased risk of
endometrial hyperplasia and carcinoma (RR 10) compared
with women who have never used it but declines once
estrogen is stopped. Use of progestogen along with the
estrogen reduces the risk of endometrial cancer. Indeed
the action of progestogen counteracts the cancer inducing
effect of the estrogen on the endometrium.11
Endometrial screening in HRT users
If on transvaginal ultrasonography the endometrial
thickness is more than 4 mm, there is a need for tissue
sampling either by biopsy or by dilatation and curettage.
6
For patients on continuous combined therapy, screening
is recommended generally once a year.
Studies of ovaries in Europe and North America show
no additional risk of ovarian cancer. No information is
available from developing countries. Several studies to find
a link between HRT and cervical cancer were undertaken
but results have been inconclusive 11.
There is no evidence that one form of estrogen is su
perior to another.
of Obstetrics and Gynaecological Societies of India, Mumbai, p.
4, 1994?
7.
Doren, M. and Schneider, H.P.G. Overall rationale for hormone
substitution therapy after the menopause. In: Update on Hor
monal Treatment in the Menopause. Ed. M.L. Hermite. Progress
in Reproductive Biol Med, Basel, Karger, Vol. 13, 1989.
8.
Yen, S.S.C. The biology of menopause. J Reprod Med 18: 287,
1977.
9.
Haney, A.F. The Physiology of the climacterium Clin Obstet
Gynecol 29: 397, 1986.
10.
Sherman, B.M., West, J.H. and Korenman, S.G. The meno
pausal transition: Analysis of LH, FSH, estradiol and progester
one concentration during menstrual cycles of older women. J
Clin Endocrinol Metab 42: 629, 1976.
11.
Progress in Human Reproduction Research (Report of a WHO
Scientific Group) No.40; p.l, 1996.
12.
Brenner, P.F. The Menopausal syndrome. Obstet Gynecol 72
(Suppl.): 6S,1988.
13.
Samsioe, G. The menopause revisited. Int J Gynecol Obstet 51:
1, 1995.
14.
Iosif, C.S. and Bekassy, Z. Prevalence of genito-urinary symp
toms in the late menopause. Acta Obstet Gynecol Scand 63:257,
1984.
To summarise, it is known that short-term treatment
ofmenopausal women with HRT for the symptomatic relief
of climacteric complaints is effective, safe and generally
well accepted. However, use of long-term HRT (for 7 yr
or more) is still controversial. In clinical practice, the
beneficial effects of long-term HRT on women's health,
mainly on osteoporosis and cardiovascular disease, must
be carefully weighed against a possible increased incidence
and mortality from breast cancer. It is necessary to provide
accurate and individual information to women about the
advantages and disadvantages of using HRT. Educating
potential users will enhance compliance, especially if
women make this decision themselves, fully informed by
their physicians. Women who agree to take HRT should
have careful follow up monitoring so as to obtain maximum
benefit for this therapy while minimizing«any risks or side
effects.
15.
Murphy, S., Khaw, K.T., May, H. and Compston, J.E. Milk Con
sumption and bone mineral density in middle aged and elderly
women. B MJ 308: 939, 1994.
16.
Compston, J.E. Hormone replacement therapy and osteoporo
sis. Br Med Bull 48: 309, 1992.
References
17.
Meade, T.W. and Berra, A. Hormone replacement therapy and
cardiovascular disease. Br Med Bull 48: 277, 1992.
1.
Research on the the menopause (Report of a WHO Scientific
Group). WHO Tech Rep Ser 670: 1, 1981.
18.
Lindsay, R. The menopause and osteoporosis, Obstet Gynaecol
87 (Suppl.): 16S, 1996.
2.
Shaaban, M.M. Menopause in the context of developing coun
tries. South to South Newsletter No.7: 6, April, 1997.
19.
3.
Oldenhave, A. and Netelenbos, C. Pathogenesis of climacteric
complaints : Ready for the change ? Lancet, 343: 649, 1994.
Garnett, T., Studd. J., Watson, N., Savvas, M. and Leather, A.
The effects of plasma estradiol therapy with estradiol and estra
diol with testosterone implants. Obstet Gynaecol 79:968,1992.
20.
Black, D.M. Screening and treatment of the elderly to reduce
osteoporotic fracture risk. Br J Obstet Gynaecol 103 (Suppl. 13):
2, 1996.
21.
Speroff, L. Postmenopausal hormone replacement therapy arid
breast cancer. Obstet Gynaecol 87 (suppl) : 44S, 1996.
4.
Khaw, K.T.,Epidemiology of the menopause. Br Med Bull 48:
249, 1992.
5.
Anklesaria, B.S. The ageing process. In: The Menopause and
HRT. Eds. R.K. Bhathena and R.P. Soonawala. The Federation
of Obstetrics and Gynaecological Societies of India., Mumbai,
p.3, 1994/
6.
