Adrenal steroids, which include corticosteroids (glucocorticoids like cortisol and mineralocorticoids like aldosterone), and adrenal androgens such as androstenedione (A4), play an important role in regulating electrolyte and water levels in the kidneys. Originally thought of having marginal biological significance, the 11-oxygenated androgens are increasingly recognized as potent steroids with significant roles in human health and disease, particularly in disorders associated with androgen excess or androgen dependence such as polycystic ovary syndrome, congenital adrenal hyperplasia and castration-resistant prostate cancer.
We constructed a detailed mathematical model for the interconversion of the oxygenated androgens (11-hydroxyandrostenedione, 11OHA4; 11-ketoandrostenedione, 11KA4; 11-ketotestoterone, 11KT; 11-hydroxytestosterone, 11OHT) based on in vitro kinetics of the individual enzymes (11-hydroxysteroid dehydrogenase type 2, HSD11B2; aldo-keto reductase type 1C3, AKR1C3; 11-hydroxysteroid dehydrogenase type 1, HSD11B1; and 17-hydroxysteroid dehydrogenase type 2, HSD17B2) and validated the model with experimental data for reconstituted systems with varying enzyme levels at the cellular level, and with inhibitor titrations of HSD11B1 in adipose tissue using the Astra-Zenica drug AZD4017.
We subsequently used the model to analyze clinical data of Chronic Kidney Disease (CKD), and PolyCystic Ovary Syndrome (PCOS) patients, in terms of relative expression levels of the four enzymes, based on plasma concentrations of the oxygenated steroids. For the CKD patients the different disease states could be described by varying HSD11B2 while keeping the other enzymes at the healthy control group values. Interestingly the estimated HSD11B2 levels correlated proportionally to the independent clinically measured eGFR values (estimated Glomerular Filtration Rate), normally used for evaluation of kidney function. The PCOS clinical data could be well described by adapting the AKR1C3 expression (together with a smaller adjustment of HSD17B2, and the implicit total androgen levels). Model simulations showed that an inhibition of AKR1C3 could bring the oxygenated androgens back to wild type levels.