Menopause 

Menopause is a universal and irreversible part of the overall aging process involving a woman's reproductive system, after which she no longer menstruates. The menopausal transition (MT) is characterized by hormonal changes and clinical symptoms that occur over a period leading up to and immediately post menopause. This period is frequently termed the climacteric, and/or perimenopause, but mostly recently is coined the menopausal transition.^{[1, 2]}

The MT characteristically begins years before menopause. Menopause, by definition, is the final menstrual period and is diagnosed after 12 months of amenorrhea and is characterized by a myriad of symptoms that include, but are not limited to, change from regular, predictable menses; vasomotor and urogenital symptoms such as vaginal dryness and dyspareunia; and sleep and mood dysfunction.^{[1, 2]}

See Medscape's Menopause Resource Center for related information.

Epidemiology

The increasing number of middle-aged and older individuals includes a concomitant and continuing rise in the number of women who live most of their lives in a hypoestrogenic state. More and more women can expect to live approximately 79 years and to experience the consequences of gonadal steroid hormone loss.

Although the time spent in menopause (now up to one third of the life cycle) has increased with the phenomenon of increasing longevity, the average age of menopause, approximately 50-51 years, has not changed since antiquity. Women from ancient Greece experienced menopause at the same age as modern women, with the symptomatic transition to menopause usually commencing at approximately age 45.5-47.5 years.^{[3, 4]} Factors that lower the age of physiologic menopause include smoking^[4] , hysterectomy, oophorectomy, Fragile X carrier, autoimmune disorders, living at high altitude, or history of certain chemotherapy medications and/or radiation treatment.

Physiology

Menopause results from loss of ovarian sensitivity to gonadotropin stimulation, which is directly related to follicular attrition. The oocytes in the ovaries undergo atresia throughout a woman's life cycle, resulting in a decline in both the quantity and quality of follicles. Thus, the variable menstrual cycle length during the transition is due to a shrinking follicle cohort size more so than follicle failure. Anovulatory cycles and absence of cyclicity become common, with a highly variable pattern of gonadotropin and steroid hormone production, estrogen insensitivity, failure of the luteinizing hormone (LH) surge, the final menstrual period, and permanent amenorrhea.^{[1, 2]} Hormonal fluctuation may not be responsible for all irregular bleeding during this period; therefore, pelvic pathology (eg, uterine fibroids, uterine polyps, endometrial hyperplasia, endometrial cancer), which becomes more prevalent during this time, must be excluded by endometrial sampling, such as endometrial biopsy (EMB) or dilatation and curettage (D&C).

During the fifth decade of life, many women are lulled into a false sense of security, thinking that they are no longer fertile because they are so close to menopause. Although fertility declines, pregnancy can still occur, as demonstrated by a relatively high rate of unintended pregnancies in women aged 40-44 years. In fact, the number of unintended pregnancies in this age group has increased over the past decade,^[5] which underscores the need for continued contraceptive practice in heterosexual couples.

A shorter menstrual cycle length is the most common change in menstrual cyclicity that occurs during the MT (< 25 d) in women who have no pelvic pathology and who continue to be ovulatory.^[6] The follicular phase of the menstrual cycle shortens because of the decreased number of functional follicles. Because these follicles, which are stimulated by follicle-stimulating hormone (FSH) during the first part of the menstrual cycle, have declined in number, less recruitment of oocytes occurs and the follicular phase shortens accordingly. However, once ovulation occurs, the luteal phase remains fairly constant, at 14 days.

Over time, as aging follicles become more resistant to gonadotropin stimulation, circulating FSH and LH levels increase. Elevated FSH and LH levels lead to stromal stimulation of the ovary, with a resultant increase in estrone levels and a decrease in estradiol levels. Inhibins are peptides of the transforming growth factor-β superfamily and are produced by the granulosa cells of the ovarian follicles in the terminal stages of development. Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels.^{[1, 2, 7]} With the commencement of menopause and a loss of functioning follicles, the most significant change in the hormonal profile is the dramatic decrease in circulating estradiol, which rapidly declines over a period of 4 years, 2 before the final menstrual period, and stabilizing approximately 2 years afterwards. Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation. Total serum testosterone levels do not change during the MT. DHEAS does decline with age. A trend of higher total cholesterol, low-density lipoprotein (LDL) and apolipoprotein B and a loss of the protective effect of high-density lipoprotein (HDL) is characteristic in menopause.^{[1, 2, 8]}

