Known Effects of Drugs on Human Sexual Differentiation

In humans (and rodents), exposure to hormonally active chemicals during sex differentiation can produce pseudohermaphroditism [21, 35]. In addition, exposure to the androgenic substances, danazol or methyltestosterone, masculinizes human females (i.e., "female pseudohermaphroditism"). Progestins act both as androgen antagonists, demasculinizing males such that they display ambiguous genitalia with hypospadias [35], and as androgen agonists, masculinizing females. Laboratory studies demonstrate that these chemicals alter sex differentiation in rodents as well [21]. The drug aminoglutethimide, which alters steroid hormone synthesis in a manner identical to many fungicides, also masculinizes human females following in utero exposure.

Diethylstilbestrol (DES) provides an unfortunate example of how in utero exposure to a potent endocrine disruptor with estrogenic activity can alter reproductive development in humans. Although a few cases of masculinized females were noted in the late 1950s, most of the effects of DES were not apparent until after the children attained puberty. Transplacental exposure of the developing fetus to DES causes clear cell adenocarcinoma of the vagina, as well as gross structural abnormalities of the cervix, uterus, and fallopian tube. These women are more likely to have an adverse pregnancy outcome, including spontaneous abortions, ectopic pregnancies, and premature delivery [41]. Some of the pathological effects that develop in males following fetal DES exposure appear to result from an inhibition of androgen action or synthesis (hypospadias, underdevelopment or absence of the vas deferens, epididymis, and seminal vesicles) and anti-Mullerian duct factor (persistence of the Mullerian ducts) [35,41,42]. DES also causes epididymal cysts, hypotrophic testes, and infertility in males. Some males have reduced ejaculate volume with reduced numbers of motile sperm, and some also experience difficulty in urination [41].

It has also been reported that DES can alter sex differentiation of the human brain. Several behavioral alterations have been observed in some DES daughters [43,44].Meyer-Bahlburg et al. [43] reported that women exposed to DES in utero were found to have less well established sex-partner relationships, and to be lower in sexual desire and enjoyment, sexual excitability, and coital functioning. In addition, Hines and Shipely [45] found that DES-exposed women showed a more masculine pattern of cerebral lateralization on a verbal task than did their sisters.

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