Cortisol Stimulates Secretion of Dehydroepiandrosterone in Human Adrenocortical Cells Through Inhibition of 3βHSD2

Context: Initiating factors leading to production of adrenal androgens are poorly defined. Cortisol is present in high concentrations within the adrenal gland, and its production rises with growth during childhood. Objective: Our aim was to characterize the effect of cortisol and other glucocorticoids on androgen secretion from a human adrenocortical cell line and from nonadrenal cells transfected with CYP17A1 or HSD3B2. Design/Setting: This study was performed in cultured cells, at an academic medical center. Methods: The effects of cortisol upon steroid production in human adrenal NCI-H295R cells were measured by immunoassay, tandem mass spectrometry, and thin-layer chromatography. The effects of cortisol upon the activities of 17, 20 lyase and 3βHSD2 were measured in NCI-H295R cells and in transfected COS-7 cells. Results: Cortisol markedly and rapidly stimulated dehydroepiandrosterone (DHEA) in a dose-dependent manner at cortisol concentrations ≥50 μm. Cortisone and 11-deoxycortisol were also potent stimulators of DHEA secretion, whereas prednisolone and dexamethasone were not. Treatment with cortisol did not affect expression of CYP17A1 or HSD3B2 mRNAs. Stimulation of DHEA secretion by cortisol was associated with competitive inhibition of 3βHSD2 activity. Conclusions: Cortisol inhibits 3βHSD2 activity in adrenal cells and in COS-7 cells transfected with HSD3B2. Thus, it is possible that intraadrenal cortisol may participate in the regulation of adrenal DHEA secretion through inhibition of 3βHSD2. We hypothesize that a rise in intraadrenal cortisol during childhood growth may lead to inhibition of 3βHSD2 activity and contribute to the initiation of adrenarche.