With cessation of ovulation, estrogen production by the aromatization of androgens in the ovarian stroma and production in extragonadal sites (adipose tissue, muscle, liver, bone, bone marrow, fibroblasts, and hair roots)^[8] continue, unopposed by progesterone production by a corpus luteum. Perimenopausal and menopausal women are thus often exposed to unopposed estrogen for long periods, which can lead to endometrial hyperplasia, a precursor of endometrial cancer. Estradiol levels decrease significantly because of loss of follicular production with menopause and postmenopause, but estrone, which is aromatized from androstenedione from nonfollicular sources, is still produced and is the major source of circulating estrogen in the postmenopausal female.

Because most conversion of androgens to estrogens occurs in adipose tissue, it is frequently assumed that obese women, who have more circulating estrogen, should have fewer complaints of vasomotor symptoms. However, this is not always the case, and vasomotor symptoms of menopause can be as frequent and severe in heavier women as they are in thinner women.

The clinical indication that menopause has occurred is the measure of an elevated FSH level. The FSH level rises more than the LH level because of the reduced renal clearance of FSH compared with LH. A slightly elevated or borderline menopausal FSH level in the transition period may not be a reliable indicator of menopause because of the wide variation of FSH and LH levels in response to increased release of gonadotropin-releasing hormone (GnRH) by the hypothalamus and increased pituitary sensitivity to GnRH. Repeated measurements of FSH and LH levels at 2- to 3-month intervals is helpful in establishing whether the woman is progressing through menopause. Women with elevated, but not postmenopausal, FSH levels are still at risk for pregnancy and contraception should still be used until FSH levels remain in the postmenopausal range.

For patient education resources, see the Women's Health Center and Bone Health Center, as well as Menopause, Female Sexual Problems, and Hormone Replacement and Osteoporosis.

The menopausal transition (MT) is a time when the physiologic changes in responsiveness to gonadotropins and their secretions occur, and it is characterized by a wide variation in hormonal levels. Women often experience a variety of symptoms that include hot flashes or flushes, insomnia, weight gain and bloating, mood changes, irregular menses, mastodynia, depression, and headache. As already noted, the length of time over which these symptoms occurs is widely variable; symptoms may begin up to 6 years before the final menstrual period and continue for a variable number of years after the final menstrual period.^{[1, 2, 3]} As the postmenopause years progress, with an accompanying loss of ovarian response to gonadotropins, associated affective symptoms of the menopause also decline.

The effects of gonadal hormone depletion can be obvious on pelvic examination, with changes noted before menopause in some women. The reproductive organs of a woman of reproductive age greatly differ in appearance from those of a woman who is menopausal. With loss of estrogen, the vaginal epithelium becomes redder because of thinning of the epithelial layer and increased visibility of the small capillaries below the surface. Later, as the vaginal epithelium further atrophies, the surface becomes pale because of a reduced number of capillaries. A decrease in urine pH leading to a change in bacterial flora may result in pruritus and a malodorous discharge. Rugation also diminishes, and the vaginal wall becomes smooth. Such changes often result in insertional dyspareunia and, for many women, eventually lead to sexual abstinence if left untreated.

Inside the pelvis, the uterus becomes smaller. Fibroids, if present, become less symptomatic, sometimes shrinking to the point that they can no longer be palpated on manual pelvic examination. Endometriosis and adenomyosis are also alleviated with the onset of menopause, and many patients with pelvic pain finally achieve permanent pain relief.

The menopausal ovary diminishes in size and is no longer palpable during gynecologic examination. A palpable ovary on pelvic examination warrants a full evaluation in all women who are menopausal or postmenopausal.

For older women, a general loss of pelvic muscle tone also occurs, and this may manifest as prolapse of reproductive or urinary tract organs (see Uterine Prolapse and Pelvic Organ Prolapse). Vaginal pressure, lower back pressure, or bulging at the vaginal introitus is common in women with prolapse. On examination, cystocele, rectocele, and uterine prolapse are obvious as causes of these symptoms.

