Increased Estrogen Rather Than Decreased Androgen Action Is Associated With Longer Androgen Receptor CAG Repeats
We also collected DNA samples from the men with the purpose of studying the common polymorphisms in genes related to reproductive hormone production and action. The current report is the first one of these studies and it was focused on the distribution, and endocrine and phenotypic effects of the common polyglutamine (CAG) repeat polymorphism in exon 1 of the androgen receptor (AR). It is now well known that the polymorphism affects the activity of AR, and variants with longer repeats encode functionally less active receptor protein. The correlations of this polymorphism with various endocrine and phenotypic features of men have been exhaustively studied. Many, though not all of these studies, demonstrate inverse correlation of the repeat length with androgenicity, suggesting that men with longer repeats have weaker overall androgen action. The phenotypes found to correlate directly with the CAG repeat length include poor spermatogenesis and male-to-female transsexualism. Shorter repeats have been associated with prostate cancer, adverse plasma lipid profile and male-type alopecia. As concerns circulating sex hormone levels or bone density, no consistent correlations have been detected. Admittedly, many of the previous studies have been underpowered to detect small differences and may have given rise to these conflicting findings.
In our study on hormone, phenotypic, and CAG repeat data on 2,878 men, we found significant correlation between the CAG repeat length and circulating levels of not only total and free testosterone but also estradiol. And when the phenotypic correlations were assessed, the only significant findings were the positive correlations with bone ultrasound parameters at the calcaneus, and inverse correlations with the level of FSH and triglycerides. These findings suggest stronger estrogen action in men with longer CAG repeats.
Conspicuously, no correlations were found with any of the parameters indicating differences in androgen action, including anthropometry, blood pressure, haemoglobin, insulin sensitivity, or sexual or prostatic function. Because of its polymorphic nature, we cannot expect strong phenotypic effects of the CAG repeat. The only significant associations we detected suggested stronger estrogen action, but not weaker androgen action, in men with longer repeats.
Because men with longer repeats had higher testosterone levels, this increase seems to compensate totally or near-totally for the decreased functional activity of the weaker AR. Therefore, no signs of androgen deficiency could be detected in these men. Because of the strong association between testosterone and estradiol levels, higher levels of the hormone are bound to be converted to estrogen at higher rates through aromatization in men with longer repeats. Since estrogen receptor activity is not affected by the AR CAG repeat length, men with longer repeats can be expected to have stronger estrogen action. This was exactly what the phenotypic findings indicated. Hence, we may have to change our interpretation of the phenotypic impact of the AR CAG repeat length. When the compensatory effects of the circulating androgen and estrogen levels are taken into account, the repeat length correlates directly with estrogen action, while the weaker AR function is totally or near-totally compensated for by higher testosterone levels. It is apparent that the phenotypic effects detected are marginal and inconsistent in the earlier studies, with insufficient sample sizes. These can only be clearly demonstrated when a sufficiently large number of samples, nearly 3000 in our study, were analyzed.
Written by Ilpo T. Huhtaniemi, MD and Fred C.W. Wu, MD, as part of Beyond the Abstract on UroToday.com
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