Endocrine Abstracts

There is a marked disparity between the amount of androstenedione (A) excreted in the urine as testosterone (T) glucuronide and the amount of A-T converted in the systemic circulation indicating that there is considerable production of testosterone within the portal circulation which is extracted by the liver. Our studies have examined the hypothesis that intra-abdominal fat is a major source of testosterone production which might contribute to insulin resistance.

The enzyme converting A-T is 17beta hydroxysteroid dehydrogenase (17HSD) of which 7 subtypes have been identified in the human. Type 3 is responsible for A-T conversion in the gonad and peripheral tissues. We have identified this isoform (17HSD-3) in preadipocytes derived from both intra-abdominal and subcutaneous human fat samples. A quantitative multiplex competitive RT-PCR assay was developed which allowed simultaneous assay of both 17HSD-3 and aromatase mRNA and A-T and A-E₁ conversion was compared in cultured preadipocytes. These studies indicated that 17HSD-3 mRNA levels and A-T conversion was substantially greater than aromatase mRNA and A-E ₁ conversion. Moreover, the level of 17HSD-3 mRNA was greater in intra-abdominal than in subcutaneous fat. Increasing central obesity increased the ratio of 17HSD:aromatase in intra-abdominal fat, suggesting that obesity accentuates intra-abdominal testosterone production. Culture of preadipocytes with dibutyryl cAMP confirmed that cyclic AMP-dependent mechanisms exist to mediate the activity of 17HSD-3. In preliminary studies, neither insulin nor LH augmented A-T conversion.

Testosterone has been shown to increase expression of beta adrenergic receptors in adipocytes and activation leads to lipolysis. Increased delivery of free fatty acids to the liver reduces insulin clearance and increases insulin resistance. These studies suggest a mechanism linking central obesity with insulin resistance and dyslipidaemia.