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Menopause is a normal stage of life. Its health consequences have only become apparent as life expectancy has increased well beyond the 6th decade of life for women. It is estimated that women living in developed countries will live at least one-third of their lives after menopause. Functionally, menopause may be considered an “estrogen withdrawal syndrome.” It is recognizable by the loss of menses and, for most women, by the appearance of signs and symptoms such as hot flashes, insomnia, vaginal atrophy, decreased breast size and reduced skin elasticity. Osteoporosis and cardiovascular disease rep- resent longer term consequences of estrogen deficiency (Fig. 24.1). Both are more indolent and less predictable than the early signs and symptoms of menopause.

Physiology of menopause
The postmenopausal ovary is small and essentially devoid of follicles. The appearance of the postmenopausal ovary, coupled with the observation that oophorectomy is associated with menopausal symptoms, led to the original theory that follicular depletion was responsible for menopause. More recent evidence suggests that menopause has origins in both the central nervous system and the ovary. In addition, men appear to experience a similar, albeit later and more subtle change, called andropause. Both changes can be referred to as “gonadopause” and associated mechanisms in the central nervous system and gonads seem to be quite extensive and to reflect the general aging process.
Fertility decreases dramatically in women beginning at about age 35 but accelerating after the age of 40. The accelerated fall after 40 may be the first sign of impending ovarian failure. Although ovarian follicles remain visible on ultrasound, attempts at artificial induction of ovulation with injected gonadotropins are largely unsuccessful after about age 45 years. This suggests that a physiologic defect develops within the oocytes or follicles prior to their depletion. About 3–4 years before menopause is apparent, serum follicle-stimulating hormone (FSH) levels begin to rise subtly and ovarian estrogen, anti-Müllerian hormone, inhibin and progesterone production falls. Menstrual cycle length tends to decrease as the follicular phase progressively shortens. Ultimately, ovulation and menstruation cease entirely. The age of onset of menopause has changed very little over time – even the Ancient Greeks mention the age of 50 as typical. Age of menopause is affected by multiple factors. Maternal menopausal age is predictive of a daughter’s menopausal age. Age of menarche does not affect age of menopause. Most agree that race and parity have no effect. Smokers enter menopause at an earlier age than nonsmokers.

Although ovarian failure is a major component of menopause, functional alterations also occur at the level of the pituitary. Changes  arise  in  the  intrinsic  rhythms  that  control  sleep  and  the neuroendocrine axes. Such changes in the circadian oscillator lead to diminished nocturnal melatonin secretion and altered sleep, decreased responsiveness of the gonadotropin axis to steroid feedback and decreased adrenal steroid production. Aging is also associated with a more general decline in central dopaminergic and noradrenergic neuronal function. Estrogen deficiency further exacerbates the dopamine deficiency by increasing the ratio of norepinephrine to dopamine.
During menopause, the decrease in ovarian estrogen and inhibin production reduces negative feedback signals to the pituitary and hypothalamus and results in a progressive rise in gonadotropin levels. Because inhibin acts exclusively to regulate FSH (Chapter 1), FSH levels rise disproportionately to luteinizing hormone (LH) levels. When in doubt, persistent elevation of serum FSH levels confirms the diagnosis of menopause. Although ovarian estrogen production essentially ceases, the ovary continues to make the androgens testosterone and androstenedione. Most of this steroid biosynthesis occurs in the hilar cells of the medulla of the gland and very little occurs in the stroma. Hilar cells share a common embryologic origin with testicular Leydig cells, the main androgen-secreting cells in the male (Chapter 5). Although ovarian estrogen production ceases at menopause, post- menopausal women are not completely estrogen deficient. Peripheral tissues such as fat, liver and kidney express the enzyme aromatase and can convert circulating androgens to estrogens. The major difference between direct ovarian estrogen secretion and peripheral conversion is that most of the estrogen produced by the latter process is estrone. Estrone is the estrogen produced from aromatization of androstenedione, the major androgen secreted by the postmenopausal ovary and adrenal gland (Chapter 2). Estrone is a very weak estrogen compared with estradiol. In the typical concentrations found in postmenopausal women, estrone does not provide protection against the long-term consequences of estrogen deficiency. Obese postmenopausal women are somewhat protected from this. Fat is a particularly rich source of aromatase activity and obese postmenopausal women can produce substantial amounts of estrone. These high quantities of endogenous estrone provide some protection against the risk of menopausal vasomotor symptoms and osteoporosis but at a cost. Prolonged exposure of the endometrium to estrogen stimulation that is unopposed by postovulatory progesterone will increase the risk for the development of endometrial hyperplasia and carcinoma (Chapter 42). The endometrium is never converted from proliferative physiology to secretory morphology and this unregulated growth favors neoplastic change. A similar risk of endometrial stimulation is present in women receiving estrogen alone for postmenopausal hormone replacement. For this reason, women who still have their uterus but require or choose postmenopausal estrogen replacement should also be given progesterone in a continuous or cyclic fashion.

