Presenting symptoms:

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.

a. Lack of estrogen may lead to hot flash/flush, sleep disturbance, palpitations, dry skin, irritable bladder, and dyspareunia.

b. Heavy irregular menses suggest progesterone deficiency.

c. Androgen deficiency manifests as decreased libido or decreased ability to reach sexual climax.

2. Osteoporosis as evidenced by decreased bone mineral density shown by X- ray,Densitometry or

    calcaneal ultrasound

3.        Cardioprotection

4        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 menopause.

Ideal  hormone replacement therapy:

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.

c)     There 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 premenopausal.  

e)     The side effects should be minimal.

Oral oestrogen preparations:

       The estrogens currently available in India are

A)   Conjugated equine estrogen(Premarin);strength: tablets of 0.625mg and 1.25mg.

B)    Estradiol valerate(Progynova)               strength: tablets of 1mg and 2mg.

C)    Estriol  (Evalon)                                     strength: 2mg tablet.

   Conjugated equine 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 estradiol.  For 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 estrogen therapy?(12,18)

    Estrogen in 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 alternatives.

    Progestin supplements: 

The only 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 has     22.Laughlin.G.A, Connor.E: Hysterectomy, Oophorectomy, and een tried.Progestins by themselves have been known to reduce hot flushes(16).

The progestins that are available are:

a)        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.

Medroxy progesterone  10mg/day for cyclical therapy and 2.5-5mg/day for combined therapy.

Dydrogesterone: 10-20mg/day for cyclical therapy and 10mg /day for combined therapy.

Micronised progesterone: 200mg/day for cyclical therapy and 100mg/day for combined therapy.

Medroxy progesterone acetate is the drug most commonly prescribed for this purpose.

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 therapy. 

Side effects of progestin therapy?(3,12,18)

    Progestin 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.

Tibolone:(5,11)

Tibolone (Livial) is a synthetic steroid  with estrogenic, and to a lesser extent,progestogenic and androgenic properties . In postmenopausal women, administration of tibolone reduces gonadotropin secretion  , 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:?(18)

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:

       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 (Clomiphene,Tamoxifen,Toremifene,Droloxifene,Idoxifene),Benzothiphenes(Raloxifene,LY353381), Naphthalenes(CP336,156), Chromans(Levormeloxifene), Phytoestrogens( Genistein,Daidzein) and conjugated estrogens(Delta 8,9-Dehydroestrone sulfate).

Phytooestrogens:

Phytoestrogens 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

women, soy (daidzin) and wheat (enterolactones) reduced hot flushes 40% and 25%,

respectively.  However, it is unclear whether these estrogens may be potent enough

to stimulate the growth of estrogen-dependent tumors (19).

Non estrogen treatments for menopausal symptoms:

Nonestrogen treatments include Steroids(Progestins,androgens),SERMs, Phytoestrogens,Nonsteroidal medications(Clonidine,lofexidine,antidopaminergic ompounds, Bellergal, Propranolol,Natural remedies( Gensing,Vitamin E, Cohash, Bee pollen) and  Life style/environmental modifications( avoidance of caffeine,layered clothing, exercise).

Natural nutritional supplements to alleviate menopausal symptoms:

     Vitamin 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 flashes.  Significant amounts of phytoestrogens also are found in cashews, peanuts,oats, corn, wheat, apples and almonds (27).

Q10 The 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 completely cured.

A  Treatment of hot flashes usually requires a dose of 1.25mg of conjugated estrogen or its equivalent.  An 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 bleeding.

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