Obstetrics and Gynecology 7 Ed.

Chapter 41

Menopause

This chapter deals primarily with APGO Educational Topic Area:

TOPIC 42 MENOPAUSE

Students should be able to define and describe the physiologic changes associated with menopause. They should outline a basic approach to evaluation and management of the perimenopausal or menopausal patient. They should identify risk factors, common presenting signs and symptoms, and physical exam findings. They should be able to counsel women about the menopausal transition including long-term changes.

Clinical Case

A 54-year-old woman comes to see you because she has been having trouble sleeping. She reports that her youngest child recently left for college, and she has just felt “off ” recently. She has been irritable with her husband and feels somewhat tired. Her husband complains that her thrashing about at night keeps him awake. Also her menstrual cycle has been irregular with her last bleeding occurring 4 months ago.

Menopause is the permanent cessation of menses after significant decrease of ovarian estrogen production. This is evidenced by 12 consecutive months with no menstrual bleeding. Perimenopause is the period before menopause, that is, the transition from the reproductive to the nonreproductive years during which ovarian estrogen production may fluctuate unpredictably. The time period during which the changes of menopause occur is called the climacteric. An increasing proportion of American women are included in these groups, because the female life expectancy has lengthened, and the number of women in this age group is expanding (Fig. 41.1).

Image MENSTRUATION AND MENOPAUSE

Although male gametes are renewed on a daily basis, female gametes are of a fixed number that progressively diminish throughout a woman’s reproductive life. At the time of birth, the female infant has approximately 1 to 2 million oocytes; by puberty, she has approximately 400,000 oocytes remaining. By ages 30 to 35 years, the number of oocytes would have decreased to approximately 100,000. For the remaining reproductive years, the process of oocyte maturation and ovulation becomes increasingly inefficient, with the continued loss of functional oocytes.

A woman ovulates approximately 400 oocytes during her reproductive years. The process of oocyte selection is complex, and new information is making the process clearer. During the reproductive cycle, a cohort of oocytes is stimulated to begin maturation, but only one or two dominant follicles complete the process and are eventually ovulated.

Follicular maturation is induced and stimulated by the pituitary release of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH binds to its receptors in the follicular membrane of the oocyte and stimulates follicular maturation, providing estradiol (E2), which is the major estrogen of the reproductive years. LH stimulates the theca luteal cells surrounding the oocyte to produce androgens as well as estrogens and serves as the triggering mechanism to induce ovulation. With advancing reproductive age, the remaining oocytes become increasingly resistant to FSH. Thus, plasma concentrations of FSH begin to increase several years in advance of actual menopause, when the FSH is generally found to be >30 mIU/mL (Table 41.1).

Menopause marks the end of a woman’s natural reproductive life. The average age for menopause in the United States is between ages 50 and 52 years (median 51.5), with 95% of women experiencing this event between ages 44 and 55 years. The age of menopause is not influenced by the age of menarche, number of ovulations or pregnancies, lactation, or the use of oral contraceptives. Race, socioeconomic status, education, and height also have no effect on the age of menopause. Genetics and lifestyle, however, can affect the age of menopause. Undernourished women and smokers, for example, tend to have an earlier menopause, although the effect is slight. Approximately 1% of women undergo menopause before the age of 40 years, which is generally referred to as premature ovarian failure (POF). Women spend roughly one third of their lifespan in menopause.

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FIGURE 41.1. Age of menopause and female life expectancy.

Contrary to popular belief, the ovaries of postmenopausal women are not quiescent. Under the stimulation of LH, theca cell islands in the ovarian stroma produce hormones, primarily the androgens testosterone and androstenedione. Testosterone appears to be the major product of the postmenopausal ovary. Testosterone concentrations decline after menopause, but remain two times higher in menopausal women with intact ovaries than in those whose ovaries have been removed. Estrone (E1) is the predominant endogenous estrogen in postmenopausal women. It is termed extragonadal estrogen because the concentration is directly related to body weight. Androstenedione is converted to E1, proportionate to the amount of fatty tissue (Table 41.2). Because estrogen promotes endometrial proliferation, obese menopausal women have a higher risk of endometrial hyperplasia and carcinoma. Conversely, slender menopausal women are at a higher risk for menopausal symptoms.

