The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome

Objective: Hyperandrogenism is a central feature of the polycystic ovary syndrome (PCOS) and might worsen insulin resistance (IR) often seen in PCOS. Androgens act through the androgen receptor (AR). A polymorphic CAG repeat sequence within the AR gene was reported to modulate its transactivation activity. Therefore, we investigated a putative interaction between testosterone and the CAG repeat length polymorphism with respect to IR. Design: In 63 PCOS women with normal glucose tolerance free testosterone, the biallelic CAG repeat length and a multiplicative interaction term were investigated by multiple linear regression analysis for an association with IR as indicated by the homeostasis model assessment of IR (HOMA-IR). Results: Free testosterone was correlated with HOMA-IR. The impact of testosterone on HOMA-IR was modified by the AR CAG length as indicated by an interaction term. This interaction remained significant after adjustment for smoking, age and body mass index. While there was a positive association of free testosterone with HOMA-IR, the interaction term was inversely associated. The model, which explained 42.5% of the variation of HOMA-IR predicted that in carriers of short CAG lengths, an increase in testosterone increased IR. This effect attenuated with rising biallelic CAG length until it turns into the opposite at a CAG length longer than 23. The results were confirmed by using CIGMA as another measure of IR. Conclusions: The association between testosterone and IR is modified by the CAG repeat polymorphism within the AR. Therefore, the evaluation of testosterone effects on IR seems to require consideration of the AR CAG repeat polymorphism in PCOS women.