The role of obesity in female reproductive conditions: A Mendelian Randomisation study

Abstract

Background: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Methods and Findings: We estimated observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive conditions using logistic regression, generalised additive models, and Mendelian randomisation (two-sample, non-linear, and multivariable) applied to data from UK Biobank and publicly available genome-wide association studies (GWAS). Body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) were observationally (odds ratios (ORs) = 1.02 - 1.87 per 1 S.D. obesity trait) and causally (ORs = 1.06 - 2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Causal effect estimates of WHR and WHRadjBMI, but not BMI, were attenuated compared to their observational counterparts. Genetically predicted visceral adipose tissue mass was causal for the development of HMB, PCOS, and pre-eclampsia (ORs = 1.01 - 3.38). Increased waist circumference also posed a higher causal risk (ORs = 1.16 - 1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06 - 1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% - 50% of the total causal effect of obesity on pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. Conclusions: In this first systematic, large-scale, genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions, we found that common indices of overall and central obesity increased risk of reproductive disorders to heterogenous extents, mediated by metabolic hormones. Our results suggest exploring the mechanisms mediating the causal effects of overweight and obesity on gynaecological health to identify targets for disease prevention and treatment.

Sex Modifies the Effect of Genetic Risk Scores for Polycystic Ovary Syndrome on Metabolic Phenotypes

“…Although other anthropometric features like hip-to-waist ratio (WHR) may be better indicators of health for some phenotypes [44], this information is not routinely collected in clinical settings or reported in EHRs. Furthermore, evidence does suggest that clinically ascertained BMI may be more informative for PCOS than WHR [45]. Finally, despite using the largest PCOS GWAS to date for this analysis, our PCOS PRS still only explains a small portion of PCOS genetic variance.…”

Analysis of HIF2α polymorphisms in infertile women with polycystic ovary syndrome or unexplained infertility

“…Here, we observed that increased BMI and metabolic disorder and insulin resistance (IR) were characteristics of infertile women with PCOS, but not UI. PCOS can lead to obesity; on the other hand, the increasing obesity epidemic, with its related metabolic disorders, is associated with an increased risk of many female reproductive conditions (19).…”

Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis

“…(36) Furthermore there is evidence that increased BMI can lead to conditions associated with decreased fertility. (37) In addition, low adiposity may contribute to reduced fertility as undernutrition may reduce functioning of the reproductive system and lead to defective concentrations of adipocyte-related regulators of endocrine processes such as leptin. (38,39) Previous research has shown a J shaped association between BMI and subfertility, (40) however it is worth noting that our analysis only evaluated linear effects.…”