Landscape of Steroid Dynamics in Pregnancy: Insights From the Maternal-Placental-Fetal Unit and Placental Models

Recent advances in analytical methods have revolutionized our understanding of steroid biochemistry. The emergence of novel steroids such as 11-oxy androgens and 11-oxy progesterones has necessitated a reevaluation of steroid biosynthesis and metabolism within the maternal-placental-fetal unit. In this study, we employed a validated liquid chromatography high-resolution mass spectrometry method to quantify 51 steroids in paired maternal serum, neonatal serum, and placenta samples from 37 healthy pregnancies. Additionally, we characterized steroid release in various placental models, including human placenta perfusion, explants, and primary trophoblast cells isolated from human term placenta. Our findings emphasize the predominance of keto derivatives of androgens in the placenta compared to hydroxylated forms, which are dominant in maternal serum and neonatal serum. We also observed high levels of classic and novel progesterones in the placenta and across all models, with significant release on the maternal side. These results suggest that the placenta possesses an active enzymatic machinery capable of producing and metabolizing novel progesterones. Furthermore, we demonstrated that the catalytic activity of 11β-hydroxysteroid dehydrogenase type 2 extends beyond cortisol regulation to hydroxylated androgens, highlighting its significance in the broader context of steroid metabolism within the maternal-placental-fetal unit. These findings contribute to our understanding of placental physiology and impact on fetal development.