Diethylstilbestrol (DES)

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Diethylstilbestrol (DES)

Diethylstilbestrol (DES) is a synthetic, nonsteroidal estrogen (a hormone that stimulates the development of sexual characteristics and which helps induce menstruation). DES was first made in 1938. Initially the substance was seen as a great scientific breakthrough, since estrogen was known to be important in women for successful reproduction. Wide-scale use of DES by pregnant women to prevent miscarriage beginning in the 1940s ended in 1971 when a link was established between the drug and development of a rare cancer called clear-cell adenocarcinoma of the vagina. Moreover, the heritability of risk has been found; the daughters of women who took DES face a higher risk of certain cancers and of structural abnormalities in the genital area.

The development of DES by British scientist Edward Dodds (1899-1973) was one in a long line of twentieth century medical advances which reflected new understanding of the female reproductive system. While doctors had observed pregnancy, childbirth, miscarriages, and infertility for centuries, they did not gain an understanding of the hormonal functions behind these processes until the twentieth century. Through a series of discoveries, researchers learned that the process of pregnancy required a complicated series of hormonal triggers to occur successfully. They also learned that hormones were critical for the development of sexual characteristics in both men and women.

An early breakthrough was the successful isolation in 1923 of estrogen, a sex hormone produced in women and, to a lesser extent, in men. Initially, the natural form of estrogen was extracted from animal ovaries, a process that was time-consuming and expensive. By 1936, the first synthetic estrogen was manufactured from plant steroids. In 1942, DES was approved by the U.S. Food and Drug Administration for use by menopausal women and for several other purposes. The drug was not approved for use by pregnant women until 1947, following reports that the drug could reduce the incidence of miscarriage.

At the time DES was first used for pregnant women, the substance was seen as a new weapon against infertility, stillbirths, and prematurity; at that time stillbirths and premature births were thought to be caused by a failure of the placenta to produce sufficient quantities of progesterone.

In the observation of practicing physicians, the substance appeared to cause no harm. Examination of more than 10, 000 infants who died of unrelated causes during this time did not reveal any DES-linked abnormalities. In retrospect, problems did not become apparent until the DES infants were no longer infants.

Signs of trouble

The largest number of DES prescriptions were ordered in 1953. By the middle 1950s, a series of studies suggested that DES did not actually help prevent miscarriages. Yet the drug continued to be given to pregnant women throughout the 1960s. Then, in the late 1960s, doctors noticed a series of cases of vaginal cancer in teenage girls and women in their twenties. This was troubling, because vaginal cancer had previously been seen primarily in much older women. By 1971, researchers had definitely linked DES to the vaginal cancer cases, and a report of the association appeared in the influential New England Journal of Medicine. That same year, the FDA prohibited the use of DES during pregnancy.

A total of about 600 cases of cancer of the cervix and vagina have been diagnosed in DES daughters. Daughters also are at higher risk of structural abnormalities of the reproductive tract and of poor pregnancy outcome. About one-half of all DES daughters experience an ectopic pregnancy, a premature birth, or a miscarriage. In addition, DES daughters are at a higher risk of infertility than women whose mothers did not take the drug.

The most common health problem reported by DES daughters is adenosis of the vagina. Adenosis is the abnormal development of glandular tissue. This occurs in 30% or more of DES daughters. About 25% of DES daughters have physical abnormalities of the cervix or vagina. Vaginal cancer occurs in less than 1 per 1, 000 females whose mothers took DES.

Daughters of women who took DES are not the only ones at higher risk of health problems. Mothers

KEY TERMS

Adenocarcinoma— Cancer of the glandular tissue.

Adenosis— Abnormal development or disease of the glands.

Cervix— The front portion, or neck, of the uterus.

Endometrium— The blood-rich interior lining of the uterus.

Epithelium— The layer of cells that covers external and internal surfaces of the body. The many types of epithelium range from flat cells to long cells to cubed cells.

Mullerian ducts— Paired structures present in the early embryo from which some of the reproductive organs develop.

who took DES face a slightly increased risk of breast cancer, and anecdotal evidence suggests that DES sons have a higher risk of testicular and semen abnormalities. Infertility and a higher risk of some types of cancer have also been reported among some DES sons.

Effects on the developing embryo

Various theories to account for the effects of DES have been presented. What is clear is that the diseases associated with DES derive from structural damage of the fetus caused by the drug. The drug is most damaging when taken early in pregnancy, when the reproductive organs are formed. (Researchers have found that daughters of mothers who took DES in their eighteenth week of pregnancy or later had fewer abnormalities.) One explanation suggests that DES exposure causes abnormal development of the Mullerian ducts, paired structures present in the early embryo. During a normal pregnancy, the Mullerian ducts form the female reproductive tract, including the uterus, the fallopian tubes, the vagina, and the cervix. DES causes the persistence of a type of glandular, or secreting, epithelial cell in the vagina. During normal development, this type of cell is transformed to a squamous, or flattened, cell. The persistence of this type of cell, researchers speculate, could make affected women more susceptible to a cancer-promoting factor. They have also suggested that vaginal cancer does not develop until after menstruation begins because this susceptible tissue reacts to estrogens released naturally in women who menstruate.

To explain the higher rate of premature deliveries and infertility in DES daughters, scientists point to the abnormal development of the cervix or endometrium in the embryo. Another possible explanation is that DES somehow causes defects in the connective tissue of the fetal cervix and uterus, so that these organs cannot develop normally.