Menopause is an important phase in a woman,s life.  Menopause essentially means permanent cessation of menstruation.  usually a woman attains menopause around the age of 45-50.  given that the average life expectancy of human beings is increasing the world over, a woman may end up spending almost a third of her life span in the post-mnopausal period, if not more.  Natural menopause is associated with lack of functioning of ovaries, which are two hormone producing organs situated near the womb or the uterus. Normally, these ovaries produce 3 hormones,viz: oestrogen, p\rogesterone and androgens.  When they stop functioning the woman faces many physical and mental changes.  Women who have their uterus removed for some reason need not face these problems if their ovaries are not removed simultaneously.  But in a few years time, the ovaries will stop functioning, and the woman will start facing menopausal symptoms.  Usually people who have their uterus removed start facing menopausal effects earlier than women who undergo natural menopause.   Women who have their ovaries removed at the time of hysterectomy(Operation of removing uterus) will face menopausal symptoms immediately and these symptoms are more severe than the symptoms of women who undergo natural menopause.  If the woman undergoes hysterectomy after she undergoes natural menopause, she may not have much difference in her menopausal symptoms, as her ovaries have almost stopped functioning anyway.  

Presenting symptoms of Menopause : 

1. Menopause entails decrease in three hormones, viz.; oestrogen,progesterone and androgens. Patients who present to a doctor due to severe menopausal symptoms usually present  due to lack of any of these This may necessitate HRT or hormone replacement therapy, where the deficient hormones are administered to the woman as medications;

a. Lack of estrogen :    This may lead to hot flash/flush, sleep disturbance, palpitations, dry skin, irritable bladder, and dyspareunia( Painful intercourse)

b.Progesterone deficiency: Heavy irregular menses suggest progesterone deficiency. This means, menopausal effects need not exactly start after menopause or stoppage of menstruation actually occurs, but may start a few months before the stoppage of menstruation.  Thus many women who suffer from heavy periods are in the perimenopausal age, that is, in the years nearing menopause.

c. Androgen deficiency: This  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. Osteoporosis literally means porous bones.  The hormone oestrogen is usually responsible for holding calcium in the bones, which in turn, leads to formation of bone matrix.  Many years after menopause, the    calcium sort of drains from the bone, making it full of holes.  The woman gets back ache as a result of it.  These changes are shown on X-ray only after considerable bone is lost from the body.  Sophisticated tests like calcaneal ultrasound and Densitometry can detect it much earlier, and remedial measures can be undertaken.  

3. Cardioprotection : It is known that women who have not undergone menopause have less chance of getting a heart attack as  compared to men of the same age.  However, once her ovaries stop functioning, the odds that a woman may get a heart attack are the same as for men of comparable age. The protection provided by oestrogen is no longer there.  However, it now (2005) known that, giving oestrogens    will not reduce this risk in post-menopausal woman. 

4    Hypothyroidism as a consequence of menopause. There is reduced production of a hormone called thyroxine, normally produced by the thyroid gland , situated in the neck.  The woman as a consequence, may tire easily, may get water logging in her body, and in extreme cases may not be able to tolerate cold.

4.    Adjuvant to treatment in Alzheimer’s disease: Alzheimer's disease is one where the woman tends to lose her memory. As brain has estrogen receptors, it is thought that giving    estrogen pills may help them tide over this disease better, along with other medications.

5.    Adjuvant to treatment of endogenous depression which may be unmasked during menopause. Women in their menopausal period may suddenly develop depressive symptoms, like easy crying, easy irritability, or sleeplessness.  These symptoms are actually due to some changes in their brain which were there even before menopause.  However, they manifest themselves at the time of menopause.  Thus it is called unmasking of depression, meaning, the depression was already there, but gets unmasked at the time of menopause.    Usually at this time, the woman also  faces an "Empty nest syndrome".  This means, till about 40 years, her house was filled with echoes of her children asking her for something or screaming for      something not done.  But suddenly they leave her and fly away to be on their own.  She suddenly feels unwanted and this adds to her symptoms of depression.  If it is severe, along with medicines to replace deficient hormones, she may need antidepressant medications.  

Hormone Replacement Therapy

  To relieve the symptoms of menopause, doctors may prescribe hormonal medications. These type of medications are called hormone replacement therapy, because, it replaces the hormones that should normally have been there.

The following questions and answers will give an insight into the therapies usually given to menopausal women.

What are the oral oestrogen preparations available and what are the doses in which they are   given?

       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^.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 is 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^. 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.  As adjuvant to treatment of depression, Alzheimer’s disease and hyptothyroidism treatment may be continued as long as the primary disease is being treated.

