Investigating the Physiological Effects of Weight Loss on Male Fertility
Phase: NA
Conditions: Male Infertility, Obesity, Weight Loss
Sponsor: Imperial College London

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uInvestigative Medicine 
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6th floor, Commonwealth Building 
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Imperial College Faculty of Medicine 
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Hammersmith Hospital 
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Du Cane Road 
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London W12 ONN 
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Investigating physiological effects of weight loss on male fertility 
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Main sponsor:  Imperial College London 
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Funders: National Institute for Health Research post-doctoral Fellowship  
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IRAS project ID: 236553 
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Study management group 
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Chief Investigator: Dr Channa N. Jayasena 
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Co-Investigators: Prof. Gary Frost, Prof Waljit Dhillo, Dr A Dimakopoulou, Mr A. Brown, Dr A Sharma 
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Study Management: Dr Channa N. Jayasena 
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Clinical queries  
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Clinical queries should be directed to Dr. Channa Jayasena who will direct the query to the appropriate 
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person.   
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Sponsor 
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Imperial College London is the research Sponsor for this study. For further information regarding the 
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sponsorship conditions, please contact the Head of Regulatory Compliance at: 
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Ms Becky Ward 
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Joint Research Compliance Office 
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Imperial College London and Imperial College Healthcare NHS Trust 
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Room 215, Level 2, Medical School Building 
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Norfolk Place, London, W2 1PG 
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Tel: 0207 594 9459 | E-mail: becky.ward@imperial.ac.uk 
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Funder  
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The NIHR Trainees Coordinating Centre 
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NIHR 
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Leeds Innovation Centre 
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103 Clarendon Road 
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Leeds, LS2 9DF 
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Tel: 0113 346 6260   
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Fax: 0113 346 6272 
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This protocol describes the proposed study and provides information about procedures for entering 
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participants. Every care was taken in its drafting, but corrections or amendments may be necessary. These 
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will be circulated to investigators in the study. Problems relating to this study should be referred, in the first 
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instance, to the Chief Investigator.  
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This study will adhere to the principles outlined in the NHS Research Governance Framework for Health and 
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Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data Protection Act and 
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other regulatory requirements as appropriate. 
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INTRODUCTION 
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An increasing number of couples find it difficult to have children i.e. they have reduced reproductive 
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capacity (NICE 2016). During the last few decades, tremendous advances have been made in the treatment 
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of women with reduced reproductive capacity e.g. in vitro fertilization therapy (IVF) and specialized clinics 
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for recurrent miscarriage. However, poor sperm quality is the causative factor in 40% of infertile couples i.e. 
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‘male factor infertility’. There is no therapy proven to increase sperm function in men with reduced 
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reproductive capacity. Consequently, the only therapeutic option for male factor infertility is assisted 
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reproductive technologies (ART) such as IVF and intra-cytoplasmic sperm injection (ICSI) (Human Fertilisation 
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and Embryology Authority 2013); these require daily hormonal injections to stimulate several egg follicles to 
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grow in the female partner. The eggs are collected surgically from the ovaries before fertilized with sperm 
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from the male partner, prior to incubation and re-implantation of embryos to the uterus. Although highly 
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effective, IVF and ICSI are invasive and have uncommon but potentially life-threatening complications for the 
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female partner such as ovarian hyper-stimulation syndrome (OHSS) (RCOG 2016). In 2013, over 20,000 ICSI 
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cycles were performed in the UK for male factor infertility, costing a total of £120M (Human Fertilisation and 
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Embryology Authority 2013). NHS funding for IVF and ICSI is restricted and diminishing. Therefore, there 
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exists an important and unmet need to develop practical and cost-effective first-line therapies for male 
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factor infertility. 
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Obesity is a common cause of reduced reproductive capacity in men. Obesity impairs fertility through 
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multiple mechanisms, including insulin resistance, and increased conversion of testosterone to oestrogen 
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(Craig et al. 2017). A recent large meta-analysis of over 20 observational studies demonstrates that obesity is 
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significantly associated with poor sperm quality (Sermondade et al. 2013). The major association of obesity 
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with poor sperm function makes weight loss a logical treatment. The most effective treatment for obesity is 
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bariatric surgery, but the acute starvation-like state induced by the surgery inhibits sperm function, making 
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this an inappropriate approach (Witalison et al. 2015). But recent evidence suggests that milder weight loss 
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could improve male fertility. Preliminary data suggest that live birth outcomes following IVF treatment are 
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significantly increased when male partners of obese women voluntarily lose 2-3kg weight when compared 
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with male partners of obese women who chose not to lose weight (Belan 2015). However, to date no 
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prospective controlled study has investigated whether weight loss can improve sperm function in obese men 
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with reduced reproductive capacity. Furthermore, it is unclear why moderate but not severe weight loss 
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improves sperm function in obese men with reduced reproductive capacity.  
