Hormones
by Catherine Schairer, Ph.D.*

Hormones, substances produced in the body, have regulatory effects on specific organs. Estrogens and progesterone are two hormones produced predominantly in the ovary of the female. Estrogens control the development of feminine body characteristics, and both estrogens and progesterone regulate the menstrual cycle and pregnancy. Androgens, which are produced predominantly in the male, determine masculine body characteristics. These hormones, or synthetic chemicals that have similar effects, are used as drugs for a variety of purposes.

Many women take "replacement" estrogens to relieve the hot flashes, vaginal dryness, and itching that may develop at menopause when ovarian function decreases. They are also taken by older women to retard bone loss. The most frequently prescribed estrogen in the United States is Premarin, a natural estrogen. Between 1962 and 1975, there was a four-fold increase in the use of estrogens for menopausal symptoms in the United States. This was followed by a parallel increase in the incidence of cancer of the endometrium, the lining of the uterus (Thomas, 1988). An explanation for the rise in incidence came from several studies which showed nine- to 14-fold increases in the risk of endometrial cancer associated with long-term use of menopausal estrogens. Subsequent studies have confirmed these earlier findings and suggest that risk is greatest among current and recent users. There is also a fairly rapid decline in risk after cessation of use, although a small increase in risk remains for former users (Brinton, 1984).

Numerous studies have shown a slightly increased risk of breast cancer in different subgroups of women who have used estrogens for a long period or at relatively high doses. A number of other studies, however, have found no increased risk associated with duration or dose, making it difficult to draw firm conclusions about the risk of breast cancer associated with the use of estrogen replacement therapy (Brinton et al., 1993).

Most evidence suggests no overall association between menopausal estrogen use and risk of ovarian cancer (Brinton, 1984), although further research is needed to determine whether replacement estrogens increase risk of specific types of ovarian tumors (Thomas, 1988). Of two studies that have examined the relationship between menopausal estrogens and eye melanoma, one found no association (Gallagher et al., 1985), and the other found a two-fold increase in risk associated with menopausal estrogen use (Hartge et al., 1989). Several studies suggest that menopausal estrogens protect against large bowel cancer (Burch et al., 1975; Furner et al., 1989), while others do not (Weiss et al., 1981; Potter et al., 1983; Davis et al., 1989).

With the recognition in the early 1980s that use of progesterone or its derivatives (collectively called progestins) may offset the increased risk of endometrial cancer associated with estrogen use, it has become increasingly common to prescribe pro- gestins in conjunction with estrogens during a portion of the monthly cycle.

The most frequently prescribed progestin in the United States is Provera (medroxy-progesterone acetate), a derivative of progesterone. While the addition of progestins to estrogen replacement therapy appears to have definite beneficial effects on endometrial cancer risk (Persson et al., 1989; Voigt et al., 1991; Brinton et al., 1993; Jick, et al., 1993), further epidemiologic studies are needed to determine the optimal regimen needed to counteract the adverse effects of estrogens, particularly after prolonged use. Data regarding the effect of estrogen/progestin replacement therapy on risk of breast cancer are limited and inconsistent. Early studies reported a protective effect of the estrogen/progestin combination, but a recent study reported an increased risk of breast cancer in long-term users of estrogens and progestin in combination (Kelsey and Gammon, 1990). Further studies are needed to clarify this issue.

In contrast to the natural estrogens most commonly used in estrogen replacement therapy, the estrogens used in oral contraceptives are synthetic. The most effective and widely used oral contraceptives are "combination" pills, taken for 21 days, that contain a fixed amount of estrogen and progestin. These "combination" oral contraceptives actually reduce a woman's risk of some cancers. Studies have uniformly shown a risk reduction of 40 to 50 percent for ovarian and endometrial cancers in women who ever used combined pills. The risk decreases with increasing duration of use, and some protective effect appears to persist for at least 10 to 20 years after discontinuation of use (Stanford, 1993, Rosenberg, 1994). However, sequential oral contraceptives, in which estrogen alone is taken during the first 14 to 16 days of the monthly cycle followed by an estrogen-progestin combination during the last five or six days, have been associated with increases in the risk of endometrial cancer (Van Leeuwen and Rookus, 1989).

