ESTROGEN

Menopause, defined as the permanent cessation of menstruation, is the final stage in the process of female reproductive aging. Because of the dramatic increase in life span during the twentieth century, the average woman in this country experiencing menopause has more than one-third of her life ahead of her, and as of the late 1990s, an estimated thirty-five million American women were postmenopausal. In practical terms, menopause can only be diagnosed "after the fact," that is, after a period of twelve months of amenorrhea (absence of menstruation). The average age of menopause is fifty-one, which is preceded by a two- to eight-year period of changing ovarian function, known as perimenopause.

In addition to the variability in the age of menopause and in the length of perimenopause, there is also great variability in the extent of menopausal symptoms. The types of symptoms reported include hot flashes (sensation of warmth, frequently accompanied by skin flushing and perspiration), insomnia, night sweats, depression, headache, backache, painful intercourse, loss of sex drive, vaginal dryness, and problems with short-term memory. Cultural differences may play a role in some of the reporting of symptoms, and it is also possible that different concepts of what is discomfort, or real lifestyle differences, such as exercise and diet, may actually diminish these phenomena in some cultures.

What causes menopause?

The immediate reason that women stop cycling is that their ovaries become depleted of eggs. Humans stop making eggs even before they are born and the seven million eggs contained in the ovaries of a five-month female fetus are all she will ever have. At birth, females have only one to two million eggs, and by puberty, only one-thirtieth of the original seven million remain. During each menstrual cycle, one egg becomes fully developed and will be ovulated. Somewhere between ages thirty-five and forty-five, the constant rate of egg loss suddenly accelerates about two-fold, so that at menopause only about one thousand eggs are left. It is believed that the alteration in the regularity of cycles compromises the feedback interaction between the ovaries and the neuroendocrine system, ultimately leading to a sharp decrease in the levels of estrogen and progesterone.

The dramatic reduction in the level of estrogen is associated with a wide variety of physiological changes that correlate with menopause. Indeed, as many as four hundred different actions of estrogen have been identified, affecting such diverse systems as circulation, brain activity, sexual behavior, bone biology, sleep patterns, intestinal absorption of food, and immune activity. Although menopause is clearly associated with such negative health effects as osteoporosis and heart disease, not all the alterations of menopause are detrimental. For example, before menopause, the risk of American women developing breast cancer doubles every three years, whereas after menopause it takes thirteen years for the risk to double again.

Effects of menopause

Menopause diminishes the incidence of gynecological cancers because estrogen and progesterone are involved in the development of these cancers in the first place. During the latter part of each menstrual cycle, to prepare the body for possible pregnancy, estrogen and progesterone cause the cells lining the milk ducts in the breast to divide. Every time a cell divides, there is a chance that errors (mutations) can occur in its genetic material, so that the more cycles a woman undergoes that involve cell division of the duct cells, the greater the chance of mutations. Conversely, when these cells become specialized to produce milk during and after pregnancy, they are no longer proliferating and therefore are less likely to undergo mutations. Thus, the rise in breast cancer during the last half of the twentieth century can probably be explained in large part by changes in the length of the total reproductive period, the number of pregnancies and more common delays in having a first child. Ironically, therefore, menopause in its modern context is actually a favorable event for women's health with respect to breast cancer.

In contrast to its beneficial effect on breast cancer incidence, menopause is detrimental to numerous aspects of health. One of the major outcomes of the decline in estrogen is the increased risk of cardiovascular disease and death from heart attacks. In the United States, cardiovascular disease is the number one killer of men starting at age thirty-five, whereas in women, it is not until after the age of sixty that cardiovascular disease becomes the number one cause of death. Indeed, heart and arterial disease kill almost ten times as many postmenopausal women in Western society as do all the gynecological cancers combined.

The second major consequence of the decline in estrogen is osteoporosis, thinning and loss of bone that can ultimately lead to wrist, hip, and vertebral fractures. Both men and women lose bone as they age, but during the first five to ten years after menopause, women experience accelerated bone loss, making them much more likely than men to suffer collapse of vertebrae, wrist fractures, and broken hips. About 20 percent of elderly women with osteoporetic hip fractures die of complications within one year, ranking osteoporosis as the twelfth greatest killer in the United States. Similar to heart disease, osteoporosis is more deadly than all the gynecological cancers combined.

Hormone replacement therapy (HRT)

Most animals in the wild do not live past menopause. By contrast, typical women in industrialized countries can expect to live more than one-third of their lives beyond their reproductive years. If living past menopause is a relatively recent phenomenon, then evolution will not have had time to adjust women's bodies to living with reduced postmenopausal hormone levels. From this perspective, perhaps HRT (used in this entry to designate both estrogen alone or in combination with progesterone) would be advantageous. On the other hand, if menopause arose during evolution as an adaptive mechanism, then women's bodies are likely to be physiologically adjusted to altered hormone levels, and upsetting that delicate balance with HRT might lead to unexpected health-damaging consequences. These two opposing theoretical possibilities are further complicated by an overwhelming amount of often conflicting data on the risks and benefits of HRT, leading to a great deal of confusion and uncertainty, even among experts, as to the optimal strategy for women who reach menopause. In this regard, decisions should also take into account the personal treatment goals, because therapy directed at some symptoms, such as hot flashes, can be short-term, whereas treatment of a chronic condition, such as osteoporosis, is usually lifelong. It should also be mentioned that the particular doses and routes of HRT can vary according to indication, with different amounts and regimens, including addition of progesterone to prevent endometrial hyperplasia.

