Progestin-induced virilisation 2762783 215347093 2008-05-27T20:17:05Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. Maternal use of [[androgen]]s or high doses of certain weakly-androgenic [[chemical synthesis|synthetic]] [[progestogen]]s ([[progestin]]s) structurally related to [[testosterone]] can [[Virilization#Prenatal virilization|masculinize]] (virilize) the [[external genitalia]] of a [[female]] [[fetus]] during susceptible times in [[pregnancy]].<!-- --><ref name="Simpson 1998">{{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}}</ref><!-- --><ref name="Carson 1983">{{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}}</ref> Some degree of fusion of the [[labioscrotal folds]] and [[urogenital folds]] and [[clitoromegaly|clitoral enlargement]] can occur if exposure occurs from the 8th through the 12th week of [[gestational age|gestation]], but only clitoral enlargement can occur if exposure occurs after the 12th week.<!-- --><ref name="Simpson 1998"/><!-- --><ref name="Carson 1983"/><!-- --><ref name="Jaffe 2004">{{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}}</ref><!-- --><ref name="Forest 2006">{{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}}</ref> This can in some cases result in [[ambiguous genitalia]].<!-- --><ref name="Simpson 1998"/> Fetal masculinization of female external genitalia is usually due to enzyme abnormalities involved in [[adrenal cortex|adrenal]] [[steroid hormone|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.<!-- --><ref name="Jaffe 2004"/><!-- --><ref name="Forest 2006"/> 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.<!-- --><ref name="Schardein 1980">{{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}}</ref> Affected females [[puberty|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, [[genital reconstructive surgery|surgical]] correction of labioscrotal fusion is relatively simple.<!-- --><ref name="Schardein 1980"/> == Dosage == The incidence of fetal masculinization of female external genitalia varies with the drug and dosage.<!-- --><ref name="Simpson 1998"/> === 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).<!-- --><ref name="Simpson 1998"/> 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]].<!-- --><ref name="Simpson 1998"/> === Progestogens === In general, [[pregnane]] derivatives ([[progesterone]], [[dydrogesterone]], [[17-Hydroxyprogesterone caproate|17α-hydroxyprogesterone caproate]], [[medroxyprogesterone acetate]], [[megestrol acetate]], etc.) do not virilize even in high dose; [[testosterone]] derivatives ([[ethisterone]]) and 19-nortestosterone ([[norethisterone]], [[norethindrone acetate|norethisterone acetate]], etc.) generally virilize, but there are exceptions (e.g. [[norethynodrel]]) that do not.<!-- --><ref name="Simpson 1998"/> The only progestogens currently used during pregnancy (for [[corpus luteum|luteal]] support in [[in vitro fertilisation|IVF]] protocols or for prevention of [[premature birth|preterm birth]] in pregnant women with a history of at least one spontaneous preterm birth) are: progesterone, 17α-hydroxyprogesterone caproate, and dydrogesterone.<!-- --><ref name="Loose 2006">{{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}}</ref> Doses of 19-nortestosterones required for virilization are 10-20 mg/day, far in excess of that associated with inadvertent [[hormonal contraception|contraceptive]] exposure during pregnancy.<!-- --><ref name="Simpson 1998"/> Genital ambiguity due to progestogen exposure is thus mostly a topic of historical concern.<!-- --><ref name="Simpson 1998"/><!-- --><ref name="Loose 2006"/> == History == === Androgens === The first drugs reported to cause fetal masculinization were the androgens methandriol and [[methyltestosterone]] in the mid 1950s.<!-- --><ref name="Schardein 1980"/><!-- --><ref name="Schardein 2000">{{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}}</ref> On June 21, 1976, the [[Food and Drug Administration|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.<!-- --><ref name="Danocrine 1976">{{cite web |author=[[Food and Drug Administration|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</ref> 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.<!-- --><ref name="Duck 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}}</ref> Between 1975 and 1990, ''Danocrine'''s manufacturer, [[Sterling Drug|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.<!-- --><ref name="Brunskill 1992">{{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}}</ref> 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 [[human chorionic gonadotropin|hCG]]-beta-subunit [[pregnancy test]] immediately prior to starting danazol therapy and use of a nonhormonal method of [[contraception]] during therapy.