Progestin-induced virilization

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Progestin-induced virilization
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Maternal use of androgens or high doses of certain weakly androgenic synthetic progestogens (progestins) structurally related to testosterone can masculinize (virilize) the vulva of a female fetus during susceptible times in pregnancy. [1] [2]

Contents

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. [1] [2] [3] [4] This can in some cases result in ambiguous genitalia. [1]

Fetal masculinization of the vulva is usually due to enzyme abnormalities involved in adrenal steroid biosynthesis, resulting in congenital adrenal hyperplasia (CAH); fetal masculinization of the vulva is much less frequently due to maternal use of androgenic steroids. [3] [4]

Fetal masculinization of the vulva due to maternal use of androgenic steroids is generally less advanced than that due to CAH, and unlike CAH, does not cause progressive virilization. [5]

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. [5]

Dosage

The incidence of fetal masculinization of the vulva varies with the drug and dosage. [1]

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 (ethinyltestosterone). [1]

Fetal masculinization of the vulva 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. [1]

Progestogens

In general, pregnane derivatives (e.g., progesterone, dydrogesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate) 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., noretynodrel, allylestrenol) that do not. [1]

The only progestogens currently used during pregnancy (e.g., 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, hydroxyprogesterone caproate, dydrogesterone, and allylestrenol. [6]

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. [1] Genital ambiguity due to progestin exposure in pregnancy is thus mostly a topic of historical concern. [1] [6]

History

Androgens

The first drugs reported to cause fetal masculinization were the androgens methandriol and methyltestosterone in the mid-1950s. [5] [7]

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. [8]

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. [9]

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. [10]

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. [11] [12]

As of 2000, there had been published reports of fetal masculinization of the vulva in: [7]

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: noretynodrel (Enovid) and norethisterone (Norlutin) in 1957, medroxyprogesterone acetate (Provera) in 1959, norethisterone acetate (Norlutate) in 1961, and dydrogesterone (Duphaston) in 1962. [13]

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. [14] [15]

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. [16]

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. [17] [18]

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). [19]

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. [20]

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. [21]

As of 2000, there had been published reports of fetal masculinization of the vulva in: [7]

  • 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. [21] [22] [23] [24] [25] [ excessive citations ]

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). [21] [22] [23] [24] [25]

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. [21] [22] [23] [24] [25] [ excessive citations ]

Related Research Articles

<span class="mw-page-title-main">Progestogen</span> Steroid hormone that activates the progesterone receptor

Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. The progestogens are named for their function in maintaining pregnancy, although they are also present at other phases of the estrous and menstrual cycles.

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Danazol</span> Chemical compound

Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. It is taken by mouth.

<span class="mw-page-title-main">Gestrinone</span> Chemical compound

Gestrinone, sold under the brand names Dimetrose and Nemestran among others, is a medication which is used in the treatment of endometriosis. It has also been used to treat other conditions such as uterine fibroids and heavy menstrual bleeding and has been investigated as a method of birth control. Gestrinone is used alone and is not formulated in combination with other medications. It is taken by mouth or in through the vagina.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Dydrogesterone</span> Chemical compound

Dydrogesterone, sold under the brand name Duphaston among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, and as a component of menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Ethisterone</span> Chemical compound

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Hydroxyprogesterone caproate</span> Medication

Hydroxyprogesterone caproate, sold under the brand names Proluton and Makena among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manufacturer, Covis Pharma, agreed to withdraw the drug from the US market. The approvals of Makena and its generics were withdrawn by the US Food and Drug Administration (FDA) in April 2023.

<span class="mw-page-title-main">Dimethisterone</span> Chemical compound

Dimethisterone, formerly sold under the brand names Lutagan and Secrosteron among others, is a progestin medication which was used in birth control pills and in the treatment of gynecological disorders but is now no longer available. It was used both alone and in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Noretynodrel</span> Chemical compound

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">19-Norprogesterone</span> Chemical compound

19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a steroidal progestin and close analogue of the sex hormone progesterone, lacking only the C19 methyl group of that molecule. It was first synthesized in 1944 in the form of a mixture that also included unnatural stereoisomers of progesterone, and this mixture was found to be at least equivalent to progesterone in terms of progestogenic activity. Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. 19-Norprogesterone was resynthesized in 1951 with an improved method, and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the Clauberg assay in rabbits, and at the time of this discovery, 19-norprogesterone was the most potent progestogen known.

<span class="mw-page-title-main">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

<span class="mw-page-title-main">Quingestrone</span> Progestin medication

Quingestrone, also known as progesterone 3-cyclopentyl enol ether (PCPE) and sold under the brand name Enol-Luteovis, is a progestin medication which was previously used in birth control pills in Italy but is now no longer marketed. It is taken by mouth.

<span class="mw-page-title-main">Bromoketoprogesterone</span> Chemical compound

Bromoketoprogesterone (BKP), also known as 9α-bromo-11-oxoprogesterone (BOP), and known by the tentative brand name Braxarone (Squibb), is an orally active progestin which does not appear to have been marketed.