Image SYMPTOMS AND SIGNS OF MENOPAUSE

Menopause is a physiologic process that can be associated with symptoms that may affect a woman’s quality of life. Decreased estrogen production can result in multiple adverse systemic effects (Fig. 41.2). Many of these symptoms can be ameliorated with hormone therapy (HT). The need for HT should be individualized based on a woman’s specific risk factors.

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Menstrual Cycle Alterations

Beginning at approximately the age of 40 years, the number of a woman’s ovarian follicles diminishes, and subtle changes occur in the frequency and length of menstrual cycles. A woman may note shortening or lengthening of her cycles. The luteal phase of the cycle remains constant at 13 to 14 days, whereas the variation of cycle length is related to a change in the follicular phase. As a woman approaches menopause, the frequency of ovulation decreases from 13 to 14 times per year to 11 to 12 times per year. With advancing reproductive age, ovulation frequency may decrease to three to four times per year.

With the change in reproductive cycle length and frequency, there are concomitant changes in the plasma concentration of FSH and LH. More FSH is required to stimulate follicular maturation. Beginning in the late thirties and early forties, the concentration of FSH begins to increase from normal cyclic ranges (6–10 IU/L) to perimenopausal levels (14–24 IU/L). During this period, women begin to experience sometimes unpleasant symptoms and signs of decreasing estrogen levels. Some women are not symptomatic yet have significant clinical effects such as early osteoporosis. Levels of FSH are 30 IU/L or more at menopause.

Hot Flushes and Vasomotor Instability

Coincident with the change in reproductive cycle length and frequency, the hot flush is usually the first physical manifestation of decreasing ovarian function and is a symptom of vasomotor instability.

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FIGURE 41.2. Effects of menopause.

Hot flushes are recurrent, transient episodes of flushing, perspiration, and a sensation ranging from warmth to intense heat on the upper body and face, sometimes followed by chills. When they occur during sleep and are associated with perspiration, they are termed night sweats. Occasional hot flushes begin several years before actual menopause. Other conditions that can cause hot flushes include thyroid disease, epilepsy, infection, and use of certain drugs.

The hot flush is the most common symptom of decreased estrogen production and is considered one of the hallmark signs of perimenopause. However, its incidence varies widely. Some U.S. studies have found that about 75% of women experienced hot flushes during the transition from the perimenopause to postmenopause. Outside the United States, rates vary even more widely, from about 10% in Hong Kong to 62% in Australia. Reasons for these differences are unknown. In the United States, prevalence rates also differ among perimenopausal women of racial and ethnic groups, with African Americans most frequently reporting symptoms (45.6%), followed by Hispanics (35.4%), whites (31.2%), Chinese (20.5%), and Japanese (17.6%). More recent studies seem to indicate that differences in body mass index (BMI) would be a more reliable indicator of the incidence of hot flushes.

Hot flushes have a rapid onset and resolution. When a hot flush occurs, a woman experiences a sudden sensation of warmth. The skin of the face and the anterior chest wall become flushed for approximately 90 seconds. With resolution of the hot flush, a woman feels cold and breaks out into a “cold sweat.” The entire phenomenon lasts less than 3 minutes. The exact cause of hot flushes has not been determined, although it seems that declining estradiol-17β secretion by the ovarian follicles plays a significant role. As a woman approaches menopause, the frequency and intensity of hot flushes increase. Hot flushes may be disabling during the day and even more so at night when they are a significant cause of clinical sleep disturbance. When perimenopausal and postmenopausal women receive HT, hot flushes usually resolve in 3 to 6 weeks, though sometimes even more rapidly, depending on the dose administered. If a menopausal woman does not receive HT, hot flushes usually resolve spontaneously within 2 to 3 years, although some women experience them for 10 years or longer. Hot flushes are not simply an uncomfortable part of the normal perimenopause and menopause insofar as they are associated with significant adverse outcomes, such as hampered job productivity and sleep deprivation.

