Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism.

In men, testosterone (T) deficiency is associated with decreased physical performance, as defined by adverse traits in body composition, namely increased body fat content and reduced muscle mass. Physical abilities in androgen-deficient men are further attenuated by lower oxygen supply due to decreased hemoglobin concentrations and by poor glucose utilization. Dysthymia and a lack of necessary aggressiveness also contribute to deteriorate physical effectiveness. Substitution of T can improve lipid and insulin metabolism as well as growth of muscle fibers and decreasing fat depots, which consequently will result in changes of body composition. Increment of bone density will further contribute to increase physical fitness. The effects of T replacement therapy (TRT) are strongly influenced by age, training, and also pharmacogenetics: the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene modulates androgen effects. In vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues. Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men as well as efficacy of TRT. Thresholds at which T treatment should be initiated, as well as androgen dosage, could be tailored according to this polymorphism.