|
KLINEFELTER SYNDROME AND ITS SIGNIFICANCE IN ANDROGEN DEFICIENCY
REVISITED
Michael Zitzmann
Institute of Reproductive Medicine, University of Munster,
Domagkstrasse 11, D-48129 Munster, Germany. zitzmann@uni-munster.de
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 (Zitzmann et al. 2003a). 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 (Zitzmann et al. 2003b).
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
(Lanfranco et al. 2004, Zitzmann et al. 2004).
In conclusion, these pharmacokinetic findings may provide the basis
for individualised testosterone substitution therapy by adjusting
the dose to the AR polymorphism.
|
