Menopause: Changes and Challenges

Menopause is defined as the cessation of menses for 12 consecutive months without any other medical cause. Caring for the postmenopausal patient is challenging, in that the benefits of vasomotor symptom relief and bone protection must be weighed against the adverse events attributed to hormone replacement therapy (HRT). Although current data do not definitively support a "one size fits all" treatment strategy, most women with bothersome symptoms will experience symptomatic improvement with HRT, with minimal medical risk. As long as both providers and patients are aware of the risks and benefits, there remains a role for HRT. Future research, however, will focus on exploring newer drug therapies that may have a less morbid risk profile with at least comparable efficacy.

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Menopause is a result of ovarian follicular depletion. Although it can occur earlier in life as a result of medical or surgical causes (eg, chemotherapy, radiation, or oophorectomy), the median age of "natural" menopause is approximately 51.4 years. The menopausal transition, or perimenopause, occurs after the reproductive years and begins approximately 4 years before the final menses. This normal process during a woman's life is frequently heralded by symptoms such as irregular menses, hot flashes, changes in mood and behavior, and tissue atrophy. Iatrogenic causes aside, menopause before age 40 years is abnormal and is referred to as primary ovarian insufficiency or premature ovarian failure.^[1]

In the years leading up to perimenopause, serum inhibin B levels begin to decrease, and this decrease results in a loss of negative feedback that is accompanied by a slight increase in serum levels of follicle-stimulating hormone (FSH). These changes manifest clinically as shorter menstrual cycles due to a shortened follicular phase (eg, 10 days rather than 14) and eventually transition to progressive periods of anovulation and unpredictable menstruation.^[2] Amenorrhea occurs once the follicular pool is depleted, at which point FSH levels remain persistently elevated for the remainder of the woman's life.^[3] A common misconception about the menopausal transition is that once ovulation ceases after menopause, the ovaries become inactive and quiescent. In fact, the postmenopausal ovary maintains a significant portion of the circulating pool of testosterone, which may have various clinically relevant effects.

Alteration of hormone profiles during and after the onset of menopause can also exert multiple effects on various organ systems. For example, low estrogen levels can lead to atrophy of hormone-dependent tissue areas (eg, vagina and external genitalia). Hormonal changes can also result in marked redistribution of fat and thickening of facial hair. Perhaps the most medically concerning process caused by menopausal hormone fluctuations is the increased rate of bone mineral density (BMD) loss, particularly during the 3 years surrounding the final menstrual period. In a study by Greendale et al, BMD loss during transmenopause (the period from 1 year before to 2 years after the final menstrual period) was 7.4%; this accounted for most of the 10.6% density loss observed in the 10-year period (5 years before to 5 years after) surrounding the final menstrual period.^[4]

Hot flashes are the most common menopausal symptom, reported in as many as 80% of women. They are typically described as a short-lived sensation of intense heat with sweating in the upper body.^[5] They are associated with flushing, anxiety, and tachycardia and can be very debilitating; one third of women who report them experience them at least 10 episodes daily.^[5,6] The prevalence of hot flashes peaks at 1 year after the final menstrual period, but 50% of women report them after 4 years and 10% after 12 years.^[7] The menopausal transition has also been linked to changes in cognitive function; however, the relation between estrogen level and brain function remains unclear. Some suggest that the fluctuating hormone levels may cause memory loss; others suggest that the cognitive disruption is simply a manifestation of depression or a consequence of sleep having been disrupted by hot flashes.^[8]

A condition associated with menopause that should prompt evaluation and early intervention is major depression. Opinions differ on whether this entity is a consequence of the decline in ovarian function or of other changes associated with menopause and aging. A within-woman longitudinal study found that higher scores on the Center for Epidemiologic Studies Depression (CES-D) scale were associated with higher levels of FSH and luteinizing hormone (LH).^[9] In addition, higher CES-D scores were found to be four times more likely during the menopausal transition than in the premenopausal state, and depression was 2.5 times more likely; these findings lent further support to the possibility that the hormonal changes of menopause may have significant effects on mood.

