1.Menopause entails decrease in three hormones, viz.;
oestrogen,progesterone and androgens. Symptoms due to lack of any of
these entails HRT or hormone replacement therapy.
of estrogen may lead to hot flash/flush, sleep disturbance,
palpitations, dry skin, irritable bladder, and dyspareunia.
irregular menses suggest progesterone deficiency.
Androgen deficiency manifests as decreased libido or decreased
ability to reach sexual climax.
Osteoporosis as evidenced by decreased bone mineral density shown by
X- ray,Densitometry or
Hypothyroidism as a consequence of menopause.
4. Adjuvant to
treatment in Alzheimer’s disease.
5. Adjuvant to
treatment of endogenous depression which may be unmasked during
Ideal hormone replacement
a) The drug
should relieve the symptom for which it is given (hot
flushes,vaginal dryness,etc.) or prevent the occurrence of certain
factors(e.g osteoporosis,ischaemic heart disease, , etc.)
b) While having
adequate effect on the target organ(ovary,bone,heart,brain,skin) it
should have least stimulatory effect on the breast and uterus thus
avoiding breast cancer and endometrial hyperplasia.
should be minimum if not no incidence of breakthrough or withdrawal
bleeding which may be considered sinister by the patient and even
some of the less
informed practitioners.Some of the clinicians may even advice
hysterectomy without knowing that the patient is on HRT which may
have been started by a physician to suppliment treatment for
Alzheimer’s disease or hypothyroidism, a psychiatrist to suppliment
antidepressant therapy or an orthopaeditian to prevent osteoporosis.
d) There are two
types of lipoproteins, the Low density lipoproteins and the High
density lipoproteins. The ideal hormone replacement should increase
the high density lipoproteins and reduce the level of low density
lipoproteins. The triglyceride levels should be lowered. This will give maximum
cardioprotection.That is, the woman’s chance of getting ischaemic
heart disease will be as low as it was while she was
e) The side
effects should be minimal.
The estrogens currently available in India are
A) Conjugated equine
estrogen(Premarin);strength: tablets of 0.625mg and 1.25mg.
strength: tablets of 1mg and 2mg.
C) Estriol (Evalon)
estrogen has been the most studied estrogen preparation. It is the gold standard
against which all other preparations are studied. Micronised
estradiol valerate is a single estrogen preparation, as opposed to
conjugated equine estrogen, which is a conjugate of different types
of estrogen. There does not seem to be any added advantage for
estradiol preparations over conjugated estrogen. Estriol has been found to
have less effect in causing breast cancer and has less uterine
stimulatory effect,as it is a weaker estrogen(27).But estriol
affords less cardioprotection compared to other estrogen
preparations .It is required in very high doses(12mg) to effect
prevention of osteoporosis by increasing bone mineral density and at
such doses the side effects may be intolerable. For treatment of hot flushes
usually double dose of estrogen (1.25mg of conjugated estrogen or
2mg of estradiol) may be needed. For prevnetion of osteoporosis,the
minimum effective dose that can increase bone mineral density may be
chosen. This may be 0.625 mg of conjugated estrogen or 1mg of
maintanance, doses as low as 0.3 mg of conjugated estrogen or 0.5 mg
of estradiol may be sufficient, but preparations containg such low
doses are as yet not available in India. Treatment should be
given on all days of the month as giving it for only 25 days has no
added advantage and some women may develop symptoms during this week
off. For the treatment of hot flushes treatment may be given for a
year and stopped for a week to see if symptoms recur(18). If they do
not recur treatment may be stopped. If they do recur, treatment may
be continued for another year after which the patient may be
re-evaluated.For prevention of osteoporosis,treatment may be given
for lifelong at the minimum dose required. This is also true for
cardioprotection. As adjuvant to treatment of depression,
Alzheimer’s disease and hyptothyroidism treatment may be continued
as long as the primary disease is being treated.
