Assessing the Prevalence of Male Obesity-Associated Gonadal Dysfunction in Severe Obesity: A Focus on the Impact of Bariatric Surgery and Surgical Approaches.

PURPOSE: Obesity is an important risk factor for secondary hypogonadism in men. Several studies evaluated the impact of bariatric surgery on gonadal function in men, proving an improvement in testosterone levels, without yet a global consensus on the impact of different surgical approaches. Objectives of the study are: to estimate the prevalence of obesity-associated gonadal dysfunction among men with severe obesity; to evaluate the response to bariatric surgery in terms of resolution of this condition, distinguishing between restrictive and restrictive-malabsorptive surgery. METHODS: We conducted a retrospective evaluation of 413 males with severe obesity (BMI 44.7 ± 8.3 kg/m2). A subgroup of them (61.7%) underwent bariatric surgery. Anthropometric assessment (weight, BMI, waist and hip circumference), metabolic (glyco-lipidic asset and urate) and hormonal (morning gonadotropin and total testosterone) assessments were carried out at baseline and 3-6 months post-surgery. RESULTS: Using a TT threshold of 2.64 ng/ml, 256 out of 413 (62%) patients were categorized as having biochemical hypogonadism. At multivariate analysis, the only parameter significantly associated with biochemical hypogonadism, was BMI value (p = 0.001). At 3-6 months after surgery, during the acute weight loss phase, only 20.1% of patients still had biochemical hypogonadism. At multivariate analysis, which included age, presurgical BMI, pre-surgical TT, surgical approach and %EWL, presurgical TT levels (p = 0.0004), %EWL (p = 0.04), and mixed restrictive-malabsorptive surgery (p = 0.01), were independently associated with the recovery of gonadal function. CONCLUSIONS: The results of this study underscore the potential reversibility of obesity-associated gonadal dysfunction through bariatric surgery, highlighting the importance of considering surgical approach.

Management of male obesity-related secondary hypogonadism: A clinical update.

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.

Clinical and Therapeutic Implications of Male Obesity.

The prevalence of obesity, a disorder linked to numerous comorbidities and metabolic complications, has recently increased dramatically worldwide and is highly prevalent in men, even at a young age. Compared to female patients, men with obesity more frequently have delayed diagnosis, higher severity of obesity, increased mortality rate, and only a minority of obese male patients are successfully treated, including with bariatric surgery. The aim of this review was to present the current state of knowledge about the clinical and therapeutic implications of obesity diagnosed in males.

Diet-induced obesity is associated with altered expression of sperm motility-related genes and testicular post-translational modifications in a mouse model.

Obesity is a metabolic disease and its relation with male subfertility has aroused a growing concern. However, it is unclear whether gene expression and post-translational modifications (PTMs), two vital molecular mechanisms regulating cellular functions, are associated with obesity-induced male reproductive dysfunction. In this study, male obesity with compromised sperm motility was induced by a high-fat diet (HFD) using a mouse model. The expression of motility related-genes, the level of histone modifications, and the global profiles of post-translational modifications (PTMs), were examined in testes of HFD and control mice by quantitative real-time PCR and western blot, respectively. Outer dense fiber protein 2, a major component of outer dense fibers in the sperm tail, is the most obviously down-regulated gene out of 11 evaluated genes, showing a reduction of about 50% RNA level in testes of obese male mice compared with that in control mice. Semi-quantitative analysis of the western blot demonstrated that ∼56% enrichment of di-methylated histone (H)3 lysine (K)36, ∼59% enrichment of 2-hydroxyisobutyrylated H4K8, ∼32% decrease of propionylated H3K23, ∼33% decrease of crotonylated H4K8, and ∼45% decrease of acetylated H3K122 and H4K8 were detected in testes of male HFD mice compared with that in control mice. In addition, male obesity up-regulated the testicular levels of ubiquitination by ∼18%, tyrosine nitration by ∼20%, lysine succinylation by ∼25%, lysine benzoylation by ∼28%, lysine malonylation by ∼32%, lysine glutarylation by ∼36%, lysine propionylation by ∼42%, lysine 2-hydroxyisobutyrylation by ∼45%, and SUMO1 modification by ∼59%, and down-regulated the testicular levels of O-GlcNAcylation by ∼12%, lysine crotonylation by ∼22%, and lysine acetylation by 35%. These findings indicate that altered gene expression and PTMs are associated with the obesity-induced male reproductive dysfunction.