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Results of this study will inform us for the first time whether Caloric Restriction using LED increases sperm 
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quality significantly when compared with standard NHS lifestyle advice in obese men with reduced 
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reproductive capacity. In addition, the study may demonstrate that LED significantly reduces levels of 
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markers associated with cardiovascular and diabetes risk in obese men with reduced reproductive capacity. 
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Results of this study are likely to be adopted by many couples and clinicians immediately, and could have a 
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positive effect on live birth rates in affected couples. 
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The aim of this study is to determine the optimum level of weight loss to improve sperm quality in obese 
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men. We will then investigate how moderate weight loss may improve reproductive function in obese men. 
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Finally, we will determine if weight loss improves sperm quality and cardio-metabolic health better than 
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standard weight loss advice in obese men with reduced reproductive capacity. 
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IMPACT: The current level of NHS expenditure on IVF therapy is unsustainable, and there exists no evidence-
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backed therapy for improving sperm count in men with reduced reproductive capacity. Weight loss via LED 
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could increase the sperm count in obese men therefore, funding this project will help the NHS develop a 
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simple and cost-effective treatment which could reduce our reliance on IVF as a first-line therapy for 
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affected couples.  
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STUDY OBJECTIVE  
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Part 1 Objective: Use caloric restriction to determine the level of weight loss associated with 
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optimum improvement of sperm concentration in men with weight-related reduced reproductive 
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capacity 
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Part 2 Objective: Measure changes in the markers of reproductive stimulation during caloric 
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restriction in men with weight-related reduced reproductive capacity 
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Part 3 Objective: Determine whether targeted caloric restriction significantly improves sperm 
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quality, glycaemic and lipid levels when compared with standard NHS dietary advice, in men with 
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weight-related reduced reproductive capacity 
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4.           Secondary Objectives: Quality of life of participants undergoing weight loss; pregnancies or live     
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               births following participation. 
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STUDY DESIGN AND PARTICIPANT ENTRY 
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Study design:  
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Parts 1, 2 and 3: Physiological, randomized, controlled study using a behavioural intervention  
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Participant recruitment: 
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Participants will be recruited from Medicine, Bariatric, Reproductive, Gynaecology clinics and department of 
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Andrology at Imperial College Healthcare NHS Trust hospitals or Patient Identification Centers. Patient 
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records will be assessed and reviewed by members of the direct care team, rather than the research team. 
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Potentially interested patients will be contacted by members of the direct care team by any of the following 
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methods of contact: verbal; phone; e-mail; text messaging e.g. SMS. If interested, they will be given a 
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participant information sheet about the study.  Paper or online adverts will also be used to enhance 
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recruitment. Men interested in participating in the study, will be contacted by the research team at least 24h 
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after being informed about the study. A member of the research team will briefly screened participants 
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against the inclusion criteria. If they broadly fit the criteria of the study, they will be invited to attend the 
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Andrology Department, Imperial College Healthcare NHS Trust later for a screening visit during which 
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informed consent will be obtained. 
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Participants will be asked to provide their  GP contact details, so that GPs can be notified by a standard 
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letter.  GPs will be given contact details of study investigators in case they have further questions. 
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Inclusion Criteria for Part 1, 2 and 3 
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4. 
