Endocrine Abstracts (2004) 8 S17

ANDROGEN ACTION AND THE MALE ADULT PHENOTYPE FROM YOUTH TO SENESCENCE

E Nieschlag, J Gromoll & M Zitzmann


Institute of Reproductive Medicine of the University of Muenster, Muenster, Germany.


Testosterone is the hormone that turns males into men and a lack of testosterone, whether of primary or secondary origin, causes hypogonadism characterized by lack of pubertal development or loss of maleness. It was generally assumed that in a man with a normal androgen receptor (AR) androgenicity is regulated by testosterone serum concentrations, slightly modified by SHBG. Only recently it became evident that variations in the AR gene influence testosterone action. 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 to co-activators and, hence, facilitate decreased androgenicity. In eugonadal men with CAGn repeat residues of normal length an influence of the polymorphism on androgen targets such as prostate, spermatogenesis, bone, hair, metabolic parameters and psychological factors has been demonstrated. In patients with Klinefelter's syndrome having two X chromosomal AR alleles, the one with the shorter CAG allele is preferentially inactive and CAGn length is positively associated with body height and bone density. Long CAGn are predictive for gynecomastia and smaller testes, while shorter CAGn are associated with a stable partnership and higher professional achievements. In hypogonadal patients under testosterone substitution target organ parameters such as haemoglobin, and prostate volume correlate inversely with CAGn length. Thus, the phenotype-genotype associations have pharmacogenetic implications, possibly providing the basis for individualized testosterone substitution therapy in which the dose can be adopted to the AR polymorphism.

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