Abstract
Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.
Highlights
Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation
Disorders affecting adrenal steroidogenesis commonly affect sexual differentiation, as exemplified by the multiple variants of congenital adrenal hyperplasia (CAH), which result either in inappropriate or disrupted androgen biosynthesis. This causes disorders of sex development (DSDs), which can manifest with external genital virilization in newborn girls (46,XX DSD) or undermasculinization of external genitalia in male neonates (46,XY DSD) [9]
Explant incubations with female tissue showed that some 17OHP entered the classic androgen biosynthesis pathway, yielding androstenedione in adrenal, ovary, and genital skin
Summary
Disorders affecting adrenal steroidogenesis commonly affect sexual differentiation, as exemplified by the multiple variants of congenital adrenal hyperplasia (CAH), which result either in inappropriate or disrupted androgen biosynthesis This causes disorders of sex development (DSDs), which can manifest with external genital virilization in newborn girls (46,XX DSD) or undermasculinization of external genitalia in male neonates (46,XY DSD) [9]. An explanation for this striking and seemingly contradictory genital phenotype in PORD has been lacking We hypothesized that this apparent paradox could be explained by the existence of an alternative pathway to androgen production that generates DHT from 17α-hydroxyprogesterone (17OHP) during human fetal sexual differentiation, thereby bypassing the classic androgen biosynthesis pathway via DHEA and testosterone, as previously proposed by us [11] and others [13, 14].
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