The effects of bariatric surgery on male and female fertility: A systematic review and meta-analysis

Highlights • Currently natural lifestyle modification is recommended over bariatric surgery in the management of infertility in obese men and women, despite natural weight loss often being an ineffective method to both lose and maintain weight loss in these individuals.• Through this meta-analysis and systematic review, we provide evidence that bariatric surgery effectively improves fertility outcomes for men and women by measurements of hormone levels and improvements in sexual function index scores.• This study demonstrates the importance and even cruciality of bariatric surgery in obese men and women who struggle with reproductive health, especially when finding it difficult to lose and maintain weight. It also proves that it is vital to continue to create and expand our knowledge with evidence-based medicine to help this cohort of patients.


Introduction
Obesity is a global epidemic estimated to affect 650 million adults worldwide with prevalence tripling over the recent decades [1]. Obesity negatively impacts the body's physiology and leads to various comorbidities, including infertility [2]. Irregular hormones and menstrual cycles are involved in the pathogenesis of infertility in obese women and poor sperm quality and hormonal disturbances contributes to infertility in obese men [3,4]. While nonsurgical weight reduction improves fertility parameters in both sexes, bariatric surgery is a more effective method in morbidly obese individuals [5,6]. Bariatric surgery improves fertility outcomes primarily through an improved hormonal profile [7]. The purpose of this study is to review the role of bariatric surgery on outcomes of fertility and reproductive function in men and women.

Patient and public involvement
The research question was designed to address a rising prevalence of a severe medical ailment-obesity and some dire consequences or associations these patients face with poor reproductive function. Patients were not directly involved in this meta-analysis and systemic review; however, all of the studies selected were either retrospective/prospective reviews or randomized control trials (RCTs) that directly interacted with patients or patient identifiable data. This study utilizes previously published and publicly available data and therefore also did not require an IRB. The results of the study will be presented upon publication to the general public.

Data sources and search strategy
This meta-analysis was carried out following the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines [8]. Moreover, all protocols enlisted in the AMSTAR 2 (21) checklist were followed. An electronic search of PubMed and Scopus was conducted from their inception to May 2021 without any language or publication year restrictions. Detailed search strategies are given in Supplementary  Table 1. We manually screened the reference list of previous meta-analyses and reviewed articles to identify relevant studies.

Study selection
The following eligibility criteria were used: (a) RCTs or observational studies with a follow-up duration of 6 months and/or 12 months; (b) male and/or female participants undergoing bariatric surgery; (c) comparison between preoperative and post-op; (d) at least one fertility outcome reported from among the following: sexual function, sex hormones, semen analysis, menstrual irregularity. Studies that did not report total FSFI (Female Sexual Function Index) or erectile function component of IIEF (International Index of Erectile Dysfunction) scores were excluded. Studies reporting data as the median, interquartile range (IQR) were not included.

Data extraction and risk of bias assessment
Articles retrieved from the systematic search were exported to the EndNote Reference Library, version X20 (Clarivate Analytics), where duplicates were screened and removed. Two independent reviewers carefully evaluated the remaining articles, and studies that met defined criteria were selected. All trials were initially short-listed based on title and abstract and then subsequently reviewed to affirm relevance. A third investigator was consulted to resolve any discrepancies. Relevant authors were contacted via email in case of missing data. If the data were still not recovered, the corresponding studies were excluded. The following outcomes were extracted: total FSFI score, IIEF component of erectile function, male: total testosterone (TT), male: free testosterone (FT), male: estradiol (E2), male: follicle-stimulating hormone (FSH), male: luteinizing hormone (LH), male: sex hormone-binding globulin (SHBG), female: TT, female: FT, female: E2, female: FSH, female: LH, female: SHBG, total sperm count, semen volume, sperm motility, sperm morphology, sperm concentration, menstrual irregularity. The following baseline and study characteristics were extracted: first author, year of publication, country, study design, study population, type of surgery, sample size, mean age, mean preoperative BMI, mean postoperative BMI, and length of follow-up. The methodological index for nonrandomized studies (MINORS) tool was used to assess the risk of bias [9].

Statistical analysis
RevMan (Version 5.4, The Cochrane Collaboration, 2020) was used for all statistical analyzes. The results of the studies were presented as mean difference (MD) or standard mean difference (SMD) for continuous variables and as risk ratios (RR) for dichotomous variables with 95% confidence intervals (CI). A p-value < 0.05 was considered statistically significant. All results were pooled using a random-effects model. Forest plots were created to assess visualize the results. Heterogeneity across studies was assessed using the I [2] statistic, with values of I [2] between 25% and 50% considered as mild heterogeneity, 50% and 75% regarded as moderate heterogeneity, and greater than 75% defined as severe heterogeneity [10]. Sensitivity analysis was performed for the following outcomes: male sex hormones, semen analysis, female sexual function (FSFI), and female sex hormones. The funnel plots were visually inspected for results with <10 studies to assess publication bias.