The ideal method to scientifically evaluate all of the effects of HRT would be to conduct a randomized trial on a large group of women who are similar in many characteristics, with half the group being given HRT and the other half, a placebo. Indeed, one such study, the so-called Women's Health Initiative, was in progress in 2001, so ultimately, more definitive and comprehensive data on the risks and benefits of HRT will probably become available. At present, however, women reaching menopause are forced to rely predominantly on data from observational, retrospective epidemiological studies. Such studies are subject to a variety of biases, such as educational and socioeconomic backgrounds that might affect the decision of a woman to begin HRT. Nevertheless, it is interesting to note that although the observational studies differ in the details, such as differences in the ages of the subjects and length of estrogen use, virtually all of the analyses demonstrated reduced risk of death among estrogen users. The most comprehensive of these studies, which followed women for more than twenty-five years and had access to all medical records, including precise estrogen doses, showed that the yearly death rate among estrogen users was about half that of nonusers. Nonetheless, because all of these studies were observational, the findings must still be interpreted with caution.

In addition to the overall risk of death, a correlation has been suggested between several specific health parameters and the use of HRT. The most convincing effects are on the process of osteoporosis. Evidence from observational studies indicates that postmenopausal hormone users have fewer fractures than nonusers and show retardation of bone loss. However, the time at which HRT must be initiated in order to protect against fracture is not known. Controversy also exists regarding the maximum age at which HRT can be initiated to be of clinical utility. Although the beneficial effects of estrogen on bone have been demonstrated in women with established osteoporosis, to achieve maximum benefits, HRT should begin at the time of cessation of menses.

The putative beneficial effect of estrogen on cardiovascular status is controversial. Many observational studies on the relation between the use of estrogen and risk events from coronary heart disease suggested lower rates among post-menopausal estrogen users versus nonusers. However, three large prospective studies in the year 2000 concluded that HRT neither prevents cardiovascular problems in healthy women nor protects women with abnormal cardiac function against future cardiovascular episodes. Thus, despite the encouraging suggestions of earlier studies and the biological plausibility of protection against coronary heart disease associated with postmenopausal HRT, the cardioprotective effect of HRT is questionable. Indeed, the American Heart Association has recently issued an advisory statement discouraging the use of HRT in situations where the sole purpose is improvement of cardiovascular health.

Possible beneficial effects of HRT against arthritis, cognitive decline and Alzheimer's disease, periodontal disease, cataract formation, and colon cancer have been proposed based on epidemiological analyses, but further research is required to confirm these results. In any case, it is clear that at the very least, HRT alleviates such non-life-threatening symptoms of menopause as hot flashes, insomnia, and depression.

Precautions regarding HRT

HRT is absolutely contraindicated in women with undiagnosed vaginal bleeding, breast or endometrial cancer, and active deep vein thrombosis. Women with previous clotting disorders, especially in the setting of pregnancy, should be specifically evaluated medically before initiating HRT. Use of HRT after a diagnosis of melanoma remains controversial, and concerns have been raised regarding the use of HRT in women with liver disease or previous gallbladder disease. Other potentially important side effects that have not been adequately analyzed include immunological changes, in light of the presence of receptors for estrogen in various immune cells.

The most controversial aspect of HRT remains the potential increase in breast cancer resulting from long-term estrogen use. There are recognized experts on each side of the debate, but the majority of studies support no significant increase in breast cancer risk in women receiving postmenopausal HRT. Clearly, resolution of this important issue requires a randomized-controlled trial with longitudinal data. In any case, for women who have proven breast cancer or who have a known risk of developing breast cancer, postmenopausal HRT is contraindicated. The safety of HRT after breast cancer remains controversial, with available evidence neither assuring safety nor proving any toxic effects.

Designer estrogens

Estrogen thus appears to be a contradictory molecule, both essential and harmful to women. Because of the dual nature of the effects of estrogen, researchers are actively seeking to identify so-called designer estrogens, chemicals that are known technically as selective estrogen receptor modulators (SERM). These substances would behave like estrogen in some tissues but block its actions in others. It is possible that one such compound, raloxifine, now prescribed for maintaining bone density in older women, may be able to protect women from osteoporosis and coronary artery disease as well as endometrial and breast cancer. Long-term studies with this and other SERMs in development may be able to protect women single-handedly from the multiple disorders that increase in prevalence after menopause. For the time being, however, each woman must weigh the known risks and benefits of the available forms of HRT and, together with information and advice from health care providers that takes into account her own health history, make her personal decision regarding whether or not to initiate HRT at the time of menopause.

Rita B. Effros

See also Cancer, Biology of; Endocrine System; Heart Disease; Longevity; Menopause; Osteoporosis.

