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 underlying mechanisms remain poorly understood. Aldoketoreductase type 1C3 (AKR1C3) is an important source of adipose androgen generation, activating androstenedione to testosterone (T). We postulated that AKR1C3 plays a critical role linking androgen metabolism and metabolic phenotype in PCOS.

We undertook in vivo deep phenotyping in ten women with PCOS and ten age/BMI-matched controls. Patients underwent oral challenge with 100mg of the androgen precursor dehydroepiandrosterone, with serum sampling every 30 min for 4 h and concomitant adipose microdialysis. Serum and adipose microdialysate androgens were measured by LC/MS. In complementary ex vivo and in vivo studies, we investigated adipose androgen generation, employing primary cultures of human adipocytes and the preadipocyte cell line SGBS. The impact of androgens upon adipose lipid metabolism was assessed through measurement of de novo lipogenesis, free fatty acid uptake (FFA) and β-oxidation.

After oral DHEA, area under the curve for serum T was higher in PCOS patients than controls, suggesting enhanced AKR1C3 activity. 5α-dihydrotestosterone (DHT) was detectable in adipose interstitial fluid and was higher in PCOS than controls. Adipose interstitial glycerol levels were reduced in PCOS patients. Subcutaneous adipose AKR1C3 mRNA expression correlated strongly with BMI. In human adipocytes, insulin up-regulated AKR1C3 expression and activity, while T increased de novo lipogenesis; both T and DHT increased FFA uptake and suppressed β-oxidation.

Here we provide integrated in vivo, ex vivo, and in vitro evidence that hyperinsulinaemia may drive adipose androgen generation through increased AKR1C3 expression and activity. This may have consequences for adipocyte function by driving lipid accumulation. Resultant adipocyte hypertrophy in PCOS 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 Wellcome Trust Clinical Research Training Fellowship (099909) to Dr Michael O’Reilly.