Regulation of androgen biosynthesis – A short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model

• Androgen production is well characterized biochemically but its regulation is poorly understood.
• CYP17A1, POR, CYB5, HSD3B2, SULT2A1 and AKR1C3 are specifically involved in androgen production.
• Dys-/regulatory events of androgen synthesis include adrenarche and PCOS.
• Several GCPR and growth factor stimulated signaling pathways regulate androgen synthesis.
• DENNDA1 gene in PCOS and MAPK14 for CYP17 phosphorylation are novel identified androgen modulators.

Regulation of androgen production is poorly understood. Adrenarche is the physiologic event in mid-childhood when the adrenal zona reticularis starts to produce androgens through specific expression of genes for enzymes and cofactors necessary for androgen synthesis. Similarly, expression and activities of same genes and products are deregulated in hyperandrogenic disorders such as the polycystic ovary syndrome (PCOS). Numerous studies revealed involvement of several signaling pathways stimulated through G-protein coupled receptors or growth factors transmitting their effects through cAMP- or non-cAMP-dependent signaling. Overall a complex network regulates androgen synthesis targeting involved genes and proteins at the transcriptional and post-translational levels. Newest players in the field are the DENND1A gene identified in PCOS patients and the MAPK14 which is the kinase phosphorylating CYP17 for enhanced lyase activity. Next generation sequencing studies of PCOS patients and transcriptome analysis of androgen producing tissues or cell models provide newer tools to identify modulators of androgen synthesis.