Associations of Estrogen Receptor Alpha and Beta Gene Polymorphisms with Sex Steroid Levels and Body Fat Content in Men

Objective: Estrogens play an important role in male physiology. We investigated the possible association of four single nucleotide polymorphisms in Estrogen Receptor alpha (ESR1) and Estrogen Receptor beta (ESR2) genes with circulating levels of sex steroids and Sex Hormone Binding Globulin (SHBG) in men. Design and Methods: SHBG, total and calculated free testosterone (TT and cal FT), estradiol (E2) and free Estradiol (FE2) were determined in a population-based cohort of 170 apparently healthy Greek men. Body mass index (BMI), waist circumference (WC) and percentage of body fat (%fat) content were measured in all participants. Genotyping for the Pvu II and Xba I polymorphisms of the ESR1 gene and for the Rsa I and Alu I polymorphisms of the ESR2 gene was performed. Results: Pvu II showed an association with E2 levels [median (IQR) pp 58.5 (42.1-73.4) pg/ml vs. Pp 48.8 (42.9-60.1) and PP 57.7 (44-70.5),p = 0.032], and with %fat [mean +/- SD pp 24.6 +/- 5.3 vs. Pp 22.4 +/- 5.2 and PP 21.2 +/- 6.7, p = 0.044], after adjustment for age and WC. Furthermore, the effect of Pvu II on E2 was independent of %fat (p = 0.038). A synergistic effect of the two ESR1 polymorphisms on E2 (p = 0.023), FE2 (p = 0.03) and %fat (p = 0.004) was present. Finally, a synergistic effect of the ESR1 and ESR2 genes on TT (p = 0.009), independent of age, WC and %fat also emerged. Conclusions: Genetic variation in ESR1 is associated with serum estradiol levels and body fat content regulation in men. Furthermore, a synergistic effect of ESR1 and ESR2 genes is exerted on serum testosterone levels.