PEDIATRICS Vol. 62 No. 6 December 1978, pp. 1160-1165
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Effect of Prenatal Estrogen Exposure on Male Genitalia

James L. Mills M.D.1 and Alfred M. Bongiovanni M.D.1

1 Department of Pediatrics, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia

The discovery of adenocarcinoma of the vagina in young women exposed to exogenous estrogens in utero led to a search for similar effects in men. Such studies were difficult because of ascertainment problems and the low incidence of the disorders being investigated. Numerous examinations of cancer registries have demonstrated an increased incidence of cancer of the testis. Secular trends suggest that this increase is not attributable to prenatal estrogen exposure. No history of exposure has been obtained in any patients with genital malignancy in the group at risk. Evaluation of relative risk for congenital malformations in a prospectively ascertained cohort disclosed increased risk for diethylstilbestrol (1.56) and ethinyl estradiol (1.89). The association of estrogen with the broad category of malformations used in this study was minimal. A relative risk of 1.60 for hypospadias was found. However, the numbers were too small to be statistically significant (and no increased risk was found by another investigator). The risk of cardiovascular disease was significantly greater in those exposed to estrogens in utero. This finding was confirmed by a study of congenital heart disease following sex hormone exposure. Four case reports of children exposed to estrogens in utero described external genitalia ranging from normal female to male with hypogonadism. The four cases seemed to have abnormal testes as a common feature. This was also noted in a fetus aborted after exposure to diethylstilbestrol. Responses to a questionnaire led one group to suggest that urethral stenosis is more common following prenatal diethylstilbestrol exposure. Long-term follow-up of men exposed in utero to diethylstilbestrol showed increased incidence of epididymal cysts, hypotrophic testis, and hypoplastic penis. Morphologically abnormal sperm, low ejaculate volume, and low sperm counts were also more common in those exposed to diethylstilbestrol.