Maternal use of

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

s or high doses of certain weakly

androgenic An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This incl ...

synthetic progestogens ( progestins) structurally related to

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

can masculinize (virilize) the

external genitalia A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, a ...

of a

female Female ( symbol: ♀) is the sex of an organism that produces the large non-motile ova (egg cells), the type of gamete (sex cell) that fuses with the male gamete during sexual reproduction. A female has larger gametes than a male. Females ...

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

during susceptible times in

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

. Some degree of fusion of the

labioscrotal folds The labioscrotal swellings (genital swellings or labioscrotal folds) are paired structures in the human embryo that represent the final stage of development of the caudal end of the external genitals before sexual differentiation. In both males a ...

and

urogenital folds The development of the reproductive system is the part of embryonic growth that results in the sex organs and contributes to sexual differentiation. Due to its large overlap with development of the urinary system, the two systems are typically ...

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 Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bin ...

. Fetal masculinization of female external genitalia is usually due to enzyme abnormalities involved in

adrenal The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...

steroid biosynthesis, resulting in

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cort ...

(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. Affected females mature normally with normal

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...

, there is almost total regression of the genital anomaly in cases of simple clitoral enlargement, and in even the most severe cases,

surgical Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

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 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. The use of danazol is limited by masculin ...

, a derivative of

ethisterone 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 gynecologica ...

(ethinyltestosterone). 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 Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally allop ...

derivatives (e.g., progesterone,

dydrogesterone Dydrogesterone, sold under the brand name Duphaston & Dydroboon among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertil ...

hydroxyprogesterone caproate Hydroxyprogesterone caproate (OHPC), sold under the brand names Proluton and Makena among others, is a progestin medication which is used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological diso ...

, medroxyprogesterone acetate,

megestrol acetate Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia.https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/ ...

) do not virilize even in high dose;

derivatives (

) and 19-nortestosterone ( norethisterone,

norethisterone acetate 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 gyn ...

, etc.) generally virilize, but there are exceptions (e.g.,

noretynodrel 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 availa ...

allylestrenol Allylestrenol, sold under the brand names Gestanin and Turinal among others, is a progestin medication which is used to treat recurrent and threatened miscarriage and to prevent premature labor in pregnant women. However, except in the case of p ...

) that do not. The only progestogens currently used during pregnancy (e.g., for luteal support in

IVF In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

protocols or for prevention of

preterm birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...

in pregnant women with a history of at least one spontaneous preterm birth) 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approved the androgen

(Danocrine), a derivative of

, 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. 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. 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 In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

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 A pregnancy test is used to determine whether a female is pregnant or not. The two primary methods are testing for the female pregnancy hormone (human chorionic gonadotropin (hCG)) in blood or urine using a pregnancy test kit, and scanning with ...

immediately prior to starting danazol therapy and use of a non-hormonal method of

contraception Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

during therapy. 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 to 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 Recurrent miscarriage is three or more consecutive pregnancy losses. In contrast, infertility is the inability to conceive. In many cases the cause of RPL is unknown. After three or more losses, a thorough evaluation is recommended by American So ...

, but oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of progesterone is low and injections of progesterone can be painful, so orally active progestins were tried beginning with

, 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. 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 (17α-ethinyl-19-nortestosterone) to prevent miscarriage were published in 1957 and 1958, respectively. In a March 1960 ''

JAMA ''The Journal of the American Medical Association'' (''JAMA'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of biom ...

'' 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. In 1961, Ciba and

Parke-Davis Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although Parke, Davis & Co. is no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history. In 1970 ...

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 (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). 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. 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 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

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. 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 Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...

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

External links

{{Female congenital malformations of genital organs Congenital disorders of female genital organs Intersex variations