Male 18-60 years of age 
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Body mass index (BMI) >30kg/m2 
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Evidence of reduced reproductive capacity (e.g. reduced sperm concentration or motility) 
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Exclusion Criteria for Part 1, 2 and 3 
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History of undescended testes, testicular surgery or mumps infection 
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Hormonal therapy such as testosterone or selective oestrogen receptor modulators 
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History of systemic cytotoxic therapy or pelvic radiotherapy 
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Chronic systemic disease, such as cardiac, renal or liver failure 
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At least one of the following: 
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Alcohol intake >30 units per week 
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Smoking daily 
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Recreational drug use at a frequency not less than weekly 
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Acute illness likely to affect the result of study  
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Impaired ability to provide full consent to take part in the study 
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An occupation requiring strenuous physical exercise that may require a high energy diet 
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Withdrawal criteria 
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The participants have the right to withdraw from the study at any time without needing to provide any 
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reason to the study investigators 
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METHODS 
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Confidentiality of participants will be protected as each one will be given an arbitrary unique ID number by a 
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member of the research team. Participants will be randomized using an online randomisation tool, such as 
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'random.org'. 
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Part 1: Participants will be randomized to receive standard NHS advice for weight loss, or one of three levels 
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of caloric restriction (e.g. 1500, 1000 and 800kcal/day) during an up to 8-week protocol. 15 participants will 
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be allocated in each of the dietary groups, so 60 participants in total. In participants randomized to one of 
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the energy deficit groups, commercially available products (approximately 200kcal per product), will be used 
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alone or in combination with normal meals to achieve the desired level of caloric intake. During each study 
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visit, body weight will be measured and body composition will be assessed using bioelectrical impedance 
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analysis. Participants will be asked to produce a semen sample and have their bloods taken by an 
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experienced member of the research team, during each study visit within Department of Andrology, 
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Hammersmith Hospital. 
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Part 2: Participants will be randomized in three groups for a period up to 16 weeks. 15 participants will be 
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allocated per group, so 45 participants in total. One group will receive standard NHS advice (control group) 
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during their study visits. The other group will receive LED during the whole protocol. The level of Caloric 
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Restriction will be based on the results of Part 1. The third group will be men undergoing weight loss via 
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bariatric surgery at Imperial College Healthcare NHS Trust as part of their routine clinical care. Participants 
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undergoing bariatric surgery will not be subject to any alterations in dietary intake when compared with 
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their routine clinical care. Blood will be collected during the morning from fasted participants for various 
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hormone levels, such as reproductive hormones and leptin measurement.  
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Part 3: Participants will be randomised to one of two groups, for a period up to 16 weeks and will receive 
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LED or standard NHS advice for weight loss. 26 participants will be allocated per group, so 52 participants in 
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total. The level of Caloric Restriction will be based on the results of Part 1. Participants will have their semen 
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analysed and bloods taken during each visit by a member of the reasearch team. They will also complete a 
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validated questionnaire at the beginning of and end of study period to assess the effect of weight loss on 
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their quality of life. Lastly, participants will be contacted by a member of the research team up to 24 months 
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following commencement of the study protocol, tto ask if they have experienced pregnancy since they were 
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last seen. 
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SCHEDULE OF STUDY VISITS   
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Screening visit (Visit 0;(Part 1, 2 and 3): 
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Consent: The participant will be greeted by a member of the research team or their NHS clinicians and will 
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be shown to a private consultation room. The researcher would then give the participant a brief verbal 
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explanation of the study, answer any questions about the study, and then seek informed, written consent. 
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Clinical History at Study Recruitment: A brief history will be taken from the patient, including past medical 
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history, drug history, family history, and reproductive history.  
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Examination: Height and weight will be measured. Testicular volume estimation will be performed using a 
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Praeder orchidometer by a member of the reaseach team. This is a simple and painless procedure which is 
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routinely performed in men with infertility. In brief, the testicular size is compared to a range of plastic or 
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wooden beads of known volume. This procedure usually takes up to 1 min to perform. 
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Collection of blood and semen: Venepuncture will be performed by a member of the research team to 
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collect a blood sample (maximum volume 20ml) to measure various hormones such as luteinising hormone 
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or testosterone. Blood hormone analyses will be performed by Department of Clinical Biochemistry, Imperial 
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College Healthcare NHS Trust in collaboration with Dr. Emma Walker (Consultant Clinical Biochemist). All 
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participants will be asked to collect their own semen into a sterile container in a designated private room in 
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the Andrology Department, Imperial College Healthcare NHS Trust. In case a participant is unable to provide 
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a semen sample on the day a new appointment will be offered. Participants will be given sufficient time to 
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produce a sample. Semen samples will be analysed for various molecular markers of sperm function such as 
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sperm concentration, sperm motility and reactive oxygen species. Semen analysis will be performed 
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according to WHO criteria for the examination and processing of human semen. 
