Progestin-induced virilisation

Maternal use of androgens or high doses of certain weakly-androgenic synthetic progestogens (progestins) structurally related to testosterone can masculinize (virilize) the external genitalia of a female fetus during susceptible times in pregnancy. cite book |author=Simpson, Joe Leigh; Kaufman, Raymond H. |year=1998 |chapter=Fetal effects of estrogens, progestogens and diethylstilbestrol |editor=Fraser, Ian S. (ed.) |title=Estrogens and Progestogens in Clinical Practice |edition=3rd ed. |location=London |publisher=Churchill Livingstone |pages=pp. 533-53 |isbn=0-443-04706-5] cite book |author=Carson, Sandra A.; Simpson, Joe Leigh |year=1983 |chapter=Virilization of Female Fetuses following Maternal Ingestion of Progestational and Androgenic Steroids |editor=Mahesh, Virendra B.; Greenblatt, Robert B. (eds.) |title=Hirsutism and Virilism: Pathogenesis, Diagnosis and Management |location=Boston |publisher=John Wright PSG Inc. |pages=pp. 177-188 |isbn=0-7236-7045-5]

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. cite book |author=Jaffe, Robert B. |year=2004 |chapter=Disorders of Sexual Development |editor=Strauss, Jerome F.; Barbieri, Robert L. (eds.) |title=Yen and Jaffe's Reproductive Endocrinology : Physiology, Pathophysiology, and Clinical Management |edition=5th ed. |publisher=Elsevier Saunders |location=Philadelphia |isbn=0-7216-9546-9 |pages=pp. 464-491] cite book |author=Forest, Maguelone G. |year=2006 |chapter=Diagnosis and Treatment of Disorders of Sexual Development |editor=DeGroot, Leslie J.; Jameson, J. Larry (eds.) |title=Endocrinology |edition=5th ed. |publisher=Elsevier Saunders |location=Philadelphia |isbn=0-7216-0376-9 |pages=pp. 2779-829] 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 (CAH); 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. cite journal |author=Schardein JL |year=1980 |title=Congenital abnormalities and hormones during pregnancy: a clinical review |journal=Teratology |volume=22 |issue=3 |pages=251–70 |pmid=7015547 |doi=10.1002/tera.1420220302]

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 (17α-ethinyl-testosterone).

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 (progesterone, dydrogesterone, 17α-hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, etc.) do not virilize even in high dose; testosterone derivatives (ethisterone) and 19-nortestosterone (norethisterone, norethisterone acetate, etc.) generally virilize, but there are exceptions (e.g. norethynodrel) that do not.

The only progestogens currently used during pregnancy (for luteal support in IVF protocols or for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth) are: progesterone, 17α-hydroxyprogesterone caproate, and dydrogesterone. cite book |author=Loose, Davis S.; Stancel, George M. |editor=Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.) |year=2006 |chapter=Estrogens and Progestins |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th ed. |pages=pp. 1541-71 |location=New York |publisher=McGraw-Hill |id=ISBN 0-07-142280-3] Doses of 19-nortestosterones required for virilization are 10-20 mg/day, far in excess of that associated with inadvertent contraceptive exposure during pregnancy. Genital ambiguity due to progestogen exposure 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. cite book |author=Schardein, James L. |year=2000 |chapter=Hormones and Hormone Antagonists |title=Chemically Induced Birth Defects |edition=3rd ed. |location=New York |publisher=Marcel Dekker |pages=pp. 281-357 |isbn=0-8247-0265-4]

On June 21, 1976, the FDA approved the androgen danazol ("Danocrine"), a derivative of ethisterone (17α-ethinyl-testosterone), 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. cite web |author=FDA |year=2007 |title=Drug details: Danocrine NDA 017557 |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails search: Danocrine]

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. cite journal |author=Duck SC, Katayama KP |month=February |year=1981 |title=Danazol may cause female pseudohermaphroditism |journal=Fertil Steril |volume=35 |issue=2 |pages=230–1 |pmid=6781937]

Between 1975 and 1990, "Danocrine"'s manufacturer, 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. cite journal |author=Brunskill PJ |month=February |year=1992 |title=The effects of fetal exposure to danazol |journal=Br J Obstet Gynaecol |volume=99 |issue=3 |pages=212–5 |pmid=1606119]

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 hCG-beta-subunit pregnancy test immediately prior to starting danazol therapy and use of a nonhormonal method of contraception during therapy. cite book |author= |year=1992 |title=Physicians' Desk Reference |edition=46th ed. |location=Montvale, NJ |publisher=Medical Economics |isbn=1-56363-003-6 |pages=pp. 2046-7] cite journal |author=Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH |month=May 1, |year=2002 |title=Timing of new black box warnings and withdrawals for prescription medications |journal=JAMA |volume=287 |issue=17 |pages=2215–20 |pmid=11980521 |doi=10.1001/jama.287.17.2215]