Side effects of
HRT can cause Nausea,dyspepsia,leg cramps,breast tenderness,vaginal
discharge and withdrawal bleeds that may be unacceptable to the
patient. The breast
tenderness and nausea may disappear in a few months. If the other
side effects bother the patient, switching over to another estrogen
preparation, reducing the dose, switching over to continuous
combined therapy are other alternatives. If HRT is being given
for osteoporosis, Alendronate is an alternative. Tibolone, known to
be a bleed free hormone, Progegesterone-only HRT are other
indication for adding progestin suppliments to oestrogen replacement
is to avoid the complication of endometrial hyperplasia which might
occur with oestrogen therapy alone. Hence progestin supplimentation
need be given only to women with intact uterus(18).
Supplimentation with progestins has to be given at least 10 days per
month to prevent endometrial hyperplasia.There are two methods of
supplimenting oestrogen therapy with progestins. 1) Cyclical
therapy: Here the progestin therapy is given for 10-12 days every
month. 2) Continuous
therapy: Progestins in lower dose is given every single day of the
month.The difference in the two regimens is that continuous therapy
is less assossiated with monthly bleeding and may be more acceptable
to the patient.Medroxy progesterone acetate in the strength of 2.5
mg is enough for this purpose. For women who have contraindications
to the use of oestrogen therapy single therapy with progestins
22.Laughlin.G.A, Connor.E: Hysterectomy, Oophorectomy, and
een tried.Progestins by themselves have been known to reduce hot
progestins that are available are:
Norethisterone b) Medroxy progesterone c) Dydrogesterone d)
Natural micronised progesterone.
Norethisterone: 1.25mg/ day
in cyclical therapy and 0.3-1.25mg /day for combined therapy.
for cyclical therapy and 2.5-5mg/day for combined therapy.
10-20mg/day for cyclical therapy and 10mg /day for combined
progesterone: 200mg/day for cyclical therapy and 100mg/day
progesterone acetate is the drug most commonly prescribed for this
Dydrogesterone and micronised
progesterone which have lesser side effects have equivalent effects
on the endometrium and provide useful alternatives for women who
experience side effects with medroxyprogesterone. Side effects of
progestins include mood symptoms such as irritability and
depression, breast tenderness, and bloating. Oestrogen increases the
level of High density
lipoproprotein cholesterol, but this effect is nullified to some
extent by synthetic progestins which are added to prevent
endometrial hyperplasia. Dydrogesterone which has a structure
closest to progesterone
and Micronised progesterone do not nullify this effect that
much, thus maintaining the cardioprotective effect of
oestrogen(11). However the price of both
these compounds is much
higher than medroxyprogesterone acetate and for the middle income
group it may be prudent to start on a less costly preparation
and to switch over to costlier drugs only in case side effects tend
to bother the patient enough to stop Hormone replacement
Side effects of
therapy might cause fluid retention and edema, backache, breast
tenderness, heavy withdrawal bleeding, headaches, aches and pains,
abdominal cramps, flatulence, mood changes as in premenstrual
syndrome, dizziness,and acne/greasy skin. Treatment could be
achieved by decreasing the dose , splitting the dose, changing the
progestin preparation ,weight reduction,etc.
(Livial) is a synthetic steroid with estrogenic, and to a
lesser extent,progestogenic and androgenic properties . In
postmenopausal women, administration of tibolone reduces
, improves climacteric complaints , and prevents the
decline (and even
increases) bone mineral density without inducing the
recurrence of menstrual bleedings.It is known as a “bleed free” HRT
and is thus expected to have better compliance. The cost of therapy
is, however ,very high and thus its use may be limited to the
affluent population only .The dose is 2.5mg once daily.
Alendronate is chemically a
biphosphonate. It can be used as an alternative to estrogen therapy
to prevent or cure osteoporosis by increasing bone mineral
density. Compared to
estrogen it has very few side effects. For women who want protection
from osteoporosis but do not want bothersome vaginal bleeding
Alendronate may be an effective alternative to oestrogen. It acts only on the
bone and it does not affect any other menopausal changes. The dose
is 5mg daily for prevention and 10mg daily for cure. The main side
effect is due to erosive esophagitis and it occurs in less than 1%
of users. It can be
prevented by taking the drug on an empty stomach with at least 6oz
of water and remaining upright for 30 minutes afterwards. It is better avoided
in patients who are already suffering from reflux esophagitis.
