Textbook Of Gynecology. Dc Dutta’s

Chapter 6. Menopause

DEFINITION

Menopause means permanent cessation of menstruation at the end of reproductive life due to loss of ovarian follicular activity. It is the point of time when last and final menstruation occurs.

The clinical diagnosis is confirmed following stoppage of menstruation (amenorrhea) for twelve consecutive months without any other pathology. As such, a woman is declared to have attained menopause only retrospectively. Premenopause refers to the period prior to menopause, postmenopause to the period after menopause and perimenopause to the period around menopause (40-55 years).

Climacteric is the period of time during which a woman passes from the reproductive to the non- reproductive stage. This phase covers 5-10 years on either side of menopause.

Perimenopause is the part of the climacteric when the menstrual cycle is likely to be irregular.

Postmenopause is the phase of life that comes after the menopause.

AGE OF MENOPAUSE

Age at which menopause occurs is genetically predetermined. The age of menopause is not related to age of menarche or age at last pregnancy. It is also not related to number of pregnancy, lactation, use of oral pill, socioeconomic condition, race, height or weight. Thinner women have early menopause. However, cigarette smoking and severe malnutrition may cause early menopause. The age of menopause ranges between 45-55 years, average being 50 years.

CLINICAL IMPORTANCE

Due to increased life expectancy, specially in affluent society, about one-third of life span will be spent during the period of estrogen deprivation stage with long-term symptomatic and metabolic complications.

ENDOCRINOLOGY OF CLIMACTERIC

AND MENOPAUSE

Hypothalamopituitary Gonadal Axis

Few years prior to menopause, along with depletion of the ovarian follicles, the follicles become resistant to pituitary gonadotropins. As a result, effective folliculogenesis is impaired with diminished estradiol production. There is a significant fall in the level of serum estradiol from 50-300 pg/mL before menopause to 10-20 pg/mL after menopause. This decreases the negative feedback effect on hypothalamopituitary axis resulting in increase in FSH. The increase in FSH is also due to diminished inhibin. Inhibin, a peptide, is secreted by the granulosa cells of the ovarian follicle. The increase of LH occurs subsequently.

Disturbed folliculogenesis during this period may result in anovulation, oligo-ovulation, premature corpus luteum or corpus luteal insufficiency. The sustained level of estrogens may even cause endometrial hyperplasia and clinical manifestation of menstrual abnormalities prior to menopause.

The mean cycle length is significantly shorter. This is due to shortening of the follicular phase of the cycle. Luteal phase length remaining constant.

Ultimately, no more follicles are available and even some exist, they are resistant to gonadotropins.

Estradiol production drops down to the optimal level of 20 pg/mL → no endometrial growth → absence of menstruation.

Estrogens

Following menopause, the predominant estrogen is estrone and to a lesser extent estradiol. Serum level of estrone (30-70 pg/mL) is higher than that of estradiol (10-20 pg/mL). The major source of estrone is peripheral conversion (aromatization) of androgens from adrenals (mainly) and ovaries. The aromatization occurs at the level of muscle and adipose tissue. The trace amount of estradiol is derived from peripheral conversion of estrone and androgens. Compared to estradiol, estrone is biologically less (about one-tenth) potent.

With times, the sources fail to supply the precursors of estrogen and about 5-10 years after menopause, there is a sharp fall in estrogen and also the trophic hormones. The woman is said to be in a state of true menopause.

Androgens: After menopause, the stromal cells of the ovary continue to produce androgens because of increase in LH. The main androgens are androstenedione and testosterone. Though the secretion of androgens from postmenopausal ovary are more, their peripheral levels are reduced due to conversion of androgens to estrone in adipose tissue. However, the cumulative effect is a decrease in estrogen: androgen ratio. This results in increased facial hair growth and change in voice.

As the obese patient converts more androgens into estrone, they are less likely to develop symptoms of estrogen deficiency and osteoporosis. But, they are vulnerable to endometrial hyperplasia and endometrial carcinoma.

