Impact of bariatric surgery, lifestyle change, and pharmacotherapy on fertility in men with obesity: a systematic review protocol.

Infertility, defined as the inability to achieve pregnancy after 12 months of unprotected sexual intercourse, is estimated to have a lifetime prevalence of approximately 1 in 6 people. 1 Infertility may have discrete causes, which are typically classified as female factor (eg, anovulation, tubal occlusion, endometriosis) or male factor (hypogonadism, azoospermia). In a large number of cases, however, the cause is multifactorial or not identified. 2 One factor contributing to infertility in both men and women is the presence of excess body fat. In the past 50 years, the prevalence of obesity, as determined by a body mass index (BMI) greater than 30 kg/m 2 , has nearly tripled, and is currently estimated to affect almost 20 billion adults. 3 Reproductive age obesity has reached epidemic proportions, with current data indicating that 40% of Americans aged 20–39 years and 23%–30% of Australians aged 25–45 years are obese, with greater rates in men compared with women. 4 , 5 Extensive research shows that female obesity impairs conception through multiple mechanisms, including disruption of the hypothalamic-pituitary-gonadal axis, impaired oocyte maturation and quality, and impaired implantation. 6 Conception rates in women with obesity (BMI >30 kg/m 2 ) are reduced by approximately 25%–33% compared with women with a BMI of <25 kg/m 2 . 7 , 8 Male obesity also has detrimental impacts on conception, with a recent meta-analysis showing that infertility rates increase by ~50% in men with obesity compared with normal weight men. 9 Whilst underlying mechanisms are not fully established, obesity is associated with multiple derangements in basic sperm parameters, such as sperm count, motility, viability, and morphology, 10 and specialized markers of fertility, such as oxidative stress in seminal fluid and sperm, 11 sperm DNA fragmentation, 11 and sperm acrosomal reaction. 12 Cohort studies indicate that male obesity likely has epigenetic effects and transgenerational consequences. 13 Combined diet and exercise interventions in infertile women with overweight and obesity are associated with increased rates of pregnancy (risk ratio 1.87 [95% CI 1.2, 1.93]) and live birth (risk ratio 2.2 [95% CI 1.23, 3.93]). 14 Infertility rates are also reduced following bariatric surgery in women with severe obesity (risk difference −0.24 [95% CI −0.42, −0.05]), 15 albeit with increased risk of pregnancy complications. 16 Current national and international guidelines recommend weight loss of approximately 5%–10% body weight for women who are overweight or obese prior to conception. 17 , 18 However, preconception guidelines provide limited information regarding male weight optimization. Fewer data are available to guide health recommendations, with the most recent meta-analyses assessing the role of weight loss in infertile couples indicating a lack of sufficient randomized studies in men to clarify the benefits of weight loss. 14 , 19 Similarly, recent meta-analyses have also identified no association between bariatric surgery and improved sperm quality, 20 although they do not assess all markers of sperm quality. There is significant evidence implicating the role of lifestyle factors in fertility outcomes. A recent systematic review highlighted that common dietary components such as coffee, alcohol, sugar, sweetened beverages, and dairy products are associated with changes in sperm parameters in observational studies. 21 Lifestyle factors such as physical inactivity, smoking, alcohol intake, and diet are also predictive of developing a “metabolically unhealthy” obesity phenotype characterized by complications such as hypertension, dyslipidemia, and diabetes, 22 which are also associated with poorer sperm parameters. 23 Improvement in basic sperm parameters has been shown repeatedly following healthy lifestyle interventions in both animal 24 and human studies. 25 , 26 A recent trial using the glucagon-like peptide analogue, liraglutide, also identified that liraglutide was effective at maintaining weight loss achieved by a very low calorie diet, and was associated with improved sperm quality. 27 Despite this, no systematic review has assessed the association between lifestyle interventions or pharmacotherapy for weight loss and fertility parameters. Further, the association between degree of weight loss achieved by these modalities and changes in fertility parameter has not been previously assessed. The primary objective of this systematic review is to determine whether specific interventions typically undertaken for health improvement or weight loss (such as dietary change/exercise, bariatric surgery, or pharmacotherapy) in fertile-age men with overweight/obesity are associated with improvement in fertility outcomes. The secondary objective is to determine whether the magnitude of weight loss achieved via these health interventions is associated with a greater improvement. A preliminary search of PROSPERO, MEDLINE, Cochrane Database of Systematic Reviews, and JBI Evidence Synthesis found no registered systematic reviews assessing the impact of multiple health interventions and weight loss on a broad range of fertility parameters in men with overweight/obesity irrespective of fertility status. A recently published meta-analysis 20 has quantified the impact of bariatric surgery on semen quality; however the meta-analysis did not assess the relationship between the magnitude of weight loss and change in semen quality An in-progress review (PROSPERO CRD42022289021) assessing the impact of bariatric surgery and sperm quality is also limited to observational prospective studies. A second in-progress review on the impact of weight loss in obese men (PROSPERO CRD42020219561) is limited by a history of subfertility. Two prior meta-analyses assessing the impact of weight loss in infertile obese populations have not identified any studies on men. 14 , 28 This review will assess retrospective or prospective studies, including experimental studies, cohort studies, case reports, case studies, and case-control studies.