<span class="mw-page-title-main">17α-Allyl-19-nortestosterone</span> Chemical compound

17α-Allyl-19-nortestosterone, also known as 3-ketoallylestrenol or as 17α-allylestr-4-en-17β-ol-3-one, is a progestin which was never marketed. It is a combined derivative of the anabolic–androgenic steroid and progestogen nandrolone (19-nortestosterone) and the antiandrogen allyltestosterone (17α-allyltestosterone). The drug is a major active metabolite of allylestrenol, which is thought to be a prodrug of 17α-allyl-19-nortestosterone.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

References

  1. 1 2 3 4 5 6 7 8 9 Simpson, Joe Leigh; Kaufman, Raymond H. (1998). "Fetal effects of estrogens, progestogens and diethylstilbestrol". In Fraser, Ian S. (ed.). Estrogens and Progestogens in Clinical Practice (3rd ed.). London: Churchill Livingstone. pp. 533–53. ISBN   978-0-443-04706-0.
  2. 1 2 Carson, Sandra A.; Simpson, Joe Leigh (1983). "Virilization of Female Fetuses following Maternal Ingestion of Progestational and Androgenic Steroids". In Mahesh, Virendra B.; Greenblatt, Robert B. (eds.). Hirsutism and Virilism: Pathogenesis, Diagnosis and Management. Boston: John Wright PSG Inc. pp. 177–188. ISBN   978-0-7236-7045-2.
  3. 1 2 Jaffe, Robert B. (2004). "Disorders of Sexual Development". In Strauss, Jerome F.; Barbieri, Robert L. (eds.). Yen and Jaffe's Reproductive Endocrinology : Physiology, Pathophysiology, and Clinical Management (5th ed.). Philadelphia: Elsevier Saunders. pp. 464–491. ISBN   978-0-7216-9546-4.
  4. 1 2 Forest, Maguelone G. (2006). "Diagnosis and Treatment of Disorders of Sexual Development". In DeGroot, Leslie J.; Jameson, J. Larry (eds.). Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp.  2779–829. ISBN   978-0-7216-0376-6.
  5. 1 2 3 Schardein JL (1980). "Congenital abnormalities and hormones during pregnancy: a clinical review". Teratology. 22 (3): 251–70. doi:10.1002/tera.1420220302. PMID   7015547.
  6. 1 2 Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–71. ISBN   978-0-07-142280-2.
  7. 1 2 3 Schardein, James L. (2000). "Hormones and Hormone Antagonists". Chemically Induced Birth Defects (3rd ed.). New York: Marcel Dekker. pp. 281–357. ISBN   978-0-8247-0265-6.
  8. ↑ FDA (2007). "Drug details: Danocrine NDA 017557". search: Danocrine
  9. ↑ Duck SC, Katayama KP (February 1981). "Danazol may cause female pseudohermaphroditism". Fertil Steril. 35 (2): 230–1. doi:10.1016/S0015-0282(16)45329-X. PMID   6781937.
  10. ↑ Brunskill PJ (February 1992). "The effects of fetal exposure to danazol". Br J Obstet Gynaecol. 99 (3): 212–5. doi:10.1111/j.1471-0528.1992.tb14501.x. PMID   1606119. S2CID   73061198.
  11. ↑ Physicians' Desk Reference (46th ed.). Montvale, NJ: Medical Economics. 1992. pp.  2046–7. ISBN   978-1-56363-003-3.
  12. ↑ Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH (May 1, 2002). "Timing of new black box warnings and withdrawals for prescription medications". JAMA . 287 (17): 2215–20. doi: 10.1001/jama.287.17.2215 . PMID   11980521.
  13. ↑ Maisel, Albert Q. (1965). "Saving the Unborn". The Hormone Quest . New York: Random House. pp.  167–81. OCLC   543168.
  14. ↑ Gross RE, Meeker IA Jr (September 1955). "Abnormalities of sexual development; observations from 75 cases". Pediatrics . 16 (3): 303–24. doi:10.1542/peds.16.3.303. PMID   13245336. S2CID   245043061.
  15. ↑ Greenblatt RB, Jungck EC (March 22, 1958). "Delay of menstruation with norethindrone, an orally given progestational compound". JAMA . 166 (12): 1461–3. doi:10.1001/jama.1958.62990120001011. PMID   13513379.
  16. ↑ Wilkins L (March 5, 1960). "Masculinization of female fetus due to use of orally given progestins". JAMA . 172 (10): 1028–32. doi:10.1001/jama.1960.03020100036007. PMID   13844748.
  17. ↑ Jones, John Morgan (1961). Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals (16th ed.). Oradell, NJ: Medical Economics. pp. 575, 750. OCLC   1644681.
  18. ↑ Parke-Davis (June 1961). "Introducing Norlutate...a new oral progestational agent twice as potent as Norlutin". Obstet Gynecol. 17 (6).
  19. ↑ Jacobson BD (October 1, 1962). "Hazards of norethindrone therapy during pregnancy". Am J Obstet Gynecol. 84 (7): 962–8. doi:10.1016/0002-9378(62)90075-3. PMID   14450719.
  20. ↑ Jones, John Morgan (1964). Physicians' Desk Reference to Pharmaceutical Specialties and Biologicals (19th ed.). Oradell, NJ: Medical Economics. p. 815. OCLC   1644681.
  21. 1 2 3 4 FDA (April 3, 1999). "Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Proposed Rule" (PDF). Fed Regist . 64 (70): 17985–8.
  22. 1 2 3 FDA (April 3, 1999). "Physician Labeling and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice" (PDF). Fed Regist . 64 (70): 18035–6.
  23. 1 2 3 FDA (November 16, 1999). "Progestational Drug Products for Human Use; Requirements for Labeling Directed to the Patient. Final Rule" (PDF). Fed Regist . 64 (220): 62110–2.
  24. 1 2 3 FDA (November 16, 1999). "Physician and Patient Labeling for Progestational Drug Products; Warnings and Contraindications. Notice" (PDF). Fed Regist . 64 (220): 62209.
  25. 1 2 3 Brent RL (2005). "Nongenital malformations following exposure to progestational drugs: the last chapter of an erroneous allegation". Birth Defects Research Part A: Clinical and Molecular Teratology. 73 (11): 906–18. doi:10.1002/bdra.20184. PMID   16206282.
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