SERMs are selective oestrogen receptor modulators. They are
estrogen look alikes and act as agonists on some sites and
antagonists on others(9) The idea is to have the
beneficial effects of HRT like prevention of osteoporosis, hot
flushes etc without troublesome effects like endometrial
hyperplasia.SERMs could be classified into(24)Triphenylethylenes
Naphthalenes(CP336,156), Chromans(Levormeloxifene), Phytoestrogens(
Genistein,Daidzein) and conjugated estrogens(Delta
are weak estrogens of plant origin. The precursors of the
biologically active compounds originate in soybean products (mainly
isoflavonoids) and whole-grain cereals, seeds, and nuts (mainly
ligands). High dietary intake of plant estrogens not only reduces
the risk for breast cancer but has been linked to fewer menopausal
symptoms. In a small study of 58 postmenopausal
soy (daidzin) and wheat (enterolactones) reduced hot flushes 40% and
respectively. However, it is unclear
whether these estrogens may be potent enough
stimulate the growth of estrogen-dependent tumors (19).
estrogen treatments for menopausal symptoms:
Nonestrogen treatments include
Bellergal, Propranolol,Natural remedies( Gensing,Vitamin E, Cohash,
Bee pollen) and Life
style/environmental modifications( avoidance of caffeine,layered
Natural nutritional supplements
to alleviate menopausal symptoms:
E,d alpha-tocopherol 100-400 IU two times per day, citrus
bioflavenoids with ascorbic acid 200 mg four to six times daily
could help. The patient
should reduce refined carbohydrate, caffeine, and alcohol
intake. Soy protein,
50mg per day has been shown to decrease the intensity of hot
amounts of phytoestrogens also are found in cashews, peanuts,oats,
corn, wheat, apples and almonds (27).
patient has been put on Premarin 0.625mg/day or Progynova 1mg /day
continuously along with medroxyprogesterone acetate 10mg/day for
10days every month. After 1 month the patient comes back.She is
better, but is not
A Treatment of hot flashes
usually requires a dose of 1.25mg of conjugated estrogen or its
alternative would be to advice her to take 60gm of soy protein every
day in addition to her tablets. It would be equivalent to 0.3mg of
premarin. When progestins are added cyclically, there may be
withdrawal bleeding which may not be acceptable to the patient.
Giving progestins continuously every day in 5mg dose may solve this
problem to some extent, but a small amount of withdrawal bleed may
still be expected occasionally. In patients who are very worried
about bleeding and who can afford it, Tibolone, 2.5mg /day is an
alternative. It is reported to cause less
1.Bachmann.G.A: Role of Androgens
in the menopause: Am J Obs & Gyn.Vol 180 • NO 3 • March
I, Bixo.M: Negative mood changes during hormone replacement therapy:
A comparison between two progestogens., Am Jobs & Gyn.Vol 183 •
NO 6 • December 2000.
replacement therapy and risk for breast cancer., Endocrinology and
Metabolism Clinics Vol 26 • NO 2 • June 1997
4.Burnett.R.G:Role of Androgens
in the Menopause: Am J Obst and Gyn.Vol 180 • NO 3 • March 1999
5.Cagnacci.A, et al: Effect
of Tibolone on Glucose and Lipid Metabolism in Postmenopausal Women:
Clinical Endocrinology and
Metabolism.,Vol 82 • NO 1 • Jan1997.
Valk-de Roo GW Continuously combined hormone replacement therapy and
bone turnover: the influence of dydrogesterone dose, smoking and
initial degree of bone turnover. - Maturitas - 1997 Dec 15;
28(2): 153-62 (Abstract).