Atrophic cystitis, when present, can mimic a urinary tract infection. Women report symptoms of urinary frequency, urgency, and incontinence. However, women are more prone to urinary tract infection during this time because of atrophic cystitis, and a urine culture should be obtained in all symptomatic women.

In addition to alterations in the pelvic organs, marked changes occur throughout the body. Skin loses elasticity, bone mineral density (BMD) declines, and dense breast tissue is replaced by adipose tissue, making mammographic evaluation easier.

The most common reason a woman presents at menopause is because of symptomatic hot flashes. Flashes, or flushes, which are unpredictable in onset and sometimes occur over many years, are reported in about 75% of women who are perimenopausal or postmenopausal. Hot flashes often cause embarrassment and discomfort, as well as sleep disturbances and emotional lability, especially if they are intense and occur frequently. Vasomotor episodes usually last a few minutes. Episodes vary in frequency from every hour to every few days.

A woman who flushes to the extent that she has major sleep disturbances may also complain of cognitive or affective disorders resulting from sleep deprivation. The vasomotor flush is described as a feeling of warmth or heat that begins from the umbilical area and moves upward toward the head, followed by sweating of the head and upper body. Other cardiovascular or neurologic symptoms (eg, palpitations, dizziness, light-headedness, vertigo) can also occur, with or without flushing, making the episode more difficult to classify as simply a climacteric symptom. Because of the wide range of symptoms, symptomatic women who have risk factors for a condition other than menopause should undergo thorough evaluation.

A study by Kim et al suggests menopause does not increase the risk of diabetes.^[9]

Although osteoporosis is one of the most pervasive conditions in older women, the condition is often not taken seriously enough by menopausal women. With proper intervention, osteopenia is a largely preventable sequela of menopause. Osteoporosis is defined as a bone mineral density (BMD) equal to or greater than 2.5 standard deviations (SDs) below the peak bone mass or T score. Osteopenia is a BMD 1.0-2.49 SDs below the T score.^[10]

In 2001, Grady and Cummings performed a meta-analysis of 22 trials with data on a total of 8800 women. They found a 27% reduction in risk of nonvertebral fractures in older women who received hormone therapy. For hip and wrist fractures, the risk reduction was 40%, increasing to 55% in women younger than 60 years.^[11] The data from the Women's Health Initiative (WHI) also demonstrated decreased bone fractures in women on hormone therapy.

Millions of women in the United States discontinued the use of hormone therapy after the findings of the WHI were released. Karim et al evaluated the impact of this cessation and found that women who discontinued hormone therapy were at a higher risk of hip fracture and lower BMD compared with women who continued hormone therapy. Furthermore, the protective association of hormone therapy with hip fracture disappeared within 2 years of cessation.^[12]

With the onset of menopause, BMD is rapidly lost because bone resorption, uncoupled from bone formation, is accelerated, whereas formation continues at the premenopausal rate. Trabecular bone is affected more than cortical bone, and bone loss is therefore more commonly observed at vertebral, coaxial, and radial sites. Normal bone loss associated with senescence is different from the accelerated bone loss observed after menopause. Bone loss in just the few years after onset of menopause may be as high as 20% of lifetime bone loss.^[11]

The overall effect of menopausal bone loss is reduction of bone strength, leading to an increased risk of fracture. The younger the woman at cessation of ovarian function, the more severe bone loss is likely to be. Similarly, the lower the woman's bone mass when entering menopause, the more severe the osteoporosis will be. Severity of osteoporosis is also related to race, being worse in whites than in Asians, and least severe in women with dark complexions. Other risk factors are smoking and slender build. Osteoclasts have been shown to have estrogen receptors, and these are hypothesized to be the mechanism by which estrogen replacement protects against osteoporosis.

Bone densitometry is the most accurate clinical predictor of osteoporosis. If bone mass is less than 1 standard deviation below the average for the specific bone measured, then the individual is at a much higher risk of fracture. Other risk factors, such as low serum estrogen level, female sex, low serum androgen level, smoking, physical inactivity, low body weight, and little exposure to sunlight are risk factors for osteopenia and osteoporosis. Bone densitometry testing is recommended for all postmenopausal women. Neither the age of initial BMD screening nor the optimal frequency of screening has been determined.

