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Reproductive Effects Caused by Diethylstilbesterol
Much of the conceptual background for the investigation of the actions of hormonally active agents (HAAs) is based on results of studies on the actions of diethylstilbesterol (DES), a potent synthetic estrogen (see Chapter 1). Because this compound is not an environmental toxicant and because to date, no known environmental toxicant has been demonstrated to be more potent than DES, its actions are not discussed extensively in the corpus of this report. Nevertheless, because some workers in the field believe that DES is an important model for the effects of other HAAs, the relevant aspects of the actions of this compound are discussed here.
There is extensive literature concerning the long-term effects of in utero exposure of humans to DES (Herbst and Bern 1981; Takasugi and Bern 1988; Mittendorf 1995) and of fetal and neonatal exposure in other animals (Vannier and Raynaud 1980; Bern et al. 1987; Brody and Cunha 1989; Newbold 1995). There is also evidence that developmental exposure to DES can alter the immune-system functioning of laboratory animals (Kalland et al. 1979; Kalland and Forsberg 1980, 1981; Ways et al. 1980; Blair 1981: Holsapple et al. 1983: Luster et al. 1984; Pung et al. 1984, 1985) and humans (Ways et al. 1987; Noller et al. 1988: Blair 1992). Effects on other tissues, such as bone, also have been noted (Migliaccio et al. 1992). However, the major concern has focused on prenatal exposure to DES and its effects on the reproductive system.
Table A-1 lists the various female and male reproductive-tract abnormalities in humans and rodents exposed prenatally to DES. Studies show that exposure to DES during the critical period of organogenesis can profoundly disturb differentiation of the reproductive organs. Some of the effects are not observed until adulthood, demonstrating the latent developmental effects of exposure to this potent estrogen.break
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Table A-2 provides estimates of adverse pregnancy outcomes in DES-exposed daughters. Because DES was used to treat women with histories of reproductive difficulties, it might be expected that their daughters also would have high-risk pregnancies independent of DES exposure. However, Barnes et al. (1980) has shown that the incidence of these unfavorable outcomes in DES daughters is not related to the obstetric history of the mothers. In fact, as shown in this table, the incidence is related to the presence of genital-tract abnormalities, which are in turn related to the gestational age of first exposure to DES.
Table A-3 presents case-control studies of testicular cancer in men in relation to prenatal exposure to DES and other hormones. Exposure assessment for these studies was problematic because none of the study protocols restricted exposure to the critical period of testicular development, and all combined prenatal exposure to all prenatal hormones, rather than to DES alone. Because prenatal DES exposure occurred in about 1% of pregnancies, the power of these studies to isolate a DES effect is limited.
Table A-4 shows the effects of exposure to DES on sperm concentration and on abnormalities of the male reproductive system.
Table A-5 presents observed effects on the mature reproductive system in workers exposed to DES and DES-like compounds.break