Bharucha, M.R. Premature menopause. In: The menopause and
HRT. Eds. R.K.Bhathena and R.P.Soonawala. The Federation
This article has been contributed by Dr.Rashmi S.Shah,
Assistant Director, Dr.Lalita S.Savardekar, Research
Officer and Dr.Shanta M.Chitlange, Assistant Director,
Institute for Research in Reproduction, Mumbai.
7
ICMR NEWS
The following meetings of various technical groups/
committees of the Council were held at New Delhi:
Meetings of Project Review Committees (PRCs) and
Task Force (TF):
PRC on Cardiovascular
Diseases, Ophthalmology,
Urology and Gastroenterology
December 12,1997
Sub-group of PRC on Hepatitis
December 16,1997
PRC on Malaria, Filariasis and
Leishmaniasis
December 19, 1997
TF on Child Psychiatry
January 15,1998
Participation of ICMR Scientists in Scientific Events:
Dr. V. Kumaraswami, Dy. Director, Tuberculosis
Research Centre, Chennai; Dr. B.V. Babu, Sr. Research
Officer, Regional Medical Research Centre, Bhubaneswar;
and Dr. K.D. Ramaiah, Sr. Research Officer, Vector
Control Research Centre, Pondicherry, participated in the
UNDP/World Bank/WHO Special Programme for
Research and Training in Tropical Diseases meeting on
Social Science Methods for Community Directed
Treatment at Mukuno, Uganda (November 17-21,1997).
Dr. Poonam Salotra, Sr. Research Officer, Institute of
Pathology, New Delhi, participated in the X Anniversary
symposium of International Centre for Genetic Engineering
and Biotechnology on Molecular Biology and
Biotechnology for Development at Trieste, Italy
(November 25-27, 1997).
Dr. M.D. Gupte, Director, Institute fdr Research in
Medical Statistics, Chennai and Officer-in-Charge, CJIL
Field Unit at Avadi, Chennai, participated in the meeting
and discussion regarding the Study on Posterior Tibial
Nerve Decompression at Bologna, Italy (December 8-14,
1997). He also participated in the meeting of the Sub-com
mittee of the WHO Steering Committee on Special Ac
tion Project to review proposals for the treatment of
paucibacillary leprosy with a single dose of rifampicin,
ofloxacin and minocycline and the seventh meeting of
SAPEL Steering Committee at Geneva (December 14-16,
1997).
Workshop on Intellectual Property Rights:
The second ICMR-TIFAC (DST) Workshop on Intellectual Property Rights was held at the Desert Medicine
Research Centre (DMRC), Jodhpur on December 12,1997.
Besides scientists of DMRC, scientists from several other
Jodhpur-based R&D Institutes also participated in this*
Workshop.
This is the second in the series of Workshops jointly
conducted by the Patent Facilitating Cell of the Technology
Information, Forecasting and Assessment Council
(TIFAC), an aqtonomous body of the Department of
Science and Technology, New Delhi and the ICMR. The
first Workshop was held at the National Institute of
Occupational Health (NIOH), Ahmedabad on August 13,
1997. Scientists from the NIOH, and the ICMR Institutes
located in the Western region of India viz., IRR, IIH, EVRC,
GRC, Mumbai and NTV, NARI, Pune also participated.
This orientation programme on emerging issues of patents
and related areas will cover all the ICMR institutions in a
phased manner.
ICMR AIDED SYMPOSIA/SEMINARS/WORKSHOPS/COURSES/CONFERENCES
Symposium/Seminar/Workshop/
Date & Place
Contact Address
Course/Conference
LXXXV Session of the Indian Science Congress
January 3-7, 1998;
(at Hyderabad)
Dr. P.K. Sai Prakash, Local Secretary of the Indian
Science Congress, Department of Chemis
try, University College of Science, Osmania Uni
versity, Hyderabad-500007.
VI Annual-Meeting of the Molecular Immunology
Forum-1998
January 12-14, 1998;
(at New Delhi)
Dr. H. Krishna Prasad, Convenor of MIF-1998,
Department of Biotechnology, All India Institute
of Medical Sciences, New Delhi-110029.
8
w
Symposium/Seminar/Workshop/
Contact Address
Date & Place
Cours e/Conference
International Conference on Changing Patterns of
Health in Developing Countries
January 21-23, 1998;
(at Vadodara)
Dr. Jayasree De, Head, Department of Geography,
M.S. University of Baroda, Vadodara-398002.
Update Ayurveda ’98
February 9-14,1998;
(at Mumbai)
Dr. S.A. Dahanukar, Professor, Department of
Pharmacology, Seth G.S. Medical College,
Mumbai-400012.
