Androgens The first drugs reported to cause fetal masculinization were the androgens
methandriol and
methyltestosterone in the mid-1950s. On June 21, 1976, the
FDA approved the androgen
danazol (Danocrine), a derivative of
ethisterone, for treatment of endometriosis, with a warning that its use in pregnancy is contraindicated because of the risk of masculinization of vulvas of female fetuses. The first case report of fetal masculinization of the vulva of a female infant born to a mother inadvertently treated in pregnancy with danazol was published in 1981. Between 1975 and 1990, the manufacturer of Danocrine,
Winthrop Laboratories, received reports worldwide of 129 pregnant women exposed to danazol, with 94 completed pregnancies and the birth of 57 female infants – 23 (40%) of whom were virilized with a pattern of clitoromegaly, fused labia and urogenital sinus formation, with genital reconstructive surgery usually, but not always, required in childhood. It is likely that the true rate of occurrence is much less than 40%, as many cases with a normal outcome would not be reported. No genital anomalies were reported where danazol therapy was discontinued before the 8th week of pregnancy. The warnings against use of danazol were progressively strengthened in the 1980s. In 1991, the FDA required a
black box warning that use of danazol in pregnancy is contraindicated because exposure to danazol in utero may result in androgenic effects on the female fetus causing vulvar masculinization. The black box warning recommends a sensitive
hCGβ-subunit pregnancy test immediately prior to starting danazol therapy and use of a non-hormonal method of
contraception during therapy. As of 2000, there had been published reports of fetal masculinization of the vulva in: The first case reports of fetal masculinization of vulvas of female infants born to mothers treated in pregnancy with high-dose ethisterone and high-dose norethisterone (17α-ethinyl-19-nortestosterone) to prevent miscarriage were published in 1957 and 1958, respectively. In a March 1960
JAMA article,
pediatric endocrinologist Lawson Wilkins at
Johns Hopkins reported on 34 cases of fetal masculinization of vulvas of female infants born from 1950 to 1959 to mothers treated with high-dose (20–250 mg/day) ethisterone to prevent miscarriage, and 35 cases of fetal masculinization of vulvas of female infants born from 1957 to 1959 to mothers treated with high-dose (10–40 mg/day) norethisterone to prevent miscarriage. In 1961,
Ciba and
Parke-Davis added the reported association of ethisterone and norethisterone with masculinization of the vulva of the female fetus to the precautions section of their advertisements to physicians and physician prescribing information. A clinical trial published in the October 1962
American Journal of Obstetrics and Gynecology reported fetal masculinization of the vulvas of 14 of 59 female infants (24%) born to mothers who began high-dose (10–40 mg/day) norethisterone treatment to prevent miscarriage in the first 12 weeks of pregnancy (11 infants had slight clitoral enlargement, 1 had marked clitoral enlargement, 2 infants had marked clitoral enlargement and partial fusion of the labioscrotal folds); fetal masculinization of the vulvas of 1 of 23 female infants born to mothers who began high-dose (10–40 mg/day) norethisterone treatment to prevent miscarriage after the 12th week of pregnancy (1 infant with slight clitoral enlargement was born to a mother who began norethisterone treatment in week 13). In 1964, Parke-Davis revised the physician prescribing information for
Norlutin (norethisterone) and
Norlutate (norethisterone acetate) to remove their indications for use in infertility, habitual abortion and threatened abortion, and add pregnancy as a contraindication to their use because of the possibility of masculinization of vulvas of the female fetus. In 1977, the FDA determined that there was no adequate evidence that progestogens (including progesterone, dydrogesterone, and 17α-hydroxyprogesterone caproate) were effective in treating threatened abortion or preventing habitual abortion and withdrew approval for those indications. As of 2000, there had been published reports of fetal masculinization of the vulva in: On January 12, 1989, after determining that progestogens did
not cause non-genital birth defects, the FDA published a notice revising the black box warning on all progestogen drugs (except contraceptives) to warn against their use during the first four months of pregnancy because of past reports of genital birth defects (an increased risk of
hypospadias in male fetuses and mild virilization of vulvas in female fetuses). On November 16, 1999, the FDA published a notice effective November 16, 2000
removing (after 22 years) the black box warning on all progestogen drugs because it was unwarranted based on scientific review of current data. ==References==