Sleep Disturbances

Declining E2 levels induce a change in a woman’s sleep cycle so that restful sleep becomes difficult and, for some, impossible. The latent phase of sleep (i.e., the time required to fall asleep) is lengthened with alterations in REM (rapid eye movement) patterns; the actual period of sleep is shortened. Therefore, perimenopausal and postmenopausal women complain of having difficulty falling asleep and of waking up soon after going to sleep. Sleep disturbances are one of the most common and disabling effects of menopause.

Women with marked sleep aberration are understandably often tense and irritable and have difficulty with concentration and interpersonal relationships. With HT, the sleep cycle is restored to the premenopausal state.

Vaginal Dryness and Genital Tract Atrophy

The vaginal epithelium, cervix, endocervix, endometrium, myometrium, and uroepithelium are estrogen-dependent tissues. With decreasing estrogen production, these tissues become atrophic, resulting in various symptoms. The vaginal epithelium becomes thin and cervical secretions diminish. Women experience vaginal dryness while attempting or having sexual intercourse, leading to diminished sexual enjoyment and dyspareunia. Atrophic vaginitisalso may present with itching and burning. The thinned epithelium is also more susceptible to becoming irritated by common skin irritants or infected by local flora. This discomfort can be relieved with systemic HT or the topical use of estrogen.

The endometrium also becomes atrophic, sometimes resulting in postmenopausal spotting. The paravaginal tissues that support the bladder and rectum become atrophic. When this is combined with the effects of childbearing, it can result in loss of support for the bladder (cystocele or anterior vaginal prolapse) and rectum (rectocele or posterior vaginal prolapse). In addition, uterine prolapse is more common in the hypoestrogenic patient. Because of atrophy of the lining of the urinary tract, there may be symptoms of dysuria and urinary frequency, a condition called atrophic urethritis. HT can relieve the symptoms of urgency, frequency, and dysuria. Loss of support to the urethrovesical junction may result in stress urinary incontinence; in some cases, pelvic muscle (Kegel) exercises may relieve some of these symptoms.

Mood Changes and Memory Changes

Perimenopausal and postmenopausal women often complain of volatility of affect. Some women experience memory loss, depression, apathy, and “crying spells.” These may be related to menopause, to sleep disturbances, or both. The physician should provide counseling and emotional support as well as medical therapy, if indicated. Because there may be a comorbid sleep disorder, such as obstructive sleep apnea and restless legs syndrome (RLS), consultation with a sleep medicine expert for consideration of an overnight sleep study may be appropriate in some cases. Although sex steroid hormone receptors are present in the central nervous system (CNS), there is insufficient evidence about the role of estrogens in CNS function to implicate a direct affective mechanism.

Skin, Hair, and Nail Changes

Some women notice changes in their hair and nails with the hormonal changes of menopause. Estrogen influences skin thickness. With declining estrogen production, the skin tends to become thin, less elastic, and eventually more susceptible to abrasion and trauma. Estrogen stimulates the production of the sex hormone–binding globulin (SHBG), which binds androgens and estrogens. With declining estrogen production, less SHBG is available, thereby increasing the level of free testosterone. Increased testosterone levels may result in increased facial hair. Moreover, changes in estrogen production affect the rate of hair shedding. Hair from the scalp is normally lost and replaced in an asynchronous way. With changes in estrogen production, hair is shed and replaced in a synchronous way, resulting in the appearance of increased scalp hair loss at a given point in time. Disturbing as physiologic scalp hair loss may be, physicians should reassure patients that the process is self-limiting and requires no therapy. Nails become thin and brittle with estrogen deprivation but are restored to normal with estrogen therapy.