 What are the progestin suppliments to be given with oestrogen? What are the preparations available in India? When and why should they be given? 

The only indication for adding progestin suppliments to oestrogen replacement is to avoid the complication of endometrial hyperplasia (Overgrowth of the lining of the uterus) which might occur with oestrogen therapy alone. Hence progestin supplimentation need not be given to hysterectomised women^. 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 also been tried.Progestins by themselves have been known to reduce hot flushes^.

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^.  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.  

 What is Tibolone?

Administration of tibolone  , 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 (Giving ordinary HRT is associated with bothersome bleeding, while giving Tibolone is associated with little bleeding)  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 .

What is Alendronate^?

Alendronate is  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.  Erosive esophagitis can cause heartburns.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 (Patients who already have heart burn). 

What is Raloxifene?

Raloxifene is used for the prevention of osteoporosis.  It does not act on the breast or the uterus and so there is no fear of breast cancer or vaginal bleeding.  However, it increase the intensity of hot flushes and is therefre avoided in women who are recently postmenopausal.  

What are the side effects of estrogen therapy^?

    Estrogen in HRT can cause migrainous headaches,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.

What are the side effects of progestin therapy?

    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. 

 What are SERMs?       

SERMs are selective oestrogen receptor modulators. They are estrogen look alikes and act as agonists on some sites and antagonists on othersThe idea is to have the beneficial effects of HRT like prevention of osteoporosis, hot flushes etc without troublesome effects like endometrial hyperplasia.

What are 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 postmenopausalwomen, soy (daidzin) and wheat (enterolactones) reduced hot flushes 40% and 25%,respectively.  

What are non estrogen treatments for menopausal symptoms?

Nonestrogen treatments include Steroids(Progestins,androgens),SERMs, Phytoestrogens,Nonsteroidal medications(Clonidine,lofexidine,antidopaminergic compounds, Bellergal, Propranolol,Natural remedies( Gensing,Vitamin E, Cohash, Bee pollen) and  Life style/environmental modifications( avoidance of caffeine,layered clothing, exercise).  Avoiding stress can reduce menopausal symptoms.  It has been researched that holding the hand over the heart and concentrating on an object of unconditional love like a pet and allowing the feeling of love to envelope her, could reduce menopausal symptoms.

What are the nutritional supplements useful in menopause?

A: 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.ISoya beans could be powdered and mixed with wheatflour or it could be boiled and consumed.  It is not dangerous if female grandchildren or men consume it.  VitaminC: 2000mg/day. Magnesium 300-800mg/day, calcium:1000-1500mg/day,Boron.2-12mg/day =5 serving of fruits/day,Vitamin D 350IU/day.

Suppose a woman had to remove her ovaries much before natural menopause , how long  should she take HRT?

A: At least till 52 years of age.

A 50 year old woman who had her last menstrual period 1 year back comes with history of  abdominal discomfort. On direct questioning, she gives history of feeling hot inspite of having to put on the fan at all times. She also complains that her children have stopped loving her and she therefore doesn’t sleep well. What treatment should she receive?

A: In a patient with vague abdominal symptoms, it is mandatory to rule out ovarian tumours or some other pelvic/abdominal pathology. Having dealt with that aspect of her presenting complaint, concentration must be given to the post-menopausal symptoms. This particular patient has come with systemic symptoms of estrogen deficiency (feeling hot, etc., and will do well with a) Oral estrogen tablets, or b) Transdermal oestrogen patches,along with progestin supplimentation for at least 10-12 days to prevent endometrial hyperplasia. Menopause doesn’t cause depression, but unmasks latent depression.   A patient with a complaint of insomnia should be questioned properly and if there are symptoms of depression, antidepressants should be added to the therapy. Endogenous depression requiring drug therapy should be diagnosed if the patient has early morning insomnia (getting up in the early morning hours and being unable to go back to sleep) ,feeling of helplessnenss, hopelessness, worthlessness, feeling unhappy without provocation, etc. This patient complains of  insomnia. If on close questioning she seems to suffer from depression(according to the symptoms mentioned), antidepressants should be added to the hormone replacement therapy.

A 65 year old woman comes with history of increased frequency of urination,and painful urination.  She doesn’t have hot flushes. 

