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THE ANDROGEN RECEPTOR
ZITZMAN, M.
Institute of Reproductive Medicine, University of Muenster, Domagkstr.
11, D-48129, Muenster, Germany.
Testosterone (T) and its metabolite dihydro-T exert their effects
on gene expression and thus effect maleness via the
androgen receptor (AR). A diverse range of clinical
conditions starting with complete androgen insensitivity
has been correlated with mutations in the AR. Subtle
modulations of the transcriptional activity induced
by the AR have also been observed and frequently assigned
to a polyglutamine stretch of variable length within
the N-terminal domain of the receptor. This stretch
is encoded by a variable number of CAG-triplets in
exon 1 of the AR gene located on the X-chromosome.
Longer triplet residues mitigate binding of androgen
receptor co-activators and, hence, facilitate decreased
androgenicity. Marked hypoandrogenic traits are seen
in patients with an elongation of more than 37 CAG
repeats; in these patients, irregular processing of
the receptor protein leads to spino-bulbar muscular
atrophy. Nevertheless, in 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 also been demonstrated. It remains to
be elucidated whether these insights are important
enough to become part of individually useful laboratory
assessments in otherwise healthy, eugonadal men. 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 in over 130 hypogonadal men initiated
on testosterone substitution therapy, we recently
demonstrated that prostate growth and volume were
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. In Klinefelter patients who have
two androgen receptor alleles, the shorter CAGn allele
is preferentially inactive. CAGn length is positively
associated with body height. Bone density and the
relation of arm span to body height are inversely
related to CAGn length. Presence of long CAGn is predictive
for gynecomastia and smaller testes, while short CAGn
are associated with a stable partnership and professions
requiring higher standards of education also when
corrected for family background. There is a trend
for men with longer CAGn to be diagnosed earlier in
life. Under testosterone substitution, men with shorter
CAGn exhibit a more profound suppression of LH levels,
augmented prostate growth and higher hemoglobin concentrations.
A significant genotype-phenotype association exists
in Klinefelter patients: androgen effects on appearance
and social characteristics are modulated by the AR
CAGn polymorphism. Effects of testosterone substitution
are pharmacogenetically modified. This finding is
magnified by preferential inactivation of the more
functional short CAGn allele. In conclusion, these
pharmacokinetic findings may provide the basis for
individualised testosterone substitution therapy by
adjusting the dose to the AR polymorphism.
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