Bone density by dual-energy x-ray absorptiometry (DXA) is the standard measure for the diagnosis of osteoporosis. However, the cost of this test is high, and the test is not universally available. The Australian Primary Care Evaluation of Clinical Tests (PROSPECT) suggests a better prescreening protocol can reduce the need for unnecessary radiologic tests at the primary care level.^[13] Assessment of risk factors such as age, prior fracture, risk of falling, and BMD are valuable in predicting fracture risk.^[14]

Currently, there are many treatment options for preventing fractures among postmenopausal women with osteoporosis. Treatments include bisphosphonates, selective estrogen receptor modulators (SERMS), calcium, vitamin D, calcitonin, monoclonal antibodies, and hormonal medications. Estrogen therapy (ET) is considered a second-line therapy for osteoporosis.^[15] Variations in osteoporosis care is common among physicians. While the majority of patients receive bisphosphonates, younger patients with fewer comorbidities and who are cared for by physicians with greater experience have a greater odds of receiving SERMS, hormone replacement therapy, or calcium and vitamin D.^[16] Oral and transdermal estrogen preparations have been approved for osteoporosis prevention in postmenopausal women who are considered at risk. Bone loss accelerates in the late menopausal transition and continues for the first few years post menopause.^[17] Postmenopausal women and elderly women should be treated early and onalong-term basis unless estrogen therapy is contraindicated.

Most bisphosphonates (alendronate, etidronate, ibandronate, risedronate, and zoledronic acid), raloxifene, calcitonin, and estrogen prevent vertebral fractures. Some bisphosphonates (alendronate, risedronate, and zoledronic acid) and estrogen prevent hip and other nonvertebral fractures. It is unknown if bisphosphonates are more effective in preventing fractures than any of the other therapies.^[15]

Bisphosphonates are the most useful pharmacological intervention and work as antiresorptives. They have been shown to have a beneficial effect on vertebral and hip fracture rates and to cause a more significant increase in BMD than raloxifene and calcitonin.^{[18, 19, 20]} Three widely used and effective bisphosphonates are alendronate, risedronate, and ibandronate. The Vertebral Efficacy With Risedronate Therapy (VERT) study was conducted at 110 centers and included 2458 postmenopausal women who had vertebral fractures. Risedronate was administered at a dose of 5 mg for 36 months and showed a statistically significant reduction in relative risk (RR) of new vertebral fractures (RR = 0.59, 95% confidence interval [CI], 18-58%). Cumulative incidence of nonvertebral fractures was also reduced.^[20]

In May 2010, the Journal of the American Medical Association reported a possible association between bisphosphonates and atypical femoral fractures.^[21] Further data should be forthcoming on this possibility, but a letter to the editor in the New England Journal of Medicine presented data to refute the extent of these atypical fractures and emphasized that overall, fracture rates are much lower in patients taking bisphosphonates compared with those not taking bisphosphonates.^[22] A recently reported population-based nationwide analysis of atypical fractures in bisphosphonate users in Sweden concludes that for the individual patient with a high risk of osteoporotic fractures, the absolute risk of osteoporotic fractures is small compared with the beneficial effects of the medication.^[23]

Both alendronate and risedronate were first introduced with daily dosing for treatment of osteoporosis. Patients can now be prescribed a weekly dose of either alendronate or risedronate, which increases their tolerability and reduces side effects. A newer bisphosphonate, ibandronate, is approved for monthly use, and zoledronic acid is approved for once-yearly use. The main adverse effects of bisphosphonates continue to be gastrointestinal upset and reflux. Patients with significant GERD should be discouraged from bisphosphonate use unless approved by a gastroenterologist. Supplementation with 1000-1500 mg of calcium per day remains a mainstay of prevention therapy, as does vitamin D supplementation and regular weight-bearing exercise. Excessive salt, animal protein, alcohol, and caffeine offset these benefits.

