Menopause

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[edit] Menopause

David L. Keefe

More than one third of the women in the United States have reached menopause, and with female life expectancy approaching 80 years, many will spend more than a third of their lives in a postmenopausal state.^[1] The first born of the baby boom generation are approaching their fifth decade, so the number of menopausal women is expected to increase further over the next 20 years. Although menopause is a natural phenomenon, the loss of ovarian estrogen production can evoke symptoms and exacerbate a number of age-related diseases, including coronary heart disease and osteoporosis. Hormone therapy alleviates menopausal symptoms and reduces the risks of coronary heart disease and osteoporosis, but may induce side effects. Thus menopausal women constitute a large and growing portion of physicians' practices for whom recognition and treatment of hypoestrogenism may improve the quality and duration of life. The physician must help the menopausal woman to weigh potential benefits against risks of hormone therapy in order to decide whether hormone therapy is the right choice for her.

[edit] DEFINITIONS

Menopause is the woman's final menstrual period. Usually defined retrospectively after 6 to 12 months of amenorrhea, menopause occurs at an average age of 51. Loss of ovarian function before age 40 is termed premature ovarian failure. The transition from reproductive to nonreproductive ovarian function, a period that spans over 10 years in most women, is the climacteric. The association of estrogen deficiency symptoms with decline in ovarian function is the menopausal syndrome.

[edit] ETIOLOGY

Natural menopause arises as a consequence of follicular depletion, a process that begins before birth and progresses throughout the life of the woman. Oocyte mitosis ceases, and oocyte and follicle atresia begins while the female herself is still in utero. At birth, oocyte number declines from over 8 million to fewer than 2 million. Most follicles degenerate before ovulating, which explains why decreasing or increasing the number of ovulations by oral contraceptive pills, pregnancy, lactation, or fertility drugs does not influence appreciably the onset of menopause. During the decade preceding the menopause (roughly corresponding to the climacteric), the rate of follicular loss accelerates. Nonetheless, some oocytes remain, even after the cessation of menstruation. Follicular atresia probably involves apoptosis. Neuroendocrine changes precede follicular exhaustion in rodents, although neuroendocrine contributions to reproductive aging in women have been less studied.

Premature ovarian failure may result from oophorectomy, radiation, chemotherapy, autoimmune disease, chromosomal abnormalities (especially Turner mosaic), infection, metabolic abnormalities or trauma. Menopause may begin at an earlier age in smokers. Often the cause of premature ovarian failure remains unclear. In some cases, ovarian biopsy can clarify the etiology of premature ovarian failure, but the associated risk and cost rarely justify its use, because the results usually do not alter clinical management.

[edit] Psychosocial Perspectives

Women from every population exhibit physiologic changes with menopause. Indeed, references to the menopause in ancient and classical texts resemble modern clinical reports.^[1] Yet, the incidence of menopause-associated symptoms varies greatly among cultures. Women from cultures that confer prestige and dignity on menopausal women report fewer symptoms than women from cultures that perceive the menopause in a more negative light. The role of menopausal women in Western culture is complex. On the one hand, Western culture increasingly deemphasizes the reproductive role of women; on the other hand, it remains emphatically youth-oriented. Not surprisingly, reactions of Western women to menopause vary according to the meaning it holds for them. Most women accept menopause as a normal stage in the cycle of life, one that they share with their mothers, sisters, and friends. Indeed, in the Massachusetts Women's Health Study, a large community survey showed that 70% of menopausal women expressed relief or neutral feelings about the cessation of menses. For many women, the menopause years are a time of personal satisfaction and professional productivity.

The physician may encounter women experiencing difficulty with menopause. For example, those who have struggled with long-term infertility may find that the finality of menopause removes their last hope of having their own child. Others see menopause as a sign of aging. Since menopause occurs at a stage of life when children leave home, partners take sick, or parents die, its meaning may become entangled with grief associated with such losses. For these women the physical nature of menopausal symptoms may be less painful to face and easier to understand than the underlying emotional turmoil. Even though physicians can offer hormone therapy to alleviate symptoms and protect against some potentially fatal diseases, the universality of the menopause and the variability of reactions to it prompt some to caution against "medicalization" of such a natural event. Because of this great diversity of reactions to the menopause, the physician must help the individual woman place menopause within the broader context of her own life, and make her a partner in every aspect of clinical decision making related to it.

