Context. A large interindividual variation in serum (free) testosterone [(F)T] levels prevails in men, underlied in part by genetic components.

Objective. To explore the hypothesis that this variability results in part from differences in androgen sensitivity and feedback loop setpoint, and to assess the role of the androgen receptor (AR) polyglutamine tract polymorphism encoded by a CAG repeat of variable length in exon 1 of the AR gene.

Design/Setting/Participants. We performed a cross-sectional analysis in two independent populations of healthy men, consisting of 2322 men aged 35 to 59y (Belstress study) and 358 men aged 25 to 45y (Siblos study), respectively.

Main Outcome Measures. Serum hormonal levels and the AR gene CAG repeat length were determined.

Results. In the Belstress population serum T and calculated FT showed a positive linear association with luteinizing hormone (LH) (P<0.001). In the 200 men with lowest FT CAG repeat number was lower than in the 200 men with highest FT (P=0.004). As studied in a larger subset of the population consisting of 857 men covering the whole FT range, FT increased progressively with CAG repeat length (p=0.003). These findings of a positive relation of FT with both LH and CAG repeat length were confirmed in the Siblos study population (both P0.001). Difference in FT between extreme quartiles of CAG repeat was 10 and 14% in the Belstress and Siblos study, respectively. In both study populations CAG repeat length was also positively associated with serum total T (p0.004).

Conclusions. The data supports the view that between subject variability in serum (F)T in healthy men is underlied in part by differences in androgen sensitivity and feedback setpoint, with a contributory role of AR polymorphism. These findings have potential implications for the interpretation of epidemiological studies, diagnosis of hypogonadism and pharmacogenetics of androgen treatment in men.