Osteoporosis

Bone demineralization is a natural consequence of aging. Diminishing bone density occurs in both men and women. However, the onset of bone demineralization occurs 15 to 20 years earlier in women than in men because of acceleration after ovarian function ceases. Bone demineralization not only occurs with natural menopause but also has been reported in association with decreased estrogen production in certain groups of young women (such as those with eating disorders or elite athletes with an exercise-associated lower BMI). Risk factors warranting earlier screening for osteoporosis are shown in Box 41.1.

Estrogen receptors (ERs) are present in osteoblasts, which suggests a permissive and perhaps even an essential role for estrogen in bone formation. Estrogen affects the development of cortical and trabecular bone, although the effect on the latter is more pronounced. Bone density diminishes at the rate of approximately 1% to 2% per year in postmenopausal women, compared with approximately 0.5% per year in perimenopausal women (Fig. 41.3). HT, especially when combined with appropriate calcium supplementation and weight-bearing exercise, can help slow bone loss in menopausal women. Weight-bearing activity such as walking for as little as 30 minutes a day increases the mineral content of older women.

Calcium is beneficial to prevent bone loss; women older than age 50 years should meet the Recommended Dietary Allowance of 1,200 mg. Calcium therapy combined with estrogen therapy is more effective than calcium alone. In addition, for those with limited sun exposure and those lacking other dietary sources, supplementation with vitamin D should be considered: 600 IU/day from ages 51 to 70 years and 800 IU/ day for ages greater than 70 years.

BOX 41.1 When to Screen for Bone Density Before Age 65 Years

Bone density should be screened in postmenopausal women younger than age 65 years if any of the following risk factors are noted:

• Medical history of a fragility fracture

• Body weight less than 127 lb

• Medical causes of bone loss (medications or diseases)

• Parental medical history of hip fracture

• Current smoker

• Alcoholism

• Rheumatoid arthritis

American College of Obstetricians and Gynecologists. Osteoporosis. Practice Bulletin 129. Washington, DC: American College of Obstetricians and Gynecologists; September, 2012.

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FIGURE 41.3. Structural bone changes with osteoporosis. (A) Normal bone. (B) Osteoporotic trabecular bone. (From Randolph JF, Lobo RA. Menopause. In: Precis: Reproductive Endocrinology. 3rd ed. Washington, DC: ACOG; 2007:185.)

Progressive, linear decrease in bone mineral mass is noted in women who do not receive HT in the first 5 to 10 years following menopause. When HT is initiated before or at the time of menopause, bone density loss is greatly reduced, although this benefit is lost 1–2 years after discontinuation. HT begun in a woman 5 or more years after menopause may still have a positive effect on bone density loss. However, osteoporosis is not the primary indication for HT. Several bisphosphonates, such as alendronate, ibandronate, and risedronate, can be used for the management of menopause-associated bone loss. These agents reduce bone resorption through the inhibition of osteoclastic activity (Table 41.3).

Selective estrogen receptor modulators (SERMs) provide another nonhormonal management option. Most estrogenic responses are mediated in the body by one of two receptors, either ERα or ERβ. SERMs are ER ligands, which act like estrogens in some tissues but block estrogen action in others. Examples include tamoxifen and raloxifene, which exhibit ER antagonist activity in the breast but agonist activity in the bone. As with the bisphosphonates, they also lack the capabilities of mitigating many of the other estrogen deprivation symptoms, such as hot flushes and sleeplessness, and may even exacerbate these symptoms.

Cardiovascular Lipid Changes

With perimenopause, changes occur in the cardiovascular lipid profile. Total cholesterol increases, high-density lipoprotein cholesterol decreases, and low-density lipoprotein cholesterol increases. HT may promote changes in the lipid profile that are favorable to the cardiovascular system. Retrospective case– control studies suggest that estrogens have a cardioprotective effect. However, data from the Women’s Health Initiative (WHI) suggest that no such protection exists in placebo-controlled clinical trials, although some have criticized these trials because of various methodological flaws, including the late age onset of treatment in a large group of the study subjects. Current trials are underway using transdermal estrogen and natural progesterone administered to women in their fifties to better understand whether earlier HT carries the same risk as shown in the WHI. At this time, HT should not be offered to patients with the primary goal of protection against heart disease.