As of 2000, there had been published reports of fetal masculinization of female external genitalia in:
* 23 cases associated with danazol (all from inadvertent use from 1975-1990)
* 13 cases associated with methandriol (all from use in the 1950s and 1960s)
* 11 cases associated with methyltestosterone (all from use in the 1950s and 1960s)

Progestogens

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: northynodrel ("Enovid") and norethisterone ("Norlutin") in 1957, medroxyprogesterone acetate ("Provera") in 1959, norethisterone acetate ("Norlutate") in 1961, and dydrogesterone ("Duphaston") in 1962. cite book |author=Maisel, Albert Q. |year=1965 |chapter=Saving the Unborn |title=The Hormone Quest |location=New York |publisher=Random House |pages=pp. 167-81 |oclc=543168]

The first case reports of fetal masculinization of external genitalia of female infants born to mothers treated in pregnancy with high-dose ethisterone (17α-ethinyl-testosterone) and high-dose norethisterone (17α-ethinyl-19-nor-testosterone) to prevent miscarriage were published in 1957 and 1958, respectively. cite journal |author=Gross RE, Meeker IA Jr |month=September |year=1955 |title=Abnormalities of sexual development; observations from 75 cases |journal=Pediatrics |volume=16 |issue=3 |pages=303–24 |pmid=13245336] cite journal |author=Greenblatt RB, Jungck EC |month=March 22, |year=1958 |title=Delay of menstruation with norethindrone, an orally given progestational compound |journal=JAMA |volume=166 |issue=12 |pages=1461–3 |pmid=13513379]

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 (20-250 mg/day) 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 (10-40 mg/day) norethisterone to prevent miscarriage. cite journal |author=Wilkins L |month=March 5, |year=1960 |title=Masculinization of female fetus due to use of orally given progestins |journal=JAMA |volume=172 |issue=10 |pages=1028–32 |pmid=13844748]

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. cite book |author=Jones, John Morgan |year=1961 |title=Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals |edition=16th ed. |location=Oradell, NJ |publisher=Medical Economics |oclc=1644681 |pages=pp. 575, 750] cite journal |author=Parke-Davis |month=June |year=1961 |title=Introducing Norlutate...a new oral progestational agent twice as potent as Norlutin |journal=Obstet Gynecol |volume=17 |issue=6]

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 (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 external genitalia 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). cite journal |author=Jacobson BD |month=October 1, |year=1962 |title=Hazards of norethindrone therapy during pregnancy |journal=Am J Obstet Gynecol |volume=84 |issue=7 |pages=962–8 |pmid=14450719]

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 external genitalia of the female fetus. cite book |author=Jones, John Morgan |year=1964 |title=Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals |edition=19th ed. |location=Oradell, NJ |publisher=Medical Economics |oclc=1644681 |pages=p. 815]

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. cite journal |author=FDA |month=April 3, |year=1999 |title=Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Proposed Rule |journal=Fed Regist |volume=64 |issue=70 |pages=17985–8 |url=http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_register&docid=99-9146-filed.pdf]

As of 2000, there had been published reports of fetal masculinization of female external genitalia in:
* 78 cases associated with ethisterone (all from use in the 1950s and early 1960s to prevent miscarriage)
* 81 cases associated with norethisterone (all from use in the late 1950s and early 1960s to prevent miscarriage)

Past FDA labeling requirements

On July 22, 1977, the FDA published a notice requiring a black box warning on all progestogen drugs (except contraceptives) to warn against their use during the first four months of pregnancy because of reports of non-genital birth defects. cite journal |author=FDA |month=April 3, |year=1999 |title=Physician Labeling and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice |journal=Fed Regist |volume=64 |issue=70 |pages=18035–6 |url=http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_register&docid=99-9147-filed.pdf] cite journal |author=FDA |month=November 16, |year=1999 |title=Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Final Rule |journal=Fed Regist |volume=64 |issue=220 |pages=62110–2 |url=http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_register&docid=99-29854-filed.pdf] cite journal |author=FDA |month=November 16, |year=1999 |title=Physician and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice |journal=Fed Regist |volume=64 |issue=220 |pages=62209 |url=http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_register&docid=99-29855-filed.pdf] cite journal |author=Brent RL |year=2005 |title=Nongenital malformations following exposure to progestational drugs: the last chapter of an erroneous allegation |journal=Birth Defects Res a Clin Mol Teratol |volume=73 |issue=11 |pages=906–18 |pmid=16206282 |doi=10.1002/bdra.20184]

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 the external genitalia 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