P450 oxidoreductase: Novel regulator of steroid synthesis and metabolism in health and disease

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The human adrenal gland produces the hormone dehydroepiandrosterone (DHEA), which is a major precursor for the production of androgens, i.e. active male hormones, in both men and women. Too much androgen in women can cause irregular periods, infertility, acne and increases the risk to diabetes and high blood pressure, summarised by the term polycystic ovary syndrome. This condition affects 5-10% of all women. We have discovered two novel mechanisms that regulate the production and the breakdown, respectively, of DHEA. Patients who have a mutation, i.e. a small spelling error in their genetic code, affecting one of the two factors we have identified, POR and PAPSS2, suffer from androgen excess. Our research will aim to find out by what mechanisms disruption of POR and PAPSS2 causes androgen excess. POR and PAPSS2 also play an important role in regulating the metabolism of drugs and hormones in the liver and thus our research will also give important insights in these mechanisms. Clarification of these two novel regulatory pathways in human physiology and disease carries clear translational potential, i.e. comes with the possibility of applying new knowledge to the development of novel therapies.