Thyroid function, sex hormones and sexual function: a Mendelian randomization study

Abstract

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: - 0.717,- 1.946; p = 2 × 10^-5) SHBG and a 0.103 nmol/l lower (- 0.051,V0.154; p = 9 × 10^-5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.

Keywords: Erectile dysfunction; Mendelian randomization; Reproductive lifespan; SHBG; Testosterone; Thyroid function.

Figure 1. Schematic diagram illustrating the study design

Thyroid function was TSH and fT4 within reference range, and subclinical hypo- and hyperthyroidism from ThyroidOmics meta-genome-wide association study (GWAS) and overt hypothyroidism from 23andMe GWAS. Within the UK Biobank, we used summary level as well as individual level data. Summary level data were from the rapid UK Biobank genome-wide association study provided by the Neale lab at: http://www.nealelab.is/uk-biobank. Summary level data from ReproGen consortium were extracted from: https://www.reprogen.org/data_download.html. SNP: single nucleotide polymorphism.

Figure 2. Inverse variance weighted (IVW) random effects causal estimates for thyroid function on sex hormones

The estimates were based on summary level data on 317,694 participants (170,101 women and 147,593 men) from the UK Biobank (UKBB). SNP: single nucleotide polymorphism. GWAS: genome-wide association study, refers to the latest ThyroidOmics GWAS for TSH (thyroid stimulating hormone) and fT4 (free tetraiodothyronine) and subclinical hypo- and hyperthyroidism, and additionally 23andMe GWAS for overt hypothyroidism. SHBG: sex hormone binding globulin. Testosterone and estradiol refer to total, and not free concentrations. CI: confidence intervals.

Figure 3. Mendelian randomization (MR) estimates for genetically increased TSH and fT4 concentrations on sex hormones

Estimates are from inverse-variance weighted (IVW) random-effects method. Analyses for TSH were stratified for association with autoimmune thyroid disease (AITD). Prior to stratification, SNPs in ABO and BCAS3 genes were excluded due to pleiotropy and low tissue specificity (Supplemental Figure 1). Analyses for fT4 were stratified by DIO1 and DIO2 genes. SNP: single nucleotide polymorphism. GWAS: genome-wide association study, refers to the latest ThyroidOmics GWAS. SHBG: sex hormone binding globulin. Testosterone and estradiol refer to total and not free concentrations. UKBB=UK Biobank. CI: confidence intervals.

Figure 4. Genetic risk score estimates for thyroid function on sex hormones

Genetic risk score was based on individual level data on concentrations of SHBG in 326,819 participants (174,006 women and 152,813 men), testosterone in 326,631 (161,477 women and 165,154 men), estradiol in 56,187 (42,134 women and 14,053 men) and FAI in 298,010 participants (146,082 women and 151,928 men) from the UK Biobank (UKBB). GWAS: genome-wide association study, refers to the latest ThyroidOmics GWAS for TSH (thyroid stimulating hormone) and fT4 (free tetraiodothyronine) and subclinical hypo- and hyperthyroidism, and additionally 23andMe GWAS for overt hypothyroidism. SHBG: sex hormone binding globulin. Testosterone and estradiol refer to total, and not free concentrations. Free androgen index (FAI)=total testosterone/SHBG. CI: confidence intervals.