Endocrine Abstracts

Insulin resistance and androgen excess are the cardinal features of polycystic ovary syndrome (PCOS). The severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated but the underlying mechanisms are poorly understood. Aldoketoreductase type 1C3 (AKR1C3) is an important source of adipose androgen generation (converting androstenedione to testosterone) and we have postulated that it may have a critical role linking androgen metabolism and metabolic phenotype in PCOS.

Ten patients with PCOS, three with insulin receptor (INSR) mutations and ten control patients underwent oral DHEA challenge with concomitant adipose tissue microdialysis. Serum and adipose androgens, and adipose glycerol levels, were sampled every 30 minutes for 4 h. In parallel, adipose androgen generation (measured using LC/MS-MS), was studied using primary cultures of human adipocytes and the preadipocyte SGBS cell line. The impact of androgens upon metabolic adipocyte phenotype was assessed through measurement of adipose lipogenesis, free fatty acid uptake (FFA) and β-oxidation.

After oral DHEA, area under curve (AUC) for serum testosterone (T) was higher in PCOS patients than controls, but highest in patients with INSR mutations, suggesting enhanced AKR1C3 activity. Adipose dihydrotestosterone (DHT) was detectable in adipose interstitial fluid and was higher in PCOS patients than controls. Furthermore, adipose tissue interstitial glycerol levels were decreased in PCOS patients. Subcutaneous adipose AKR1C3 mRNA expression correlated strongly with BMI. In human adipocytes, insulin up-regulated AKR1C3 expression and activity. T increased de novo lipogenesis, while both T and DHT increased FFA uptake and suppressed β-oxidation.

Hyperinsulinaemia may drive adipose androgen generation through increased expression and activity of AKR1C3, with consequences for adipocyte function, driving lipogenesis and increasing free fatty acid uptake. Resultant adipocyte hypertrophy could lead to increased insulin resistance, fuelling a vicious circle of hyperinsulinaemia, adipose androgen generation and increased lipid accumulation.

Disclosure: This work was supported by the Wellcome Trust (Clinical Research Training Fellowship 099909 to Dr. Michael O’Reilly).