Progestin-induced virilisation
Encyclopedia
Maternal use of androgen
s or high doses of certain weakly androgenic synthetic
progestogens (progestin
s) structurally related to testosterone
can masculinize (virilize) 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
(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
, 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.
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
.
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.
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.
in the mid 1950s.
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.
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, Danocrines 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.
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.
As of 2000, there had been published reports of fetal masculinization of female external genitalia in:
, 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.
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.
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.
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 (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:
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
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.
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s or high doses of certain weakly androgenic synthetic
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
progestogens (progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s) structurally related to testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
can masculinize (virilize) the external genitalia of a female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
during susceptible times in pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
.
Some degree of fusion of the labioscrotal folds
Labioscrotal folds
The 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 and females the two swellings merge:* In the female, they become the posterior labial commissure...
and urogenital folds and clitoral enlargement
Clitoromegaly
Clitoromegaly is an abnormal enlargement of the clitoris ....
can occur if exposure occurs from the 8th through the 12th week of gestation
Gestational age
Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation age....
, 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
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
steroid biosynthesis
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
, resulting in congenital adrenal hyperplasia
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
(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
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
normally with normal fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
, there is almost total regression of the genital anomaly in cases of simple clitoral enlargement, and in even the most severe cases, surgical
Genital reconstructive surgery
Genital reconstructive surgery refers to surgery performed on the genitalia of infants, children, or adults for the purpose of correcting birth defects or other anatomic abnormalities, or for the purpose of transforming normal genitalia of one sex into genitalia resembling the other...
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 steroidSex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
currently utilized in women that can cause virilization of female fetuses when administered in usually administered doses is the androgen danazol
Danazol
Danazol is a derivative of the synthetic steroid ethisterone, a modified testosterone. Also known as 17alpha-ethinyl testosterone. Before becoming available as a generic drug, Danazol was marketed as Danocrine in the United States. It was approved by the U.S. Food and Drug Administration as the...
, a derivative of ethisterone
Ethisterone
Ethisterone is a progestogen hormone.The first orally active progestin, ethisterone , the 17α-ethynyl analog of testosterone, was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin and marketed in Germany in 1939 as Proluton C...
(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
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
.
Progestogens
In general, pregnanePregnane
Pregnane is, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane and 5β-pregnane ....
derivatives (progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, dydrogesterone
Dydrogesterone
Dydrogesterone is a progestogen hormone. The brand name is Duphaston and manufactured by Abbott .Dydrogesterone was first introduced to the market in 1961, and is currently approved in over 100 countries worldwide...
, 17α-hydroxyprogesterone caproate
17-Hydroxyprogesterone caproate
17α-Hydroxyprogesterone caproate is a synthetic steroid hormone that is similar to medroxyprogesterone acetate and megestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid ....
, medroxyprogesterone acetate, megestrol acetate, etc.) do not virilize even in high dose; testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
derivatives (ethisterone
Ethisterone
Ethisterone is a progestogen hormone.The first orally active progestin, ethisterone , the 17α-ethynyl analog of testosterone, was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin and marketed in Germany in 1939 as Proluton C...
) and 19-nortestosterone (norethisterone
Norethisterone
Norethisterone is a molecule used in some combined oral contraceptive pills, progestogen only pills and is also available as a stand-alone drug...
, norethisterone acetate
Norethindrone acetate
Norethisterone acetate or norethindrone acetate is a progestin used in contraception. It is the acetate ester of norethisterone....
, etc.) generally virilize, but there are exceptions (e.g. norethynodrel
Norethynodrel
Norethynodrel was the progestin used in Enovid, the first oral contraceptive....
) that do not.
The only progestogens currently used during pregnancy (for luteal
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
support in IVF
In vitro fertilisation
In vitro fertilisation is a process by which egg cells are fertilised by sperm outside the body: in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
protocols or for prevention of preterm birth
Premature birth
In humans preterm birth refers to the birth of a baby of less than 37 weeks gestational age. The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging...
in pregnant women with a history of at least one spontaneous preterm birth) are: progesterone, 17α-hydroxyprogesterone caproate, and dydrogesterone.
Doses of 19-nortestosterones required for virilization are 10-20 mg/day, far in excess of that associated with inadvertent contraceptive
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
exposure during pregnancy.
Genital ambiguity due to progestogen exposure is thus mostly a topic of historical concern.
Androgens
The first drugs reported to cause fetal masculinization were the androgens methandriol and methyltestosteroneMethyltestosterone
Methyltestosterone is a 17-alpha-alkylated anabolic steroid used to treat men with a testosterone deficiency. It is also used in women to treat breast cancer, breast pain, swelling due to pregnancy, and with the addition of estrogen it can treat symptoms of menopause...
in the mid 1950s.
On June 21, 1976, the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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.
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, Danocrines manufacturer, Winthrop Laboratories
Sterling Drug
Sterling Drug was a global pharmaceutical company based in the United States, known as Sterling-Winthrop, Inc. after the merger with Winthrop-Stearns Inc. and then as Sterling Winthrop Pharmaceuticals, whose primary product lines included diagnostic imaging...
, 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
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
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
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
-beta-subunit pregnancy test
Pregnancy test
A pregnancy test attempts to determine whether or not a woman is pregnant.These markers are found in urine and blood, and pregnancy tests require sampling one of these substances. The first of these markers to be discovered, human chorionic gonadotropin , was discovered in 1930 to be produced by...
immediately prior to starting danazol therapy and use of a nonhormonal method of contraception
Contraception
Contraception is the prevention of the fusion of gametes during or after sexual activity. The term contraception is a contraction of contra, which means against, and the word conception, meaning fertilization...
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 1975-1990)
- 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)
Past use for prevention of miscarriage
In the 1940s, some studies suggested that progesterone could prevent threatened abortion and might prevent habitual abortionHabitual abortion
Habitual abortion, recurrent miscarriage or recurrent pregnancy loss is the occurrence of three or more pregnancies that end in miscarriage of the fetus, usually before 20 weeks of gestation...
, but oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of progesterone is low and injections of progesterone can be painful, so orally active progestins were tried beginning with ethisterone
Ethisterone
Ethisterone is a progestogen hormone.The first orally active progestin, ethisterone , the 17α-ethynyl analog of testosterone, was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin and marketed in Germany in 1939 as Proluton C...
, 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.
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.
In a March 1960 JAMA
Journal of the American Medical Association
The Journal of the American Medical Association is a weekly, peer-reviewed, medical journal, published by the American Medical Association. Beginning in July 2011, the editor in chief will be Howard C. Bauchner, vice chairman of pediatrics at Boston University’s School of Medicine, replacing ...
article, pediatric endocrinologist
Pediatric endocrinology
Pediatric endocrinology is a medical subspecialty dealing with variations of physical growth and sexual development in childhood, as well as diabetes and other disorders of the endocrine glands....
Lawson Wilkins
Lawson Wilkins
-References:...
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
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
and Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
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 black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
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
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
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.