For many women, the onset of menopause signals the beginning of aging. It is at this time of life that many women begin to notice changes in their physical appearance and may develop minor health problems. It is also a time when children
may be leaving home, partners may be thinking about retirement, and the women’s own work situation may be changing. A woman’s experience of menopause is shaped by the psychological, social, and cultural context in which she lives (3). The woman whose partner leaves her or who develops health problems during midlife will clearly view the menopause very differently than will the healthy, active woman who gets a job promotion. Women who had hoped for children now realize they will never have any. Many women at midlife also join the “sandwich generation,” who are responsible simultaneously for child rearing and for the care of aging parents. Caring for sick relatives may especially burden women at risk for depressive and anxiety symptoms and may rob them of their autonomy and ability to care for themselves (although some women feel enriched and empowered by their caregiving roles) (4). Women also may be affected by the ill health of their spouses or friends, and those women entering retirement may face a marked decrease in standard of living.

In North America and Europe, women are also affected by the substantial difference between the way society views middle-aged women and the way it views middle-aged men. Too often women of this age group are seen as being “over the hill,” while men of a similar age are seen as “mature,” “experienced,” and at the peak of their prowess (5). These perceptions have obvious repercussions in the workplace.

Perceptions and symptoms of women at midlife also vary across cultures. In some cultures women gain respect and support as they age; in others they are marginalized. It is well known that women in Japan experience few menopausal symptoms, while many women in North America experience severe vasomotor symptoms. Body image concerns are common at midlife. New wrinkles appear, abdominal obesity is common, and fitness may decline. Arthritis may appear, and physiologic breast atrophy and hot flashes announce to the woman, and sometimes her associates, that menopause has arrived.

Changes in sexuality also occur at midlife. Reduced libido, thinning and drying of the vaginal lining as a result of decreasing estrogen levels, and societal attitudes toward midlife women’s sexuality may all play a role. (See Chapter 15 of this book, on women’s sexuality and sexual disorders.) Several studies have found that the partner’s sexual health is probably the strongest determinant of women’s sexual activity, particularly if sexual activity is solely defined as penetrative vaginal intercourse. It is too easy to attribute all the changes at this time of life to hormonal fluctuations rather than looking at the woman’s relationship with her partner and their total life context.

Factors known to influence the health of women as they age include education, socioeconomic status, gender-based division of domestic chores, abuse, violence, access to health care, and paid employment (6). Women more often work in informal sectors, as part-time workers, or in family businesses where they are less likely to be protected by pension plans, health insurance, and other benefits. Cognitive abilities greatly affect women’s quality of life. Early symptoms of forgetfulness as a symptom of benign aging may begin in the postmenopausal period and lead to anxieties about incipient Alzheimer disease or other dementias. The fact that most women age well and remain cognitively intact is often overlooked.

During the last five years, public interest in menopause has increased enormously. Wholesale advocacy of hormone replacement therapy was shattered in 2002 when the Women’s Health Initiative published the unexpected negative outcomes
of its investigations, which threw both women and their physicians into uncertainty about the best medical management of menopause (7).

The average age of menopause in North American and European women is 51.3 years, but 1% of women have a premature menopause before the age of 40. Women who are smokers and those who have been diagnosed with depression are likely to have an earlier age of onset of menopause (8). Menopause is defined as 12 consecutive months of amenorrhea, and it is diagnosed retrospectively. Well before menopause, however, most women begin to experience symptoms of the transition, a phase termed perimenopause. As ovarian function declines, folliclestimulating hormone (FSH) concentration rises in an attempt to stimulate resistant ovarian follicles. Luteinizing hormone (LH) and inhibin B also decrease, and when all ovarian follicles have been depleted, the ovary stops producing significant amounts of estrogen. Because there is no further corpus luteum formation, progesterone secretion also stops. Elevated FSH and LH concentrations may be used to confirm the diagnosis of perimenopause, but such measurements are often unreliable because fluctuations are common. Menstrual cycles may become irregular, longer, and often heavier (9). Episodes of amenorrhea and vasomotor symptoms such as hot flashes may be experienced. It is during perimenopause that women experience most of the physiologic symptoms described in the next section and may be more prone to psychological symptoms.

The Massachusetts Women’s Health Study and the Study of Women’s Health Across the Nation (SWAN) found that the perimenopausal transition usually began about four years before the cessation of menstrual periods. Previous studies have shown that mean serum sex hormone-binding globulin decreases by 43% from four years before and two years after the final menstrual period (10).