Menopausal women also experience many changes in sexual function. One of the most common problems is dyspareunia (difficult or painful intercourse), which is a consequence of vaginal atrophy (present in 10-40% of menopausal women). Thinning of the epithelium and loss of vaginal elasticity result in narrowing and shortening of the vagina. Additionally, vaginal secretions decrease, and the pH becomes more alkaline, altering the flora and increasing the risk of infection. Because the atrophy is directly related to a hypoestrogenic state, HRT can be highly effective in improving dyspareunia. However, the use of lubricants (preferably water-based rather than alcohol-based) or of mineral or vegetable oils can also be recommended.^[5]

In healthy women older than 45 years, menopause is a retrospective clinical diagnosis that can only be made when menstrual cycles have stopped for at least 12 months without any other identifiable cause. When cessation of menses occurs in younger women, particularly those younger than 40 years, other causes must be ruled out. The initial workup in this age group should include human chorionic gonadotropin (hCG), thyroid-stimulating hormone (TSH), prolactin, FSH, and estradiol. Depending on risk factors and accompanying signs and symptoms, other disease-specific tests may be required. For example, conditions that can present with symptoms mimicking those of perimenopause include pregnancy, thyroid dysfunction (hyperthyroidism and hypothyroidism), hyperprolactinemia, and pheochromocytoma. If a diagnosis of primary ovarian insufficiency (premature ovarian failure) is made, additional tests should be performed to identify the cause.^[10]

Many symptoms associated with menopause have been successfully managed with postmenopausal HRT, including hot flashes (vasomotor symptoms) and vaginal atrophy. Although HRT has been central to the treatment of these conditions, the results of the Women's Health Initiative (WHI), perhaps the best-known prospective study examining this issue, have added controversy and complexity to the routine prescription of HRT in the postmenopausal population.^[11-13] For example, the estrogen-progestin arm of the study was prematurely discontinued because of the increased risk of invasive breast cancer and heart attack among women receiving combined therapy, which was not sufficiently offset by the benefits of HRT (eg, reduced risk of colon cancer and hip fractures). However, critics of the study results have suggested that a major reason for the unexpected increase in morbidity in the WHI may be that the average patient age in the study was 63.2 years, which considerably exceeds the average age of patient in which HRT is typically used.

Despite the morbidities that may be associated with HRT, estrogen therapy is clearly effective for many menopause-related symptoms. For example, the Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) study randomly assigned postmenopausal patients to receive oral conjugated equine estrogens (CEE) at a dosage of 0.625, 0.45, or 0.3 mg/day; all estrogen dosages were given both with and without medroxyprogestereone acetate (MPA) at a dosage of 2.5 or 1.5 mg/day.^[14] Patients experienced a significant reduction in the number and severity of hot flashes after as little as 3 weeks of therapy. The average frequency of hot flashes fell from 9/day at baseline to 2/day after 1 year of therapy. Reductions in hot flash frequency and severity were reported in all arms of the study (including both CEE alone and CEE plus MPA). Studies exploring other potential therapeutic effects of CEE have found that patients also report improvements in sleep quality, length of rapid-eye-movement (REM) sleep, and sleep latency.^[15]

The menopausal transition is followed by a gradual thinning of vaginal epithelium (vaginal atrophy), along with decreases in vaginal secretions and pH. In many women, these changes result in significant dryness, dyspareunia, discharge, itching, and, in more severe cases, bleeding, as well as vulvovaginal fissures and stenosis. These changes also increase the risk of urinary tract and vaginal infections. Studies examining these conditions have established a role for local vaginal therapy. The main advantage of local therapy over systemic delivery (eg, via transdermal patches or oral pills) is that very little systemic absorption occurs; serum levels of estradiol remain in the postmenopausal range, and endometrial safety is maintained when minimal doses are used (eg, vaginal ring [Estring®; shown], 10-25 μg vaginal pill twice weekly, or the equivalent). However, any bleeding warrants prompt evaluation.^[11]

Images courtesy of Pfizer Inc.