Raloxifene is a SERM and acts directly on estrogen receptors in the bone to decrease resorption. In clinical trials with up to 8 years of follow-up, raloxifene reduces significantly vertebral, but not nonvertebral, fracture risk.^[24]

Calcitonin is a peptide hormone that acts by inhibiting osteoclasts, which are involved in bone resorption activity. A decreased vertebral fracture rate has been demonstrated with this therapy, as has a small increase in BMD in older women. Serum calcium levels must be monitored in patients taking this drug.

Raloxifene, tamoxifen, and estrogen increase the risk of thromboembolic events.^[15]

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in men and postmenopausal women. Menopause increases the risk for women still further, independent of age. Prior to menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years. After menopause, women come to have similar risks of CAD as men of the same age. As a result, the rate of death in women from CAD is increasing. The Framingham study was pivotal in showing the relationship between menopause and increased cardiovascular mortality rate.^[25]

The Women's Health Initiative (WHI) was a randomized controlled trial that addressed the issue of whether postmenopausal women should take hormone therapy or estrogen therapy for prevention of CAD.^{[26, 27]} More than 27,000 healthy women participated in the WHI. The study found that hormone therapy and estrogen therapy are not indicated for the prevention of CAD. Emerging analyses of WHI data from the Estrogen-Alone Trial, a double-blind, placebo-controlled, randomized clinical trial, evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among postmenopausal women with prior hysterectomy and after a mean of 7.1 years of follow up, suggests that treatment effects differed by age. Compared with older women, younger women receiving CEE had a lower risk of CAD.^[28]

This further suggests that immediate use of hormone therapy/estrogen therapy in the early postmenopausal time may reduce the risk of CAD and the clear difference in age interactions for CEE use, greater safety, and possible benefit among women in their 50s, with potential harm to older women, were observed for coronary heart disease, total myocardial infarction, colorectal cancer, total mortality, and the global index of chronic diseases.^[28] The WHI clearly demonstrates that women more than 9 years postmenopause should not be started on hormone therapy or estrogen therapy for CAD prevention.

Initiating hormone therapy or estrogen therapy in the immediate peri- or postmenopausal time is believed to be beneficial because significant atherosclerotic changes have not yet occurred. Once 9 years have passed since menopause, the arterial damage seems to have commenced. Studies are ongoing to prove these theories in humans and primate models. Studies of hormones and atherosclerotic arterial plaques in ovariectomized monkeys show promise in this area.^{[29, 30]} Further evidence in support of estrogen's protective effects when used within a few years of menopause has come from the subanalysis by Manson et al in 2007, which showed that coronary artery calcification was less in the women placed on oral conjugated equine estrogen than those on placebo.^[31]

Data from the National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation suggests that by using the quantitative measurements of the timing and type of menopause and hormone therapy use, earlier initiation was associated with less angiographic coronary artery disease in women with natural but not surgical menopause.^[32]

The benefit of estrogen on cardiovascular mortality rates is due to many factors. One mechanism appears to be estrogen's effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different^[33] and that triglycerides, HDL, and lipoprotein(a) may be more significant in women.^[34]

Women with elevated lipoprotein(a) levels should be treated more aggressively, and the treatment considered should include estrogen therapy, as well as a statin. A positive relationship between estrogen therapy and the reduction of primary cardiovascular risk has been demonstrated in several studies, and the reduction in risk in women who are taking estrogen therapy may be similar to the risk reduction of those receiving specific lipid-lowering therapy.^[35] However, given the WHI data, neither hormone therapy nor estrogen therapy should be given for CAD at this time. The primary indication for hormone therapy/estrogen therapy is symptomatic relief of vasomotor symptoms.

The Heart and Estrogen/Progestin Replacement (HERS) Study,^{[36, 37, 38]} a study of 2763 postmenopausal women with known CAD, compared the effect of continuous combined hormone therapy versus that of placebo over an average of 4.2 years. No beneficial reduction of CAD event rates was initially observed in the hormone therapy groups. In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, which offset a later reduction in risk in the hormone therapy group. An 11% reduction in LDL level and a 10% increase in HDL level were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids, and that estrogen alone is not adequate therapy for secondary prevention of CAD.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, which included 875 healthy postmenopausal women, compared various CAD risk factors as predictors of outcomes in women who received various hormone therapy regimens by randomizing the participants to receive placebo or 1 of 5 regimes of estrogen/progestin therapy.^[39] All treatment groups showed an overall improvement in HDL and LDL levels compared to the placebo group. The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups; however, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.