<!-- --><ref name="PDR 46">{{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}}</ref><!-- --><ref name="Lasser 2002">{{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=[[Journal of the American Medical Association|JAMA]] |volume=287 |issue=17 |pages=2215–20 |pmid=11980521 |doi=10.1001/jama.287.17.2215}}</ref> As of 2000, there had been published reports of fetal masculinization of female external genitalia in:<!-- --><ref name="Schardein 2000"/> * 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 [[Miscarriage#Forms and types|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.<!-- --><ref name="Maisel 1965">{{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}}</ref> 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.<!-- --><ref name="Gross 1955">{{cite journal |author=Gross RE, Meeker IA Jr |month=September |year=1955 |title=Abnormalities of sexual development; observations from 75 cases |journal=[[Pediatrics (journal)|Pediatrics]] |volume=16 |issue=3 |pages=303–24 |pmid=13245336}}</ref><!-- --><ref name="Greenblatt 1958">{{cite journal |author=Greenblatt RB, Jungck EC |month=March 22, |year=1958 |title=Delay of menstruation with norethindrone, an orally given progestational compound |journal=[[Journal of the American Medical Association|JAMA]] |volume=166 |issue=12 |pages=1461–3 |pmid=13513379}}</ref> In a March 1960 ''[[Journal of the American Medical Association|JAMA]]'' article, [[pediatric endocrinology|pediatric endocrinologist]] Lawson Wilkins at [[Johns Hopkins University School of Medicine|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.<!-- --><ref name="Wilkins 1960">{{cite journal |author=Wilkins L |month=March 5, |year=1960 |title=Masculinization of female fetus due to use of orally given progestins |journal=[[Journal of the American Medical Association|JAMA]] |volume=172 |issue=10 |pages=1028–32 |pmid=13844748}}</ref> In 1961, [[Novartis|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.<!-- --><ref name="PDR 16">{{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}}</ref><!-- --><ref name="Norlutate 1961">{{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}}</ref> 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).<!-- --><ref name="Jacobson 1962">{{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}}</ref> 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.<!-- --><ref name="PDR 19">{{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}}</ref> 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.<!-- --><ref name="FDA 1999a">{{cite journal |author=[[Food and Drug Administration|FDA]] |month=April 3, |year=1999 |title=Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Proposed Rule |journal=[[Federal Register|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}}</ref> As of 2000, there had been published reports of fetal masculinization of female external genitalia in:<!-- --><ref name="Schardein 2000"/> * 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.<!-- --><ref name="FDA 1999a"/><!-- --><ref name="FDA 1999b">{{cite journal |author=[[Food and Drug Administration|FDA]] |month=April 3, |year=1999 |title=Physician Labeling and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice |journal=[[Federal Register|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}}</ref><!-- --><ref name="FDA 1999c">{{cite journal |author=[[Food and Drug Administration|FDA]] |month=November 16, |year=1999 |title=Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Final Rule |journal=[[Federal Register|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}}</ref><!-- --><ref name="FDA 1999d">{{cite journal |author=[[Food and Drug Administration|FDA]] |month=November 16, |year=1999 |title=Physician and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice |journal=[[Federal Register|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}}</ref><!-- --><ref name="Brent 2005">{{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}}</ref> 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).<!-- --><ref name="FDA 1999a"/><!-- --><ref name="FDA 1999b"/><!-- --><ref name="FDA 1999c"/><!-- --><ref name="FDA 1999d"/><!-- --><ref name="Brent 2005"/> 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.<!-- --><ref name="FDA 1999a"/><!-- --><ref name="FDA 1999b"/><!-- --><ref name="FDA 1999c"/><!-- --><ref name="FDA 1999d"/><!-- --><ref name="Brent 2005"/> == References == {{reflist|2}} [[Category:Intersexuality]]