Study design and search strategy determined by all authors. AP wrote the manuscript, with all authors editing and proofreading. All authors have read and approved the final manuscript.

• Is there a change in markers of fertility in men with overweight/obesity treated with i) bariatric surgery; ii) lifestyle interventions, including dietary change and exercise; or iii) pharmacological treatment for weight loss? •Is there a dose–response relationship between change in weight and markers of fertility after i) bariatric surgery; ii) lifestyle interventions, including dietary change and exercise; or iii) pharmacological treatments for weight loss?

The proposed review will be conducted in accordance with JBI methodology for systematic reviews of etiology and risk. 30 The review has been registered on PROSPERO (CRD42022349665). The search strategy will aim to identify both published and unpublished studies. Five databases will be searched (PubMed, Embase [Ovid], Cochrane Central Register of Controlled Trials, Web of Science Core Collection, Scopus) for relevant articles. Unpublished data will be identified through searches of ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry platform. The reference lists of all full-text articles will also be reviewed to capture any missing literature. Search terms were identified from an initial limited search of PubMed and Embase (Ovid). Keyword and index search terms were identified in the 4 following categories: i) male, man, men, paternal; ii) obesity, overweight, overnutrition; iii) weight loss, nutrition therapy, lifestyle, exercise, diet, weight reduction, nutrition, bariatric surgery, metabolic surgery, pharmacotherapy, glucagon-like peptide; and iv) fertility, infertility, pregnancy, conception, fetal, assisted reproduction, stillbirth, miscarriage, semen, semen volume, spermatozoa, sperm count, motility, morphology, sperm maturation, aspermia, oligospermia, DNA damage, DNA fragmentation, reactive oxygen species, and lipid peroxidation. A full search strategy for PubMed is shown in Appendix I . Where multiple iterations of a word exist (eg, fertile, fertility), truncation will be used. The search strategy will be adapted as required for each database. Only studies published/translated into English will be considered for inclusion, as the reviewers are fluent only in English. Studies with an English abstract that are subsequently identified at full-text review as written in another language (without English translation) will be reported in the final review. If the abstract and full text are entirely written in a language other than English, they will not be reported, as the reviewers will be unable to determine if relevant. No date limitations will be applied. All identified citations will be collated in the JBI System for the Unified Management, Assessment and Review of Information 31 (JBI SUMARI; JBI, Adelaide, Australia). Titles and abstracts will be assessed by 2 independent reviewers against the inclusion criteria. Relevant articles will be subsequently reviewed in full text by 2 independent reviewers. In cases of discrepancies not resolved by discussion, a third reviewer will be consulted. Reasons for exclusion of articles at full text will be reported in the systematic review. The results of the search and study selection will be reported and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. 32 Eligible studies will be critically appraised by 2 independent reviewers for methodological quality using the standard JBI critical appraisal checklist for experimental, quasi-experimental, cohort, case-control, and case report studies. 30 , 33 , 34 Authors of papers will be contacted to request additional data where required. Any discrepancies between reviewers will be resolved via discussion or through a third reviewer. The critical appraisal outcomes will be displayed in a table with associated discussion. All studies will undergo data extraction and synthesis; however, specific comment on the quality of results will be made when results are determined. Data will be extracted from relevant studies by 2 reviewers independently using a data extraction form developed by the reviewers. The extracted data will include specific details such as author, year of publication, journal of publication, participants, study