Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract

Abstract

The potential estrogenicity and teratogenicity of triphenylethylene antiestrogens were examined in 54 genital tracts isolated from 4- to 19-week-old human female fetuses and grown for 1 to 2 months in untreated athymic nude mice or host mice treated by subcutaneous pellet with the antiestrogens clomiphene and tamoxifen or the synthetic estrogen diethylstilbestrol (DES). In specimens grown to a gestational age equivalent of 15 weeks or less, the vagina and urogenital sinus were lined by an immature squamous epithelium, which were similar in both drug-treated and untreated specimens. Proliferation and maturation of the squamous vaginal epithelium were observed in specimens treated with clomiphene, tamoxifen, or DES only when grown to a gestational age equivalent of 16 weeks or more. Formation of endometrial and cervical glands proceeded in 87 per cent (13 of 15) of control specimens grown to a gestational age equivalent of 13 weeks or more in untreated hosts. By contrast, age-matched drug-treated specimens contained glands in only 44 per cent (12 of 27) of specimens. In the developing uterine corpus of untreated controls, the uterine mesenchyme segregated into inner (endometrial stroma) and outer (myometrial) layers; whereas in drug-treated specimens, condensation and segregation of the mesenchyme were greatly impaired. The fallopian tube was also affected by clomiphene and tamoxifen (and to a lesser extent by DES) in that its epithelium was hyperplastic and disorganized. The complex mucosal plications characteristic of the fallopian tube were also distorted in drug-treated specimens. These results emphasize the heretofore unrecognized estrogenicity and potential teratogenicity of triphenylethylene antiestrogens on the developing human genital tract and emphasize the need for caution to prevent inadvertent exposure of the developing fetus to these compounds.