14.18: Sex Hormones in Women

Sources and Control of Secretion

Young adult women produce two main sex steroids: estrogen and progesterone. There are two main forms of estrogen: estriol and estrone. Estriol, which constitutes approximately 60 percent of total estrogen, is more powerful than estrone.

Before menopause, almost all estrogen and progesterone come from follicle cells, which surround the developing egg cells in the ovaries (Figure 14.1). Follicle cells also secrete inhibin. Stroma cells, which surround each group of follicle cells, secrete some testosteronelike hormone. Almost all of this hormone is converted to estrogen by the follicle cells. In addition, small amounts of estrogen, testosterone, and androstenedione are produced by the adrenal cortex, but these secretions do not play a significant role in women unless the ovaries are removed or menopause occurs.

Secretion of estrogen, progesterone, and inhibin by the ovaries is controlled by mechanisms that result in dramatic and rhythmic increases and decreases in hormone levels. These hormone cycles are accompanied by cycles of development and degeneration of follicles, egg cells, and the uterine lining.

The negative feedback mechanisms that control the secretion of estrogen, progesterone, and inhibin are similar to those which regulate testosterone and inhibin in men. However, in women a positive feedback mechanism becomes operative for a few days at about the middle of each cycle. This mechanism results in high LH levels, which cause ovulation. The high blood levels of estrogen and progesterone that also occur then produce a negative feedback effect again, resulting in decreasing LH and FSH levels; degeneration of the follicle; diminishing estrogen and progesterone levels; destruction of the uterine lining; and finally, menstruation. These changes lead to the next cycle.

Sex hormone secretion can be influenced by various brain activities; this may result in irregular cycles or the cessation of cycles.

Effects

The main effects of estrogen include (1) developing and maintaining reproductive system structures, including the breasts but not the ovaries, (2) developing and maintaining female secondary sex characteristics (e.g., fat deposits on the hips and thighs, female pattern of hair distribution), (3) maintaining low blood levels of LDLs and high levels of HDLs, and (4) increasing and maintaining bone matrix. Estrogen seems to affect bone matrix in several ways. These ways include directly stimulating osteoblasts; increasing the secretion or effectiveness of calcitonin; inhibiting the effects of parathormone on bone cells; and inhibiting the production and effects of IL-6. IL-6 stimulates osteoclast activity and bone removal.

Progesterone stimulates the development of glandular tissues in the uterine lining and breasts. These functions become important only if a woman becomes pregnant or nurses her child. Finally, as in men, testosterone stimulates interest in sexual activity.

Age Changes

Before Menopause

At about age 45 the length of each male cycle begins to shorten because the time between the end of one cycle and ovulation in the next cycle decreases. Since this phase of the cycle produces much estrogen, its shortening results in a decline in estrogen secretion, and estrogen levels fall. These levels become so low that an increasing number of cycles do not produce a positive feedback effect, and ovulation does not occur. These changes seem to be caused initially by a decrease in the responsiveness of the ovaries to FSH and LH.

Because of these changes, there is less progesterone production, less development of the uterine lining, and an increasing number of cycles with little or no menstrual flow. Since menstrual flow is the most noticeable indicator of female cycles, the occasional absence of menstrual flow when it is expected indicates that the cycles are becoming irregular. By age 50 to 51 progesterone is essentially absent, menstrual flow happens less than once each year, ovarian and menstrual cycles (uterine cycles) have ended, and menopause has occurred.

After Menopause

When menopause occurs, estrogen secretion by the ovaries and blood estrogen levels decline quickly. During the four years after menopause estrogen secretion by the ovaries dwindles to zero. Blood estrogen levels do not reach zero, however, because small amounts of estrogen are produced by conversion of testosterone and androstenedione to estrogen and by the adrenal cortex. In spite of this estrogen production, blood estrogen levels usually drop to slightly below the lowest levels that were present during premenopausal hormone cycles. Furthermore, postmenopausal estrogen levels may be less than 5 percent of those present during midcycle estrogen peaks before menopause. The low estrogen levels reached within a few years after menopause do not fluctuate cyclically.

As with testosterone levels in older men, estrogen levels among postmenopausal women show considerable variation. Obese women generally have higher levels because fat tissue converts much androstenedione to estrogen. In extreme cases these elevated estrogen levels may equal or exceed average levels in premenopausal women. However, the estrogen in postmenopausal women is not as potent as that in premenopausal women because most postmenopausal estrogen is estrone rather than estriol.

Testosterone secretion from both the ovaries and the adrenal glands in postmenopausal women declines slightly, resulting in a small decrease in the already low blood levels. This testosterone has a greater impact, however, because the ratio of testosterone to estrogen increases.

Effects of Age Changes

Up to the time of menopause slow age changes in sex hormones result in gradually shorter and increasingly irregular menstrual cycles.

Temporary Effects

As menopause occurs, ovarian sex hormone levels plummet, causing many menopausal women to experience temporary signs and symptoms that are often considered part of menopause. Among these common phenomena, hot flashes involve sudden dilation of skin blood vessels in the head and neck, which often spreads downward over other regions. Affected women may feel a sense of pressure in the head, followed by sensations of heat or burning in areas where vessel dilation is occurring. The affected areas appear flushed, and profuse sweating may occur. Hot flashes seem to be caused by low estrogen levels.