The Nurses' Health Study demonstrated an approximately 11% risk reduction for primary cardiovascular disease in postmenopausal women using hormone therapy compared with women who had never used hormone therapy, irrespective of duration of use.^[40] The risk reduction did not appear to be dose dependent. However, these data have been eclipsed by the WHI.

The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by estrogen therapy.^[41] Progression of early atherosclerosis in postmenopausal women who smoked, as measured by carotid intimal thickness, was greater over time than in women who smoked and were on estrogen therapy.^[42] Monkey studies have shown that coronary vasculature has a favorable response to conjugate equine estrogens.^{[43, 44]} These findings continue to be investigated by further studies in humans, in the breakdown of age groups in the WHI data, and in animal studies.^{[45, 30, 43]}

Estrogen therapy is known to benefit postmenopausal women in a multitude of ways, mostly through the relief of vasomotor symptoms associated with the postmenopausal time. Estrogen is also beneficial for the prevention and treatment of osteoporosis. Much controversy exists about the use of estrogen and breast cancer. Some studies show an increased risk of breast cancer with postmenopausal estrogen use, whereas others show a decrease. Estrogen's possible link to cancer is also suggested by the fact that the risk of breast cancer is increased in women with an earlier age at menarche and a later age at menopause. With early age at pregnancy, however, and the interruption of menstrual hormonal changes, a reduction in risk is observed. The role of estrogen in the development of breast cancer continues to be studied.

In the Women's Health Initiative (WHI), the incidence of breast cancer increased in the estrogen/progestin versus placebo arm of the study (38 vs 30 per 10,000 person years; hazard ratio [HR]=1.26]). However, the incidence of breast cancer decreased in the estrogen only versus placebo arm of the study (26 vs 33 per 10,000 person years [HR=0.77]).^{[26, 27]} Additional follow-up in patients from the WHI suggested similar results: Breast cancer incidence and mortality were increased in those in the estrogen plus progestin group when compared with those in the placebo group.^[46] The role of combined estrogen-plus-progesterone therapy (associated with most of the breast cancer risk) continues to be puzzling in the development of breast cancer.

Data suggest a slightly increased RR with estrogen use at approximately 1.1-1.3,^{[47, 48]} but not all the evidence supports this finding.^[49] The risk appears to be related to duration of use, with longer-term users being more affected.^[50]

Data suggest that the addition of sequential progestin to the regime increases the RR of subsequently developing breast cancer beyond the risk of estrogen alone, although the suggestion has been made that continuous combined hormone therapy using much smaller doses of progestin attenuates this risk.^[51] Most earlier studies evaluating breast cancer risk and estrogen therapy were conducted at a time when the progestin in hormone therapy was administered on a cyclical basis.

Notably, women with a history of using hormone therapy have more localized tumors as well as better survival rates. That is, women receiving hormone therapy who are diagnosed with breast cancer are found to have more favorable staging at the time of diagnosis,^[48] including smaller tumor size, negative lymph node involvement, and more well-differentiated tumor histology.^{[52, 53, 54, 55, 56, 57, 58, 59, 60]}

A beneficial effect on breast cancer mortality rates has been shown in postmenopausal women who have received hormone therapy compared with controls who have no prior history of hormone therapy use.^[47] Study findings do not agree on whether this is due to earlier detection or to effects of the therapy itself on breast tissue. The general belief is that any increase in risk is small and that each patient should be evaluated as a candidate for estrogen therapy or hormone therapy on an individual basis, with consideration of the overall balance of risks and benefits. An essential precept in the management of menopause is that each individual is unique and that therapy should be tailored accordingly. The main indication for hormone therapy and estrogen therapy at this time is the relief of vasomotor symptoms.

