Investigating physiological effects of weight loss on male fertility

Abstract

Infertility is an emotionally devastating condition for a couple. It is defined as the inability to conceive following 1 year of regular unprotected intercourse. Infertility affects 15% of couples with nearly 50% of cases due to poor sperm quality in the male partner. i.e. ‘male factor infertility’. There are currently no approved pharmacological therapies to directly stimulate spermatogenesis; anti-oestrogens and aromatase inhibitors have limited effectiveness for the treatment of oligospermia and their usage is not supported by current clinical guidelines. Consequently, the only therapeutic option for male factor infertility is assisted reproductive technologies (ART), such as intra-cytoplasmic sperm injection (ICSI) which although effective are resource limiting and unaffordable for many couples worldwide. Therefore, there exists an important and unmet need to develop practical and cost-effective therapies for male factor infertility. Over the last 50 years, whilst sperm quality has declined, obesity has doubled in prevalence. Evidence suggests an association between obesity and male infertility, which makes weight loss a plausible answer to this rising endemic problem. Currently, bariatric surgery is the most effective treatment for obesity leading to major weight loss. However, effects on semen parameters are controversial, with some studies suggesting that the acute starvation-like state induced by bariatric surgery paradoxically reduces sperm function. Recent observational reports have suggested that milder dietary weight loss is associated with improved semen quality and DNA fragmentation index (DFI) in men with obesity and infertility. Low energy diet (LED) is a safe, well-tolerated and established method of achieving modest weight loss which could therefore provide a novel, non-pharmacological therapy for men with obesity-related male factor infertility. However to date, there are currently no prospective randomised controlled studies investigating whether weight loss via LED can improve sperm quality in obese men. Additionally, it is unclear what level of weight loss would be ideal to optimise sperm quality in obese men. This thesis outlines the first ever three randomised controlled studies investigating the physiological effects of weight loss by LED on sperm quality in obese fertile (study 1 and 2) and infertile men (study 3) respectively. I hypothesized that some, but not all, degrees of weight loss would significantly improve sperm concentration in men with obesity, with a potential threshold of weight loss in men leading to improvements 3 in sperm quality. I have measured novel molecular markers, such as seminal reactive oxygen species (ROS) and DFI, associated with male infertility in obese men undergoing weight loss. Collectively, these results will extend our understanding of the physiological effects of weight loss on sperm quality in obese men. This could potentially lead to larger studies determining the effect of weight loss on live birth rates in couples affected by obesity-related male infertility.