Endocrine Abstracts

JOINT3303

Maternal and fetal adrenal derived androgen precursors are trafficked through the placenta throughout human fetal development. Most of these androgen precursors are steroid substrates for the biosynthesis of estrogens in the placenta, which evades harmful androgen excess. The placenta therefore serves as a key organ in the fetal-(adrenal and liver)-placental unit. Androgens in the 11oxy-pathway have recently been profiled in placental tissue, amniotic fluid and in maternal and newborn serum, which underscores their importance during fetal development, but also their potential to cause damage if in excess. Adrenal androgen excess readily occurs in classic congenital adrenal hyperplasia (CAH), with CAH marked by 11oxy-androgen (11OxyA) excess. 11OxyAs are in addition not readily converted to estrogen metabolites. Therefore, the dynamic of 11OxyA metabolism in placental steroidogenesis requires investigation to better understand their role in fetal development, especially in the developing CAH fetus. In this study, 11OxyA metabolism was traced in placental cells models (BeWo and Jeg-3 choriocarcinoma cells), and in healthy term placental S9 fractions and explants. Steroid profiling using liquid chromatography-mass spectrometry enabled the quantification of precursor and downstream steroid metabolites following the addition of steroid substrates (1 µM) after 48 hrs in cells, 24 and 48 hrs in explants, and 15 min in S9 fractions. Looking at the cell models, directional 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) activity was favoured, producing 11-ketoandrostenedione (11KA4). 11KA4 was in turn converted to 11-ketotestosterone (11KT), while the opposite reaction did not readily occur. Conversions in placental S9 fractions showed the rapid metabolism of 11KA4 (92%), similar to the classic- and 16-hydroxy-androgens, however 11KT was not readily metabolised (25%). Furthermore, the 11βHSD2 activity in placental explants firstly converted 11β-hydroxyandrostenedione to 11KA4 (after 24 h), after which 11KT was produced (after 48 h). To summarise, our data show that the placenta is an active 11OxyA metabolising organ, favouring the biosynthesis and metabolism of 11KA4. We show that while 11βHSD2 and aromatase activities normally safeguard the fetus from glucocorticoid and classic androgen excess, these enzymatic activities either ‘activate’ or do not apply to the 11OxyAs, respectively. Therefore, if in excess, as in CAH, the 11OxyAs would be suitable steroid substrates for placental steroidogenesis, potentially producing active metabolites which prevail over classic androgens.