Diminished estrogen levels in postmenopausal women result in increased osteoclast activity and bone resorption, which can lead to reduced skeletal mass and osteopenia or osteoporosis. As a result, the standard of care is to perform BMD testing with dual-energy x-ray absorptiometry (DXA) for women who have been through menopause and are at least 65 years old. Earlier BMD testing may be warranted in women who have one or more of the following risk factors: smoking; long-term glucocorticoid steroid use; low body weight; rheumatoid arthritis; history of nontraumatic bone fracture; excessive alcohol consumption; and conditions associated with osteoporosis, such as untreated hyperthyroidism, hyperparathyroidism, early menopause, chronic malnutrition, or chronic liver disease.

Historically, estrogen replacement was commonly used to prevent bone loss, but because of its significant risk profile, it is no longer recommended as first-line therapy. Alternatives (eg, bisphosphonates, raloxifene, bazedoxifene, and parathyroid hormone) exist that offer significant bone protection while avoiding the risks associated with HRT. Estrogen therapy, however, may be considered when mainstay therapy is poorly tolerated or ineffective.^[11] Although not all women need medication to support bone health, all postmenopausal women should be encouraged to consume a diet replete with calcium and vitamin D. The use of calcium and vitamin D supplements remains controversial in asymptomatic postmenopausal women. The Endocrine Society suggests 800-1000 mg/day of calcium and 1500-2000 IU/day of vitamin D; the Institute of Medicine suggests 800-1000 mg/day of calcium and 400 IU/day of vitamin D.^[16,17] The US Preventive Services Taskforce found insufficient evidence that calcium and vitamin D supplementation prevented fractures in noninstitutionalized postmenopausal women.^[18] There was agreement that vitamin D supplementation helps prevent falls in women older than 65 years, though calcium supplementation appears to increase the risk of renal stones slightly.

Many investigators have suggested that estrogen may play a protective role against heart disease because of the observed increase in cardiovascular-related disease and death after age 50 years. Evidence for this correlation includes data from the Study of Women's Health Across the Nation (SWAN), which suggests that women experience a very specific 10-15% increase in lipids at menopause. Despite this, there are conflicting data regarding whether there is a role for estrogen supplementation in disease prevention.^[3] The American Heart Association has recommended that HRT not be used for primary prevention of cardiovascular disease.

Patients and providers should be aware of existing data on various cancer risks associated with HRT. Estrogen, like progesterone, can be a growth-stimulating hormone for certain types of breast cancer, but it is unknown whether hormone supplementation can induce new cancer growth. Study findings suggest that HRT may increase the risk of breast cancer and that the risk increases with longer use. For example, the WHI found that breast cancer risk increased in those taking combined estrogen-progesterone therapy but not in posthysterectomy patients taking estrogen alone.^[12,13] A study of a subset of patients from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort found a potential association between higher baseline circulating prolactin levels and increased breast cancer risk in postmenopausal women receiving HRT.^[19] HRT does not, however, appear to increase the risk of ovarian cancer significantly, though there may be a very slight increase after 10 years of use. The risk of endometrial cancer should also be taken into account; women with an intact uterus should be placed on a progestational agent to avoid the approximately two- to threefold increase in the endometrial cancer risk noted when estrogen is used alone. Finally, HRT is associated with a 50% decrease in the relative risk of colon cancer; the WHI observed this effect in the combined estrogen-progestin arm but not in the estrogen-only arm.

The estrogen regimen should be tailored to the individual needs and characteristics of the patient and should use the lowest dosage that alleviates symptoms. For example, at equivalent dosages, transdermal estrogen preparations carry a lower risk of venous thromboembolism (VTE) and cause less of an increase in triglyceride levels. Oral estrogen preparations yield greater decreases in low-density lipoprotein (LDL) and increases in high-density lipoprotein (HDL). In women with only vaginal symptoms, systemic estrogen therapy may not be needed; most of these patients respond to local estrogen therapy with an estrogen-impregnated ring or a low-dose vaginal tablet. Symptoms and possible side effects should be evaluated at 3-6 months to give the patient and provider an opportunity to switch or modify the type and dosage of HRT. Absolute contraindications to HRT include hormone-related cancer, active liver disease, history of hormone-induced thromboembolism, vaginal bleeding of unknown etiology, and pregnancy. Relative contraindications include chronic liver disease, severe hypertriglyceridemia, history of endometrial cancer, history of breast cancer, and active heart disease.

