Further decoding of the molecular and biochemical pathways is necessary for a comprehensive understanding of normal and abnormal sexual determination and differentiation. Based on the known molecular defects of impaired human sexual development, recent achievements in the field of functional genomics and proteomics offer unique opportunities to identify the genetic programs downstream of these pathways, which are ultimately responsible for structure and function of a normal or abnormal genital phenotype. Hopefully this knowledge will lead to better medical decisions in patients with androgen insensitivity due to AR defects and will open pathways for the development of individual therapeutic options.

The highly polymorphic nature of glutamine residues within the AR protein, which is encoded by the CAG repeat polymorphism within the AR gene, causes a subtle gradation of androgenicity among individuals. This modulation of androgen effects may be small but continuously present during a man's lifetime, thus exerting effects that are measurable in many tissues as various degrees of androgenicity (Fig. 3.5). It remains to be seen whether these insights are important enough to become part of individually useful laboratory assessments. The pharmacogenetic implication of this polymorphism seems to play an important role as modulator

Increasing number of CAG triplets

Decreasing androgenicity

Affected parameters:

Prostate growth and prostate cancer Spermatogenesis Bone tissue Lipid metabolism and body composition Vascular endothelial functions Personality traits Hair growth



Neurological disorders


Diabetes mellitus

Ineffective spermatogenesis

Fig. 3.5 The inverse association between the number of CAG repeats in the AR gene and functionality of the AR protein. Longer CAG tracts result in lower transcription of target genes and, thus, lower androgenicity. Expansion of the encoded polyglutamine stretch to beyond probably 38 leads to the neuromuscular disorder X-linked spinobulbar muscular atrophy (SBMA), a condition in which defective spermatogenesis and undervirilization are observed. Conversely, low numbers of CAG repeats are associated with increased androgenicity of susceptible tissues.

of treatment effects in hypogonadal men. Further studies are required to decide whether these insights should sublimate into individualized aspects of testosterone therapy, e.g. adaptation of dosage or surveillance intervals.

3.7 Key messages

• A defective androgen receptor may lead to variable phenotypes of androgen insensitivity in humans.

• In infants and children stimulation of the gonads with human chorionic gonadotropin is necessary for evaluation of gonadal hormone synthesis.

• In young infants laboratory findings may demonstrate variable testosterone values; thus the discrimination of androgen insensitivity from other causes of ambiguous genitalia is difficult.

• The stanozolol-based sex hormone-binding globulin androgen sensitivity test is a helpful functional test in androgen insensitivity, albeit not discriminatory in infants and patients with somatic mutations of the androgen receptor.

• Definitive diagnosis of androgen insensitivity is based on the analysis of a mutation in the androgen receptor gene.

• Some androgen receptor defects leading to partial androgen insensitivity may be overcome by high-dose androgen therapy.

• The CAG repeat polymorphism in exon 1 of the androgen receptor gene modulates androgen effects: testosterone effects are attenuated according to the length of triplet residues.

• Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men in various tissues and psychological traits.

• The pharmacogenetic implications of this polymorphism are likely to play a significant role in future testosterone treatment of hypogonadal men as treatment effects are markedly influenced by the number of CAG repeats, at least in the prostate.

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