Sex differences in substrates and clearance products of cortisol and corticosterone synthesis in full-term human umbilical circulation without labor: Substrate depletion matches synthesis in males, but not females

Abstract

Background: Antenatal impacts on the hypothalamus- pituitary-adrenal axis affect health throughout later life and the impacts on developing males and females often differ. The female fetus at full-term (sampled as scheduled Caesarian section without antecedent labor) both receives more cortisol in umbilical venous blood and adds more cortisol to umbilical arterial circulation than the male. The current study was designed to expand our knowledge of sex-specific, fetal, adrenal steroid synthesis and clearance pathways.

Methods: Paired, full-term, arterial and venous umbilical cord samples were taken at the time of scheduled Caesarian delivery (N = 53, 33 male). Adrenal glucocorticoids (cortisol, corticosterone), cortisol precursor steroids (17-hydroxyprogesterone, 11-deoxycortisol), and cortisol and corticosterone metabolites (cortisone and 11-dehydrocorticosterone), as well as gonadal steroids (testosterone and androstenedione), were quantified by liquid chromatography coupled to tandem mass spectrometry.

Results: Both sexes preferentially added corticosterone. Males added more testosterone than females. The female fetus had higher umbilical cord (arterial and venous) concentrations of cortisol, as well as higher total steroid molarity summed across the six adrenal steroids, than males. Depletion of substrate pools of 17-hydroxyprogesterone, 11-deoxycortisol, and cortisone could account for only 20% of net female cortisol synthesis. In contrast, increased fetal synthesis of cortisol was balanced by equivalent molar depletion of substrate pools when the fetus was male.

Conclusions: Preferential fetal corticosterone synthesis in both sexes, and higher concentrations of cortisol in females were confirmed. Differences in adrenal steroidogenesis pathway function in full-term males and females might underlie antenatal programming of hypothalamic-pituitary-adrenal axis function in later life.

Keywords: Corticosterone; Cortisol; Elective caesarian section; Fetal steroidogenesis; Sex difference; Testosterone.