Sex, electrons and the adrenal why endocrinology excites
This lecture will cover clinical-experimental and molecular studies elucidating the role and regulation of the adrenal steroid dehydroepiandrosterone (DHEA), a crucial precursor of human sex steroid synthesis. DHEA and its sulphate ester DHEAS are the most abundant steroids in the human circulation and their intraadrenal synthesis represents a recent evolutionary development, only observed in higher mammals. Only humans and higher non-human primates show an age-specific pattern of DHEAS secretion with levels increasing from age 610 years (`adrenarche'), reaching its maximum during the third decade, followed by a gradual decline from middle age onwards (`adrenopause'). Adrenal DHEA serves as the major source for female androgen synthesis and several studies have demonstrated a beneficial role of DHEA replacement in patients with adrenal insufficiency.
Individuals with completely inactivating mutations in the CYP17A1 gene encoding the enzyme responsible for DHEA biosynthesis produce no DHEA and thus no sex steroids at all. Consequently, affected boys present with a female phenotype, 46,XY disordered sex development (46,XY DSD). Recently, a novel form of congenital adrenal hyperplasia, combined CYP17A1 and CYP21A2 deficiency, has been shown to be caused by mutant P450 oxidoreductase (POR), which provides electrons to all microsomal CYP enzymes including CYP17A1 and CYP21A2. While the disruption of DHEA synthesis by mutant POR readily explains 46,XY DSD in some affected boys, the observation of severe virilisation in affected girls, 46,XX DSD, despite low circulating androgens appeared counterintuitive. However, recent studies have provided evidence for the existence of an alternative pathway to androgens in early human life, explaining the development of 46,XX DSD.
DHEA can be inactivated to DHEAS by DHEA sulphotransferase (SULT2A1), thereby preventing the conversion of DHEA to active androgens. SULT2A1 requires the sulphate donor PAPS for catalytic activity. Recent work has identified inactivating mutations in PAPSS2 encoding human PAPS synthase 2 as the cause of androgen excess in a girl with premature pubarche, hyperandrogenic anovulation and undetectable DHEAS. These observations indicate PAPSS2 deficiency as a monogenic cause of androgen excess and highlight the crucial role of DHEA sulphation as a gatekeeper to human androgen synthesis.