Menopause is the permanent cessation of menstruation after the loss of ovarian function. The median age at menopause in the United States is 52.6 years, with 1% of women experiencing menopause before age 40 (43). Menopause is a process (derived from the Greek words meno or month and pausis or cessation) that can only be defined retrospectively after 12 months of amenorrhea. The phase from the onset of
irregular menses to menopause is called “perimenopause,” which has an average duration of 5 years. It includes the year after cessation of menses. This time is also referred to as the “climacteric,” which is the transition from reproductive to nonreproductive life. A woman is perimenopausal if serial follicle-stimulating hormone (FSH) levels are elevated (>20 IU/L) and estradiol is low (<60 pg/mL). During perimenopause, ovarian function is variable, with a shortened follicular phase and an increase in defective ovulation and anovulation. Other symptoms (e.g., hot flashes and night sweats) also occur. It is not a time of steady estrogen decline; instead, it is marked by peaks and valleys. This feature can be clinically frustrating because it can lead to fluctuating symptoms (e.g., changes in seizure and headache frequency).

The hypothalamic-pituitary axis changes dramatically during and before menopause. The most marked change is the increased secretion of FSH by the pituitary gland. Luteinizing hormone (LH) levels remain in the normal range despite a rise in FSH before menopause. With menopause, LH levels rise and plateau. The increased levels of FSH and LH are secondary to loss of negative feedback from lower circulating estrogen levels. Additionally, ovarian follicles no longer release inhibin, which normally suppresses FSH.

With cessation of menstruation, a decline occurs in estradiol concentration that is dramatic for the first 12 months; the decline then becomes gradual. The concentration of estrone, a weaker estrogen, also falls after menopause. Peripheral aromatization of adrenal androgens in adipose tissue, muscle, and skin becomes the major source of estrogens after menopause. Obese postmenopausal women have higher levels of circulating estrogen because of increased aromatization in adipose tissues.

Progesterone levels in perimenopausal women can be normal, but luteal-phase progesterone typically declines. Women can go through long phases of amenorrhea with absent progesterone secretion. With menopause, levels decline to approximately 30% of the concentration present in young women during the follicular phase of the menstrual cycle. The main source of progesterone becomes the adrenal gland. Peripheral conversion of steroids to progesterone is not seen in nonpregnant women.

With aging, ovarian androgen secretion declines. A shift in the pattern of androgen secretion occurs with the maintenance of testosterone at the expense of androstenedione. With the fall in androstenedione, a major source of testosterone, circulating levels of testosterone cannot be maintained, and serum levels decline. Typically, the decline in circulating androgens begins before menopause.

Steroid hormones exert powerful effects on the brain, beginning shortly after conception and continuing throughout life. Sex steroids are highly lipophilic and readily cross the blood-brain barrier. The brain is well known as a target site of peripheral steroid hormones; however, it is also the site of de novo synthesis of steroid hormones from cholesterol (55). Steroid hormones influence function by immediate membrane effects and by genomic effects. Genomic effects are delayed, taking days to occur, and their effects are sustained for days to weeks after hormone exposure. Steroid hormones bind intranuclear receptors and act as transcription factors that regulate gene expression. Their diversity and magnitude suggest that hormonal therapy may be helpful to treat or prevent neurologic conditions that are sensitive to hormones.

Stroke, one of the leading causes of death in the United States, is a primary cause of adult disability. Although stroke is more common in men, the overall mortality rate is higher in postmenopausal women (14% vs. 20%) (10). Aspirin may be less effective in platelet aggregation inhibition in women compared to men with a prior history of ischemic cerebrovascular disease (13). Gender also plays a role in response to carotid endarterectomy. Restenosis rates are significantly higher in women (14%) versus men (3.9%), with a mean follow-up period of 25 months (28).

Stroke risk factors are identical in men and women, although women carry the added burden of risks associated with pregnancy, hormonal contraception, and the effects of hormonal decline after ovarian failure. Basic science research suggests favorable neuroprotection and reduced neuronal injury after ischemic stroke with estrogen, but clinical trials do not support the basic research predictions (Table 5-2). Vascular endothelium and smooth muscle bind estrogen with high affinity. Estrogen promotes vasodilatation
and alters both short-term and long-term vasomotor tone. Its actions depend on changes in renin, angiotensin-converting enzyme, nitric oxide, and prostaglandins (38). Estrogen favorably alters serum lipid concentrations through mediation of hepatic apoprotein genes. It decreases serum cholesterol, lowers low-density lipoprotein (LDL) cholesterol, and increases serum high-density lipoprotein (HDL) cholesterol. Coadministration of progesterone blunts these lipid effects because progesterone alone tends to raise LDL and lower HDL cholesterol.

There are four large clinical trials that have evaluated the effects of HRT on stroke risk and do not support a role in prevention. The Framingham Heart Study showed that postmenopausal use of HRT resulted in an increased risk of stroke (30). The Women’s Estrogen for Stroke Trial did not find a significant effect on stroke prevention for oral estradiol versus placebo in women with a recent stroke or transient ischemic attack (57). The same results were found for women with coronary heart disease who were treated with oral conjugated equine estrogen and progesterone in the Heart and Estrogen-Progestin Replacement Study (50). The Women’s Health Initiative study examined healthy women taking conjugated equine estrogen alone if they had a prior hysterectomy or in combination with medroxyprogesterone if they had an intact uterus (2,60). Women were between the ages of 50 and 79 years at baseline and were generally healthy. Women taking estrogen and progesterone had an elevated overall stroke risk of 30% compared with women taking placebo, and ischemic stroke was increased by 40%. For women without an intact uterus on estrogen alone, the risk of ischemic stroke was increased by 40% compared with women on placebo. Neurologists now inform patients that HRT cannot be recommended for stroke prevention.

Neuropsychological reviews indicate that, although healthy women and men demonstrate similar performance on many cognitive tasks, men score better on constructional, visuospatial, and objective manipulation tasks, whereas women excel in verbal memory, word discrimination, and verbal fluency measures. Such differences may be mediated by both long-term and short-term exposure to steroid hormones.

Evidence indicates that specific aspects of memory covary with sex steroids in men and women. Alterations in performance are noted across the menstrual cycle in normal women, with higher estradiol levels linked to better verbal memory (41). In postmenopausal women, estrogen users attained higher scores on specific cognitive tasks of immediate and delayed paragraph recall. No changes were found in other cognitive tasks or in tests of spatial memory (29). This suggests a specific—not global—effect in some women. In contrast, progesterone can reduce cognitive performance. In one study, oral progesterone given to healthy young women resulted in impaired symbol copying, fatigue, and confusion, along with reduced immediate verbal recall scores (21).

Alzheimer’s disease (AD), the most common of the dementias, is a degenerative disease characterized by the gradual onset of progressive symptoms, including memory loss and other cognitive deficits, personality change, and executive dysfunction, ultimately requiring monitored assistance with activities of daily living. Currently, 4.5 million Americans are affected, and by 2050, 14 million will suffer from this disease (15). Incidence increases with age; one in 10 people are affected by age 65, and nearly one in two people are affected by age 85. Women have a higher predilection for Alzheimer’s disease, independent of age.