Image PREMATURE OVARIAN FAILURE

The diagnosis of POF applies to the approximately 1% of women who experience menopause before the age of 40 years. The diagnosis should be suspected in a young woman with hot flushes and other symptoms of hypoestrogenism and secondary amenorrhea (e.g., a woman seeking treatment for infertility). The diagnosis is confirmed by laboratory findings of menopausal FSH levels (>30 mIU/mL). Interestingly, hot flushes are not as common as might be expected in this group of patients. The diagnosis has profound reproductive and emotional implications for most patients, especially if their desires for childbearing have not been fulfilled, as well as metabolic and constitutional implications. There are many causes of premature loss of oocytes and premature menopause; some of the more common causes are discussed below. Given its potential dramatic impact, POF demands a careful workup in order to identify the underlying cause and permit appropriate management.

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Genetic Factors

Several factors influence a woman’s reproductive lifespan. Genetic information that determines the length of a woman’s reproductive life is carried on the distal long arm of the X chromosome. Partial deletion of the long arm of one X chromosome results in POF. Total loss of the long arm of the X chromosome, as seen in Turner syndrome, results in ovarian failure at birth or in early childhood. When suspected, these diagnoses can be established by careful mapping of the X chromosome. Additionally, screening for premutations for the fragile X syndrome should be performed because of its association with POF. These patients are at risk for having children with mental disabilities. Evaluation for any Y chromosome material should also be performed, because, if identified, oophorectomy should be performed because of the risk of cancer in these patients.

Autoimmune Disorders

Some women develop autoantibodies against thyroid, adrenal, and ovarian endocrine tissues. These autoantibodies may cause ovarian failure. These women may need HT for the indications described above; some will spontaneously resume ovarian function.

Smoking

Women who smoke tobacco can undergo ovarian failure some 3 to 5 years earlier than the expected time of menopause. It is established that women who smoke metabolize E2 primarily to 2-hydroxyestradiol. The 2-hydroxylated estrogens are termed catecholestrogens because of their structural similarity to catecholamines. The catecholestrogens act as antiestrogens and block estrogen action. The effects of smoking should be considered in smokers who are experiencing symptoms of estrogen deficiency and be part of routine menopausal counseling.

Alkylating Cancer Chemotherapy

Alkylating cancer chemotherapeutic agents affect the membrane of ovarian follicles and hasten follicular atresia. One of the consequences of cancer chemotherapy in reproductive age women is loss of ovarian function. Young women being treated for malignant neoplasms should be counseled of this possibility and advised that they may be candidates for follicular retrieval and cryopreservation as a means for attempting future pregnancy.

Hysterectomy

Surgical removal of the uterus (hysterectomy) in reproductive age women is associated with hormonal aspects of menopause some 3 to 5 years earlier than the expected age. The mechanism for this occurrence is unknown. It is likely to be associated with alteration of collateral ovarian blood flow resulting from the surgery.

Image MANAGEMENT OF MENOPAUSE

The changes of menopause result from declining 17-β estradiol production by the ovarian follicles. 17-β estradiol and its metabolic byproducts, E1 and estriol, are used in HT, the objective of which is to diminish the signs and symptoms of menopause.

Estrogen Therapy

Several different estrogen preparations are available through various routes of administration, including oral medications, transdermal preparations, and topical preparations. When administered orally, 17-β estradiol is oxidized in the enterohepatic circulation to E1. 17-β estradiol remains unaltered when it is administered transdermally, transbuccally, transvaginally, intravenously, or intramuscularly (IM). Unfortunately, IM E2 administration results in unpredictable fluctuations in plasma concentration. When E2 is administered across the vaginal epithelium, absorption is poorly controlled, but remains at very low levels when appropriately used. Pharmacologic plasma concentrations of E2 can result when excessive amounts are used. Transdermal administration of E2 results in steady, sustained estrogen blood levels and may be a preferable alternative to oral dosing for many patients.