With the onset of menopause, the ovarian production of estradiol, progesterone, and testosterone almost ceases. Changes occur in the amount of total estrogen as 17β-estradiol decreases and estrone, a less active form of estrogen (resulting from the conversion of testosterone and androstenedione by the enzyme aromatase), becomes the predominant estrogen after menopause (11). Declining estrogen levels are considered responsible for most of the symptoms discussed in the next section.

Estrogen receptors occur in most cells in the body but are particularly numerous in the brain, breast, and the urogenital system. The occurrence of abrupt hormonal changes, especially in estrogen, during the perimenopause has effects on many organ systems. It is not fully understood how estrogen works in the brain, but estrogen α and β receptors are particularly active in the medial amygdala, hippocampus, and limbic systems—the same areas that are so salient for emotions. Estrogens act through nuclear receptors as transcription factors by binding as dimers to specific response elements in DNA and regulating the expression of targeted genes. Estrogens may rapidly up-regulate or down-regulate the excitability of neurons and may exert an agonistic effect on serotonergic activity by increasing the number of serotonergic receptors, the uptake of the neurotransmitter, and the synthesis of serotonin (18). Accordingly, it is not surprising that rapid changes of estrogen during perimenopause may result in affective perturbations in some women.

Progesterone receptors are also found in the limbic system and hypothalamus (19). Progesterones may act as hypnotics and anxiolytics and also may have a negative effect on mood, resulting in dysphoria and irritability (20). Women who are prescribed progesterone (progestins) as a part of hormone therapy to prevent the increased risk of endometrial carcinoma incurred by unopposed estrogen frequently report negative mood symptoms during the interval they are taking progestins.

Testosterone and all other androgens decrease significantly with aging. Produced by the adrenal glands and ovaries, androgens include dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Plasma testosterone levels appear to correlate with women’s sexual drive, and lower testosterone levels during perimenopause may lead to a lack of sexual desire and interest. Studies have explored the clinical utility of exogenous testosterone in enhancing libido, sexual response, and mood (21). The side effects of this treatment may include acne, hirsutism, and deepening of the voice as well as increased risk of cardiovascular disease. Although exogenous testosterone is currently a popular treatment, the effects of its long-term use in women have not been studied sufficiently.

DHEA and DHEAS may have a positive effect on mood, and women with higher levels may be less likely to experience depressive symptoms (22). Continuing studies are exploring the use of DHEA for depression in menopausal women (23).

Selective estrogen receptor modulators (SERMs) are synthetic compounds that act as estrogen agonists or antagonists on selected organs (24). Although tamoxifen and raloxifene are the only ones currently available for clinical use, numerous SERMs are currently being investigated for their ability to target specific organs and to avoid others. These new chemicals represent an exciting area for future research, but it is not currently possible to determine their full effects on the central nervous system or in the modulation of mood or cognition.

A variety of other substances with potential therapeutic effects are being investigated, including phytoestrogens and herbal preparations. Of the many herbal preparations that have been advocated for the treatment of perimenopausal symptoms, most have been disproved in double-blind, randomized control trials (RCTs) There is however, some continuing interest in use of black cohosh, for which both positive and negative trials have been reported (25,26).

The psychiatric literature has long included descriptions of mood disorders in perimenopausal and menopausal women. Early investigators (27) described a mixed depressive and anxiety state combined with vasomotor symptoms and other somatic symptoms. Involutional melancholia, a severe form of depressive illness with psychotic features, was described in earlier editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-II and DSM-III). Studies during the 1970s (28,29) disputed the existence of involutional melancholia, and the diagnosis was subsequently dropped from the DSM.

More recently, new evidence is emerging that depression may accompany menopausal transition in some women (30).

Although most longitudinal community-based studies do not show an increase in depressive symptoms or depressive illness in menopausal women, some that have looked specifically at the perimenopausal stage have found a positive association (30,31,32). However, 45% of perimenopausal women attending gynecologic outpatient clinics have clinically significant scores on depressive rating scales (10,33,34). The SWAN study (35) measured psychological distress; symptoms included sadness, anxiety, and irritability for at least two weeks. The results of this cross-sectional survey found that perimenopausal women had significantly more psychological distress than premenopausal or postmenopausal women. A recent prospective study (30) focused on the increased likelihood of depressive symptoms during transition to menopause and the decreased likelihood after menopause, after adjusting for history of depression, severe premenstrual syndrome, poor sleep, age, race, and employment. Measurements of hormone levels provided corroborating evidence that the changing hormonal milieu contributes to dysphoric mood during transition to menopause.