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Small effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men

¹ Department of Endocrinology, 9 K12 I.E, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium² , Department of Public Health³ Biostatistical Unit, Ghent University, Ghent, Belgium⁴ Montefiore Institute – Bioinformatics, University of Liège, Liège, Belgium⁵ StepGen cvba, Merelbeke, Belgium⁶ Department of Medical Genetics, Ghent University, Ghent, Belgium

(Correspondence should be addressed to J-M Kaufman; Email: jean.kaufman{at}ugent.be)

Objective: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat.

Design and patients: A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men.

Measurement: Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique.

Results: The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT.

Conclusion: To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.