Workshop on Application of Iontophoresis, Sonopho
resis and Hyperthermia in Drug Delivery
February 27-28, 1998;
(at Manipal)
Dr. N. Udupa, In-charge Principal and Professor,
College of Pharmaceutical Sciences, Manipal-576119.
International Conference on Nonlinear Dynamics and
Brain Functioning
February 5-11, 1998;
(at Bangalore)
Dr. N. Pradhan, Convenor of the Conference,
Department of Psychopharmacology, National
Institute of Mental Health & Neurosciences,
Bangalore-560029.
COUNCIL’S TRAINING PROGRAMMES FOR 1938-99
Leprosy
At the Central JALMA Institute for Leprosy, Agra:
•
Multidrug Therapy Orientation Course in Leprosy for
■ Medical Officers (April 6-17, August 17-28, October
26-November 6; and December 7-18,1998).
Virology
At the National Institute of Virology, Pune:
•
Diploma in Medical Virology (July 1998-May 1999).
•
M.Sc. in Applied Nutrition (June 1,1998-February.28,
1999).
•
Postgraduate Certificate Course in Nutrition (Decem
ber 1,1998-February 28, 1999).
Laboratory Animal Technology
At the National Centre for Laboratory Animal Science,
National Institute ofNutrition, Hyderabad:
•
At the Enterovirus Research Centre, Mumbai:
•
Workshop on Isolation and Identification of Poliovi
ruses (January 19-29,1998).
Training Course for Laboratory Animal Technicians
(June 16-July 31, 1998).
Occupational Health
Reproductive Biology
At the National Institute of Occupational Health,
Ahmedabad:
At the Institute for Research in Reproduction, Mumbai:
•
Orientation Course on Occupational Health for Indus
trial Medical Officers (February 17-28, 1998).
•
Training Course on Environmental Hygiene Practice
(November 16-20,1998).
•
Workshop on Andrology for Clinicians (November 1630, 1998)'
Endocrinology
At the National Institute of Nutrition, Hyderabad:
•
Annual Certificate Course on Endocrinological Tech
niques and their Applications (August I-September
15,'1998).
Nutrition
At the National Institute of Nutrition, Hyderabad:
Biomedical Statistics
At the Institutefor Research in Medical Statistics, Chennai:
•
Basic Course in Statistics for Postgraduate Medical
-Students (July 1998).
•
Basic Course in Statistics for Medical Officers
(November 1998).
9
GUIDELINES FOR EXCHANGE OF HUMAN BIOLOGICAL MATERIAL FOR
BIOMEDICAL RESEARCH PURPOSES
F.No. L. 19015/53/97-IH (Pt.)
GOVERNMENT OF INDIA
Ministry of Health & F.W.
Department of Health
N innan Bhawan
NEW DELHI
the 19th November, 1997
OFFICE MEMORANDUM
Subject: Guidelines for Exchange of Human Biological Material for Biomedical Research Purposes.
The Ministry of Health & Family Welfare issued an Office Memorandum No. L. 20025/90/90-F, dated 27th February,
1992 which permitted the restricted transfer of biological material abroad under certain circumstances for research/
diagnostic purposes. The Office Memorandum also indicated that the Director-General, 1CMR, would be the nodal
point to clear all such proposals.
2.
The heed for revised/expanded guidelines has been felt over the past two years. Accordingly, the Ministry of
Health & Family Welfare have taken necessary steps in this regards.
3.
The revised guidelines in respect of HUMAN BIOLOGICAL MATERIAL, in supersession of this Ministry’s
Office Memorandum f4o. L. 20025/90/90-F, dated 27th February, 1992 are prescribed as under :
I.
Definition
Human material 'with potentialfor use in biomedical research:
Organs and parts of organs; Cells and tissues; Sub-cellular structures and cell products; Blood; Gametes (sperm^^
and ova); Embryos and foetal tissues; Wastes (urine, faeces, sweat, hairs, epithelial scales, nail clippings, placenta etc.);
Cell lines from human tissues.
The sources of these materials could be from patients following diagnostic or therapeutic procedures, autopsy
specimens, donations of organs or tissues from living or dead persons, foetal tissues, body wastes or abandoned tissues.
Human material could also be held in tissue banks and used for research.
H.
Transfer
Guidelines for considering requests for transfer of biological material abroad for research/diagnostic purposes and
requests for transfer ofbiological materialfrom abroad to Indian Institutionsfor research purposes :
(i) Exchange of material for diagnostic or therapeutic purposes for individual cases may be done without restriction,
if this exchange is considered necessary by the doctors) in-charge of the patient. No permission needs to be sought from
10
(ii) Exchange of material from and to recognised laboratories such as WHO Collaborating Centres or WHO Reference
Centres may be allowed as part of their routine activities relating to quality control, quality assurance, comparison with
reference material etc., without having to seek permission from any authority.