[edit] EPIDEMIOLOGY

Cessation of ovarian function by the fifth or sixth decade is a universal phenomenon among women. Indeed, females of most mammalian species undergo reproductive failure by midlife, leading some sociobiologists to hypothesize that midlife loss of reproductive capacity among aging females confers survival value to species. Because of the aging world population, the number of menopausal women is increasing. Almost 60% of the U.S. population aged 65 or older, and over 70% of the population aged 85 or older, are women. Improved public health and health care in developing countries have ensured survival of increasingly large numbers of women into the menopausal years, so globally more than 470 million women are menopausal. Since hypoestrogenism contributes to debilitating chronic diseases, such as coronary heart disease and osteoporosis, the evaluation and treatment of the menopause have enormous public health and clinical implications.

Although menopause is a universal experience, only about 40% of menopausal women seek treatment for symptoms related to estrogen deficiency. As discussed above, reporting of menopausal symptoms depends on complex psychosociobiologic interactions. Differences in the incidence of menopausal symptoms reflect not only cultural influences on symptom reporting, but also genetic variation in body habitus, which directly affects estrogen levels by influencing rates of aromatization. Variation in dietary consumption of plant estrogens (phytoestrogens) also may influence development of symptoms, although evidence in support of this hypothesis is still preliminary.

[edit] PATHOPHYSIOLOGY

After menopause the ovary becomes small and fibrotic, and takes on a pitted surface.^[1] Microscopically, decreased numbers of primordial follicles and increased numbers of fibroblasts, interstitial cells, and connective tissue appear, reflecting atrophy of the ovarian cortex and hyperplasia of the medulla. Considerable variation in the degree of interstitial hyperplasia exists, which explains in part the variation in levels of ovarian steroidogenesis reported in menopausal women.

The pattern of steroidogenesis changes after the menopause. Before menopause steroidogenesis is cyclical; during the follicular phase the graafian follicle secretes estradiol-17β; then during the luteal phase the corpus luteum secretes progesterone and estradiol-17β. After menopause, production of ovarian estrogen and progesterone virtually ceases. Less potent estrogens, principally estrone, are produced from androgens by the enzyme aromatase, located in adipose, muscle, and brain. Considerable differences in the extent of extraovarian estrogen formation exist among menopausal women, which may explain in part differences in the incidence of estrogen-related symptoms. High circulating levels of luteinizing hormone maintain androgen secretion from interstitial and hilar cells within the ovary, which is why oophorectomy of menopausal women reduces circulating testosterone by 50% and androstenedione by 30%, but barely affects estrogen production.

Although absolute levels of androgens also decrease, estrogen levels decrease so significantly at menopause that the ratio of circulating androgens to estrogens actually increases after menopause. Since androgens and estrogens interact at a number of levels (e.g., they down-regulate each other's receptors and reciprocally influence sex hormone binding globulin levels), an increased androgen/estrogen ratio unmasks androgenic activity in some women. Women undergoing surgical menopause experience much greater decline in androgen levels.

The manifold effects of estrogen deprivation on menopausal women should come as no surprise, since estrogen receptors appear throughout the body, where they regulate many critical functions. Estrogen receptors appear in highest concentrations in reproductive tissues, such as breast and urogenital tract, and in phylogenetically ancient parts of the brain involved in regulation of the neuroendocrine and autonomic nervous systems. Measurable levels of estrogen receptor also appear in many other tissues, including liver, blood vessels, and bone.

Estrogen receptors are part of the steroid hormone receptor superfamily. When bound to hormone, steroid receptors attach to specific DNA sequences, called hormone response elements, to regulate transcription of steroid-sensitive genes. Some products of steroid receptor–induced transcription themselves regulate transcription, which creates a cascade of regulatory events within the cell. Extremely rapid effects of estrogens, especially on some tissues that lack detectable levels of estrogen receptor, suggest that sex steroids also may act independently of their receptors.

[edit] PATIENT EVALUATION

[edit] Symptomatology

Estrogen deficiency symptoms usually begin during the climacteric, at first interspersed with symptom-free periods. As menopause approaches, they may become increasingly frequent and severe. Most symptoms associated with menopause can be explained by the effects of estrogen deprivation on sensitive tissues. Hot flushes and sleep disturbance, the most common symptoms of the menopause, arise from the effects of estrogen deprivation on those parts of the brain that regulate body temperature and sleep, respectively. Hot flushes typically begin in the chest, spread to the face, and last seconds to minutes. They may be associated with anxiety and palpitations, and are followed by profuse sweating and shaking. Some women experience up to 20 episodes per 24-hour period, and most women find hot flushes increase in frequency at night. Eating, stress, or alcohol may trigger hot flushes. In at least 50% of women they abate spontaneously within 5 years after the menopause, even without hormone therapy. Women who develop premature ovarian failure before attaining adult levels of estrogen (e.g., Turner's syndrome patients) do not report hot flushes. Sleep disturbance is characterized by frequent nocturnal awakenings, which may be associated with hot flushes. Sleep apnea also has its onset after the menopause in some women.