A 42-year-old woman presents to the office for evaluation of abnormal uterine bleeding. She states that over the past year, her cycles have become unpredictable. She reports experiencing depressed mood and fatigue and complains of hair loss, dry skin, constipation, and weight gain. On physical examination, the patient's hair appears brittle and strawlike (shown).

Which of the following tests is likely to be the most valuable for making the diagnosis?

1. Prolactin
2. TSH
3. FSH
4. Beta-hCG

Answer: A. TSH.

Although the incidence of hypothyroidism is not affected by menopause, it does increase with aging. Symptoms of either hypothyroidism or hyperthyroidism may mimic common changes seen with menopause. For example, abnormally low thyroid function will affect several organs and systems and may be manifested by decline of cognitive function, depression, constipation, cold intolerance, and menstrual abnormalities. On the other hand, hyperthyroidism can present with menstrual abnormalities, night sweats, hot flashes, and mood changes. The appropriate test for this patient is the TSH level, which is likely to be elevated in this case.

A 41-year-old woman presents to the office for evaluation of amenorrhea. She states that she has regular menstrual cycles every 30 days but has not had one for the past 2 months. She has been feeling nauseated and has recently noticed that her bra is fitting more tightly. She denies experiencing heat or cold intolerance, night sweats, hot flashes, visual changes, depressed mood, changes in her sleep, or any other symptoms.

Which of the following is the most likely cause of this patient's symptoms?

1. Anorexia
2. Pregnancy
3. Pituitary adenoma
4. Premature ovarian failure

Answer: B. Pregnancy.

Although there is a significant decline in fertility after age 35 years, pregnancy should always be considered as a potential cause of amenorrhea in the female population of reproductive age.

A 45-year-old woman presents to the office for evaluation of abnormal uterine bleeding. She has noticed that her cycles have become unpredictable over the past year, and she recalls occasionally skipping 1 or 2 months between menses. On further questioning, she cites a history of galactorrhea and mentions that she has difficulty driving because she has to turn her head every time she wants to see the rear-view mirror. A representation of her visual field test is shown.

Which of the following tests is likely to be most useful for confirming the diagnosis?

1. Prolactin
2. TSH
3. FSH
4. Beta-hCG

Answer: A. Prolactin.

In this patient, assessment of the serum prolactin level would most likely identify an abnormality in the hypothalamic-pituitary-ovarian axis (shown). Disruption of this highly sensitive system can affect gonadotropin-releasing hormone (GnRH) pulsatility and interfere with the menstrual cycle, giving rise to oligomenorrhea. Furthermore, when elevated prolactin levels are due to the presence of a pituitary adenoma, the compression of the optic chiasm can cause bitemporal hemianopsia.

A 47-year-old woman presents to the office for evaluation of hot flashes. She states that over the past year, she has been suffering from sudden episodes of feeling warm and sweating profusely. These episodes usually take place at night, without any specific triggers, and last several minutes. She is concerned because even though she has always had normal blood pressure, she measured it two nights ago during one of these episodes and found it to be 190/120 mm Hg. Today, in the office, her blood pressure is 118/67 mm Hg.

As confirmed by the image shown, which of the following organs is most likely to be the source of this patient's complaints?

1. Thyroid
2. Liver
3. Adrenal gland
4. Bladder

Answer: C. Adrenal gland.

Pheochromocytoma, a typically benign tumor of the adrenal glands, is characterized by the unregulated random secretion of epinephrine into the vascular system, which leads to hot flashes and night sweats. Such symptoms can easily be misinterpreted as perimenopausal vasomotor symptoms. However, the concomitant presence of hypertensive crises during these episodes raises the index of suspicion for a pheochromocytoma, which necessitates surgical removal.