ESPE Yearbook of Paediatric Endocrinology

Eur J Endocrinol 2021;185:K7–K11 doi: 10.1530/EJE-21-0312

Brief Summary: Steroid profiling of 10 placentas of healthy full-term neonates (five male and five female) using liquid chromatography-tandem mass spectrometry revealed the presence of C11-oxy C₁₉ steroids (androgens) in the fetal-placental unit at term – pointing to alternative androgen pathways in this unit.

The authors introduced for the first time the relevance of the C11-oxy androgens (also termed 11-oxygenated androgens) in the human placenta, which forms an integral part of the fetal-placental unit. Previously, the adrenal precursor metabolite to C11-oxy androgens, 11β-hydroxyandrostenedione (11OHA4), had been measured only in amniotic fluid between 15–32 weeks post conception [Hampl et al., 1990] and biosynthesised by the fetal adrenal by 16 weeks post conception [Villee and Driscoll 1965; Duffer and Villee 1969]. In this study, 11OHA4, together with 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT) were quantified in term placental tissue taken from the fetal side, in the order of 11KA4 > 11KT > 11OHA4 > 11OHT. The biosynthesis of C11 keto-metabolites in the placenta is expected due to the high expression of placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), however unexpectedly, these authors show that the placenta is an androgen producing organ and underscores that the placenta doesn’t only shuttle steroids from the maternal unit to the fetal unit and back, but contributes to active steroidogenesis. This study is elegantly complemented by a subsequent study which quantified the C11-oxy androgens in neonatal cord blood, once more reporting high levels of 11KA4 [He et al., 2022].

It is worth mentioning that, while 11KT was quantified at lower levels compared to 11KA4, 11KT is a potent androgen and its contribution to human steroid-related diseases and disorders has become increasingly noticeable since 2012. The biosynthesis of this androgen in the fetal-placental unit therefore becomes a focus point for future research endeavours, to determine the role of this androgen in fetal development, with a follow-up research endeavour being unravelling the origin of the C11-oxy androgens in the fetal-placental-maternal unit. Indeed, adrenal 11OHA4 could originate from the fetal adrenal and/or the maternal adrenal (circulation) serving as the precursor to placental 11KA4 and 11KT biosynthesis. As the presence of the C11-oxy androgens has now been established in maternal circulation and in placental and fetal tissues, it becomes clear that the next crucial step will be to determine their impact on human fetal development.

References: 1. Hampl R, Sûlcová J, Zwinger A, Stárka L. 11β-Hydroxyandrostenedione in human amniotic fluid. Exp. Clin. Endocrinol. 1990;96(3):325–327, DOI: doi.org/10.1055/s-0029-1211028. 2. Villee DB, Driscoll SG. Pregnenolone and progesterone metabolism in human adrenals from twin female fetuses. Endocrinology. 1965;77(4):602, DOI: 10.1210/endo-77-4-602. 3. Dufau ML, Villee DB. Aldosterone biosynthesis by human fetal adrenal in vitro. Biochem. Biophys. Acta. 1969;176:637–640, https://doi.org/10.1016/0005-2760(69)90232-X.4. He X, Banker M, Puttabyatappa M, Padmanabhan V, Auchus RJ. Maternal 11-ketoandrostenedione rises through normal pregnancy and is the dominant 11-oxygenated androgen in cord blood. J Clin Endocrinol Metab. 2022;107(3):660–667, DOI: 10.1210/clinem/dgab793.