Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged...

Low vitality is a common symptom of testosterone deficiency; however, clinical trial results remain inconclusive regarding the responsiveness of this symptom to hormone replacement.

The aim of the present study was to determine if the relationship between circulating testosterone levels and vitality would be moderated by the CAG repeat length in the androgen receptor (AR) gene, which influences the receptor's sensitivity to testosterone.

We examined 676 men in the Vietnam Era Twin Study of Aging when they were, on average, 55.4 years old (SD = 2.5). Salivary testosterone levels were measured by using 3 samples collected at waking on 3 nonconsecutive days. The average testosterone level was classified as low, normal, or high based on 1-SD cutoffs. Analyses were conducted using multilevel, mixed linear models, which accounted for the nonindependence of the twin data, and adjusted for the effects of age, ethnicity, BMI, chronic health conditions, depressive symptoms, and sleep quality.

Vitality was measured using the 36-item Short Form (SF-36) vitality subscale.

We observed a significant interaction between salivary testosterone and the AR-CAG repeat length. When the repeat length was short, men with low testosterone had significantly lower vitality. As the AR-CAG repeat length increased, the magnitude of the testosterone effect decreased.

The observed interaction between testosterone and variation in the AR gene suggests that men with more sensitive ARs, as indicated by a shorter AR-CAG repeat, are more likely to experience symptoms of age-related testosterone deficiency.

Strengths of the present study include our use of a large community-based sample, the use of multiple testosterone measurements, and the availability of a comprehensive set of covariates that may impact the association of interest. Limitations include the homogeneous nature of the sample with respect to ethnicity, the brevity of the 36-item Short Form vitality subscale, and our inability to establish change in testosterone levels because of the cross-sectional nature of data.

The association between testosterone and vitality appears to be clinically meaningful and is in part dependent on variation in the AR gene. Panizzon MS, Bree K, Hsieh T-C, et al. Genetic Variation in the Androgen Receptor Modifies the Association Between Testosterone and Vitality in Middle-Aged Men. J Sex Med 2020;17:2351-2361.