Progesterone: A trace amount of progesterone detected is probably adrenal in origin.

Gonadotropins

The secretions of both FSH and LH are increased due to absent negative feedback effect of estradiol and inhibin or due to enhanced responsiveness of pituitary to GnRH. Rise in FSH is about 10-20 fold whereas that of LH is about 3-fold. GnRH pulse section is increased both in frequency and amplitude. During menopause, there is fall in the level of prolactin and inhibin. Fall in the level of inhibin (see ch. 7), lead to increase in the level of FSH from the pituitary. Ultimately, due to physiologic aging GnRH and both FSH, LH decline along with decline of estrogens.

ORGAN CHANGES

Ovaries shrink in size, become wrinkled and white. There is thinning of the cortex with increase in medullary components. There is abundance of stromal cells which have got secretory activity.

Fallopian tubes show feature of atrophy. The muscle coat becomes thinner, the cilia disappear and the plicae become less prominent.

The uterus becomes smaller and the ratio between the body and the cervix reverts to the 1:1 ratio. The endometrium becomes thin and atrophic. In some women, however, with high endogenous estrogens, the endometrium may be proliferative or even hyperplastic. The cervical secretion becomes scanty.

The vagina becomes narrower due to gradual loss of elasticity. The vaginal epithelium becomes thin. The rugae progressively flatten. There is no glycogen. Doderlein’s bacillus is absent. The vaginal pH becomes alkaline. Maturation index (parabasal, intermediate and superficial cells) is 10/85/5.

The vulva shows features of atrophy. The labia becomes flattened and the pubic hair becomes scantier. The end result is a narrow introitus.

Breast fat is reabsorbed and the glands atrophy. The nipples decrease in size. Ultimately, the breasts become flat and pendulous.

Bladder and urethra undergo similar changes to those of the vagina. The epithelium becomes thin and is more prone to damage and infection. There may be dysuria, frequency, urge or even stress incontinence.

Loss of muscle tone leads to pelvic relaxation, uterine descent and anatomic changes in the urethra and neck of the bladder. The pelvic cellular tissues become scanty and the ligaments supporting the uterus and vagina lose their tone. As such preexisting weakness gets aggravated.

BONE METABOLISM

Normally, bone formation (osteoblastic activity) and bone resorption (osteoclastic activity) are in balance depending on many factors (age, endocrine, nutrition, and genetic). Following menopause, there is loss of bone mass by about 3-5% per year. This is due to deficiency of estrogen. Osteoporosis is a condition where there is reduction in bone mass but bone mineral to matrix ratio is normal.

Osteopenia (WHO) refers to bone mineral density (BMD) that is >1.0 to < 2.5 standard deviation (SD) below the young adult mean bone mass (“T” score). Osteoporosis is >2.5 SD below the young adult mean. A “Z” score is the BMD of the patient compared to average bone mass for same age sex and weight. A“Z” score >ISD below the mean is abnormal. Postmenopausal woman runs a high risk for fracture of bones due to osteoporosis. Parathyroid hormone (PTH) and IL-I are involved in osteoporosis. Estrogen prevents osteoporosis by several mechanisms. It inhibits osteoclastic activity and inhibits release of IL-I by monocytes. Estrogen increases absorption of calcium from the gut, stimulates calcitonin secretion from the C cells of the thyroid and increases 1, 25 dihydroxy vitamin D. All these lead to increased bone mineralization.

CARDIOVASCULAR SYSTEM

Risk of cardiovascular disease is high in postmenopausal women due to deficiency of estrogenEstrogen prevents cardiovascular disease by several ways. It increases HDL (particularly HDL 2) and decreases LDL and total cholesterol. It inhibits platelet and macrophage (foam cell) aggregation at the vascular intima. It stimulates the release of nitric oxide (NO) and prostacycline from vascular endothelium to dilate the blood vessels. It prevents atherosclerosis by its antioxidant property.