The relationship between oral contraceptive use and risk of breast cancer remains unresolved despite numerous studies. Although many studies have found that oral contraceptive use does not increase risk of breast cancer in most women, most, but not all, studies have reported that long-term use at an early age increases risk in women under the age of 45 years (Kelsey and Gammon, 1990). Prolonged use of oral contraceptives has also been linked to an increased risk of cervical cancer (Brinton, 1991), but some doubt remains as to the causality of this association. Substantial increases in the risk of liver cancer have also been associated with oral contraceptive use in developed countries where this cancer is very rare (Rosenberg, 1991). However, no such elevation in risk has been detected in countries where hepatitis B virus is endemic and liver cancer rates are high (WHO, 1989). Present evidence suggests that there is no causal link between oral contraceptive use and cutaneous melanoma, cancers of the kidney, the colon, the gallbladder, or tumors of the pituitary (Milne and Vessey, 1991).

Depot-medroxyprogesterone acetate (DMPA), a long-acting progestational injectable contraceptive, has been approved for contraceptive use in more than 90 countries, including the United States. However, concern that DMPA might increase the risk of breast cancer in women delayed its approval in the United States until 1992. Although data are limited, there appears to be no overall increase in breast cancer risk among women who have used this form of contraception. However, a two-fold increase in the risk of breast cancer in women who started using DMPA in the previous five years has been reported, suggesting that DMPA may accelerate the growth of preexisting tumors (Skegg, 1995). Data on DMPA use and risk of other cancers are also limited, but suggest no association with cervical or ovarian cancer (WHO, 1993), or liver cancer (WHO 1991), and a protective effect against endometrial cancer (WHO, 1993).

DES (diethylstilbestrol), a synthetic chemical with estrogenic properties, has also been linked to risk of cancer. It was used for the prevention of miscarriage and late complications of pregnancy during the late 1940s and 1950s. Following several studies in the late 1950s that reported no beneficial effect of DES, use of the drug gradually tapered off (Vessey, 1989). In 1971, prenatal DES exposure was linked in young women to clear-cell adenocarcinoma of the vagina, a rare form of cancer. Subsequent studies have also linked prenatal DES exposure to clear-cell adenocarcinoma of the cervix. Results from a number of studies suggest that a woman exposed to DES in utero has about a one in 1,000 chance of developing a clear-cell adenocarcinoma of the vagina or cervix by the age of 34 years (Vessey, 1989). There is little evidence, however, that prenatal exposure to DES increases risk of other types of cervical or vaginal cancers (Thomas, 1988).

Studies have shown that males exposed to DES in utero have a greater frequency of abnormalities of the reproductive tract than those not exposed. One of these abnormalities, failure of the testes to descend into the scrotum, is known to increase the risk of testicular cancer. In several studies, a higher proportion of males with testicular cancer were also exposed to DES in utero compared to study subjects without testicular cancer (IARC, 1987).

Studies of breast cancer in women who were themselves treated with DES to prevent abortion have yielded inconsistent results and further studies are needed to determine whether the possible association is causal (Thomas, 1988). Data on development of other types of cancer in women exposed to DES during pregnancy are too limited to draw firm conclusions (IARC, 1987).

Synthetic androgens are used in the treatment of renal conditions, various types of anemias, endocrine disorders, and generalized weakness. They are also used by athletes and body builders to enhance development of skeletal muscles. Individual cases of liver cancer have been linked to the use of these substances, but well-designed studies are needed to confirm or refute a causal relationship with oral contraceptives (IARC, 1987).

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* From the Environmental Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland

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