These flashes usually last approximately four minutes but may last from a few seconds to over 30 minutes. It is difficult to estimate the incidence among menopausal women because of the extreme individual variations in the intensity of hot flashes. Hot flashes in some women are barely noticeable, while other women may be briefly disabled or may be awakened by very intense flashes.

In approximately 85 percent of menopausal women who experience hot flashes, the flashes occur for more than a year after menopause. They continue to occur for up to five years in 25 to 50 percent of the women who experience them after menopause.

Other consequences of altered sex hormone levels during and shortly after menopause may include depression, anxiety, irritability, nervousness, fatigue, and impaired memory and ability to concentrate. Some of these psychological changes may result from sleep disturbances caused by low estrogen levels or nocturnal hot flashes. All these undesirable features usually subside. These and other effects from menopause vary greatly among different cultures.

Permanent Effects

Since hot flashes and the psychological alterations accompanying menopause are almost always temporary, they do not seem to fit the definition of age changes. Other changes caused primarily by the paucity of estrogen after menopause are permanent unless estrogen levels are raised, and many of these changes intensify into very old age. They include shrinkage and decreased functioning of all reproductive system structures; alterations in secondary sex characteristics (e.g., shrinkage of the breasts, increase in visible facial hair, decrease in axillary and pubic hair); increases in LDLs and decreases in HDLs; and more rapid loss of bone matrix.

The changes resulting from plunging estrogen levels and menopause are diverse. As for the reproductive system, the loss of childbearing ability is considered by some people to be a negative effect which can lead menopausal women into depression or other psychological disturbances. Others view the loss of childbearing ability as a positive outcome because it eliminates concerns about unwanted pregnancies. As a result, some women have an increase in sexual activity. Other consequences of reproductive system changes that follow menopause are discussed in Chapter 13.

Alterations in secondary sex characteristics after menopause are often considered cosmetically undesirable. Other changes in the skin include decreased secretion by apocrine sweat glands and sebaceous glands and an increased incidence of skin abnormalities. The changes in blood lipoproteins raise the risk of developing atherosclerosis and its complications (e.g., heart attacks, strokes). Shrinkage of the urethra promotes urinary stress incontinence. Finally, the rapid loss of bone matrix is a main risk factor for type I osteoporosis.

Estrogen Replacement Therapy

Since many target structures retain much of their responsiveness to estrogen, many postmenopausal changes can be slowed, stopped, or reversed by administering estrogenlike substances. This type of treatment is often called estrogen replacement therapy (ERT).

Benefits

In many women ERT reduces or eliminates hot flashes. It also restores low LDL levels and high HDL levels, lowering the risk of atherosclerosis, and it seems to maintain cognitive functions and reduce the risk of getting Alzheimer's disease. To be most effective against osteoporosis, ERT should begin within six months after menopause, before significant bone loss has occurred. Furthermore, prevention of osteoporosis may require ERT for 10 or more years after menopause because stopping ERT allows the rate of bone resorption to increase to pretreatment levels. Postmenopausal prevention of osteoporosis may also require measures such as exercise, calcium supplements, and vitamin D supplements.

Risks

Estrogen replacement therapy is especially recommended for women who have an early menopause and those at high risk for developing osteoporosis. Because ERT increases the risks of certain disorders (e.g., thrombus formation, breast cancer, gallbladder disease, endometrial cancer), it is not recommended for women with risk factors for certain conditions. These conditions include breast cancer or other reproductive system cancers; circulatory abnormalities such as high blood pressure, thrombus formation, and varicose veins; liver or gallbladder disease; or endometriosis. Women who are heavy smokers or are obese are also poor candidates for ERT.

The risks from ERT can be greatly reduced in several ways. These include using small doses of estrogen; administering estrogen by injection rather than orally; administering estrogen in cycles that mimic natural cycles; and administering low levels of certain progesterone like substances (progestins). Cyclic administration of estrogen, especially when supplemented with progestins, often results in continued uterine cycles and periodic menstrual flow, which is usually less than premenopausal menstrual flow. However, no egg cells are produced and pregnancy is impossible.

In conclusion, ERT can relieve several serious consequences of low estrogen levels in postmenopausal women. Though ERT increases certain risks somewhat, it greatly reduces others. Therefore, the net effect in many women is an increase in the quality of life and life expectancy.

Alternatives

For some women, the risks from estrogen supplementation are too high when compared with the possible benefits. Scientists have found artificial compounds that promote some beneficial effects from estrogen supplements (e.g., reduce risk of atherosclerosis, reduce bone thinning) while not increasing certain risks from estrogen supplements (e.g., blood clots, cancers). Examples include tamoxifen and raloxifene. Other alternatives to traditional estrogen supplement therapy are being developed and evaluated. These alternatives include using different methods of estrogen administration (e.g., skin patches, vaginal creams); minimizing other risk factors (e.g., high fat diet); increasing alternative beneficial practices (e.g., improved diet; exercise; vitamin and calcium supplements; exercise; foods containing natural estrogens; herbal remedies).