MENSTRUATION PATTERN PRIOR TO MENOPAUSE

Any of the following patterns are observed:

i. Abrupt cessation of menstruation (rare).

ii. Gradual decrease in both amount and duration. It may be spotting or delayed and ultimately lead to cessation.

iii. Irregular with or without excessive bleeding. One should exclude genital malignancy prior to declare it as the usual premenopausal pattern.

MENOPAUSAL SYMPTOMS

In majority, apart from cessation of menstruation, no more symptoms are evident. In some women symptoms appear. The important symptoms and the health concerns of menopause are:

 Vasomotor symptoms

 Urogenital atrophy

 Osteoporosis and fracture

 Cardiovascular disease

 Cerebrovascular disease

 Psychological changes

 Skin and Hair

 Sexual dysfunction

 Dementia and cognitive decline.

Vasomotor symptoms: The characteristic symptom of menopause is “hot flush”. Hot flush is characterized by sudden feeling of heat followed by profuse sweating. There may also be the symptoms of palpitation, fatigue and weakness. The physiologic changes with hot flushes are perspiration and cutaneous vasodilatation. Both these two functions are under central thermoregulatory control. Low estrogen level is a prerequisite for hot flush. Hot flush coincides with GnRH pulse secretion with increase in serum LH level. It may last for 1-10 minutes, and may be at times unbearable. Sleep may be disturbed due to night sweats. The thermoregulatory center in association with GnRH center in the hypothalamus is involved in the etiology of hot flush. Gonadotropins (LH) are thought be involved.

Genital and urinary system: Steroid receptors have been identified in the mucous membrane of urethra, bladder, vagina and the pelvic floor muscles. Estrogen plays an important role to maintain the epithelium of vagina, urinary bladder and the urethra. Estrogen deficiency produces atrophic epithelial changes in these organs. This may cause dyspareunia and dysuria.

Vagina: Minimal trauma may cause vaginal bleeding. Dyspareunia, vaginal infections, dryness, pruritus and leucorrhea are also common. The urinary symptoms are: urgency, dysuria and recurrent urinary tract infection and stress incontinence.

Sexual dysfunction: Estrogen deficiency is often associated with decreased sexual desire. This may be due psychological changes (depression anxiety) as well as atrophic changes of the genitourinary system.

Skin and hair: There is thinning, loss of elasticity and wrinkling of the skin. Skin collagen content and thickness decrease by 1-2% per year. “Purse string” wrinkling around the month and “crow feet” around the eyes are the characteristics. Estrogen receptors are present in the skin and maximum are present in the facial skin. Estrogen replacement can prevent this skin loss during menopause. After menopause, there is some loss of pubic and axillary hair and slight balding. This may be due to low level of estrogen with normal level of testosterone.

Psychological changes: There is increased frequency of anxiety, headache, insomnia, irritability dysphasia and depression. They also suffer from dementia, mood swing and inability to concentrate. Estrogen increases opioid (neurotransmitter) activity in the brain and is known to be important for memory.

Dementia: Estrogen is thought to protect the function of central nervous system. Dementia and mainly Alzheimer disease are more common in postmenopausal women.

Osteoporosis and fracture: Following menopause there is decline in collagenous bone matrix resulting in osteoporotic changes. Bone mass loss and microarchitectural deterioration of bone tissue occurs primarily in trabecular bone (vertebra, distal radius) and in cortical bones. Bone loss increases to 5% per year during menopause. Osteoporosis may be primary (Type 1) due to estrogen loss, age, deficient nutrition (calcium, vit. D) or hereditary. It may be secondary (Type 2) to endocrine abnormalities (parathyroid, diabetes) or medication (see p. 62). Osteoporosis may lead to back pain, loss of height and kyphosis. Fracture of bones is a major health problem. Fracture may involve the vertebral body, femoral neck, or distal forearm (Colles’ fracture). Morbidity and mortality in elderly women following fracture is high.

Detection of osteoporosis: Computed tomography (CT) and specially the dual-energy X-ray absorptiometry (DEXA) are reliable methods to assess the bone-mineral density. Total radiation exposure is high with CT than DEXA.