7.Ebeling.P.R, AtleyL.M,et al, Bone
Turnover Markers and Bone Density Across the Menopausal
Transition: Journal of Clinical
Endocrinology and Metabolism Vol 81 • NO 9 • September 1, 1996
8.Ferenczy A Endometrial
histology and bleeding patterns in post-menopausal women taking
sequential, combined estradiol and dydrogesterone. - Maturitas -
1997 Apr; 26(3): 219-26 .
Rebar.R: Hormone replacement for the new millennium., Current
Reproductive Endocrinology., Vol 27 • NO 3 • September
10.Gelfand.MD: Role of Androgens
in the menopause., Am J Obs & Gyn Vol 180 • NO 3 • March
Conjugated Estrogens Combined With Sequential Dydrogesterone or
Medroxyprogesterone Acetate in Postmenopausal Women: Effects
Lipoproteins, Glucose Tolerance, Endometrial Histology, and
Bleeding., The Journal of The North American Menopause Society Vol.
4, No. 1, pp. 10 – 18. 1997
menopause, indegene website.
13.Greendale.G.A, Sowers.M.F: The
menopause transition., Endocrinology and Metabolism Clinics
Vol 26 •
NO 2 • June 1997.
M, Christau S,et al: Tibolone reduced menopausal symptoms with less
bleeding compared to
Evidence-based Obstetrics & Gynecology,Vol 1 • NO 3 • Sep
15.Hammond.C: Straight Talk on
HRT: Benefits and Limitations Women’s Health Treatment Updates - ©
Nonestrogen management of menopausal symptoms., Endocrinology
Clinics Vol 26 • NO 2 • June 1997.
17.Hill.D.A, Weiss N.S. et al, Continuous
combined hormone replacement therapy and risk of
endometrial cancer., American
J Obs and Gyn.Vol 183 •
NO 6 • December 2000.
18.Johnson.S.R: Menopause and
hormone replacement therapy., Medical Clinics of North America Vol
82 • NO 2 • March 1998.
RG Prevention and management of osteoporosis: consensus statements
from the Scientific Advisory Board of the Osteoporosis Society of
Canada. – Canadian Medical Assossiation Journal - 1996 Oct 1;
ALM, Burger CW, et al: Micturition Complaints in Postmenopausal
Women Treated With Continuously Combined Hormone Replacement
Therapy: A Prospective Study., Maturitas, 31:143-149, 1999.
Kothari.S, Thacker.H.L: Screening risk assessment of the menopausal
patient., Medical Clinics of North America Vol 83 • NO 6 • November
Hysterectomy, Oophorectomy, and Endogenous Sex Hormone
Older Women: The Rancho Bernardo Study . Year Book of Obstetrics,
Gynecology, and Women’s Health 2001
Subcutaneous Adipose Tissue Metabolism at Menopause:Importance of
Body Fatness and Regional Fat Distribution., J Clinical
Endocrinology and Metabolism
Vol 85 •
NO 7 • July 2000.
24.Menopause Management for the
Millennium [Women’s Health Clinical Management Volume 1 - © 1999
al: Prevention of Early Postmenopausal Bone Loss with Cyclical
Etidronate Therapy., J Clinical
Endocrinology and Metabolism.Vol 82 • NO 9 • Septmber 1, 1997
et al: Oral 17beta-Estradiol Continuously Combined with
Serum Lipoprotein Concentrations in Healthy Postmenopausal Women., J
Clinical Endocrinology and Metabolism Vol 82 • NO 11 • November 1,
27.Northrup.C: Complementary and
Alternative Therapies in Primary Care., Primary Care; Clinics in
Office Practice Vol 24 • NO 4 • December 1997.
28.Orwoll.E.S, Nelson.H.D: Does
Estrogen adequately protect postmenopausal women against
osteoporosis: An iconoclastic
perspective., J Clin Endocrinology and Metabolism Vol 84 • NO 6 •
June 1, 1999.
29.Palmer.D, Regimens for
prescribing hormone replacement therapy: Aust Prescr 1994;17;13-6.
30.Verghese J., Kuslansky.G: Cognitive
performance in surgically menopausal women on estrogen.,
Neurology,Vol55 • NO 6 •
September 26, 2000.
31.Walsh.B.W: Extensive personal
experience The Individualized Approach to Menopause Management
Clinical Endocrinology and MetabolismVol 84 • NO 6 • June 1,