BIBLIOGRAPHY

Austad, S. A. Why We Age. New York: John Wiley & Sons, 1997.

Bellantoni, M. F., and Blackman, M. R. "Menopause and Consequences." In Handbook of the Biology of Aging. Edited by E. Schneider and J. Rowe. San Diego: Academic Press, Inc., 1996. Pages 415–430.

Greendale, G. A.; Lee, N. P.; and Arriola, E. A. "The Menopause." Lancet 353 (1999): 571–580.

Grodstein, F.; Stampfer, M. J.; Colditz, G. A.; Willett, W. C.; Manson, J. E.; Joffe, M.; Rosner, B.; Fuchs, C.; Hankinson, S. E.; Hunter, D. J.; Hennekens, C. H.; and Speizer, F. E. "Postmenopausal Hormone Therapy and Mortality." New England Journal of Medicine 336 (1997): 1769–1775.

Jordan, V. C. "Designer Estrogens." Scientific American, October 1998, pp. 60–67.

Mosca, L. M.; Collins, P.; Herrington, D. M.; Mendelsohn, M. E.; Pasternak, R. C.; Robertson, R. M.; Schenck-Gustafsson, K.; Smith, S. C.; Taubert, K. A.; and Wenger, N. K. "Hormone Replacement Therapy and Cardiovascular Disease: A Statement for Health-care Professionals from the American Heart Association." Circulation 104 (2001): 499–503.

Wise, P. M.; Krajnak, K. M.; and Kashon, M. L. "Menopause: The Aging of Multiple Pacemakers." Science 273 (1996): 67–70.

Estrogen

Estrogen is not one hormone, it is the name used to denote either of two steroid hormones. These hormones are noted for their role in the development of the secondary sexual characteristics of females. In mammals the most abundant (and most potent) estrogen is estradiol (a dialcohol : note the "-diol" suffix), followed by estrone (a ketone : note the -one suffix). As is true for the other steroid hormones, the major biosynthetic pathway for estrogen begins with cholesterol (C₂₇). The figure shows the major metabolic intermediates in the usual synthesis of estrogen, starting with cholesterol, proceeding to pregnenolone (C₂₁), an androgen (C₁₉), and then estrogen (C₁₈). Estrogen has an alcohol functional group at the C3 and C17 positions, and a methyl group at C13. A unique aspect of estrogen biosynthesis is the conversion (catalyzed by the enzyme aromatase) of the A ring to an aromatic ring.

Estrogen is produced in the ovaries and secreted into the blood, whereupon it enters target cells throughout the body. It enters the cells via passive diffusion and binds to specific proteins called estrogen receptors ,

which reside in the cell nuclei. In the absence of estrogen, these receptors are functionally inactive. The binding of estrogen to a receptor activates the receptor, which can then bind to specific sites on the DNA to stimulate the transcription of a highly specific set of genes. As a result, the metabolism and the character of the cell changes.

In addition to its role in the development of the secondary sex characteristics in females, estrogen has important physiological functions in the cardiovascular, immune, and central nervous systems, as well as its effects on the growth and maturation of the long bones. It is also implicated in a number of diseases (including breast and uterine cancers) and in postmenopausal health problems, such as atherosclerosis, osteoporosis, and diminution of cognitive functions. Because these conditions, especially female cancers, are associated with estrogen, a number of anticancer treatments involve estrogen blockade: drugs that prevent estrogen from binding to its receptors. As a result, the receptors remain in an inactive form.

EDWARD DOISY (1893–1986)

Before Edward Doisy earned the Nobel Prize for his research on vitamin K, he studied female hormones. It was at this time in 1936 that he isolated estradiol. In rodents without ovaries, small injections of this isolated compound were able to replicate the same behavior and biological processes as if the ovaries were still present.

—Valerie Borek

see also Steroids.

William M. Scovell

Bibliography

Kimball, J. W. (1994). Biology. New York: W. C. Brown. Available from <http://biology-pages.info>.

oestrogens Steroid sex hormones, derived from cholesterol, which are produced mainly in the ovaries and placenta. This group of hormones, which includes oestradiol (the most active female hormone), oestriol, and oestrone, not only promote maturation of the female reproductive system but are important for controlling the menstrual cycle, production of ova, and maintenance of pregnancy.

Saffron A. Whitehead

oestrogen One of a group of female sex hormones, produced principally by the ovaries, that promote the onset of secondary sexual characteristics (such as breast enlargement and development in women) and control the oestrous cycle (menstrual cycle in humans). Oestradiol is the most important. Oestrogens are secreted at particularly high levels during ovulation, stimulating the uterus to prepare for pregnancy. They are used in oral contraceptives (with progestogens) and as treatment for various disorders of the female reproductive organs. Small amounts of oestrogens are produced by the adrenal glands and testes.

es·tro·gen / ˈestrəjən/ • n. any of a group of steroid hormones that promote the development and maintenance of female characteristics of the body. Such hormones are also produced artificially for use in oral contraceptives or to treat menopausal and menstrual disorders.DERIVATIVES: es·tro·gen·ic / ˌestrəˈjenik/ adj.