Biochemical parameters to detect bone loss are measurement of urinary calcium/creatinine and hydroxyproline/creatinine ratios.

Cardiovascular and cerebrovascular effects: Oxidation of LDL and foam cell formation cause vascular endothelial injury, cell death and smooth muscle proliferation. All these lead to vascular atherosclerotic changes, vasoconstriction and thrombus formation (see p. 59).

Risks of ischemic heart disease, coronary artery disease and strokes are increased.

DIAGNOSIS OF MENOPAUSE

1. Cessation of menstruation for consecutive 12 months during climacteric.

2. Appearance of menopausal symptoms ‘hot flush’ and ‘night sweats’.

3. Vaginal cytology - showing maturation index of at least 10/85/5 (Features of low estrogen).

4. Serum estradiol : < 20 pg/mL.

5. Serum FSH and LH: >40 mlU/mL (three values at weeks interval required).

MANAGEMENT

PREVENTION

Spontaneous menopause is unavoidable. However, artificial menopause induced by surgery (bilateral oophorectomy) or by radiation (gonadal) during reproductive period can to some extent be preventable or delayed.

Counseling: Every woman with postmenopausal symptoms should be adequately explained about the physiologic events. This will remove her fears, and minimize or dispel the symptoms of anxiety, depression and insomnia. Reassurance is essential.

TREATMENT

NONHORMONAL TREATMENT

 Lifestyle modification includes: Physical activity (weight bearing), reducing high coffee intake, smoking and excessive alcohol. There should be adequate calcium intake (300 mL of milk), reducing medications that causes bone loss (corticosteroids)

 Nutritious diet—balanced with calcium and protein is helpful

 Supplementary calcium—daily intake of 1-1.5 g can reduce osteoporosis and fracture

 Exercise—weight bearing exercises, walking, jogging

 Vitamin D—supplementation of vitamin D3 (1500-2000 lU/day) along with calcium can reduce osteoporosis and fractures. Exposure to sunlight enhances synthesis of cholecalciferol (vitamin D3) in the skin

 Cessation of smoking and alcohol

 Bisphosphonates prevent osteoclastic bone resorption. It improves bone density and prevents fracture. It is preferred for older women. Women should be monitored with bone density measurement. Drug should be stopped when there is severe pain at any site. Commonly used drugs are etidronate and alendronate. Alendronate is more potent. Ibandronate and zolendronic acid are also effective and have less side effects. Bisphosphonates when used alone cannot prevent hot flushes, atrophic changes and cardiovascular disease. It is taken in empty stomach. Nothing should be taken by mouth for at least 30 minutes after oral dosing. Patient should remain upright for 30 minutes. Side effects include gastric and esophageal ulceration, osteomyelitis and osteonecrosis of the jaw

 Fluoride prevents osteoporosis and increases bone matrix. It is given at a dose of 1 mg/kg for short-term only. Calcium supplementation should be continued. Long-term therapy induces side effects (brittle bones)

 Calcitonin inhibits bone resorption. Simultaneous therapy with calcium and vitamin D should be given. It is given either by nasal spray (200 IU daily) or by injection (SC) (50-100 IU daily). It is used when estrogen therapy is contraindicated.

 Selective estrogen receptor modulators (SERMs) are tissue specific in action. Of the many SERMs, raloxifene has shown to increase bone mineral density, reduce serum LDL and to raise HDL2 level. Raloxifene inhibits the estrogen receptors at the breast and endometrial tissues. Risks of breast cancer and endometrial cancer are therefore reduced. Raloxifene does not improve hot flushes or urogenital atrophy.

Evaluation of bone density (hip) should be done periodically. Risks of venous thromboembolism is increased

 Clonidine, an alpha adrenergic agonist may be used to reduce the severity and duration of hot flushes. It is helpful where estrogen is contraindicated (hypertension)

 Thiazides reduce urinary calcium excretion. It increases bone density specially when combined with estrogen.

 Paroxetine, a selective serotonin reuptake inhibitor, is effective to reduce hot flushes (both the frequency and severity).

