Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father and Child Cohort Study
Authors: Hernáez Álvaro , Lee Yunsung , Page Christian M. , Skåra Karoline H. , Håberg Siri E. , Magnus Per , Njølstad Pål R. , Andreassen Ole A. , Corfield Elizabeth C. , Havdahl Alexandra , Fraser Abigail , Burgess Stephen , Lawlor Deborah A. , Magnus Maria C. 
Published: January 2023

ABSTRACTAims/hypothesisObservational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. We aim to establish whether impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) are causally related to infertility (having tried to conceive for ≥ 12 months or used assisted reproduction technologies to conceive) by Mendelian randomization (MR) analyses in women and men.MethodsWe conducted two-sample MR analyses, in which we used genome-wide association summary data that were publicly available for the cardiometabolic risk factors, and sex specific genome-wide association studies of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study (68,882 women [average age 30, involved in 81,682 pregnancies] and 47,474 of their male partners [average age 33, 55,744 pregnancies]). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity (we checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification). Findings were corrected for multiple comparisons by the Bonferroni method (8 exposures:p-value < 0.00625).ResultsIn women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/L): OR 1.60, 95% CI 1.17 to 2.18,p-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin in women (and possibly higher fasting insulin in men) causing infertility, but findings were imprecise and did not pass ourp-value threshold for multiple testing. Results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility.Conclusions/interpretationGenetic instruments suggest that higher fasting insulin may increase infertility in women.TWEETMendelian randomization suggests that higher fasting #insulin levels increase the risk of #infertility in women. @alvaro_hernaez @theCEFH @Folkehelseinst @ERC_Research #MendelianRandomizationRESEARCH IN CONTEXTWhat is already known about this subject?Observational evidence suggests impaired glucose tolerance, higher lipid concentrations, and higher blood pressure is associated with fertility problems.What is the key question?Are fasting glucose, glycated hemoglobin, fasting insulin, LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure causally related to infertility in women and men?What are the new findings?Two-sample Mendelian randomization suggests that higher fasting insulin levels increase the risk of infertility in women. There was also evidence of higher glucose and glycated hemoglobin in women (and maybe higher fasting insulin in men) causing infertility, but results were imprecise and did not pass ourp-value threshold for multiple comparisons.Findings for lipids and blood pressure were close to the null, suggesting that these did not have a causal role on infertility.How might this impact on clinical practice in the foreseeable future?Treatments to lower fasting insulin levels may reduce the risk of infertility in women.