Literature search results
The initial search yielded 5238 citations. After applying the predetermined inclusion/exclusion, 43 articles were ultimately included (38 prospective, three retrospectives, two not reported). The PRISMA flow chart (Fig. 1) summarizes the results of our literature search.

Study characteristics and risk of bias assessment
A total of 1,765 subjects are included in the analysis, out of which 753 are male and 1003 are female. Twenty-two studies reported male fertility outcomes, eighteen studies reported female fertility outcomes, and three studies reported both male and female fertility outcomes. The mean age of the individuals in the pooled sample at baseline is 36.88 ± 6.11 years (38.55 ± 5.83 years for males; 35.21 ± 6.40 years for females). The weighted mean BMI at baseline is 46.51 ± 6.28 kg/m 2 (46.60 ± 6.42 kg/m 2 for males; 46.42 ± 6.15 kg/m 2 for females), which reduced to 26.70 ± 4.22 kg/m 2 (30.14 ± 4.6 kg/m 2 for males; 23.26 ± 3.84 kg/m 2 for females) postoperatively at the 12-month follow-up. More than one type of bariatric surgery was performed in 18/43 studies (41.86%). Study characteristics and baseline demographics of the patients are summarized in Table 1. The mean MINORS score of included studies is 13 ± 1.25, ranging from eleven to sixteen, indicating moderate to high-quality evidence for non-randomized studies. Detailed assessment of each study is given in Supplementary Table 3. Visual assessment of funnel plots suggested that small studies appeared to be missing for male TT, FT, and SHBG ( Supplementary Fig. 6).
Outcome analysis: Figs. 2 and 3 summarize the results of the study.

Sexual function
Adequate data was provided for the component of erectile function of IIEF in 3 out of 43 studies in 101 patients. Bariatric surgery increased erectile function scores at 12 months follow-up (MD 4.01; 95% CI 1.63-6.39; P < 0.0010) ( Supplementary Fig. 1).
For semen volume and sperm motility, removal of the Carette et al.
Sensitivity analysis showed a decrease in the heterogeneity of 83%-44% after removing the study by Hernàndez et al.

Discussion
We evaluated the effects of bariatric surgery on fertility in both males and females by analyzing changes in sex hormone levels, sperm parameters, menstrual irregularities, and sexual function.

Effects of bariatric surgery on male fertility
Our meta-analysis showed that one year after surgery, the levels of TT, FT, FSH, LH, and SHBG increased significantly in males, while estradiol showed a significant decrease. Along with improvements in sex hormones, our analysis showed a substantial increase in the erectile function domain of IIEF at 12-month follow-up. Unlike sex hormones and erectile function, sperm parameters, i.e., total sperm count, sperm motility, semen volume, and sperm concentration, except sperm morphology, did not significant change.
Multiple factors improve sex hormones in massively obese men postbariatric surgery. Adipose tissue is a significant source of estrogen production in men and women as it contains the enzyme aromatase cytochrome P450 converting testosterone to estradiol (E2) [15]. Increased estradiol production can also inhibit the secretion of LH and FSH from the pituitary, which can decrease testosterone (both free and total) synthesis and spermatogenesis and ultimately lead to infertility. Low levels of SHBG in obesity decrease testosterone levels. Hyperinsulinemia or the low-grade inflammation and changes in proinflammatory/anti-inflammatory cytokines (i.e., TNF α, IL-1 β, and adiponectin) are also derived from adipose tissue [16]. Our study shows that the substantial loss of adiposity after bariatric surgery reduces aromatase activity, improves insulin sensitivity, regulates sex hormone levels, decreases E2 production, and increases testosterone hormone levels, SHBG FSH, and LH in the body [17]. This automatically regulates spermatogenesis. Bariatric surgery also regulates androgen and proinflammatory cytokine levels and, therefore, reduces erectile dysfunction [7]. According to our analysis, bariatric surgery did not significantly affect semen analysis parameters. The observational and controlled prospective study by Carette et al. (N = 26) reported worsened sperm parameters at postoperative follow-up of 1-year; which can be attributed to the nutritional deficiencies commonly seen after bariatric surgery [13]. Nutritional deficiency of vitamins and minerals, including iron and calcium, are crucial for spermatogenesis, and therefore the lack thereof may lead to the insignificant improvement on sperm quality parameters. In our analysis, the prospective study, Fariello et al. (N = 15) did not show significant improvement in the 12th postoperative month in all sperm parameters [18]. Whether bariatric surgery improves sperm parameters is controversial and requires further research.

