Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study.

Nellie Y Loh,Edward Humphreys,Raymond Noordam,Fredrik Karpe,Jeremy W Tomlinson,Constantinos Christodoulides

doi:10.1530/eje-21-0703

Nellie Y Loh, Edward Humphreys + Show 4 more

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https://doi.org/10.1530/eje-21-0703

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Journal: Acta Endocrinologica	Publication Date: Jan 20, 2022
Citations: 17	License type: CC BY 4.0

Affiliation: University of Oxford, Leiden University

Abstract

ObjectiveEpidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR).Design and MethodsAs genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa.ResultsIn women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2.ConclusionsAdipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.

Highlights

Body fat distribution is an independent risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD)
Because most circulating testosterone is bound to sex hormone binding globulin (SHBG) and is biologically inactive, we focused on non-SHGB-bound testosterone (BioT)
Demonstrated uniform directions to inverse-variance weighted (IVW) Mendelian Randomisation (MR) for all significant associations, except for that between bioavailable serum testosterone (BioT) and BMI, which was directionally inconsistent in the MR-Egger model and was associated with directional pleiotropy (MR-Egger intercept = 0.001)

Summary

Introduction

Body fat distribution is an independent risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whilst upper-body (android) fat, especially visceral adipose tissue (VAT), accumulation is associated with increased CVD risk due to deranged glucose and lipid metabolism, lower-body (gynoid) fat distribution provides protection against T2D and atherosclerosis (1). Women generally have more fat mass (2). Premenopausal women typically have a greater proportion of subcutaneous AT (SAT), in the gluteofemoral depot, whilst men generally accumulate more upper-body fat and have a higher proportion of VAT than women (2, 3). Glycaemic, and blood pressure (BP) traits have been described, with women having a lower CVD risk factor burden compared to men (4). Men have an elevated risk of T2D, CVD, and all-cause mortality than women during middle age (3, 4)

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