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Mechanisms of Disease: pharmacogenetics of testosterone therapy in hypogonadal men

Nature Clinical Practice Urology volume 4, pages 161–166 (2007)Cite this article

Abstract

A defective, mutated androgen receptor may lead to variable phenotypes of androgen insensitivity in humans. Also, the CAG repeat polymorphism in exon 1 of the androgen receptor 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 various tissues and psychological traits in healthy eugonadal men: the longer the repeat tracts, the less pronounced is the androgen effect when individuals with similar testosterone concentrations are compared. Furthermore, as effects of testosterone substitution are markedly influenced by the number of CAG repeats, the pharmacogenetic implications of this polymorphism are likely to have a significant role in future testosterone treatment of hypogonadal men. Thresholds at which testosterone treatment should be initiated, as well as androgen dosage, might be tailored according to the receptor polymorphism.

Key Points

  • The CAG repeat polymorphism in exon 1 of the androgen receptor 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 in various tissues and is associated with different psychological traits; the longer the repeat tracts, the less pronounced is the androgen effect when individuals with similar testosterone concentrations are compared

  • Effects of testosterone substitution are markedly influenced by the number of CAG repeats in retrospective studies

  • The pharmacogenetic implications of this polymorphism are likely to have a significant role in future testosterone treatment of hypogonadal men as initiation thresholds of testosterone treatment and androgen dose might be tailored according to an individual's receptor polymorphism

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Figure 1: Display of the X-chromosome with the AR gene
Figure 2: Data from a 'humanized' androgen receptor mouse model with three breeding lines having either 12, 21 or 48 CAG repeats in exon 1 of the androgen receptor
Figure 3: Hypothetical model of androgen effects

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Authors and Affiliations

  1. M Zitzmann is a Senior Physician at the Institute of Reproductive Medicine, Westfälische Wilhelms Universität, Münster, Germany.,

    Michael Zitzmann

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  1. Michael Zitzmann
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Correspondence to Michael Zitzmann.

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The author declares no competing financial interests.

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Zitzmann, M. Mechanisms of Disease: pharmacogenetics of testosterone therapy in hypogonadal men. Nat Rev Urol 4, 161–166 (2007). https://doi.org/10.1038/ncpuro0706

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