 Gabapentin is an analog of gamma-aminobutyric acid. It is effective to control hot flushes.

 Phytoestrogens containing isoflavones are found to lower the incidence of vasomotor symptoms, osteoporosis and cardiovascular disease. It reduces the risk of breast and endometrial cancer.

 Soy protein is also found effective to reduce vasomotor symptoms. Soy protein acts as SERMS.

HORMONE REPLACEMENT THERAPY (HRT)

The HRT is indicated in menopausal women to overcome the short-term and long-term consequences of estrogen deficiency.

Indication of Hormone Replacement Therapy

i. Relief of menopausal symptoms (see p. 59).

ii. Prevention of osteoporosis (see p. 60).

iii. To maintain the quality of life in menopausal years.

Special group of women to whom HRT should be prescribed:

 Premature ovarian failure

 Gonadal dysgenesis

 Surgical or radiation menopause

HRT and Osteoporosis: HRT prevents bone loss and stimulate new bone formation. HRT increases BMD by 2-5% and reduces the risk of vertebral and hip fracture (25-50%). Estrogen is found to play a direct role, as receptors have been found in the osteoblasts. Women receiving HRT should supplement their diet with an extra 500 mg of calcium daily. Total daily requirement of calcium in postmenopausal women is 1.5 g.

HRT is thought to be cardiovascular protective.

LDL on oxidation produces vascular endothelial injury and foam cell (macrophage) formation. These endothelial changes ultimately lead to intimal smooth muscle proliferation and atherosclerosis. Estrogen prevents oxidation of LDL, as it has got antioxidant properties.

TABLE 6.2

RISK FACTORS FOR CARDIOVASCULAR DISEASE

• Hypertension

• Smoking habit

• Familial hyperlipidemia

• Impaired glucose tolerance

In postmenopausal women, there is some amount of insulin resistance and hyperinsulinemia.

Hyperinsulinemia induces atherogenesis. Estrogen improve glucose metabolism.

RISKS OF HORMONE REPLACEMENT THERAPY

aEndometrial cancer: When estrogen is given alone to a woman with intact uterus, it causes endometrial proliferation, hyperplasia and carcinoma. It is therefore advised that a progestogen should be added to ERT to counter balance such risks.

bBreast cancer: Combined estrogen and progestin replacement therapy, increases the risk of breast cancer slightly (RR 1.26). Adverse effects of hormone therapy are related to the dose and duration of therapy.

cVenous thromboembolic (VTE) disease has been found to be increased with the use of combined oral estrogen and progestin (Table 6.3). Transdermal estrogen use does not have the same risk compared to oral estrogen.

dCoronary heart disease (CHD): Combined HRT therapy shows a relative hazard (RR, 1.29) of CHD. Hypertension has not been observed to be a risk of HRT.

eLipid metabolism: An increased incidence of gallbladder disease has been observed following ERT due to rise in cholesterol (in bile).

fDementia, Alzheimer disease are increased.

AVAILABLE PREPARATIONS FOR HORMONE REPLACEMENT THERAPY

The principal hormone used in HRT is estrogen. This is ideal for a woman who had her uterus removed (hysterectomy) already. But in a woman with an intact uterus, only estrogen therapy leads to endometrial hyperplasia and even endometrial carcinoma. Addition of progestins for last 12-14 days each month can prevent this problem. Commonly used estrogens are conjugated estrogen (0.625-1.25 mg/day) or micronized estradiol (1-2 mg/day). Progestins used are medroxyprogesterone acetate (2.5-5 mg/ day), micronized progesterone (100-300 mg/day) or dydrogesterone (5-10 mg/day).

Considering the risks, hormone therapy should be used with the lowest effective dose and for a short period of time. Low dose oral conjugated estrogen 0.3 mg daily is effective and has got minimal side effects. Dose interval may be modified as daily for initial 2-3 months then it may be changed to every other day for another 2-3 months and then every third day for the next 2-3 months. It may be stopped thereafter if symptoms are controlled.

