Androgens are precursors for sex
steroids and are predominantly produced in the human gonads and the adrenal cortex. They are important for intrauterine and postnatal sexual development and human reproduction. Although human
androgen biosynthesis has been extensively studied in the past, exact mechanisms underlying the regulation of
androgen production in health and disease remain vague. Here, the knowledge on human
androgen biosynthesis and regulation is reviewed with a special focus on human adrenal
androgen production and the hyperandrogenic disorder of
polycystic ovary syndrome (PCOS). Since human
androgen regulation is highly specific without a good animal model, most studies are performed on patients harboring inborn errors of
androgen biosynthesis, on human
biomaterials and human (
tumor) cell models. In the past, most studies used a candidate gene approach while newer studies use high throughput technologies to identify novel regulators of
androgen biosynthesis. Using genome wide association studies on cohorts of patients, novel PCOS candidate genes have been recently described. Variant 2 of the DENND1A gene was found overexpressed in PCOS theca cells and confirmed to enhance
androgen production. Transcriptome profiling of dissected adrenal zones established a role for BMP4 in
androgen synthesis. Similarly, transcriptome analysis of human adrenal NCI-H295 cells identified novel regulators of
androgen production.
Kinase p38α (
MAPK14) was found to phosphorylate
CYP17 for enhanced
17,20 lyase activity and RARB and ANGPTL1 were detected in novel networks regulating
androgens. The discovery of novel players for
androgen biosynthesis is of clinical significance as it provides targets for diagnostic and
therapeutic use.