(iii) Where exchange of material is envisaged as part of a collaborative research project, the project proposal as a whole
must be routed through the appropriate authorities (details under III below) for evaluation and clearance. The exchange
of human material should be an integral part of a collaborative project, which should have been approved by the Institutional
Review and Ethics Committees, and not be a separate activity.
(iv) The availability of facilities within India for carrying out certain investigations need not prevent collaboration with
scientists in other countries for the same investigations including transfer of human material, if required.
(v) On the issue of technology transfer/training of Indian scientists abroad/training of foreign scientists and students in
India, and visits by the foreign collaborators to their Indian partners’ laboratories to work with Indian material, there
should be no restrictions on the visits of scientists to the laboratories concerned. However, any field work to be undertaken
in the community and other sensitive issues would have to be regulated according to the rules of the Government.
|(vi) In order to protect the rights of the Indian study subjects as well as Indian scientists/organisations, Memoranda of
Understanding and/or Agreements on Material Transfer should be entered into between the collaborating partners (Indian
and Foreign). These should, according to the requirements of case under consideration, include items pertaining to
identification of the collaborating or sending/receiving parties, background, the material to be transferred and its quantities,
purpose of transfer, the research to be carried out using the material, confidentiality, intellectual property rights, filing of
patents, arrangements for future commercial exploitation, reporting, publication rights, indemnification, termination .of
agreement, assignation or transfer of agreement/rights, safety norms to be observed, shipping arrangements, ‘qualified
user’ information, and any other matter that may be relevant to the particular exchange of material.
III. Mechanism
Mechanism for processing requestsfor transfer ofbiological material abrdadfor research/diagnostic purposes :
(i) Agencies and departments such as ICMR, CSIR, ICAR, DBT, and DST could make use of these guidelines and
take decisions accordingly on the requests from their respective institutions.
(ii) The Directorate-General of Health Services/Ministry of Health & Family Welfare could utilise the guidelines and
take decisions on the requests from the DGHS/Health & Family Welfare Ministry administered institutions, as also on
referrals, if any, from any other government agency/department not covered under (i) above.
(iii) Autonomous institutions and institutions of national stature such as PGIMER, Chandigarh; AIIMS, New Delhi;
Sree Chitra Tirunal Institute of Medical Sciences & Technology, Thiruvananthapuram; andSanjay Gandhi Postgraduate
Institute of Medical Sciences, Luknow, and similar institutions of national stature, could be empowered to take decisions
on their in-house proposals for foreign collaboration, by following the guidelines.
(iv) Private institutions engaging in collaboration directly with foreign institutions should send their requests to ICMR.
If, however, they are also collaborating with an Indian institution as part ofthe collaborative programmes with a foreign
institution (for example, between a private institution and CSIR lab. collaborating with a foreign institution), then the
appropriate central agency (CSIR in the example cited) may decide on the request according to all relevant guidelines.
(v) Biomedical research project proposals for foreign collaboration from Medical Colleges, Universities and Institutions
under the UGC may be routed through ICMR.
11
(vi)
State health authorities may take the decision in respect of institutions under their administrative control.
(vii) All foreign collaborative projects in biomedical research (after scrutiny and decision by the respective agencies/
departments as described above from (i) to (vi) are to be placed before the Health Ministry Screening Committee
(HMSC) for final endorsement. This would mean that all institutions, agencies and departments would have to send their
proposals to the ICMR for obtaining such endorsement by the HMSC, as ICMR is the Secretariat for the HMSC at
present.
(viii) is essential for information to be available in a central location. This could be the secretariat of the HMSC, i.e.
It
the ICMR Headquarters.
IV. Exchange of Biological Material for Commercial Purposes
Guidelinesfor exchange ofbiological materialfor commercial purposes :
The ICMR has been advised to set up a committee consisting of experts from relevant fields for deciding each
proposal on a case-by-case basis and to furnish their views to the Government for consideration. The committee, in
addition to biological material, will also consider proposals involving transfer of medicinal plants and biological molecules
developed in the laboratories, after seeking inputs from the relevant experts, if such transfer is for commercial purposes
and a proposal in this regard is received from the Foreign Investment Promotion Board (FIPB). A minimum of three
months time would be required to process the FIPB proposals.
sd/-
(Ashok Mehta)
Under Secretary of the Govt, of India
EDITORIAL BOARD
Chairman
Director-General
ICMR
Members
Dr. Badri N. Saxena
Dr. Bela Shah
Dr. Lal it Kant
Editor
Dr. N. Medappa
Printed and Published by .Shri J.N. Mathur for the Indian Council of Medical Research, New Delhi
at the ICMR Offset Press, New Delhi-110 029
R.N. 21813/71
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