Virilization of the Female Fetus with Maternal Danazol Exposure

Danazol is a carbon 17-alkylated derivative of ethinyltes-tosterone. It is described as a pituitary-ovarian axis inhibitor with weak androgenic activity. Thirty-six reports of unintended exposure to danazol during pregnancy have come to the attention of the manufacturer and eight others to that of the Food and Drug Administration. Evidence is lacking that any of these pregnancies was started during danazol administration. More likely, therapy was initiated unintentionally after pregnancy was established. Sometimes the instruction to begin therapy during menstruation is not observed. Ovulation bleeding or bleeding early in pregnancy can be confused with menstruation. Seven of the pregnancies terminated in abortion, and the outcome for an additional 14 is not known. Among 22 completed pregnancies, seven male and 15 female offspring were delivered. Of these there were five normal female offspring and 10 of whom had virilization (Table 1). One male had multiple congenital anal formation. All of the mothers were receiving the 800-mg dose, and there was no concurrent administration of other hormones. No case of virilization has been observed in which danazol had been discontinued before the period of androgen receptor sensitivity (from the 8th week of embryogenesis). The time of discontinuation is not known in the reported normal outcomes. Determination of the exact duration of pregnancy, however, is unreliable because of menstrual irregularities in many of these women. None of the female offspring were observed to have abnormalities of the internal genitalia. An ovarian hernia was seen in one case. Transient adrenal-genital syndrome was reported in another. The duration of observation was insufficient to identify long-term effects. Continuation of nonhormonal contraception is recommended during danazol therapy.