The Androgen Receptor CAG Repeat Polymorphism and X-Chromosome Inactivation in Australian Caucasian Women with Infertility Related to Polycystic Ovary Syndrome

AbstractPolycystic ovary syndrome (PCOS) is a frequent heterogenic disorder with a familial background. Androgenic effects, determining the clinical features of the syndrome, are mediated by the androgen receptor (AR), whose activity is modulated by a genetic polymorphism. We investigated the role of the CAG repeat polymorphism of the androgen receptor in PCOS.In the infertility unit of a university clinic, 72 PCOS patients were compared with 179 ovulatory controls undergoing a standardized diagnostic work-up. The number of CAG repeats was determined by PCR, labelling with IR-800 and PAGE. X-chromosome inactivation was assessed by a methylation-sensitive assay.Compared to controls, PCOS patients displayed a shorter mean CAG repeat length, encoding for higher AR activity (P=0.001). CAG repeat length correlated inversely with oligomenorrhea, a central androgen dependent feature of the syndrome (P=0.005). In a binomial regression analysis including BMI, LH and free testosterone, CAG repeat length was identified as an independent risk factor for PCOS (P=0.002).The CAG repeat polymorphism could constitute one of the genetic factors modulating the syndrome’s phenotype, contributing to its clinical heterogeneity and associated metabolic consequences.

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

Acta Endocrinologica ◽

10.1530/eje.1.02195 ◽

2006 ◽

Vol 155 (1) ◽

pp. 127-130 ◽

Cited By ~ 38

Author(s):

Matthias Möhlig ◽

Annette Jürgens ◽

Joachim Spranger ◽

Kurt Hoffmann ◽

Martin O Weickert ◽

...

Keyword(s):

Insulin Resistance ◽

Androgen Receptor ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Free Testosterone ◽

Cag Repeat ◽

Repeat Polymorphism ◽

Ovary Syndrome ◽

Interaction Term ◽

The Impact

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.

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