Effects of bariatric surgery on female fertility
Unlike in obese males, obese females had a significant decrease in TT and FT after bariatric surgery. Bariatric surgery also led to lower E2 levels and increased LH, FSH, and SHBG levels. Sexual function reflected by FSFI scores also improved. A previous meta-analysis by Wen et al. did not show a statistically significant improvement in FSFI [19]. Although we found a statistically significant decrease in menstrual irregularities in the 6th postoperative month, we did not observe any statistically significant change at the 12-month follow up.
Although obesity leads to androgen deficiency in men, it causes excessive androgen production in women. The reduction of testosterone post-bariatric surgery can be due to increased synthesis of SHBG, which  is otherwise inhibited by obesity-related insulin resistance and hyperinsulinemia [20]. The improved insulin sensitivity also helps in decreasing ovarian androgen production [16]. With extensive weight loss, the aromatization of testosterone decreases leading to better regulation of the FSH/LH ratios after surgery. Studies on whether sexual dysfunction in women improves after surgery are inconsistent thus far. These studies find that obese women with anovulatory cycles increased their chances of conception with bariatric surgery; improved insulin sensitivity with a significant drop in insulin levels after surgery helps regulate menstrual cycles, and therefore directly affects the chances of conception [16]. As mentioned above, we found a statistically significant improvement in menstrual irregularities at 6-month follow-up; however, the lack of significant changes observed at 12-month follow-up can be explained by a small pooled sample size since only 2 studies were available to review. The results of this meta-analysis highlight the integral correlation between bariatric surgery and the reproductive hormone levels and sexual function in men and women.
Future research is required to further strengthen the evidence and highlight the role of underlying comorbidities e.g., diabetes, and hypertension on the outcomes of fertility in men and women.

Limitations
Our meta-analysis has several limitations. First, there was significant heterogeneity in the analysis of all results except the IIEF erectile function domain, sperm morphology, sperm concentration, and estradiol in women. This may be attributed to the absence of RCTs, different types of bariatric surgery, variable patient populations, and small population sizes of the included studies. Second, we did not evaluate sperm DNA fragmentation; only semen analysis was assessed to analyze any changes in the quality of sperm post-surgery. Third, although we improved on previous studies by analyzing all data at a specific followup time to reduce heterogeneity, this meta-analysis showed effects of bariatric surgery only up to one year. Long-term complications were not  evaluated. Fourth, investigation of the influence of bariatric surgery on sexual function by self-reported questionnaires may be subject to response bias. Fifth, sexual function may also be affected by the quality of life, body image, and psychological state associated with weight loss; however, we did not analyze these factors. Finally, we did not evaluate fertility as a separate outcome to determine the incidence of successful pregnancies after surgery in infertile individuals due to the lack of studies that meet our eligibility criteria.

Conclusion
The results of our meta-analysis showed bariatric surgery significantly improves reproductive hormone levels and sexual function in men and women. Larger RCTs with longer follow-up times are essential to confirm our conclusions. Inconsistencies in the results of menstrual irregularities at six and twelve-month follow-up, inconclusive results of sperm analysis, and heterogeneity in several outcome analyses require higher-quality studies in the future to effectively conclude the role of bariatric surgery on outcomes of fertility in men and women.

Ethical approval
As this study uses publicly available data published online, this study did not need IRB approval.

Sources of funding for your research
There is no funding for this research.

Author contribution
Abdullah Qureishicontributed to study design and concept, writing the paper, and finalizing the paper prior to pubmission Syeda Hafsa Qadri contributed to study design, data collection, writing the paper Sejal Lund contributed to data collection, data analysis and writing the paper Ushna Sunain Ansari contributed to data collection, data analysis and writing the paper Amna Arif contributed to data collection and writing the paper Amatul Rehman Durdana contributed to data collection and writing the paper Rabeata Maryam contributed to data collection and writing the paper Mahinn Saadi contributed to writing the paper Muhammad Zohaib contributed to writing the paper Muhammad Khuzzaim Khan contributed to writing the paper Areesha Waseem contributed to writing the paper Sophia Dar contributed to writing the paper, editing and finalizing the paper Talal Almas contributed to writing the paper, editing and finalizing the paper.

Data availability statement
Publicly available data was used available on pubmed.gov.

Registration of research studies
1. Name of the registry: 2. Unique Identifying number or registration ID: 3. Hyperlink to your specific registration (must be publicly accessible and will be checked):

Guarantor
Sophia Dar and Talal Almas accept full responsibility for the work and the conduction of the study.

Permission to reproduce material from other sources
Not needed because publicly available data was used.

Provenance
Not commissioned.

Peer review
Externally peer-reviewed.

Consent
This study did not directly involve patient care and has no patient identifiers.

Declaration of competing interest
None of the authors have any conflicts of interest in this study.

Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi. org/10.1016/j.amsu.2022.103881.