Symptoms of oestrogen deficiency like hot flushes lasts only for a few postmenopausal years in the majority of women.  In very few women the symptoms last for a few decades. In the older woman population, symptoms like pruritus in the private parts, dry vagina, burning in the vaginal area, excessive white discharge, painful urination, involuntary passage of ruine, increased urinary frequency, leaking of urine while coughing or laughing, inability to hold the feeling of voiding urine,etc may be due to lack of oestrogen in the local tissues. Lack of acidity in the vaginal area is also responsible . Estrogen through the vaginal route is the most effective one for treatment for atrophic changes.Vaginal symptoms could also be treated with either intravaginal estrogen or the standard oral or transdermal regimens. There may be some initial systemic absorption of vaginal estrogen through the thin atrophic vaginal mucosa; however, once mucosal integrity is restored with local therapy, systemic absorption of E2 is usually not a concern. Therefore, vaginal estrogen alone is an option for women who need treatment only of genitourinary atrophy.   This particular patient with urinary symptoms should be evaluated for urinary tract infections, diabetes,etc., But along with whatever treatment she gets she would benefit with the addition of hormone replacement therapy. Since she has only local symptoms, she probably needs only vaginal estrogen cream.Estriol cream (Evalon)and dinoestrol creams are locally available in India. Therapy should be given daily for 2 weeks and then reduced to 2-3times/week.A few weeks may be needed to resolve symptoms.  If local creams are not acceptable or not available, oral/transdermal route of therapy supplimented with progesterone may be tried.

A 60 year old woman comes with history of severe backache. She has history of a fall many years back, after which her back always used to bother her, but of late it has become too nagging, so she has decided to seek medical help.  As she feels her uterus may be the problem  for her backache, she has decided to seek the help of a gynaecologist.

A:  90% of backaches are caused due to problems of the back itself. Thus after ruling out pelvic causes of backache, one may need to look for ligamentous strains, osteoarthritis etc., as causes of backache,and treat it.  In addition, as the lady is in the postmenopausal group it is mandatory that one look for osteoporosis .Lack of estrogen in the postmenopausal age group leads to trabecular bone loss and this can aggravate backaches and increase the incidence of fractures .  Osteoporosis can be diagnosed on ordinary X-rays only after considerable amount of bone is lost. Diagnosis of osteoporosis is best made by measuring bone mineral density with dual energy x-ray absorptiometry (DEXA). According to the WHO, a bone mineral density below 2.5 standard deviations for the young-normal control constitutes a diagnosis of osteoporosis. This investigation is costly. Calcaneal ultrasound, which is less sensitive and accurate than DEXA, is much less costly and may be good enough for the majority of patients.  Both these investigations are available in many centres in India.  But for the vast majority of patients in India, investigations like DEXA or calcaneal ultrasound are out of reach, either because it is not available at nearby centres or because it is too costly for them to afford it.  In such circumstances one could start the patient on Hormone replacement therapy or Alendronate therapy on a presumptive diagnosis of osteoporosis. Even in cases where  there is no osteoporosis Hormone replacement therapy  is indicated as it prevents osteoporosis.  Along with hormone replacement therapy supplimentation with calcium should be given. Patients on Estrogen replacement therapy should ingest a total of 1200mg of calcium along with a daily intake of vitaminD 400iu-800IU.  Vitamin K2 and antioxidants like vitamins C and E also prevent bone resorption. Other  nonpharmacologic interventions include weight-bearing exercise.

Does Hormone replacement therapy with the currently used estrogen-progesterone tablets increase the chance of  breast cancer?  

There have been many studies on the effect of estrogen replacement therapy on the breast. Many studies have reported a slight increase in the incidence of breast cancer in women using estrogen therapy for longer than 5-10 years. No study has recorded an increased risk of breast cancer for women using HRT for short periods (i.e<5 years). For those patients who are prescribed estrogens for short durations for symptom relief, one need not ask for yearly mammograms purely on the basis of the woman taking HRT.For the well informed woman reassurance can be given that short durations of HRT has not proved to have increased the incidence of breast cancer. For durations of greater than 5-10 yr, most but not all  studies have found an increase in breast cancer risk,probably in the order of 2% excess risk per year of estrogen treatment ,but the design of most of these studies is such that  this finding is not conclusive.

 Who are the women for whom HRT should be given?  

Women for Whom Systemic Estrogen Replacement is Optional

     1.No family history of cardiovascular disease before the age of 65.

    2.Aerobic exercise for 20 to 30 minutes at least three times a week.

    3.Normal lipid profile with HDL cholesterol greater than 35.

    4.No family history of osteoporosis.

    5.Nor family history of Alzheimer's disease.

    6.Nonsmoker.  

 Women for Whom Estrogen is Probably Beneficial

    1.Strong family history for heart disease.

    2.Smoker.

    3.Sedentary lifestyle.

    4.Hypertension and/or unfavorable lipid profile.

    5.Diabetes.

    6.Strong family history for Alzheimer's disease.

    7.Unwilling or unable to make life-style changes in diet and exercise.