Urogenital atrophy, manifesting as urinary frequency, dysuria, dyspareunia, genital bleeding, and occasionally stress urinary incontinence, results from the effects of estrogen deprivation on the bladder, urethra, and associated pelvic supports. Amenorrhea, which may be preceded by luteal phase defects, shortening of menstrual cycle length, or menstrual irregularity, results from loss of cyclic estrogen and progesterone effects on the endometrium. Decreased estrogen/androgen ratio contributes to mild hirsutism and breast atrophy in some women.

Decreased sex drive may arise from urogenital atrophy or psychodynamic reactions to menopause. Women who have undergone oophorectomy may experience decreased libido because of loss of ovarian androgen production. More controversial is the role of estrogen deprivation on mood and cognitive function.

Declining fertility and fecundity, which begin more than a decade before the menopause, even before detectable alterations in menstrual cyclicity, result largely from declining oocyte developmental potential, and possibly from abnormal endometrial receptivity.

Some menopausal women present with symptoms associated with osteoporosis, such as back pain, kyphoscoliosis, and decreased height (revealed earliest by changing dress hem length). Coronary heart disease in menopausal women may present with classic angina, but atypical angina may be more common. Early detection of coronary heart disease symptoms is especially critical in menopausal women, because their outcome after myocardial infarction may be worse than men (see Chapter 45 ). Osteoporosis and heart symptoms typically appear in women only several years past menopause.

[edit] Physical Examination

Physical examination of the menopausal woman reveals atrophy of sex steroid–dependent tissues. Skin on the vulva thins, vaginal epithelium becomes dry and loses rugations, the cervix and uterus decrease in size, and the portio of the cervix becomes friable. Breasts decrease in size and fullness. Such observations provide more reliable assessment of the state of estrogenization than measurement of circulating estradiol-17β because these tissues reflect overall estrogen effects, whereas the estradiol-17β level measures only one of many bioactive estrogens. Some women develop mild hirsutism in response to declining estrogen/androgen ratio. Older postmenopausal women may have kyphoscoliosis and spinous tenderness from osteoporotic vertebral fractures.

Physical examination of the menopausal woman should include careful examination of the breasts and associated lymph nodes, and of the cervix, vagina, uterus, adnexa, vulva, and rectum to screen for evidence of malignancy. A Pap smear and stool guaiac should be obtained.

[edit] DIAGNOSIS

[edit] Diagnostic Procedures

Although the physical examination provides a sensitive "bioassay" for the state of estrogenization, a number of laboratory assays can confirm the presence of hypoestrogenism. Levels of estradiol-17β less than 40 pg/ml, follicle stimulating hormone (FSH) greater than 20 mIU, and vaginal cytology exhibiting parabasal cells signal ovarian failure. A number of accurate and reliable methods exist to quantify bone density. Standard x-rays reflect only late-stage osteoporosis, but quantitative bone densitometry using single or dual photon absorptiometry or other methods measures bone demineralization with greater sensitivity. The role of broad-based radiographic screening for osteoporosis is controversial at present, but most physicians agree that bone densitometry should include women who need osteoporosis risk assessment in order to weigh potential risks against benefits of hormone therapy.

Risks for a number of life-threatening diseases, such as coronary heart disease, stroke, breast cancer, and osteoporosis, increase after the menopause. Most risks for these conditions can be determined by interview and physical examination, but cholesterol screening, mammography, and occasionally bone densitometry studies may provide additional information.

Women experiencing premature menopause should have a cosyntropin (Cortrosyn) stimulation test. Thyroid stimulating hormone (TSH), calcium, and phosphorus levels should be evaluated for associated hypoadrenal, hypothyroid, and hypoparathyroid states, respectively.

[edit] Differential Diagnosis

The interview and physical examination must search for evidence of conditions that mimic menopause, especially in young women with premature ovarian failure. Carcinoid, pheochromocytoma, or systemic mastocytosis can present with flushing, but usually can be differentiated by concomitant attacks of diarrhea, hypertension, or hypotension, and the absence of other signs of hypoestrogenism.

Hyperprolactinemia lowers estrogen levels, usually does not cause vasomotor instability, but does cause galactorrhea. Hyperandrogenic states arising from functioning adrenal or ovarian tumors produce more marked virilization with more rapid progression than the mild and insidious hirsutism that appears in some menopausal women. Hypothalamic amenorrhea differs from menopause by its lack of hot flushes and decreased rather than increased FSH levels. Patients with osteoporosis should be evaluated for primary hyperparathyroidism, hyperthyroidism, or hypercortisolism.

