Progestin-induced virilization


Maternal use of androgens or high doses of certain weakly androgenic synthetic progestogens structurally related to testosterone can masculinize the external genitalia of a female fetus during susceptible times in pregnancy.
Some degree of fusion of the labioscrotal folds and urogenital folds and clitoral enlargement can occur if exposure occurs from the 8th through the 12th week of gestation, but only clitoral enlargement can occur if exposure occurs after the 12th week. This can in some cases result in ambiguous genitalia.
Fetal masculinization of female external genitalia is usually due to enzyme abnormalities involved in adrenal steroid biosynthesis, resulting in congenital adrenal hyperplasia ; fetal masculinization of female external genitalia is much less frequently due to maternal use of androgenic steroids.
Fetal masculinization of female external genitalia due to maternal use of androgenic steroids is generally less advanced than that due to CAH, and unlike CAH, does not cause progressive virilization.
Affected females mature normally with normal fertility, there is almost total regression of the genital anomaly in cases of simple clitoral enlargement, and in even the most severe cases, surgical correction of labioscrotal fusion is relatively simple.

Dosage

The incidence of fetal masculinization of female external genitalia varies with the drug and dosage.

Androgens

The only sex steroid currently utilized in women that can cause virilization of female fetuses when administered in usually administered doses is the androgen danazol, a derivative of ethisterone.
Fetal masculinization of female external genitalia has resulted from doses of danazol as low as 200 mg/day, whereas 800 mg/day is the usual initial dose when danazol is used to treat severe endometriosis.

Progestogens

In general, pregnane derivatives do not virilize even in high dose; testosterone derivatives and 19-nortestosterone generally virilize, but there are exceptions that do not.
The only progestogens currently used during pregnancy are: progesterone, hydroxyprogesterone caproate, dydrogesterone, and allylestrenol.
Doses of 19-nortestosterones required for virilization are 10 to 20 mg/day, far in excess of those associated with inadvertent contraceptive exposure during pregnancy. Genital ambiguity due to progestin exposure in pregnancy is thus mostly a topic of historical concern.

History

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, 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 external genitalia of female fetuses.
The first case report of fetal masculinization of the external genitalia 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 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 external genitalia 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 female external genitalia in:

Past use for prevention of miscarriage

In the 1940s, some studies suggested that progesterone could prevent threatened abortion and might prevent habitual abortion, but oral bioavailability of progesterone is low and injections of progesterone can be painful, so orally active progestins were tried beginning with ethisterone, followed by other progestins as they became available: noretynodrel and norethisterone in 1957, medroxyprogesterone acetate in 1959, norethisterone acetate in 1961, and dydrogesterone in 1962.
The first case reports of fetal masculinization of external genitalia of female infants born to mothers treated in pregnancy with high-dose ethisterone and high-dose norethisterone 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 external genitalia of female infants born from 1950 to 1959 to mothers treated with high-dose ethisterone to prevent miscarriage, and 35 cases of fetal masculinization of external genitalia of female infants born from 1957 to 1959 to mothers treated with high-dose norethisterone to prevent miscarriage.
In 1961, Ciba and Parke-Davis added the reported association of ethisterone and norethisterone with masculinization of external genitalia 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 external genitalia of 14 of 59 female infants born to mothers who began high-dose norethisterone treatment to prevent miscarriage in the first 12 weeks of pregnancy ; fetal masculinization of external genitalia of 1 of 23 female infants born to mothers who began high-dose norethisterone treatment to prevent miscarriage after the 12th week of pregnancy.
In 1964, Parke-Davis revised the physician prescribing information for Norlutin and Norlutate 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 external genitalia of the female fetus.
In 1977, the FDA determined that there was no adequate evidence that progestogens 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 female external genitalia in:
On July 22, 1977, the FDA published a notice requiring a black box warning on all progestogen drugs to warn against their use during the first four months of pregnancy because of reports of non-genital birth defects.
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 to warn against their use during the first four months of pregnancy because of past reports of genital birth defects.
On November 16, 1999, the FDA published a notice effective November 16, 2000 removing the black box warning on all progestogen drugs because it was unwarranted based on scientific review of current data.