Effect of Hormone Replacement Therapy on Plasma Lipoproteins and Apolipoproteins, Endothelial Function and Myocardial Perfusion in Postmenopausal Women with Estrogen Receptor-α IVS1–397 C/C Genotype and Established Coronary Artery Disease

Abstract

Effect of hormone replacement (HRT) therapy on plasma lipoproteins and apolipoproteins, endothelial function and myocardial perfusion in postmenopausal women with estrogen receptor-α (ER-α) IVS1–397 C/C genotype and established coronary artery disease. Background/Aims: Associations between various ER-α polymorphisms and clinical phenotypes have been studied, including lipid levels and coronary atherosclerosis. We studied 48 postmenopausal women to determine the effect of ER-α IVS1–397 polymorphism on the response to treatment with HRT. Methods: The study had a randomized, double-blind, placebo-controlled and crossover design. Patients were divided into two groups according to ER-α IVS1–397 polymorphism: CC genotype (n = 9); CT or TT genotype (n = 39). HRT was given continuously for 4 weeks, with 4-week washout periods between the treatment periods. Brachial artery Doppler and Tl-201 scintigraphy were performed at the end of each treatment period. Results: HRT lowered total cholesterol, LDL-c and Apo-B levels from baseline values (all p < 0.05) and to a similar degree in CC and CT/TT genotype patients. HRT increased estradiol, HDL-c and Apo A-1 levels relative to baseline values, but to a greater degree in CC patients (p = 0.04, 0.05 and 0.04 by ANOVA, respectively). HRT increased peak forearm blood flow, brachial artery diameter during reactive hyperemia and endothelium-dependent dilation in both groups, but to a greater degree in CC patients (p = 0.03, 0.03 and 0.04 by ANOVA, respectively). Summed stress and rest scores were also more markedly reduced in CC patients (p = 0.04 and 0.05, respectively). The increase in estradiol levels was strongly correlated with the improvement in endothelium-dependent dilation (r = 0.66, p < 0.01), which in turn showed negative correlation with summed stress (r = –0.62, p < 0.01) and rest scores (r = –0.52, p < 0.05) in the CC genotype group. Conclusion: These data suggest that the improvement in endothelium-dependent dilation and the reduction in perfusion abnormalities by increasing estradiol levels with HRT in postmenopausal women with coronary artery disease may differ with respect to different genotypes, the effect being more prominent in those patients with ER-α IVS1–397 CC genotype.

Effect of estrogen receptor-alpha (ESR1) gene polymorphism on high density lipoprotein levels in response to hormone replacement therapy

“…However, Herrington et al (26) reported that postmenopausal women who were ESR1 PvuII CC carriers, as well as those with several other closely linked intron 1 polymorphisms, had an increase in HDL cholesterol levels after HRT. Later, these results were supported by the observation that postmenopausal women with an ESR1 PvuII CC genotype had an increase response of HDL, apolipoprotein A1, vascular reactivity, and myocardial perfusion to HRT (27). On the other hand, Huang et al (28) have reported that healthy postmenopausal women with the CC or TC genotype in ESR1 PvuII restriction had higher serum total cholesterol and LDL cholesterol concentrations.…”

Modulators of Vascular Sex Hormone Receptors and their Effects in Estrogen-Deficiency States Associated with Menopause

“…phenotypes [20]. Post-MW with the ER IVS1-397 polymorphism C/C genotype (recessive) has more prominent increases in HDL and apolipoprotein A-1 levels compared to those with the dominant phenotype, as well as a greater degree of increased peak forearm blood flow, brachial artery diameter, and endothelium-dependent dilation [21]. In post-MW with established CAD and being treated with estrogen alone or estrogen plus progesterone, a two-fold greater increase in HDL levels was seen in women with the ER IVSI-401 polymorphism C/C genotype as compared to those without the polymorphism and undergoing the same treatment regimen [22].…”

Cardiovascular risk in women: the impact of hormone replacement therapy and prospects for new therapeutic approaches

“…As these receptors are also targeted by hormones administered exogenously, it is not surprising that these polymorphisms also influence the response to HT. Polymorphisms in the ER-α gene have been linked to more prominent increases in serum HDL:LDL cholesterol concentrations, improvements in endothelial function [44] and reductions in serum E selectin concentrations [45]. Polymorphisms in the progesterone receptor may similarly have an impact on the response to HT [46].…”