Signs and symptoms
Hot flashes
Hot flashes or flushes occur in about 75% of menopausal women. Nocturnal hot flashes often wake a woman from sleep and may produce significant sleep deprivation or insomnia. During a hot flash most women note a sensation of pressure in their head followed by a flush of heat or burning. This sensation begins on the head or neck area and passes over the entire body. Sweating invariably accompanies the flush. While there are profound physiologic changes associated with hot flashes, the mechanism by which estrogen deficiency produces this symptom is not known. The physiologic changes include an initial increase in skin conductance and then temperature, a reflection of peripheral vasodilatation. Core body temperature subsequently drops by an average of 0.2°C. Circulating estrogen levels do not change before or after the flash but LH, cortisol, dehydroepiandrosterone (DHEA), androstenedione and the proopiomelanocortin (POM-C) derived peptides all do. It is believed that the hot flash represents an initial change in central thermoregulation that elicits a number of compensatory mechanisms. These mechanisms transiently raise, but ultimately reduce the core body temperature to the new set point. Central nervous system catecholamines are involved in hypothalamic temperature regulation and the impact of estrogen deficiency on noradrenergic neuronal function likely has a role in hot flashes. Some hypothesize that estrogen deficiency predisposes to vasodilatation within the hypothalamus. This results in an increase in hypothalamic temperature and a response favoring a reduction in the core body temperature.
In addition to hot flashes, most menopausal women experience vaginal atrophy and changes in their breasts and skin. Vaginal atrophy can lead to decreased vaginal lubrication. This may be physically uncomfortable, may predispose to urinary tract infections and may result in dyspareunia during intercourse. These changes are directly related to the loss of estrogen stimulation in target tissues and can largely be reversed by estrogen replacement.

Bone changes
Bone loss in women actually begins at about age 30. It accelerates at menopause. The most rapid bone loss occurs in the first 3–4 years after menopause. Bone loss occurs more quickly in women who smoke and in very thin women. African-American race and fluoride treatment of the water supply are associated with a lower incidence of osteoporosis. The most common site of osteoporosis-related fractures is the vertebral body, an effect that may be noted clinically as back pain and the development of a “dowager’s hump.” The upper femur, humerus, ribs and distal forearm are also frequently affected by postmenopausal bone loss. Upper femoral fractures that involve the hip joint may be life-threatening because of an accompanying risk of venous thromboembolic disease.
Osteoporosis resulting from prolonged estrogen deficiency involves a reduction in the quantity of bone without alterations in its chemical composition. Bone formation by osteoblasts is normal in estrogen- deficient women but the rate of bone resorption by osteoclasts is increased. Trabecular bone is affected first, followed by cortical bone. Estrogen appears to antagonize the effects of parathyroid hormone (PTH) on calcium mobilization. This may occur as a direct effect of estrogen on bone because estrogen receptors have been found on bone cells in culture.

Cardiovascular changes
Estrogen receptors are present on blood vessels and estrogen appears to clinically decrease vascular resistance and increase blood flow. One potential mechanism by which estrogen may improve blood flow is through its demonstrated ability to decrease the production of endothelin, a potent vasoconstrictor, by vascular endothelium. Estrogen therapy is also associated with an increase in high-density lipoproteins and decrease in low-density lipoproteins. Despite these mechanistic findings, the results of several recent large population studies have suggested that postmenopausal hormone replacement therapy (HRT) may have untoward cardiovascular effects. These results need to be taken in context with risks and benefits weighed for a particular patient. For instance, one arm of the Women’s Health Initiative, which is the largest randomized trial of HRT, showed that use of combinations of estrogen and progestin in the treatment of postmenopausal women resulted in seven additional cases of heart disease, eight pulmonary emboli, eight strokes and eight additional cases of breast cancer among 10 000 women treated for 1 year. At the same time, there were six fewer cases of colon cancer and five fewer hip fractures. This resulted in 20 women who were harmed by therapy out of 10000 undergoing treatment. Although recent data have relaxed prohibitions somewhat, postmenopausal estrogen replacement regimens in the years after release of the results of the Women’s Health Initiative have been severely retstricted, with most practitioners limiting therapy to the treatment of hot flashes and vaginal atrophy. When given, estrogen has typically been provided in the lowest dose and for the shortest duration possible. Alternative medications and delivery systems for postmenopausal hormone replacement are under investigation.