Exon 1 of the androgen receptor (AR) gene contains a variable number of CAG triplets, (CAGr)n which encode a polyglutamine stretch of variable length in the N-terminal domain of the receptor. Experimental evidence has accumulated in demonstrating that the length of this stretch influences the transcriptional activity induced by the AR and therefore modulates target organs responsiveness to androgens.
The (CAGr)n is inversely associated with the transcriptional activity of target genes. The (CAGr)n has been analysed in a variety of cross-sectional studies, investigating its influence on clinical conditions and parameters affected by T action, such as bone density, spermatogenesis, mood variations, cognitive functions and hair development in both men and women. Zitzmann et al have correlated the prostate growth induced by T replacement therapy in hypogonadal men with (CAGr)n, demonstrating an impressive modulating effect by the CAGr polymorphism. A role of the (CAGr)n has been also demonstrated in determining the androgenicity of an individual: hypoandrogenized patients compared to a control group have an increased (CAGr)n (24.0 vs 21.5) with a significant shift toward higher numbers.
We will two patients affected by the same disease, that is congenital selective hypogonadotropic hypogonadism, treated with similar doses of androgens. Androgenization, though, was completely different, as the pictures will show: one had a female hair pattern, no beard, no hair in the chest and lower abdomen, pubic hair 3, depressed mood, the other one was well androgenized, with extraordinary male hair pattern, good muscular development, married with children. The first one had a (CAGr)n equal to 30 the second one 15.
Our data further support a pharmacogenetic approach which stresses the evaluation of AR polymorphism to be performed before initiating a long term androgen replacement treatment to provide satisfactory androgen effect at target organs.