Our data show that the numbers of TTTAn repeats in the aromatase polymorphism may have a small contribution when compared to weight on estradiol levels in obese men. Failure to demonstrate a more clear effect of the polymorphism on estradiol levels appears attributable to an interaction between the effects of weight and the polymorphism on estradiol levels. In this regard, we found that the effect of increasing degrees of obesity on estradiol levels depends on the number of TTTAn repeats in the aromatase polymorphism, as does the decline in estradiol levels with weight loss. Thus, the interaction of weight and estradiol levels in men varies according to this polymorphism. Our population included only obese men, in another population that includes normal and overweight men in addition to obese men, the effect of TTTAn repeats may be more pronounced. Another limitation that precluded the statistical significance is the small sample in our study.
The effect of aromatase polymorphism on the estrogen metabolism in men has been reported in previous work. Gennari et al studied the effect of aromatase polymorphism in bone metabolism. found that men with higher numbers of TTTAn repeats (more than 9) on both alleles had higher estradiol value and higher estradiol to testosterone ratio when compared with men lower number of TTTAn repeats on both alleles. This difference in hormonal profile at baseline was also reflected in a higher lumbar bone mineral density in men with higher numbers of TTTAn repeats (more than 9) on both alleles. This difference was reduced when the authors corrected for BMI, suggesting a stronger effect of obesity on estradiol and bone density than the aromatase polymorphism.(20
) These results are consistent with our observations although our study population included no men of normal weight. Our data suggest further, however, that the effect of weight on estradiol is more pronounced in the high TTTAn repeat group than in the low TTTAn repeat group, such that correcting for BMI might be expected to have different outcomes for different allelic groups for the TTTAn polymorphism. A previous study by Van Pottelbergh et al, who did not find a correlation between aromatase polymorphism and reproductive hormones until he they excluded men with the lowest (25th
percentile) and highest (75th
percentile) BMIs. In this same study, men who were carrier of the polymorphism with the higher number of TTTAn repeats were less likely, after an average 3.4 years of follow-up, to reduce their bone mineral density at the total distal forearm and mid-subregion when compared to men with the shorter TTTAn repeat allelic variant.(21
) Our data suggest that the correlation between weight and estradiol among subjects in Van Pottlebergh's data may have been obscured by the “subpopulation of men with lower TTTAn repeats for whom the weight-E2 relationship is damped. Together our data taken with these studies shows that the effect of obesity dominates the effect of the TTTAn repeats on estradiol levels, but to a lesser degree for men with lower repeat numbers among whom the weight to estradiol relationship is blunted.
The polymorphism studied in this our paper is located in intron 4 of the CYP19 gene. A biological plausibility of the relation between TTTAn repeats and aromatase activity may be attributed to a possible linkage to other polymorphisms in the promoter or other regulatory area of the CYP 19A1 gene. In factThere are several SNPs that were described in the aromatase genes such as the (3'UTR) C>T change (rs10046)(36
), and the deletion/insertion polymorphism located in the intron 4, IVS4 [-/TCT](rs11575899), Arg264Cys and Val80Val (G/A). (36
) These polymorphisms have been linked to various clinical conditions with conflicting results. (40
) The deletion/insertion polymorphism [-/TCT] has been suggested to affect the relation between TTTAn polymorphism and estrogen levels. We have screened a group of men from the same population for the deletion/insertion polymorphism [-/TCT] and found that it did not strengthen the relation between the TTTA polymorphism and estradiol levels (data not shown). Other polymorphisms are of uncertain clinical significance. There are 2 coding SNPs that have been described, Arg264Cys and Val80Val (G/A), these polymorphism were not associated estrogen-dependent end points.(40
) Another coding SNP, Trp39Arg, was associated with less active aromatase protein in a Japanese population. (14
) A recent report found that the (rs2470152) SNP (G→A) located in intron 1 of the CYP 19A1 gene to be highly correlated to estrogen levels in in two populations of 1041 young and 4490 older men. (41
A direct role of the TTTAn polymorphism on transcriptional or post transcriptional pathways of the aromatase enzyme remains to be demonstrated. The aromatase enzyme is known to have several tissue specific promoters.(4
) The expression of CYP19A1 in adipose tissue is dependent on promoter I.4 regulated by class I cytokines and other activators such as TNFα and glucocortcoids.(42
) Our data show that the various allelic forms of the TTTAn polymorphism account for differential effects of weight on estradiol levels; this may, for instance, imply that this polymorphism may be related to differential expression of aromatase in fatty tissue through activation or repression of fat tissue specific promoter. In conclusion, the TTTAn aromatase polymorphism may influences the levels of estradiol in men by differentially modulating the quantitatively greater effects of obesity.