Longitudinal serum and urine steroid metabolite profiling in a 46,XY infant with prenatally identified POR deficiency

Ono, Hiroyuki; Numakura, Chikahiko; Homma, Keiko; Hasegawa, Tomonobu; Tsutsumi, Seiji; Kato, Fumiko; Fujisawa, Yasuko; Fukami, Maki; Ogata, Tsutomu

doi:10.1016/j.jsbmb.2017.12.008

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…4 D ). This result corroborates a previous report on urine steroid metabolite excretion in a 46,XY infant affected by PORD, which also described increased 5α-androsterone but unremarkable etiocholanolone excretion (38). Of note, the POR A287P-homozygous patients in our study had higher excretion of 5α-17HP and 5α-androsterone than the compound-heterozygous patient, who can be expected to have less alternative pathway activity due to the greater impairment of residual POR function.…”

Section: Resultssupporting

confidence: 92%

Alternative pathway androgen biosynthesis and human fetal female virilization

Reisch

Taylor

Nogueira

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Resultssupporting

confidence: 92%

Alternative pathway androgen biosynthesis and human fetal female virilization

Reisch

Taylor

Nogueira

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…This result corroborates a previous report on urine steroid metabolite excretion in a 46,XY infant affected by PORD, which also described increased 5α-androsterone but unremarkable etiochaolanolone excretion (38). Of note, the POR A287P homozygous patients in our study had higher excretion of 5α-17HP and 5αandrosterone than the compound heterozygous patient, who can be expected to have less alternative pathway activity due to the greater impairment of residual POR function.…”

Section: Androgen Biosynthesis In Neonates With Congenital Adrenal Hysupporting

confidence: 92%

Alternative pathway androgen biosynthesis and human fetal female virilization

Reisch

Nogueiras

Asby

et al. 2019

Preprint

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Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted towards 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 (adrenal, 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.SIGNIFICANCEIn the classic androgen biosynthesis pathway, testosterone is converted to 5α-dihydrotestosterone, a step crucially required for normal male genital virilization. Congenital adrenal hyperplasia (CAH) due to P450 oxidoreductase deficiency (PORD) is an inborn disorder that disrupts classic androgen biosynthesis. However, some affected girls present with severe genital virilization at birth. We hypothesized that this is explained by a prenatally active, alternative biosynthesis pathway to 5α-dihydrotestosterone. We show that adrenals and genital skin cooperate to produce androgens via the alternative pathway during the major period of human sexual differentiation and that neonates with PORD still produce alternative pathway androgens during the first weeks of life. This indicates that alternative pathway androgen biosynthesis drives prenatal virilization in CAH due to PORD.

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“…4D). This result corroborates a previous report on urine steroid metabolite excretion in a 46,XY infant affected by PORD, which also described increased 5α-androsterone but unremarkable etiocholanolone excretion (38). Of note, the POR A287P-homozygous patients in our study had higher excretion of 5α-17HP and 5α-androsterone than the compound-heterozygous patient, who can be expected to have less alternative pathway activity due to the greater impairment of residual POR function.…”

Section: Androgen Biosynthesis In Neonates With Congenital Adrenalsupporting

confidence: 92%

Alternative pathway androgen biosynthesis and human fetal female virilization

Reisch¹,

Ae²,

Ef³

et al. 2020

ESPE

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Longitudinal serum and urine steroid metabolite profiling in a 46,XY infant with prenatally identified POR deficiency

Cited by 7 publications

References 19 publications

Alternative pathway androgen biosynthesis and human fetal female virilization

Alternative pathway androgen biosynthesis and human fetal female virilization

Alternative pathway androgen biosynthesis and human fetal female virilization

Alternative pathway androgen biosynthesis and human fetal female virilization

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