Medical Physiology, 3rd Edition


Menopause, or the climacteric, signals the termination of reproductive function in women. Cyclic reproductive function ceases, menstruation comes to an end, and childbearing is generally no longer possible. Also occurring are significant physiological changes (Table 55-3 ) that have a major impact on health.

TABLE 55-3

Menopausal Syndrome and Physical Changes in Menopause



Vasomotor instability

Hot flashes

Night sweats

Mood changes

Short-term memory loss

Sleep disturbances


Loss of libido

Atrophy of the vaginal epithelium

Changes in vaginal pH

Decrease in vaginal secretions

Decrease in circulation to vagina and uterus

Pelvic relaxation

Loss of vaginal tone

Cardiovascular disease


Alzheimer disease

Only a few functioning follicles remain in the ovaries of a menopausal woman

Progressive loss of ovarian follicular units occurs throughout life (see pp. 1120–1121). In the United States, puberty generally occurs at an age of ~12.5 years (see p. 1088) and menopause at 51.5 years. At menopause and during the ensuing 5 years, the ovary contains only an occasional secondary follicle and a few primary follicles in a prominent stroma. The massive loss of oocytes over the reproductive life of a woman—from 300,000 at puberty (see p. 1121) to virtually none at menopause—is the result of the process of atresia during reproductive life.

During menopause, levels of the ovarian steroids fall, whereas gonadotropin levels rise

The loss of functional ovarian follicles is primarily responsible for menopause in primates. Even before the onset of menopause, significant hormonal changes occur very early during reproductive life. Because of a gradual decline in the number of follicles, the decreased ovarian production of estradiol reduces the negative feedback to the anterior pituitary and leads to increased levels of FSH. Increased levels of FSH are seen as early as 35 years of age, even though cyclic reproductive function continues. When compared with younger women, older—but premenopausal—women have diminished estradiol production and decreased luteal function during natural cycles. Diminished inhibin production by the aging ovary may also contribute to the sharp rise in FSH levels that occurs in the perimenopausal period of life (see Fig. 53-11A ).

During menopause, estradiol levels are generally <30 pg/mL, and progesterone levels are often <1 ng/mL of plasma. Both these values are somewhat less than the lowest levels seen during the menstrual cycle of a younger woman (see Fig. 55-6). Ovarian production of androstenedione is minimal during menopause, although androstenedione production by the adrenal cortex remains normal.

Because the output of estrogens, progestins, and inhibins from the ovaries falls to very low levels during menopause, negative feedback on the hypothalamic-pituitary-ovarian axis (see Fig. 55-3) becomes minimal. As a result, levels of FSH and LH may be higher than those seen during the midcycle surge in premenopausal women—the futile attempt of the axis to stimulate follicular development and production of the female sex steroids. During menopause, the anterior pituitary still secretes FSH and LH in pulses, presumably after cyclic release of GnRH from the hypothalamus (see Fig. 53-11A ). Although gonadotropins cannot generally stimulate the postmenopausal ovary, it appears that the gonadotrophs in the anterior pituitary can respond to exogenous GnRH (Box 55-4 ).

Box 55-4

Hormone Replacement Therapy During Menopause

Although the mean age at menopause is ~51.5 years, changes in hormone secretion patterns begin much earlier. Increases in levels of FSH occur as early as 35 years of age. The mechanisms responsible for this change remain to be elucidated. However, it is clear that ovarian function begins to diminish far in advance of a woman's last menstrual period. The increase in gonadotropin secretion is probably a result of decreased folliculogenesis leading to decreased secretion of sex steroids and inhibin and thus lowered negative feedback on the gonadotrophs during the perimenopausal period.

The characteristic changes associated with menopause are primarily the result of low circulating estrogen levels. Estrogens are very important regulatory hormones in females. In addition to their roles in reproductive processes, these hormones have profound effects on several other physiological systems (see Table 55-3).

Hormone replacement therapy (HRT) is indicated during menopause to alleviate menopausal syndrome and to prevent or diminish the physical changes that occur as a result of estrogen deficiency. Menopausal HRT consists of estrogen and progestin administration. The reason for administering progestins is that the endometrium is at significant risk of neoplasia from unopposed actions of estrogens. Thus, progestins are not generally administered to women who have had hysterectomies. Estrogen replacement is very effective against menopausal syndrome as well as against osteoporosis. However, because of side effects (e.g., menstruation) and concern about endometrial and breast cancer, compliance with HRT is often compromised.

The selective estrogen receptor modulators (SERMs) comprise a group of structurally dissimilar compounds that interact with ERs. SERMs act as either estrogen agonists or estrogen antagonists, depending on the target tissue and hormonal status of the individual. The mechanisms by which SERMs elicit their sometimes opposite effects in specific tissues are complex. SERMs such as tamoxifen and raloxifene have estrogen-agonist effects on bone and the cardiovascular system, but estrogen-antagonist effects in reproductive tissue. The estrogen-antagonist effects of SERMs may reflect classic competition for ERs. The ideal SERM for HRT would have all the beneficial effects of estrogens—including alleviating menopausal syndrome, protecting against cardiovascular and Alzheimer disease, and acting as estrogen agonists in certain reproductive tissues—without their carcinogenic side effects.





Upper motor neuron



Significantly impaired

Lower motor neuron



Less impaired