Login to Access Video or Poster Abstract: MP91-13
Sources of Funding: National Institute on Aging (K08-AG047903, R01-AG018386, R01-AG022381, R01-AG022982, R01-AG018384)

Introduction

Controversy still exists regarding the efficacy of testosterone replacement therapy (TRT) for symptomatic hypogonadism. A recent multi-site randomized controlled study of men undergoing TRT failed to show an improvement in several symptom domains, among them is vitality. We hypothesized that differences in androgen sensitivity would obscure symptom improvement for a subset of individuals. Androgen sensitivity is related to the number of trinucleotide (CAG) repeats on exon 1 of the androgen receptor (AR) gene. We sought to examine the regulatory role of this genetic polymorphism on the relationship between testosterone and vitality in middle-aged men

Methods

Participants were men from the Vietnam Era Twin Study of Aging (N=696). Average waking, salivary free-testosterone level was acquired on 3 non-consecutive days. The AR gene CAG repeat length was derived using a combination of PCR fragment analysis and Sanger sequencing. Vitality was evaluated with the SF-36Vitality scale. We tested the interaction between low testosterone (low-T) and CAG repeat length while controlling for age, ethnicity, smoking status, BMI, heart disease, hypertension, diabetes, and the correlated nature of the twin data. Low-T was defined as being ? 1 SD below the mean for the 3-day average value

Results

Mean age of the participants was 56.4 years (SD = 2.6) with average CAG repeat length of 22 (range: 8-37). We observed a significant interaction effect between low-T and AR CAG repeat length. In men with a short variant of the AR gene (< 21 repeats), representing greater androgen sensitivity, there was a significant effect of low-T on vitality (p < 0.01). Men with low-T and the short AR gene were on average 10 points lower on the Vitality scale relative to men with normal T and the same genotype. This effect was not observed in men with either medium (21-23 repeats) or long (? 24 repeats) variants of the AR gene. Without the interaction effect in the model, neither low-T nor the AR gene had a significant effect on vitality

Conclusions

These results demonstrate that the relationship between low-T and vitality is regulated, in part, by variation in the AR gene. The effect of low-T on vitality was observed only when the genetically-determined sensitivity of the androgen receptor is at its greatest. Variations in the AR gene, bestowing differential androgen sensitivity, are potential targets for personalized therapy of hypogonadism. Future studies are needed to determine how genetic information can be used to improve the efficacy of TRT

Funding

National Institute on Aging (K08-AG047903, R01-AG018386, R01-AG022381, R01-AG022982, R01-AG018384)