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 α ( ESR1) and Estrogen Receptor β ( 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.