methods, intervention, initial weight/BMI, post-intervention weight/BMI, follow-up duration fertility parameters, and data analysis methods (see Appendix II ). Any disagreements between reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted for any additional information required. Where possible, a meta-analysis will be conducted to answer the review questions. If there are insufficient data for a meta-analysis, a narrative synthesis will be conducted. This will involve identifying the number of studies reporting each type of intervention, degree of weight loss, duration of follow-up, and degree of changes in parameters. For the first review question, mean and standard deviation will be calculated using equations established by Wan et al . 35 For studies that report “median (minimum, maximum),” equations 2, 7 (n ≤50), and 9 (n ≤50) will be used, whereas for studies reporting “median (interquartile range),” equations 14, 15 (n ≤50), and 16 (n>50) will be used. The effect of individual health interventions will be assessed through meta-analyses of change in sperm outcomes before vs after intervention. Assessment of heterogeneity will be considered mild when the inconsistency statistic I 2 <30% 36 and fixed-effects models will be employed; otherwise, random-effects models will be used. The meta-analyses will be conditional on having at least 2 studies (per intervention type and outcome), and for surgical studies, 1 study will be required in addition to those analyzed in the most recent meta-analysis. 20 For the second review question, when there are at least 5 studies on an individual health intervention, the influence on degree of weight loss on sperm outcomes will be assessed in random-effects meta-regressions, with the inclusion of absolute weight loss as an effect moderator. Publication bias will be assessed using the Egger test and funnel plots. If no evidence of publication bias is apparent, then a P value <0.05 will be considered significant. All statistical analysis will be performed using R package metafor (Free Software Foundation, Inc., Boston, USA).

The review will consider human studies of reproductive-age men (age 25 to 30 kg/m 2 ) or obesity (BMI >30 kg/m 2 ) or racially appropriate cutoffs for overweight or obesity. Whilst BMI is an imperfect tool to measure adiposity, it is currently the standard measure of obesity used in most studies. 29 The age cutoff of 50 years has been chosen, as most men will undergo planned reproduction prior to this age, thereby ensuring that results are generalizable to couples attempting to conceive. If specific age inclusion criteria are not provided, the mean and standard deviation of age will be used to ensure most cases are aged <50 years. The primary exposure of interest is an intervention undertaken to improve health that is typically associated with a degree of weight loss, specifically assessing the following methods: lifestyle change (dietary/exercise intervention), bariatric surgery, or pharmacotherapy (with medications known to induce weight reduction). Diet and exercise have been grouped together, as these are often undertaken concurrently. Each cohort of methods will be reviewed individually to determine whether undertaking that intervention is associated with a change in male fertility. The second component of the review will use the cohorts identified above; however, we will review the degree of weight loss achieved within each intervention and determine whether this is associated with the change in male fertility, rather than the intervention itself. The degree of change of 2 separate classes of outcomes will be assessed: direct measures of fertility and semen quality. Direct measures of fertility include time to conception, fecundity rate, and assisted reproduction outcomes (fertilization rate, embryo development, implantation rate, pregnancy rate). Semen quality measures will include semen volume, sperm concentration/count, motility and morphology, sperm DNA damage, lipid peroxidation, and reactive oxygen species. Where fertility is assessed, maternal factors will be controlled for to minimize maternal influence. The review will incorporate all retrospective or prospective study designs, including experimental studies, cohort studies, case reports, case studies, and case-control studies.