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All samples will be anonymised with a unique study code, and stored in Andrology Department, Imperial 
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College Healthcare NHS Trust. Samples will be analysed in Imperial College Healthcare NHS Trust and 
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disposed after the study has finished. 
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Study visits 1-7 (Part 1): Participants will each undergo an up to 8-week protocol and will be asked to attend 
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up to 8 visits (Screening visit + Visits 1-7) during the study period. Visits would involve brief history, weight 
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measurement, blood pressure, body composition analysis and advice on total daily caloric intake. Blood and 
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semen will be additionally collected as outlined in the screening visit. This would take 30 to 60min to 
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perform. 
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Study visits 1-7 (Part 2): See Figure 2. All participants will attend regular visits to assess their reproductive 
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function, before and during the commencement of their dietary regime (bariatric surgery as part of routine 
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clinical care, NHS advice or LED). Obese men will each undergo an up to 16-week protocol and will be asked 
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to attend up to 8 visits during the study period. 
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Study visits 1-7 (Part 3): See Figure 3. Participants will each undergo a maximum of 16-week protocol with 
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up to 8 study visits. During each study visit, body weight and blood pressure will be measured. Body 
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composition will be assessed using bioelectrical impedance analysis. Participants will be asked to produce a 
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semen sample during each study visit within Department of Andrology, Hammersmith Hospital. Semen 
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analysis will measure different parameters such as seminal volume, sperm concentration, total and 
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progressive sperm motility, and sperm morphology, reactive oxygen species and sperm DNA fragmentation 
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index. During each visit, blood will be collected during the morning from fasted participants for different 
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hormones and metabolic parameters such as testosterone, glucose and cholesterol levels. Finally, we will 
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study the effects of weight loss on the quality of life via a validated questionnaire, such as the 'Moorehead-
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Ardelt Quality of Life Questionnaire II'. We will contact participants via phone or email up to 24 months 
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following commencement of the study protocol, to ask if they have experienced pregnancy since they were 
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last seen. 
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Contact of participants with fertility problems which have not been diagnosed previously: 
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If tests performed during the study highlight clinically significant infertility issues which have not been 
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highlighted previously, the study team would facilitate appropriate NHS treatment, by providing any 
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information needed for their GP to make a referral for specialist clinical care. 
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Statistical considerations: 
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Sample size: The sample size calculations have undergone national, external peer review by the Fellowships 
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committee of the National Institute for Health Research (NIHR). Calculations were performed by an 
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independent statistician (Dr. Les Huson, Senior Statistician, NIHR Imperial Clinical Research Facility), and used 
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assumptions based on clinical experience including anticipated participant drop-outs.  
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We will use mean levels of sperm concentration during the study period as a primary endpoint, which should 
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have less variability in levels when compared with sperm concentration during a single study visit alone.  
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Part 1: Under the assumption that the mean final sperm concentration in the control group will be 2 mill/ml, 
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and that, in the group having maximum calorie deficit the mean final sperm concentration will be 12 mill/ml 
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(a 6-fold increase), 12 subjects in each of the dietary groups will give greater than 90% power to detect a 
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statistically significant linear trend in increased sperm concentration across the groups [Pinheiro J Biopharm 
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Stat 2006]. This calculation assumes that the between-patient standard deviation in sperm concentration is 6 
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mill/ml, which is a conservative estimate based on doubling the standard deviation observed in a sample of 
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data from 1000 patients treated in the Andrology Department at Hammersmith Hospital. Note also that the 
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sample size of 12 per group matches the recommendation made by Julious [Pharm Stat 2005] for pilot and 
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exploratory studies in cases where there is uncertainty about effect sizes. Based on previous experience, we 
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anticipate a 20% drop-out rate, so will recruit 15 participants per group i.e. 60 participants in total. 
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Part 2: A sample size of 12 per group (as for study 1). Based on previous experience, we anticipate a 20% 
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drop-out rate, so will recruit 15 participants per group i.e. 45 participants in total. 
