Reduced androgen activation in peripheral blood mononuclear cells in polycystic ovarian syndrome – a compensatory mechanism for hyperandrogenaemia?

Androgen excess is a key feature of polycystic ovarian syndrome (PCOS). Pre-receptor regulation contributes to this with increased activation of testosterone (T) to 5α-dihydrotestosterone (DHT) by 5α-reductase type 1 (SRD5A1), as we have shown previously in PCOS (Lancet 1990, 335:431; JCE&M 2003, 88:2760). Peripheral blood mononuclear cells (PBMCs) are easily accessible and a useful model for studying pre-receptor regulation in the immune compartment. We have previously shown that PBMCs express SRD5A1 and the androgen receptor (AR) and that SRD5A1 activity is enhanced in age-advanced men (JCE&M 2005, 90:6283). To test the hypothesis whether this represents an adaptive mechanism to the concurrent decrease in circulating androgens, we here sought to analyse SRD5A1 activity in PBMCs from women with PCOS (n=12, age (mean±SEM) 24±1.1yrs, BMI 28±1.5kg/m²) and in healthy controls matched for sex, age and BMI. SRD5A1 activity was assessed in freshly isolated PBMCs by incubation with radiolabelled precursors, measuring the conversion of androstenedione (4-dione) to 5α-androstanedione (5α-dione) and of T to DHT. Global 5α-reductase activity was analysed by measuring the 24-h urinary excretion of 5α-reduced androgen and glucocorticoid metabolites by GC/MS. Circulating 4-dione and free T were significantly higher in PCOS (p<0.001) as were clinical signs of hyperandrogenism (Ferriman-Gallwey score 7.0±1.1 vs. 2.0±0.4, p<0.001). PCOS patients showed an increased urinary excretion of 5α-reduced steroids (p<0.05) confirming systemically enhanced SRD5A1 activity. However by contrast, SRD5A1 activity in PBMCs was significantly decreased in PCOS (4-dione to 5α-dione, p<0.05; T to DHT, p<0.01). These findings suggest that a reduced SRD5A1 activity in PBMCs compensates for increased circulating androgen levels found in PCOS, similar to the converse finding of enhanced SRD5A1 activity in elderly men with a decline in circulating androgens. This might represent an adaptive mechanism that keeps AR activation within lymphocytes at a steady level.