Genetic polymorphisms and obesity influence estradiol decline during the menopause

Abstract

Summary Objectives Obesity and genetic variation in aromatase and type 1 17-β hydroxysteroid dehydrogenase (HSD) could influence the E2 trajectory of decline during the menopause transition. Design and participants E2 trajectories during the menopause transition (phenotype) were identified using 5934 data points acquired annually from 681 women in Study of Women’s Health across the Nation (SWAN), a multiethnic study of the mid-life. E2 trajectories were related to CYP19 and type I 17-βHSD single-nucleotide polymorphisms (SNPs) and obesity. Results logE2 trajectories began to decline precipitously 2 years before the final menstrual period (FMP). The trajectory of the logE2 decline varied with genotypes and obesity. logE2 rates of decline were greater in nonobese women than in obese women, P < 0.05. Women with the CYP19rs936306 CT variant had logE2 rate of decline that was 54% as rapid as the rate of decline of women with the TT variant, P < 0.05. logE2 rate of decline in women with the CYP19rs749292 GG variant was two-thirds the rate of logE2 decline in women with the AG variant, P < 0.05. logRates of E2 decline with 17-βHSD SNPs (rs2830, rs592389, and rs615942) varied according to genotype within obesity groups. Within each obesity group, logE2 rate of decline was greater in heterozygous variants and much less in homozygotes (P < 0.05). Obese women with selected CYP19 and 17-β HSD gene variants had remarkably different E2 trajectories around the FMP, resulting in different postmenopausal E2 levels. The rate of the E2 decline and the subsequent postmenopausal E2 levels may be relevant to oestrogen-sensitive chronic diseases including cancers.

A Polymorphism at the 3'-UTR Region of the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor, Anastrozole, in Metastatic Breast Carcinoma

“…17-β-HSD-1 is an independent prognostic factor in breast cancer in both pre- and post-menopausal patients [26]. Polymorphisms in the 17-β-HSD-1 gene have been shown to alter E2 levels in postmenopausal women [27]. There was almost a 34%–46% difference in postmenopausal E2 level according to obese vs. nonobese and 17-β-HSD-1 polymorphisms.…”

Aromatase ( CYP19A1 ) gene variants, sex steroid levels, and late‐life depression

“…and rs749292 have been associated with lower testosterone-toestradiol ratio and higher rates of estradiol decline during the menopause transition, but this was not found in Caucasian women (Sowers et al, 2006;Sowers et al, 2011). Among postmenopausal women, the T allele of rs10046 was significantly associated with higher estradiol levels and higher estradiol to testosterone ratio in only one (Dunning et al, 2004) of four studies (see for review Olson, Bandera, & Orlow, 2007).…”

“…The rs1902586 is positioned within the brain-specific promoter/first Some studies have also examined the association between CYP19A1 polymorphisms and sex hormone levels, although findings have not been consistent, and this may differ in pre-and postmenopausal women and according to ethnicity (De Castro et al, 2005;Dunning et al, 2004;Sowers et al, 2011;Sowers, Wilson, Kardia, Chu, & Ferrell, 2006). The minor homozygotes of rs936306 and rs749292 have been associated with lower testosterone-toestradiol ratio and higher rates of estradiol decline during the menopause transition, but this was not found in Caucasian women (Sowers et al, 2006;Sowers et al, 2011).…”

“…The rs1902586 is positioned within the brain-specific promoter/first Some studies have also examined the association between CYP19A1 polymorphisms and sex hormone levels, although findings have not been consistent, and this may differ in pre-and postmenopausal women and according to ethnicity (De Castro et al, 2005;Dunning et al, 2004;Sowers et al, 2011;Sowers, Wilson, Kardia, Chu, & Ferrell, 2006). The minor homozygotes of rs936306…”

“…Such effect may actually occur in up to 50% of all gene association studies, particularly in Europeans (Comings & MacMurray, 2000). Heterosis has been reported with certain CYP19A1 polymorphisms for testosterone level (Sowers et al, 2006), estradiol decline (Sowers et al, 2011), Alzheimer's disease (Song et al, 2019), coronary heart disease (Wang et al, 2016), as well as endometriosis in Caucasian but not Asian women (Yi, Yang, Lan, & Xi, 2016 (Comings & MacMurray, 2000). Another explanation is based on an inverted U-shaped response curve in which either too little or too much gene expression is deleterious, with optimal gene expression occurring in heterozygotes.…”