Vulvar dermatoses or neoplasia may be mistaken for menopausal urogenital atrophy, and excoriations on atrophic vulva menopausal women may be mistaken for neoplasia. Only biopsy can distinguish these. Any white, erythematous or raised vulvar lesions should be biopsied in women of all ages.

Sleep disturbance, decreased sex drive, and hot flushes associated with hypoestrogenism may resemble anxiety and mood disorders. A history of anxiety and mood disorders antedating the menopause may suggest a functional etiology for these symptoms. However, many physicians will prescribe hormone therapy if other signs and symptoms suggest hypoestrogenism. Symptoms remaining after hormonal treatment of the hypoestrogenic state may require additional psychotherapeutic and/or psychopharmacologic intervention.

[edit] MANAGEMENT

Hormone replacement therapy (HRT) effectively treats most symptoms associated with menopause, and prevents disease and prolongs life even in asymptomatic women. In women who cannot tolerate HRT, a number of nonhormonal alternatives exist that provide some symptomatic relief and/or disease prevention.

A major potential benefit of hormone therapy is reduced risk of cardiovascular disease.^[2][3][4][5] Cardiovascular disease is the leading cause of death among women in developed countries, accounting for 50% of all deaths in women over age 50. The incidence of cardiovascular disease increases fiftyfold after menopause. Consistent evidence from observational studies demonstrates that unopposed estrogen reduces the risk for coronary heart disease by 35% to 50%, although only randomized, controlled clinical trials, which are still underway, can demonstrate conclusively cardioprotective effects of estrogen. The mechanisms underlying hormone therapy's cardioprotective effects remain incompletely understood. Hormone therapy induces favorable changes in lipid factors, but recent evidence indicates that changes in lipids account for only 20% of its cardioprotective effects.

Addition of progestin to estrogen also probably reduces the risk of coronary heart disease, although the magnitude of risk reduction cannot be estimated with current data. Indeed, the cardioprotective effects of combined regimens may depend on the dose and chemical structure of the specific progestin employed. Since progestins that structurally resemble androgens induce androgenic side effects, they can abrogate some of the beneficial effects of estrogen.

Hormone therapy with estrogen or estrogen/progestin also reduces the risk for osteoporosis-related hip fracture by 25% and for vertebral fractures by over 50% (see Chapter 45 ).^[6]

Estrogen deprivation increases osteoporosis because it increases bone turnover. Since estrogen deficiency increases bone resorption more than formation, it causes a net decrease in bone density. Hormone therapy rapidly restores normal levels of bone resorption and formation. Progestins do not counteract estrogen's protective effect on bone. The protective effects of hormone therapy are greatest when they are initiated before menopause, but even women with advanced osteoporosis may experience improvement.

These potential benefits must be weighed against possible risks and side effects of hormone therapy. The risks of hormone therapy have been overestimated by studies based on oral contraceptive pills and on unopposed estrogen. Hormone therapy provides levels of estrogenic activity close to that encountered in premenopausal women, whereas even the lowest-dose oral contraceptive pills contain estrogenic activity many times greater than that provided by hormone therapy. Furthermore, the addition of progestin to estrogen lowers the risk of endometrial cancer associated with estrogen replacement therapy to below that of women who take no hormone therapy at all.^[7] Other side effects attributed to sex steroids based on studies of oral contraceptive pill users, such as hypertension and thromboembolic disease, also generally do not apply to hormone therapy.

The most troubling, but at the same time most controversial, risk attributed to hormone therapy is increased lifetime probability of breast cancer.^[8][9][10] Data are extensive, but conclusions are inconsistent concerning the risk of developing breast cancer in women taking estrogen. The fact that men almost never get breast cancer and the fact that early menarche and late menopause increase risk for breast cancer are consistent with the hypothesis that extending the duration of the exposure to estrogens by hormone therapy may increase breast cancer risk. However, data suggest that women who use estrogen therapy for less than 5 years probably do not increase their risk of breast cancer. The risk for breast cancer may increase slightly among women who take estrogen for longer than 15 years, and may be concentrated among those with other risk factors, but here the data are less conclusive.

Contrary to early reports, progestins do not protect against breast cancer. Indeed, fundamental studies on the effects of sex steroids on breast tissue predict that combination therapy may increase risk for breast cancer, and some preliminary clinical studies corroborate this.