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Part 3: On the conservative assumption that NHS dietary advice under research conditions will increase 
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sperm concentration from 2 to 6mill/ml (3-fold), which is half of the 6-fold effect size anticipated during LED 
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(see Study 1 analysis plan), then 22 per group would give 90% power to detect a statistically significant 
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increased sperm concentration between groups (alpha=0.05, two-sided). This calculation assumes that the 
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standard deviation in sperm concentration is 6 mill/ml, which is a conservative estimate based on doubling 
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the standard deviation observed in a sample of data from 1000 patients treated in the Andrology 
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Department at Hammersmith Hospital. Based on previous experience, we anticipate a 20% drop-out rate, so 
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will recruit 26 participants per group i.e. 52 participants in total. 
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Figure 1. Summary of study 1 protocol 
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Figure 2. Summary of study 2 protocol 
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NHS ADVICE (Control)
• Body weight, waist circumference, body composition. blood pressure
• Serum LH, FSH, testosterone, SHBG, E2, HbA1c, fasting glucose, fasting 
lipids
• Adipokines: leptin, IL6 and TNF
• Semen analysis, DNA fragmentation, semen reactive oxidative species
• Completion of questionnaires (visit one and last visit only)
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COMPLETED 
WEEKS OF 
PROTOCOL:
Screening
LED
Bariatric surgery (observation)
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12
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N=45 (3 groups of 12)
Baseline 
monitoring 
Intervention
 
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Figure 3. Summary of study 3 protocol 
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NHS ADVICE (Control)
• Body weight, waist circumference, body composition. blood pressure
• Serum LH, FSH, testosterone, SHBG, E2, HbA1c, fasting glucose, 
fasting lipids
• Semen analysis, DNA fragmentation
• Completion of questionnaires (visit 1 and week 20 only)
Intervention
COMPLETED 
WEEKS OF 
PROTOCOL:
Screening
LED (weight loss and maintenance)
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12
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N=52 (2 groups of 26)
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Baseline 
monitoring 
 
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SAFETY AND PROTECTION OF PARTICIPANTS 
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Venepuncture may cause mild pain or discomfort. Some inconvenience and embarrassment to participants 
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may result from answering questions about their health, providing semen samples and undergoing testicular 
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volume assessment. This will be explained to participants in the information sheet prior to consent being 
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sought. 
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To minimise any risks, inconvenience or embarrassment to participants, the study will be performed by a 
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clinician or allied healthcare professional experienced in performing the above procedures. Participants will 
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have phone or e-mail access to a study investigator during the study to raise any concerns or issues relating 
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to their involvement.  
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As part of the study some participants will be given LED in the form of liquid products to take for a maximum 
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of 16 weeks. LED are routinely given for 6 months (Rolland C et al 2009; Li et al 2014) and are commercially 
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available and considered highly safe, so is not anticipated to have associated risks Lifestyle advice should be 
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given to all patients as part of routine primary care, so we do not anticipate randomization to the simple 
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lifestyle advice group to unduly disadvantage the healthcare of patients. 
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ADVERSE EVENTS 
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Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.  
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Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that: 
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Results in death 
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Is life-threatening – refers to an event in which the subject was at risk of death at the time of the 
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event; it does not refer to an event which hypothetically might have caused death if it were more 
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severe 
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 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
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 
Results in persistent or significant disability or incapacity 
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 
Is a congenital anomaly or birth defect 
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Medical judgment will be exercised in deciding whether an AE is serious in other situations.  Important AEs 
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that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardize the 
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subject or may require intervention to prevent one of the other outcomes listed in the definition above, will 
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also be considered serious. 
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Reporting Procedures 
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All adverse events should be reported.  Depending on the nature of the event the reporting procedures 
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below will be followed.  Any questions concerning adverse event reporting should be directed to the Chief 
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Investigator in the first instance. 
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Non serious AEs: All such events, whether expected or not, will be recorded.  
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Serious AEs: An SAE form will be completed and faxed to the Dr. Channa Jayasena within 24 hours.  
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However, hospitalisation, serious illness or death due to unrelated pre-existing conditions, and 
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hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs. 
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All SAEs should be reported to the London Bridge REC committee where in the opinion of the Chief 
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Investigator, Dr. Channa Jayasena, the event was: 
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‘related’, i.e. resulted from the administration of any of the research procedures; and 
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‘unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence 
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Reports of related and unexpected SAEs will be submitted within 15 days of the Chief Investigator, becoming 
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aware of the event. Dr. Channa Jayasena will also notify the Sponsor of all SAEs.  