Oral estrogen regime: Estrogen—conjugated equine estrogen 0.3 mg or 0.625 mg is given daily for woman who had hysterectomy.

Estrogen and cyclic progestin: For a woman with intact uterus estrogen is given continuously for 25 days and progestin is added for last 12-14 days.

Continuous estrogen and progestin therapy

Continued combined therapy can prevent endometrial hyperplasia. There may be irregular bleeding with this regimen.

 Subdermal implants: Implants are inserted subcutaneously over the anterior abdominal wall using local anesthesia. 17 0 estradiol implants 25 mg, 50 mg or 100 mg are available and can be kept for 6 months. This method is suitable in patients after hysterectomy. Implants maintain physiological E2 to E1 ratio.

 Percutaneous estrogen gel: 1 g applicator of gel, delivering 1 mg of estradiol daily, is to be applied onto the skin over the anterior abdominal wall or thighs. Effective blood level of oestradiol (90-120 pg/mL) can be maintained.

 Transdermal patch: It contains 3.2 mg of 17 P estradiol, releasing about 50 pg of estradiol in 24 hours. Physiological level of E2 to E1 is maintained. It should be applied below the waist line and changed twice a week. Skin reaction, irritation and itching have been noted with their use.

 Vaginal cream: Conjugated equine vaginal estrogen cream 1.25 mg daily is very effective specially when associated with atrophic vaginitis.

It also reduces urinary frequency, urgency and recurrent infection. Women with symptoms of urogenital atrophy and urinary symptoms and who do not like to have systemic HRT, are suitable for such treatment.

 Progestins: In patients with history of breast carcinoma, or endometrial carcinoma, progestins may be used. It may be effective in suppressing hot flushes and it prevents osteoporosis. Medroxyprogesterone acetate 2.5-5 mg/day can be used.

LNG-IUS (see p. 480) with daily release of 10 microgram (see below) of levonorgestrel per 24 hours, it protects the endometrium from hyperplasia and cancer. At the same time it has got no systemic progestin side effects. Estrogen can be given by any route. It can serve as contraception and HRT when given in a perimenopausal women.

 Tibolone: Tibolone is a steroid (19-nortestosterone derivative) having weakly estrogenic, progestogenic and androgenic properties. It prevents osteoporosis, atrophic changes of vagina and hot flushes. It increases libido. Endometrium is atrophic. A dose of 2.5 mg per day is given.

Duration of HRT Use

Generally, use of HRT for a short period of 3-5 years have been advised. Reduction of dosage should be done as soon as possible. Menopausal women should maintain optimum nutrition, ideal body weight and perform regular exercise.

Individual woman should be given informed choice as regard the relative merits and possible risks of continuing HRT.

PROGRESS IN HORMONE REPLACEMENT THERAPY

Low Dose HRT—Women with intact uterus with 0.3 mg conjugated equine estrogen (CEE) and Medroxy Progesterone acetate (MPA) 1.5 mg is found effective to control the vasomotor symptoms. Similarly 1 mg of estradiol and norethisterone acetate 0.5 mg orally, are also effective and have significant bone sparing effect. Progestogen is added in the HRT to minimize the adverse effects of estrogen. Hormone therapy should be used with lowest effective dose and for the short period of time as possible. Dose interval may be modified (see above) before stopping the therapy. To minimize the systemic adverse effects of progestogen, Levonorgestrel intrauterine delivery system (LNG-IUS) is being used. It is primarily used as a contraceptive (see p. 480). Estrogen component is delivered by oral or by transdermal route or as an implant. A small size LNG-IUS has been developed that releases 10 µg LNG per day. This reduced size LNG-IUS is suitable for the postmenopausal women as the size of the uterus is also small (p. 501).

ABNORMAL MENOPAUSE

Premature Menopause: If the menopause occurs at or below the age of 40, it is said to be premature (details in p. 463). Often, there is familial diathesis.

Treatment by substitution therapy is of value (details in p. 531).

Delayed Menopause: If the menopause fails to occur even beyond 55 years, it is called delayed menopause.