For most women the most annoying side effect of hormone therapy is vaginal bleeding. In women with a uterus, estrogen therapy produces unpredictable vaginal bleeding in up to 40% of treated women per year. The addition of progestins on a monthly basis synchronizes bleeding, but often replaces it with symptoms of weight gain, irritability, and depression attributable to the progestin. Other side effects associated with estrogen therapy include breast tenderness, bloating, and headache. However, in most women these symptoms are mild. Often they improve after several months of therapy.

Before prescribing hormone therapy, the physician should explain these risks and benefits. Although public health considerations dictate that most menopausal women at least consider hormone therapy, the decision to begin it ultimately must be reached only after balancing potential risks and benefits for the individual. The physician should uncover pertinent risk factors, then discuss feelings and beliefs the woman has regarding menopause and hormone therapy in order to help her make a rational decision about hormone therapy. For example, the physician may counsel a woman that five times more women die of heart disease each year than from breast cancer, and that hormone therapy reduces the risk of heart attack by 30% to 50%, while its effect on breast cancer is still controversial. Yet, the woman who has a strong family history of breast cancer and minimal risk factors for heart disease very reasonably may elect to refuse hormone therapy and pursue alternatives, such as bisphosphonates or selective estrogen receptor modulators (SERMS). Conversely, women who have coronary heart disease risks are likely to benefit from hormone therapy, even if they are also at increased risk for breast cancer.

Hormone therapy can be given as unopposed estrogen, unopposed progestin, or estrogen/progestin combination regimens. Women who have undergone hysterectomy do not need progestin therapy. Women who have a uterus require combined estrogen/progestin therapy. Combined regimens include estrogen plus cyclic progestin and estrogen plus continuous progestin. The continuous combined regimen may eliminate vaginal bleeding if the uterus becomes atrophic. However, usually months of irregular bleeding ensue before this goal is attained. A wide variety of hormone preparations are available (Box 42-1).

Women presenting with symptoms of hypoestrogenism and prolonged amenorrhea electing continuous estrogen and cyclic progestin should take an estrogen alone until symptoms abate. The estrogen is then titrated to achieve the minimal effective dose, a process that may take up to 2 months. Such a short course of unopposed estrogen carries minimal risk for the endometrium in such patients and enables the physician to adjust one hormone at a time. Furthermore, for many women the progestin creates the biggest barrier to compliance. Delaying progestin therapy until the abatement of menopausal symptoms enhances trust in the physician-patient relationship, and increases patient motivation to work through the optimization of the progestin dose. Progestin is added at a low dose for at least 12 days, beginning the first of each month (a schedule that helps the woman remember when to take progestin). If bleeding begins before day 10 of the progestin, the progestin dose is increased.

Women presenting with irregular menses, even in association with evidence of hypoestrogenism, and women who develop vaginal bleeding on hormone therapy must undergo evaluation to exclude endometrial cancer. The ease and accuracy of office biopsy largely has supplanted operative dilation and curettage, but suspicious histology, inadequate tissue, technical difficulty (especially in older women with a stenotic cervical os), and persistently irregular bleeding are all indications for operative fractional curettage. Some physicians perform a transvaginal ultrasound at the first sign of unexpected bleeding. An endometrial stripe less than or equal to 5 mm nearly excludes the risk of endometrial hyperplasia and allows the patient to avoid a painful endometrial biopsy. After exclusion of neoplasia, perimenopausal dysfunctional uterine bleeding should be treated by monthly progestin therapy.

Contraindications to hormone therapy include breast cancer; other estrogen-dependent malignancies; acute liver, pancreatic, or gallbladder disease; chronically impaired liver function; or undiagnosed vaginal bleeding (Box 42-2). Relative contraindications include previous venous thrombophlebitis, strong family history of breast cancer, or other estrogen-dependent malignancy. For these women, clonidine or ergot preparations reduce hot flushes. Dietary supplementation with calcium reduces osteoporosis risk, although not as completely as estrogen, and exercise and restriction of dietary cholesterol and fat consumption reduce coronary heart disease risk (Table 42-1). SERMS act as estrogen receptor agonists in some tissues, but as antagonists in other tissues. Tamoxifen and raloxifene, two currently available SERMS, spare bone and protect the heart, although not as well as estrogen, and protect the breast from the proliferative effects of estrogen. They also can exacerbate hot flushes. Such "designer estrogens" some day may provide patients with the advantages of estrogen without the side effects or risks. However, for the present they provide only partial protection against the effects of estrogen deprivation. Bisphosphonates, such as Alendronate, reduce the risk of osteoporosis, but do not provide the cardioprotection nor the symptom relief provided by estrogens.

Table 42-1 Alternatives to Estrogen Therapy

[edit] REFERENCES