Insulin resistance and androgen excess are the cardinal features of polycystic ovary syndrome (PCOS). Severity of hyperandrogenism and metabolic dysfunction in PCOS are closely correlated, but underlying mechanisms remain poorly understood. Aldoketoreductase type 1C3 (AKR1C3) is a key 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 100 mg of the androgen precursor DHEA, with serum sampling every 30 min for 4 h and concomitant adipose microdialysis. Androgens in serum and adipose microdialysate were measured by tandem mass spectrometry. Non-targeted serum metabolomics analysis was performed pre- and post-DHEA. In complementary ex vivo and in vitro studies, we investigated adipose androgen generation, employing primary human adipocyte culture and the preadipocyte SGBS cell line. The impact of androgens upon adipose lipid metabolism was assessed through measurement of de novo lipogenesis, free fatty acid (FFA) uptake and β-oxidation.
At baseline, 5α-dihydrotestosterone (DHT) was detectable in PCOS adipose interstitial fluid but not in controls. After DHEA, adipose tissue DHT increased significantly (P=0.04); adipose glycerol levels decreased in PCOS more than in controls (P=0.04 for AUC), indicative of suppression of lipolysis. Serum metabolomics indicated significant upregulation of lipid and catabolic metabolism in PCOS. Subcutaneous adipose AKR1C3 mRNA expression correlated with BMI (P<0.001). In human adipocytes, insulin up-regulated AKR1C3 expression and activity, while DHT increased de novo lipogenesis and suppressed β-oxidation (P=0.03 for both).
Here we provide integrated in vivo, ex vivo, and in vitro evidence that insulin drives adipose androgen generation through increased AKR1C3 expression and activity, fuelling a vicious circle of hyperinsulinaemia, adipose androgen generation and lipid accumulation. This identifies AKR1C3 as a promising therapeutic target in PCOS.