The association of estrogen and memory function is an intriguing area of research. Normal aging itself induces a decline in certain cognitive capabilities, and a lack of estrogen may contribute to this process. If this is the case, postmenopausal estrogen therapy may be able to preserve this function and slow or even prevent decline in certain cognitive functions. An inherent difficulty in this area of study is the limitations of objective cognitive testing for functions such as memory. In the past, estrogen therapy has been associated with better performance on memory testing in postmenopausal women than in postmenopausal controls who were not receiving estrogen therapy.^{[61, 62]} The estrogen effect is one of slowing the decline of preserved memory function. Data from the WHI do not show improvement in cognitive function in women taking either hormone therapy or estrogen therapy.^{[26, 27]}

Currently, data suggest that women have a higher incidence of Alzheimer disease than men, even after allowing for the longer life span of women, because Alzheimer disease is primarily an age-related condition.^[63] In earlier studies, estrogen therapy appeared to reduce the relative risk of developing Alzheimer disease and/or to delay its onset.^{[64, 65]} Estrogen has not been demonstrated to show an improvement in cognitive function in patients with Alzheimer disease; that is, it cannot reverse previous cognitive decline and therefore has no role as a sole treatment modality in Alzheimer disease. WHI data concurs with this view.

Menopausal transition (MT) is frequently a time of depressive symptoms associated with direct hormonal effects through variation in levels and changes in life circumstances and secondary to effects such as estrogen-related sleep disturbance and vasomotor symptoms. However, major depression is associated with the female sex at all ages, and objective demonstration of a cluster of cases around menopause has been difficult, although this appears to be anecdotally true.

Regardless of whether the criteria for a definitive diagnosis of major depression are met, depressive symptoms should always be considered in the context of level of functioning; any impairment warrants consideration of intervention.

In all but a very few cases, distinguishing the etiology of the symptoms as menopausal versus primary depression is usually not possible. Treatment of depressive symptoms with estrogen in perimenopause, the postpartum period,^[66] and premenstrual syndrome is common, with observed resultant improvement in functioning and mood, both subjective and objective, in many clinical instances. Clinical depression, however, warrants treatment with antidepressants, with estrogen showing benefit as adjuvant therapy in this scenario. Short-term use of estrogen during times of estrogen fluctuation seems to be of some benefit.^[67]

The microcellular effects of estrogen in the CNS have yet to be clearly outlined but may reveal intricate processes by which estrogen has a direct effect in CNS functioning. One of these processes may turn out to be a reduction in free radical damage by estrogen therapy.

Gonadotropin secretion increases dramatically after menopause. FSH levels are higher than LH levels, and both rise to even higher levels than in the surge during the menstrual cycle. The FSH rise precedes that of LH. FSH is the diagnostic marker for ovarian failure. LH is not necessary to make the diagnosis. The large cyclical variation of estradiol and estrone observed during the menstrual years ceases, and fluctuation in levels is small and inconsequential, with the mean being very much lower. The levels of circulating estradiol have very different ranges before and after menopause, and these levels are obviously much lower in menopause. Smears of the vaginal epithelium provide a composite picture of endogenous and exogenous estrogen stimulation over time; the more estrogen, the greater the number of superficial cells.

No specific changes related to menopause have been found in thyroid function.

Other markers of ovarian aging include anti-Müllerian hormone (AMH) and Müllerian-inhibiting substance (MIS), which are produced by granulosa cells of all follicles. These markers may be the earliest and most effective way to measure progress toward menopause. Testing is not sufficiently developed to become a standard of care at this time. Consequently, an increase in serum FSH and decreases in estradiol and inhibin are the major endocrine changes that occur during the transition to menopause.^{[1, 2]}

Endometrial biopsy can show a range of endometrial appearances, from mildly proliferate to atrophic. No secretory changes are observed after menopause because no ovulation occurs, and therefore no corpus luteum forms to produce progesterone. Endometrial hyperplasia is a sign of hyperstimulation by estrogen from either endogenous sources or replacement therapy and may be a precursor of endometrial cancer. Endometrial hyperplasia can also be suggested by ultrasonography (an endometrial thickness of >5 mm), which is useful in trying to exclude hyperplasia and cancer of the endometrium in postmenopausal women.

