A New Model for Adrenarche: Inhibition of 3β-Hydroxysteroid Dehydrogenase Type 2 by Intra-Adrenal Cortisol

We propose that the normal adrenarche-related rise in dehydroepiandrosterone (DHEA) secretion is ultimately caused by the rise in cortisol production occurring during childhood and adolescent growth, by the following mechanisms. (1) The onset of childhood growth leads to a slight fall in serum cortisol concentration due to growth-induced dilution and a decrease in the negative feedback of cortisol upon ACTH secretion. (2) In response, ACTH rises and stimulates increased cortisol synthesis and secretion in the growing body to restore the serum cortisol concentration to normal. (3) The cortisol concentration produced within and taken up by adrenocortical steroidogenic cells may rise during this time. (4) Cortisol competitively inhibits 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2)-mediated conversion of 17αOH-pregnenolone to cortisol, causing a further fall in serum cortisol, a further decrease in the negative feedback of cortisol upon ACTH, a further rise in ACTH, and further stimulation of adrenal steroidogenesis. (5) The cortisol-mediated inhibition of 3βHSD2 also blocks the conversion of DHEA to androstenedione, causing a rise in adrenal DHEA and DHEA sulfate relative to androstenedione secretion. Thus, the combination of normal body growth plus inhibition of 3βHSD2 by intra-adrenal cortisol may cause normal adrenarche. Childhood obesity may hasten this process by causing a pathologic increase in body size that triggers these same processes at an earlier age, resulting in the premature onset of adrenarche.