The common causes are constitutional, uterine fibroids, diabetes mellitus and estrogenic tumor of the ovary. The cases should not be neglected. In the absence of palpable pelvic pathology, diagnostic curettage should be done and an early decision of hysterectomy should be taken in the face of increased incidence of endometrial carcinoma.

Artificial Menopause: Permanent cessation of ovarian function done by artificial means, e.g. surgical removal of ovaries or by radiation is called artificial menopause.

Surgical Menopause: Menstruating women who have bilateral oophorectomy, experience menopausal symptoms (see p. 59). It is sometimes more troublesome than natural menopause.

Radiation Menopause: The ovarian function may be suppressed by external gamma radiation in women below the age of 40. The castration is not permanent. The menstruation may resume after 2 years and even conception is possible. Intracavity introduction of radium can cause castration effect by destroying the endometrium and also by depressing the ovarian function. The menopausal symptoms are not so intense as found in surgical menopause or menopause following external radiation.

KEY POINTS

> Menopause means permanent cessation of menstruation at the end of reproductive life due to ovarian follicular inactivity. The average age being 50 years. Menopause is genetically predetermined. It is not related to the number of pregnancies, race, socioeconomic conditions, education, height, weight, age at menarche or age of last childbirth.

> The initial endocrine change with the onset of menopause is decreased ovarian inhibin production and increase in pituitary FSH release. The amount of estrogen replacement in menopause is not dependent upon the level of FSH.

> There is gradual elevated levels of first the FSH and then LH. Simultaneously, estradiol levels fall to optimal 20 pg/mL when menopause sets in. There is increased androgen secretion from the ovarian stroma and from the adrenal. A trace amount of progesterone is adrenal in origin.

> Diagnosis is from the classic symptom of ‘hot flush' (50%) and confirmed by elevated FSH levels to >100 mIU/ mL and serum estradiol <20 pg/mL.

> In menopause, there is depletion of ovarian follicles with degeneration of granulosa and theca cells. Stromal cells produce androgens, which are converted to estrogens in peripheral body fat. Obese postmenopausal women, have higher levels of estrone, less hot flushes and osteoporosis. But risk of developing endometrial cancer is high for them.

> Benefits of HRT are: Improvement in vasomotor symptoms, urogenital atrophy, increase in BMD, reduced risk of vertebral and hip fractures, reduction colorectal cancer and possibly cardioprotection (see p. 62). Estrogen reduces the risk of late onset Alzheimer's disease. It is beneficial in symptomatic women.

> Risks of HRT are: Endometrial cancer, breast cancer, VTE and coronary heart disease (see p. 62).

> For a woman with intact uterus, progestin (for last 12-14 days) must be combined with estrogen. Otherwise unopposed estrogen therapy will increase the risk of endometrial hyperplasia and adenocarcinoma. Estrogen without a progestin is recommended for a postmenopausal women who had hysterectomy.

> Contraindications to HRT include undiagnosed genital tract bleeding, estrogen dependent neoplasm in the body, history of venous thromboembolism, active liver disease and gallbladder disease (see p. 62).

> Estrogen may be administered orally, subdermal implants, vaginal cream, percutaneous gel or by transdermal patch. Provided the women is monitored during the period of therapy (see Table 6.4), HRT can be continued as long as the benefits are desired. However, low dose and short period of therapy (3-5 years) is currently recommended.

> Dual energy X-ray absorptiometry (DEXA) is the most accurate method to measure bone density.

> Indications of estrogen therapy in menopause are: Presence of vasomotor symptoms, prevention of atrophic vaginitis, urethritis and osteoporosis. Estrogen increases calcium absorption and reduces bone reabsorption.

> LDL cholesterol increases the risk of coronary artery disease (CAD) while HDL protects CAD. Estrogen therapy decreases LDL cholesterol and increases HDL.

> Premature menopause is one when the menstruation stops at or below the age of 40. Delayed menopause is one when menopause fails to occur even beyond 55 years.



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