Combined Estrogen and Progestin Therapy

The administration of continuous unopposed estrogens can result in endometrial hyperplasia and an increased risk of endometrial adenocarcinoma. Therefore, it is essential to administer a progestin in conjunction with estrogens in women who have not undergone hysterectomy. Progestins may include any variety of synthetics, such as medroxyprogesterone acetate and norethindrone or micronized progesterone. To achieve this protective effect, the progestin chosen may be given continuously in low doses or sequentially in higher doses. Sequential dosing is usually for 10 or 12 days of each calendar month. Progestins, particularly medroxyprogesterone acetate, may be associated with unacceptable side effects, such as affective symptoms and weight gain. If estrogen is administered alone because of unacceptable side effects of progestins, then it is imperative to counsel the patient about the need for yearly endometrial biopsy.

There are two principal regimens for HT. Continuous estrogen replacement with cyclic progestin administration results in excellent resolution of symptoms and cyclic withdrawal bleeding from the endometrium. One of the difficulties of this method of therapy is that many postmenopausal women do not want a return of menstrual bleeding. As a result, many physicians and patients choose to avoid the problem of cyclic withdrawal bleeding by the daily administration of both an estrogen and a low-dose progestin.

There are a variety of estrogen preparations available. Most perimenopausal and menopausal women respond to one of these preparations, all of which ameliorate acute menopause symptoms and relieve vaginal atrophy. The administration of progestins for 10 to 12 days of each month converts the proliferative endometrium into a secretory endometrium, brings about endometrial sloughing, and prevents endometrial hyperplasia or cellular atypia. Continuous oral progestin therapy or a levonorgestrel intrauterine device may be used to produce endometrial atrophy.

Numerous preparations combining estrogen and progestins are available in both oral and transdermal formulation. The most widely used contain a combination of conjugated equine estrogens and medroxyprogesterone acetate in one tablet. Newer preparations include a combination of micronized estradiol and norethynodrel acetate or ethinyl estradiol and norethindrone acetate. Transdermal preparations include a combination of micronized estradiol and norethindrone acetate. Low-dose oral contraceptives may also be used to relieve the vasomotor symptoms of menopause.

Image CAUTIONS IN HORMONE THERAPY

The results of the WHI in 2002 revealed epidemiologic findings that have modified the contemporary use of HT. This large, multicenter, randomized clinical trial (approximately 17,000 women) studied the effects of HT, dietary modification, and calcium and vitamin D supplementation as related to heart disease, fractures, breast cancer, and colorectal cancer. Although there are features of this study that are not applicable to many younger menopausal patients, the overall results suggested that when compared with placebo, a combination of conjugated equine estrogens and continuous low-dose medroxyprogesterone acetate resulted in an increased risk of heart attack, stroke, thromboembolic disease, and breast cancer, with a reduced risk of colorectal cancer and hip fractures. One arm of the study reviewed the same outcomes in women taking unopposed estrogen and found that these women had no increased risk of cardiac events and a trend toward decrease in breast cancer compared to women on combined therapy.

Some of the data contradicted prior large-scale observational studies, and, therefore, many physicians have changed their practice regarding HT to center more on the relief of short-term symptoms of estrogen deprivation, including hot flushes, sleeplessness, and vaginal atrophy. Although reappraisals of the study have focused on its flaws, current opinion suggests that initiation early in menopause is associated with a good risk/benefit ratio, with preference for the transdermal route. Nonetheless, the current recommendations from numerous organizations, including the American College of Obstetricians and Gynecologists, are that HT should only be used for the short-term relief of menopausal symptoms and should be individually tailored to a woman’s need for treatment (Box 41.2).

