Pharmacogenetics of testosterone action

view presentation | view presentation transcript | view curriculum vitae  | print this page

Professor Eberhard Nieschlag  and M. Zitzmann; Institute Of Reproductive Medicine Of The University, Müenster, Germany

Testosterone (T) exerts its effects on gene expression via the androgen receptor (AR). Modulations of the transcriptional activity induced by the AR can be assigned to a polyglutamine stretch of variable length within the receptor. This stretch is encoded by a variable number of CAG-triplets in exon 1 of the AR gene. Longer triplet residues mitigate binding of androgen receptor co-activators and, hence, facilitate decreased androgenicity. In eugonadal men with CAG repeat residues of normal length, an influence of the polymorphism on androgen target tissues such as the prostate, spermatogenesis, bone, hair, metabolic parameters and psychological factors has been demonstrated. Extending these findings to pharmacogenetic considerations, a possible modulation of androgen effects during T administration has to be considered. This aspect could gain clinical significance especially in older men as these patients are more likely to develop unwanted androgen-related side-effects. In regard to prostate enlargement during T substitution, we recently demonstrated that prostate growth and volume are markedly influenced by the CAG repeat polymorphism. The findings were more pronounced in men older than 40 years and seem to put patients with a repeat chain of 20 or less triplets at an increased risk of developing an enlarged organ. These pharmacokinetic findings may provide the basis for individualised testosterone substitution therapy by adjusting the dose to the AR polymorphism.