The main reason to treat symptoms of the menopausal transition (MT) and actual menopause are to provide relief of vasomotor symptoms, reduce the risk of unwanted pregnancy, avoid the irregularity of menstrual cycles, preserve bone, lower risk of disease, and improve the quality of life.

The time to begin therapy depends on the patient's presenting complaints, if any, and medical history. It is the opportune time to conduct a health evaluation, identify risk for osteoporosis and other specific diseases, and assess for alterable behavioral risk factors. Whether a woman is transitioning or menopausal helps in choosing the most suitable type of therapy. Counseling regarding hormone therapy is different depending on their age and hysterectomy status. Many factors, including personal history, family history, smoking, peer and commercial influences, culture, need for contraception, ethnicity, and economics, also play roles in the final decision, and all must be carefully weighed by the clinician and patient together.

Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches. SERMS and estrogen increase the risk of thromboembolic events.^[15] Unexplained adverse effects are often the reason for discontinuation of therapy, and reassuring counseling as well as options and dose combinations should be tried before therapy is stopped.

Hormone therapy can be administered systemically through the oral, transdermal, or topical routes or locally via the vaginal route using cream, ring, or tablet. Topical preparations are used solely to treat vaginal symptoms.

Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, venous thrombosis, and personal history of breast cancer. Well-differentiated and early endometrial cancer, once treatment for the malignancy is complete, is no longer an absolute contraindication. Progestins alone may relieve symptoms if the patient is unable to tolerate estrogens.

Oral estrogens have been suggested to have an association with a higher risk of recurrent venous thromboembolism among postmenopausal women.^[68] However, transdermal estrogens may be safe with respect to venous thromboembolism risk.

Alternative products, ranging from herbal preparations to dietary supplements that contain various phytoestrogens, are reputed to ease the transition from perimenopause to postmenopause and are widely available. However, these agents have not undergone the same scrutiny in randomized controlled trials as the pharmaceutical products. Over-the-counter herbal products and phytoestrogens, including soy, are assumed to act the same as their pharmaceutical counterparts, but the herbal and vitamin industry is currently unregulated by the FDA.

In a double-blind, randomized controlled trial, Lui et al observed a mild but significant favorable effect on body composition (eg, weight, BMI, fat percentage) in postmenopausal women after 6 months of soy protein supplementation compared with milk protein. Each group also received isoflavones.^[69]

However, in another randomized, double-blind trial that compared 200 mg of soy isoflavone supplementation with placebo, no difference was seen in BMD or menopausal symptoms between the two groups.^{[70, 71]}

In women who cannot (due to a history of breast cancer) or choose not to take estrogen therapy/hormone therapy and suffer from hot flashes or flushes, the selective serotonin reuptake inhibitors (SSRIs) and SNRIs (in particular, venlafaxine) have been shown to alleviate vasomotor symptoms.

A study by Freeman et al found that the use of 10-20 mg/d of escitalopram, an SSRI, can be useful in reducing and alleviating more severe hot flashes.^[72]

Japanese traditional medicines like keishibukuryogan and kamishoyosan have also shown to reduce the circulating interleukin (IL)–8 level in perimenopausal women and to decrease circulating monocyte chemotactic protein-1 level in postmenopausal women.^[73]

A study by Freeman et al suggests that the median duration of hot flashes actually exceeds the timeframe that is generally accepted in clinical practice.^[74] Identifiable risk factors such as menopausal stage, race, and BMI should be considered when creating individualized treatment and evaluating the risk-to-benefit ratio of hormone replacement or other therapies.

Estrogens and progestins are prescribed for preventive and therapeutic indications. The expectations for either use are very different. Relief of vasomotor and vaginal symptoms is the primary indications for hormone therapy. These preparations are the most effective therapies available for vasomotor-related symptoms and remain the criterion standard for their treatment. Effective treatment can be achieved with lower doses than traditionally used. Women who experience frequent sleep disruption at night due to hot flashes may find relief in a daily dose of synthetic conjugated estrogens-B as low as 0.3 mg.^[75]

The duration of use should be dictated by individual symptoms and related risks. The benefits of hormone therapy are clear for women who initiate therapy close to menopausal age, but they are considered riskier with use and advancing age. Additional and ongoing studies will help determine risks and potential benefits of longer-term therapy.