HT in women with prior history of breast and endometrial cancer is controversial. Currently, prospective studies are underway using low-dose HT in women with a prior history of limited-lesion, successfully treated breast cancer. Similar studies in women with prior treated limited-lesion endometrial cancer have been completed and show no increased risk of recurrence for estrogen users.

BOX 41.2 Contraindications to Hormone Therapy

• Undiagnosed abnormal genital bleeding

• Known or suspected estrogen-dependent neoplasia except in appropriately selected patients

• Active deep vein thrombosis, pulmonary embolism, or a history of these conditions

• Active or recent arterial thromboembolic disease (stroke and myocardial infarction)

• Liver dysfunction or liver disease

• Known or suspected pregnancy

• Hypersensitivity to hormone therapy preparations

Image ALTERNATIVES TO HORMONE THERAPY

Because of the controversy surrounding HT, many women are seeking alternative therapies. When counseling patients, physicians must take a holistic approach. Most women seek relief of the most common symptom of menopause—hot flushes—but as noted above, menopause affects women in different ways. As women age, their risk for heart disease begins to rise and, therefore, it is important to advocate heart-healthy lifestyle changes. Likewise, preventive counseling about osteoporosis, as previously discussed, should also be included. Alternative therapies for the short-term treatment of common symptoms of menopause include the following:

• Soy and isoflavones may be helpful in the short-term (≤2 years) treatment of vasomotor symptoms. Given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.

• St. John’s wort may be helpful in the short term (<2 years) for treatment of mild to moderate depression in perimenopausal women and in the short term (<8 weeks) for amelioration of hot flashes.

• Black cohosh may be helpful in the short-term (≤6 months) treatment of women with vasomotor symptoms.

• Soy and isoflavone intake over prolonged periods may improve lipoprotein profiles and protect against osteoporosis. Soy in foodstuffs may differ in biological activity from soy and isoflavones in supplements.

• Bioidentical hormones, various plant hormones combined and compounded by pharmacies, have not been shown to be superior to traditional hormonal therapy and are also potentially more risky than pharmaceutical-grade hormonal therapy because of inherent inconsistencies in their preparation. More studies need to be performed.

Most well-controlled studies of the common over-the-counter (OTC) remedies have not shown dramatic, long-term improvements. In addition, many of these OTC botanical supplements are not U.S. Food and Drug Administration regulated. Consequently, there is little quality control. Patients need to be informed that “natural” does not necessarily mean safe. Moreover, many of these products have undesired side effects. Many soy products interact with thyroid medications, and dong quai and red clover potentiate warfarin and other anticoagulants.

One of the most commonly used off-label medications is progesterone. Numerous randomized, placebo-controlled studies have demonstrated its efficacy, usually in the form of medroxyprogesterone acetate, in the treatment of hot flushes. Selective serotonin-reuptake inhibitors have also been used with some success. In randomized, double-blind studies, venlafaxine, paroxetine, and fluoxetine were all shown to significantly decrease hot flushes. In addition, both gabapentin and cetirizine were found to provide moderate relief of vasomotor symptoms.

Lastly, patients should be advised of the potential relief achieved by lifestyle changes, such as eating a healthy diet that is less than 30% fat and rich in calcium, getting regular exercise, maintaining a healthy weight, avoiding smoking, limiting alcohol intake, and getting regular health care. These practices may not only help relieve some menopausal symptoms, but also help prevent other health problems.

Clinical Follow-Up

On physical examination, speculum examination reveals a dry, irritated vaginal mucosa. Given this information, a serum follicle-stimulating hormone level is obtained and reported back as 34 mIU/mL, consistent with menopause. The risks and benefits of appropriately time-limited estrogen therapy are explained to the patient, who elects treatment. At 6 months she remarks on improvement with her problems but her husband dourly notes that she moves her legs about at night and that his sleep is not improved. A sleep medicine physician is consulted, a sleep study is performed, and restless legs syndrome (RLS) is diagnosed. With treatment of her RLS, the husband’s complaints are gone 6 months later in follow-up.

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