Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status

Abstract

Sex steroid hormones have multiple effects on lipid metabolism. We investigated the association between two common single nucleotide polymorphisms of the estrogen receptor 2 gene (ESR2), 1082G4A and 1730A4G, and PROGINS polymorphism of the progesterone receptor gene (PGR) with lipoprotein levels in a cross-sectional study with 472 women of European descent. The women were classified into three subgroups according to hormonal status, premenopausal women (n ¼ 187; mean age ¼ 3479.7 years), postmenopausal women exposed to hormone replacement therapy (HRT) (n ¼ 118; 5676.7 years) and postmenopausal women unexposed to HRT (n ¼ 167; 5879.8 years). The premenopausal and postmenopausal women exposed to HRT, both carriers of G/A genotype, exhibited LDL-C (P ¼ 0.027 and 0.001, respectively) and T-chol levels (P ¼ 0.035 and 0.001, respectively) lower than carriers of G/G genotype. This association was not observed in postmenopausal women unexposed to HRT. These results suggest that ESR2 1082G4A genotype may influence LDL-C levels in women with abundant estrogen levels, due to either endogenous or exogenous sources. INTRODUCTIONEndogenous and exogenous sex steroid hormones have multiple effects on lipid and lipoprotein metabolism. The oral estrogen replacement therapy (ERT) in postmenopausal women decreases serum total cholesterol (T-chol) and lowdensity lipoprotein cholesterol (LDL-C) concentrations, as well as increases serum high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. 1 The effects of combined (estrogen plus progestin) hormone replacement therapy (HRT) are uncertain; the addition of a progestogen to estrogens tends to attenuate the increase in serum HDL-C and the decrease in LDL-C, obtained with ERT, although this effect seems to be related to the dose and to androgenic potency of the progestogen. 2 The beneficial changes in these lipoproteins should be associated with at least 30-35% decline in coronary heart disease (CHD) incidence. 3 However, the results from the Heart and Estrogen/Progestin Replacement Study (HERS) 4 and the Women's Health Initiative (WHI) trial 5 demonstrated that oral HRT does not provide cardiovascular benefit or even some evidence of cardiovascular harm.

Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

“…However, Almeida et al 29 did not observe a similar association in postmenopausal women on estrogen therapy after 4 months of treatment. Although we detected associations between ER-α XbaI polymorphisms and tamoxifen-induced lipid changes, we observed none with ER-α PvuII.Almeida et al 30 have recently reported an association between ER-β and the response of serum lipids in 472 women unexposed or exposed to estrogen therapy for at least 4 months. They found that LDL-cholesterol concentrations were associated with ER-β 1082 G-A (rs1256049) in pre-or postmenopausal women if they received estrogen.…”

“…Almeida et al 30 have recently reported an association between ER-β and the response of serum lipids in 472 women unexposed or exposed to estrogen therapy for at least 4 months. They found that LDL-cholesterol concentrations were associated with ER-β 1082 G-A (rs1256049) in pre-or postmenopausal women if they received estrogen.…”

“…It is possible, as others have suggested, that SNPs that do not cause amino-acid change may alter gene expression, affect the folding of mRNA, or be in linkage disequilibrium with a functional site. 2,30 Moreover, the role of polymorphisms in genes that code for the coregulator proteins of the ERs and that may alter their binding to ligands such as tamoxifen is not clear. Other investigators have shown that tamoxifen interferes with synthesis of cholesterol in hepatic cells by inhibition of the conversion of precursor lipids 31 and that tamoxifen is a potent inhibitor of sterol Δ8-isomerase, a cholesterol synthetic enzyme.…”

Association between ESR1 and ESR2 gene polymorphisms and hyperlipidemia in Chinese Han postmenopausal women

“…In another study, mean LDL and total cholesterol concentrations in premenopausal or postmenopausal women with higher estrogen exposure were lower in those with the GA genotype for 1082A4G than in those with the AA genotype in Brazilians of European descent. 29 Conversely, Domingues-Montanari et al 46 reported that no association with MI was observed for 1082A4G or 1730A4G in the Spanish population. In this study, we did not find any association of 1082A4G (rs1256049) and 1730A4G (rs4986938) with hyperlipidemia.…”

“…24,25 1082A4G (rs1256049) and 1730A4G (rs4986938) of ESR2 might have a role in CVDs 26,27 and lipid profile. 28,29 Most of the evidence was reported from the Western population; however, little was known about the SNP distributions of ESRs and their relationships with hyperlipidemia in Chinese women. In our study, we measured serum estrogen concentration and sequenced four representative SNPs, namely PvuII (rs2234693) and XbaI (rs9340799) of ESR1 and 1082A4G (rs1256049) and 1730A4G (rs4986938) of ESR2.…”