Endocrine Abstracts

Dehydroepiandrosterone (DHEA) is the crucial androgen precursor and hyperandrogenaemia is a major feature in Polycystic Ovary Syndrome (PCOS). DHEA sulfate (DHEAS) is generated from DHEA by DHEA sulfotransferase (SULT2A1) activity. The conversion of DHEAS to DHEA by steroid sulfatase has been reported to be of minor significance in human adults and only desulfated DHEA can be converted toward androgens. Therefore, SULT2A1 activity represents the rate-limiting step regulating the ratio of biologically active DHEA and inactive DHEAS. Here we have measured serum DHEA and DHEAS in PCOS patients (n=89; age range 18-44 years) and controls (n=47; 19-45 yrs). In PCOS patients we also analyzed urinary DHEA excretion by GC/MS and sequenced the coding region of the SULT2A1 gene. Serum analysis identified a distinct PCOS subgroup characterized by normal DHEAS but high DHEA (>50 nmol/l, i.e. >90th percentile of controls) with an increased DHEA/DHEAS ratio (>7.5, i.e. >90th percentile of controls). Serum DHEAS in this subgroup (n=25) did not differ from the remaining PCOS cohort (n=64) or controls. However, this subgroup had significantly higher DHEA levels (86.5plusminus32.7 nmol/l) than other PCOS patients (n=64; 36.2plusminus13.7 nmol/l) or controls (33.2plusminus19.0 nmol/l) (all p<0.0001). Similarly, the DHEA/DHEAS ratio was significantly higher in the subgroup than in other PCOS patients or controls (all p<0.0001). Serum ADG, a marker of peripheral androgen generation, was higher in the subgroup than in controls (p<0.05) while remaining PCOS and controls did not differ significantly. Furthermore, urinary DHEA excretion was higher in the PCOS subgroup than in other PCOS patients (3800plusminus2245 vs. 670plusminus420 μg/24h, p<0.001). Sequencing of the SULT2A1 coding region did not reveal mutations other than two intronic SNPs occurring with similar frequency in both PCOS groups. Our findings indicate that a defect in the DHEA/DHEAS shuttle will be the culprit driving hyperandrogenism and disease in a distinct PCOS subgroup.