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STATISTICS AND DATA ANALYSIS 
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The analysis plan was made with Dr. Les Huson, Senior Statistician, NIHR Imperial Clinical Research Facility. 
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Currently planned are the analyses below: 
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Part 1: Fertility, endocrine and metabolic markers in major groups with different caloric deficit will 
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be compared using one-way ANOVA. 
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Part 2: Hormone profiles during 8-hour studies were analysed using ANOVA. 
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 
Part 3: We anticipate that data will be normally distributed. Parameters will be compared in the LED 
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group and group on lifestyle advice using an unpaired two-tailed t-test or equivalent non-parametric 
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tests if required 
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Changes in fertility markers will be correlated with endocrine markers (e.g. Testosterone) using 
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linear regression. 
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We also anticipate distributing questionnaires in a maximum of 52 patients. Qualitative analysis 
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methods will be utilised to provide a summary of the participants answers to the questionnaire. 
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REGULATORY ISSUES  
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Ethics approval 
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The Chief Investigator, Dr. Channa Jayasena, has sought approval from the XXXXX. The study will be 
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submitted for Health Research Authority Approval (HRA) at Imperial College Healthcare NHS Trust. The Chief 
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Investigator will obtain confirmation of capacity and capability approval  from the Joint Research Compliance 
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Office before accepting participants into the study. The study will be conducted in accordance with the 
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recommendations for physicians involved in research on human subjects adopted by the 18th World Medical 
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Assembly, Helsinki 1964 and later revisions.   
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Consent 
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Patients attending clinic appointments at Imperial College Healthcare NHS Trust will be informed by a 
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member of staff in the department (clinician, nurse, clinical scientist or receptionist) that a research study is 
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being performed in the department, and they will be given a participant information sheet to explain aspects 
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of the study. If the patient would like to participate, they will be given an appointment to attend the 
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Andrology Department at Hammersmith Hospital at a later date. On arrival to the Andrology department, a 
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member of the research team researcher would then give the patient a brief verbal explanation of the study, 
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answer any questions about the study, and then obtain informed, written consent if the patient was still 
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happy with give this.  
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Data handling, record keeping and sample storage 
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Results of the tests performed during this study could result in incidental findings which are clinically 
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significant (i.e. need further medical assessment). Personal contact details are therefore required for 
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communication with the patients participating in the study. This information is held solely for 
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communication between researchers and participants. 
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Data security measures are in place at all times according to Imperial College’s Information Security Policy. 
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Consent forms containing personal data in paper form will be held in the study master file, which will be kept 
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in a locked office cabinet within a locked office within the Section of Investigative Medicine, Commonwealth 
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Building, Imperial College Faculty of Medicine, Hammersmith Hospital. Technical measures, for example use 
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of encryption tools will be used to protect personal data held in electronic form. This data will be accessible 
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to study investigators.  
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Personal details stored on NHS computers will be password-protected, and only accessed by researchers 
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involved in the study. Participants will be given an arbitrary personal study code number which will be used 
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throughout the study and in data analysis. 
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Data will be stored for 10 years according to Imperial College Data Management policy. Processing of 
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personal data including its collection, use, storage, adaptation, dissemination or disposal will follow the 
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principles as set out in the Data Protection Act 1998. 
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Indemnity 
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Imperial College London holds negligent harm and non-negligent harm insurance policies which apply to this 
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study. 
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Sponsor 
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Imperial College London will act as the main Sponsor for this study.  Delegated responsibilities will be 
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assigned to the NHS trusts taking part in this study. 
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Funding 
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This is a National Institute for Health Research post-doctoral Fellowship funded project. 
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Audits 
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The study may be subject to inspection and audit by Imperial College London under their remit as sponsor 
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and other regulatory bodies to ensure adherence to GCP and the NHS Research Governance Framework for 
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Health and Social Care (2nd edition). 
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STUDY MANAGEMENT 
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The day-to-day management of the study will be coordinated through Dr Channa Jayasena. 
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PUBLICATION POLICY 
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We aim to disseminate data generated during the study via publication in peer reviewed medical journals, 
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presentation at conferences and publication in the lay press as appropriate. During publication the data will 
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be completely anonymised and no personal information will be published. Participant confidentiality will be 
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maintained throughout. 
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Principle investigator: Dr. Channa Jayasena 
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c.jayasena@imperial.ac.uk Tel: 0208 383 3242. 
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