Androgenic Hormone
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
First trimester in utero exposure of female fetuses to exogenous testosterone or its derivatives causes clitoral hypertrophy, fused or partial fused labia, and, possibly, absent vagina. These varying degrees of masculinization are referred to as nonadrenal female pseudohermaphroditism. Exposure to testosterone hormones at any gestational age is associated with clitoral hypertrophy (1). However, to cause labial–scrotal fusion, exposure must occur before the 10th or 11th fetal week when female differentiation of external genitalia is complete (1). Other than the genital abnormalities, testosterone and its derivatives do not appear to cause structural defects. Only one report of nongenital malformations after testosterone exposure has been published, but this association lacks confirmation. However, a study in monkeys has suggested that long-term potentially permanent changes in the central nervous system of female offspring may result from in utero testosterone exposure. Apparently, this has not been studied in humans. Testosterone and its derivatives are contraindicated at any time during pregnancy.
FETAL RISK SUMMARY
Testosterone is a natural hormone with androgenic and anabolic properties. Testosterone and its derivatives (e.g., methyltestosterone) are primarily indicated as replacement therapy in male hypogonadal disorders secondary to various causes. Preparations of testosterone products are available for oral, buccal, topical, and IM administration. About 80% of testosterone is bound to sex-hormone-binding globulin. Several metabolic pathways of testosterone have been identified, including aromatization to form estrogenic derivatives. The plasma elimination half-life of testosterone is in the range of 10–100 minutes (2). Testosterone rapidly crosses the human placenta to the embryo or fetus (3).
In a 1987 study, testosterone exposure of female rhesus monkeys in utero appeared to have induced irreversible changes in the pattern of luteinizing hormone secretion in adult life (4). Seventeen female monkey pseudohermaphrodites (exposed in utero) and 24 normal females were studied at about 13–14 years of age. All subject and control animals demonstrated evidence of ovulatory menstrual cycles. The 17 monkeys with pseudohermaphroditism had been exposed in utero to testosterone that had resulted in external genital masculinization/obliteration of the external vaginal orifice or clitoromegally alone (degree of genital masculinization was dependent on the timing of exposure). Compared with controls, significant increases in the ratio of luteinizing hormone to follicle-stimulating hormone in the luteal and follicular phases of the ovulatory menstrual cycles were measured in the pseudohermaphrodites (4).
A 1957 report cited several animal studies published in the late 1940s and early 1950s that had demonstrated that administration of testosterone or its derivatives to pregnant animals resulted in masculinization of female fetuses (5). A later report also reviewed the animal data and specifically evaluated the dose and fetal age associated with masculinization of female fetuses (3).
Testosterone and its derivates are contraindicated in pregnancy because they cause virilization of female fetuses (5–16). Two case reports, one in 1953 and another in 1955 (both in German), were the first to describe female pseudohermaphroditism in human infants after exposure to a testosterone derivative (methylandrostenediol; methandriol) (6) or testosterone/methyltestosterone/estradiol (7).
The first English language cases of nonadrenal human female pseudohermaphroditism secondary to maternal use of testosterone were published in 1957. A woman was treated with oral methyltestosterone 20 mg/day for alopecia starting in the 7th week of pregnancy and continuing irregularly until term (total dose 1.5 g) (5). During treatment, the woman noted a deepening voice, hirsutism, and a male-pattern of body hair, as well as partial resolution of her alopecia. Sex of the newborn, which initially appeared to be male, was not established until 7 months of age when the diagnosis of female pseudohermaphroditism was made (5). In the second case, a woman at 10 weeks’ gestation was treated with two doses of testosterone (100 mg IM on day 1 and 3) and 51 days of oral methyltestosterone (30 mg/day) for nausea and vomiting of pregnancy (8). The therapy was discontinued because of the woman’s deepening voice. A 3.4-kg infant was delivered at term who had cyanosis and bradycardia of short duration. Although the sex was ambiguous (small penis, undescended testes), the infant was raised as a male. Detailed examination at 6 months of age revealed the infant to be a female (8).
Other cases have described nonadrenal female pseudohermaphroditism secondary to exposures to methyltestosterone or testosterone, sometimes in combination with estradiol or other estrogens, in the 1st trimester (9–16). In each of these cases, examination of the newborn infant usually revealed a hypoplastic penis, cryptorchidism, and hypospadias. The actual diagnosis of female sex with clitoral hypertrophy, with or without fused labia, and an occasionally absent vagina, was made weeks to months after birth. Surgery was usually required to correct the genital abnormalities. In two cases, the infants had been exposed to methyltestosterone or testosterone during the first 12 or 16 weeks of pregnancy (13,14). They were later diagnosed as females and the genital abnormalities were corrected surgically. In their early 20s, both had normal pregnancies and gave birth to healthy infants (14,15). In another case, the mother received daily oral methyltestosterone from the 14th week until term for breast engorgement (3). In addition, she was given four IM doses of testosterone (total dose 115 mg) between the 14th and 35th weeks of gestation. Except for clitoral hypertrophy, no other signs of virilization were observed in the infant or the mother (3).
The only report of structural defects, other than genital, associated with the use of testosterone appeared in a 1953 article (17). Three infants with limb anomalies had been exposed during the 1st trimester to a combination of testosterone and progesterone.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 26 of whom were exposed to a group of miscellaneous hormones during the 1st trimester (18). Among the 26 cases, 3 were exposed to testosterone, 4 to methandrostenolone, and 1 each to methyltestosterone, fluoxymesterone, and an unspecified male hormone. There were no congenital malformations observed in the 26 exposures (18).
BREASTFEEDING SUMMARY
Testosterone, usually combined with an estrogen, has been used to suppress lactation and to treat postpartum breast pain and engorgement (19–29). Testosterone suppresses lactation apparently by prolactin inhibition (29). Although the amount of testosterone administered was very large, no cases of virilization or other adverse effects attributable to the androgen have been reported. The combination, however, is no longer used because the estrogen–testosterone combination was associated with frequent rebound lactation and an increased incidence of postpartum thromboembolic disease (29).
Although testosterone inhibits prolactin, suckling or any breast manipulation may antagonize the inhibitory effect (21). This has been shown in cases where a mother has received the testosterone–estrogen combination, then changed her mind and breastfed her infant. The amounts of testosterone excreted into milk have apparently not been determined. The absence of reports of adverse effects in nursing infants probably indicates that the short-term exposure is benign. However, the effects from long-term maternal use of testosterone or its derivatives on a nursing infant have not been studied. Therefore, breastfeeding should be halted if these agents are required.
References
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