Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study

Abstract

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = −1.31, 95% CI −2.43; −0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.

Sex‐specific and hormone‐related differences in vascular remodelling in atherosclerosis

“…Menopause goes hand in hand with 10%–15% higher circulating LDL‐cholesterol and triglyceride levels and a reduction in high‐density lipoprotein (HDL)‐cholesterol 54 . Together with this less favourable lipid profile after menopause, various studies also demonstrated a rise in blood pressure, which may be a direct effect of hormonal changes on the vasculature and metabolic changes related to ageing 55–57 . Endothelial dysfunction starts in early menopause even before signs of subclinical atherosclerosis 58 and while healthy endothelium is sensitive to the vasodilator properties of oestrogens, this reverses when vascular stiffness and atherosclerotic disease develop over time 59 .…”

“…with this less favourable lipid profile after menopause, various studies also demonstrated a rise in blood pressure, which may be a direct effect of hormonal changes on the vasculature and metabolic changes related to ageing. [55][56][57] Endothelial dysfunction starts in early menopause even before signs of subclinical atherosclerosis 58 and while healthy endothelium is sensitive to the vasodilator properties of oestrogens, this reverses when vascular stiffness and atherosclerotic disease develop over time. 59 All of these detrimental phenomena contribute to an increased rate of MI in women after menopause.…”

Mechanisms of ovarian aging in women: a review

“…This type of study will not be discussed in this review, and readers interested are encouraged to read references [176,177]. However, it should be noted that studies existed usually focusing on how age at menopause affects certain traits, instead of discussing how some traits impact age at menopause [178,179]. Apparently, the later one is what clinicians most care about in order to withstand ovarian aging and is needed to be developed.…”

Late age at menopause positively associated with obesity-mediated hypertension

“…However, several studies have demonstrated a positive association between age at menopause and hypertension [6][7][8]. Additionally, a positive association between age at menopause and obesity has been reported [9,10].…”