Title: Targeted caloric restriction to improve sperm quality in obese men with infertility
Funder: Department of Health and Social Care

Abstract: Background: One in seven couples has infertility. Poor sperm quality is one of the most common causes of infertility. There is currently no recommended therapy to increase sperm function in male factor infertility. Consequently, couples with male infertility require assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI), which are invasive and may cause serious complications. Furthermore, 120M is spent in the UK annually on ART for male infertility, which is unsustainable. The NHS therefore needs to develop a simple and cost-effective first-line therapy to improve sperm function for couples with male factor infertility. Most infertile men are obese or overweight. A large meta-analysis demonstrates that obesity is strongly associated with poor sperm quality. Bariatric surgery induces a starvation-like state induced which could inhibit sperm function, making this an inappropriate therapy for male infertility. Observational data suggest that modest weight loss could improve the chance of successful IVF treatment. However, no prospective controlled study has investigated whether weight loss can improve sperm function in obese men with infertility. Low energy diet (LED) is an established and safe method of weight loss, replacing normal diet with liquid nutritional products. Following ethical approval, I generated pilot data in five obese men with infertility undergoing a 4-week LED with 800kcal daily caloric intake. Mean weight loss was 7.6kg and sperm concentration increased by a median of 6-fold (range 0.19 to 9-fold) versus baseline sperm concentration. My pilot data suggests that LED therefore provides a potential novel therapy for men with obesity-related infertility. To assess the therapeutic potential of LED in couples with male infertility, three questions need to be answered. What is level of caloric restriction using LED will produce the greatest improvement in sperm function? How does the moderate weight loss during LED improve reproductive function in obese men? Does LED improves sperm quality and markers of cardio-metabolic health better than standard NHS weight loss advice in obese men with infertility? Plan of investigation: Study 1: I will perform a dose-finding study determining which practically achievable level of dietary energy restriction (-600, -1000 or -1500kcal/day deficit) gives the greatest improvement of sperm function when compared with normal diet, in obese men with infertility. Study 2: I will determine if LED can restore levels of the hypothalamic marker of reproduction called LH pulse amplitude, which is significantly reduced in men with obesity. Study 3: I will perform a randomized controlled study determining whether targeted caloric restriction significantly improves sperm quality, glycaemic and lipid levels when compared with standard NHS dietary advice, in obese men with infertility.Impact of study: The only recommended treatments for male infertility (IVF and ICSI) are increasingly unaffordable for the NHS. The proposed studies would determine for the first time if LED provides a simple, first-line therapy for couples with male infertility associated with obesity. Furthermore, it could pave the way to future studies determining how effectively weight loss intervention reduces future risks of cardiovascular and metabolic disease, in obese men with infertility. Potential healthcare and financial benefits to the NHS could be dramatic, by rationalizing IVF and ICSI treatment, and by modifying the lifestyle of obese men at a time when they may be most receptive to healthcare advice.

Lay abstract: What do we know already? Infertility affects one in seven couples in the UK. Infertility puts enormous strain on personal relationships, and can be socially marginalising for affected couples. Nearly half of the time, infertility is caused by the female partner being unable to release eggs properly (female factor infertility'). In most other cases, infertility is caused by the male partner having a low sperm count (male factor infertility'). In vitro fertilization (IVF) therapy has revolutionised the treatment for female factor infertility, by using hormones to help the woman release lots of eggs. These eggs are collected surgically, fertilised by her partner's sperm, and then placed back in the womb. Unfortunately, there is currently no therapy recommended to improve a man's sperm count. Couples with male factor infertility therefore require IVF therapy for the female partner. Although highly effective, IVF therapy is a major surgical procedure which can rarely cause life-threatening complications. About 120 million is spent in the UK each year using IVF to treat couples with male infertility, but NHS funding for IVF therapy is reducing and has even stopped in some parts of the UK. Couples with male infertility therefore need a simple, safe and cost-effective first-line treatment for improving a man's sperm count, which could reduce the need for IVF in couples with male infertility. Obesity is a major cause of male infertility. Excessive fat tissue interrupts hormonal signals within the brain and testicles which are required for sperm production. Several large studies demonstrate that obese men have poorer levels of healthy sperm than non-obese men. Weight loss (bariatric) surgery cannot effectively improve sperm quality in obese men; this is unsurprising, since extreme starvation (such as following bariatric surgery) is known to suppress sperm production. However, a study has shown that couples undergoing IVF treatment are more likely to get pregnant if the male partner loses modest amounts of weight in the year beforehand. I have performed a pilot study giving a 'Low Energy Diet' (consisting of liquid shakes with an 800 daily calorie intake) to five obese men with infertility. Over a 4 week period, these men lost 7kg and an improvement in sperm count was seen in the all 5 men. My pilot data suggest that a mild degree of weight loss may increase the sperm count in obese men with infertility.What is the justification for doing this study? There is tremendous inequality in the healthcare of couples with male infertility, since its sole treatment (IVF) is highly expensive and its provision in the NHS is subject to cost-pressures. A growing number of men with infertility are obese. My pilot data suggests that short-term dietary weight loss could improve sperm count in obese men with infertility. I therefore predict that short-term dieting could provide a simple, safe and affordable method for improving sperm count in men with infertility.What do I want to do? My pilot study suggests that a Low Energy Diet (LED) could be used to increase sperm count in men with infertility. But we currently do not know what level of dieting using LED will improve sperm count the most. I will therefore compare the sperm count achieved during three different strengths of LED in obese men with infertility. This will allow me to identify the best LED for increasing sperm count in obese men with infertility. Secondly, I will study how LED may restore the healthy pattern of hormonal activity needed for sperm production, in obese men with infertilty. Finally, I will perform a head-to-head' study determining whether LED is better than standard NHS advice at improving fertility and pregnancy rates in obese men. During this study, I will also check if LED reduces levels of sugar and cholesterol in the blood, which are known risk factors for developing heart disease and diabetes in the future. What impact will the study have for the NHS? The current level of NHS expenditure on IVF therapy is unsustainable, and there exists no evidence-backed therapy for improving sperm count in couples with male infertility. My pilot work suggests that LED could increase the sperm count in obese men. Funding this project will help the NHS develop a simple and cost-effective treatment which could reduce our reliance on IVF as a first-line therapy in couples with obesity-related male factor infertility. Furthermore, the proposed treatment could reduce risk factors for developing heart disease and diabetes in obese men, at a time when they are most likely to listen to advice.

Research activity codes: 6.7 PHYSICAL
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR;METABOLIC AND ENDOCRINE