Potential Cardiovascular and Metabolic Beneficial Effects of ω-3 PUFA in Male Obesity Secondary Hypogonadism Syndrome.

Long-chain ω-3 polyunsaturated fatty acids (PUFAs) are fundamental biocomponents of lipids and cell membranes. They are involved in the maintenance of cellular homeostasis and they are able to exert anti-inflammatory and cardioprotective actions. Thanks to their potential beneficial effects on the cardiovascular system, metabolic axis and body composition, we have examined their action in subjects affected by male obesity secondary hypogonadism (MOSH) syndrome. MOSH syndrome is characterized by the presence of obesity associated with the alteration of sexual and metabolic functions. Therefore, this review article aims to analyze scientific literature regarding the possible benefits of ω-3 PUFA administration in subjects affected by MOSH syndrome. We conclude that there are strong evidences supporting ω-3 PUFA administration and/or supplementation for the treatment and management of MOSH patients.

Male Obesity Associated Gonadal Dysfunction and the Role of Bariatric Surgery.

Obesity is an ever growing pandemic and a prevalent problem among men of reproductive age that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the precision and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and preclinical data support these findings. Clinical studies on the impact of medically induced weight loss on serum testosterone concentrations and spermatogenesis is promising but may show differential and unsustainable results. In contrast, literature has demonstrated that weight loss after bariatric surgery is correlated with an increase in serum testosterone concentrations that is superior than that obtained with only lifestyle modifications, supporting a further metabolic benefit from surgery that may be specific to the male reproductive system. The data on sperm and semen parameters is controversial to date. Emerging evidence in the burgeoning field of genetics and epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to a comprehensive view of the impact of obesity on subsequent generations. Furthermore, conveying the potential impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Healthcare professionals treating male infertility and obesity need to adapt their practice to assimilate these new findings to better counsel men about the importance of paternal preconception health and the impact of novel non-medical therapeutic interventions. Herein, we summarize the pathophysiology of obesity on the male reproductive system and emerging evidence regarding the potential role of bariatric surgery as treatment of male obesity-associated gonadal dysfunction.

Male Obesity-related Secondary Hypogonadism - Pathophysiology, Clinical Implications and Management.

The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. The resulting hypogonadism by itself can worsen obesity, creating a self-perpetuating cycle. Obesity-induced hypogonadism is reversible with substantial weight loss. Lifestyle-measures form the cornerstone of management as they can potentially improve androgen deficiency symptoms irrespective of their effect on testosterone levels. In selected patients, bariatric surgery can reverse the obesity-induced hypogonadism. If these measures fail to relieve symptoms and to normalise testosterone levels, in appropriately selected men, testosterone replacement therapy could be started. Aromatase inhibitors and selective oestrogen receptor modulators are not recommended due to lack of consistent clinical trial-based evidence.

Effects of obesity on sperm retrieval, early embryo quality and clinical outcomes in men with nonobstructive azoospermia undergoing testicular sperm aspiration-intracytoplasmic sperm injection cycles.

The objective of this study was to assess the effects of body mass index (BMI) on sperm retrieval, early embryo quality and clinical outcomes in patients with nonobstructive azoospermia (NOA) undergoing testicular sperm aspiration-intracytoplasmic sperm injection (TESA-ICSI). A total of 3,005 infertile couples were evaluated between January 2010 and June 2017, including 1585 normal-weight (BMI < 25 kg/m2 ), 847 overweight (BMI 25-29.99 kg/m2 ) and 573 obese (BMI ≥ 30 kg/m2 ) patients. We found no significant relationship between BMI and sperm retrieval rate (22.4%, 24.3% and 25.1%, p = 0.327) or sperm motility. Among the 705 patients with NOA who underwent TESA-ICSI cycles, obese individuals had lower T levels and higher E2 levels than normal-weight and overweight individuals. However, there were no significant differences in other male hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], or prolactin [PRL]) among the groups. We also found that the sperm parameters, embryo quality and clinical outcomes of patients with NOA undergoing TESA-ICSI were not influenced by high BMI levels. In conclusion, this study demonstrated a lack of obvious effects of obesity on sperm retrieval, early embryo quality and clinical outcomes in infertile men undergoing TESA-ICSI cycles, although T and E2 levels were affected.

Impact of weight loss on sperm DNA integrity in obese men.

The objective of the study was to determine whether weight loss in obese men improves their fertility with respect to DNA fragmentation index and morphology. Collected fertility parameters included DFI and morphology. Body mass index (BMI) was calculated for all patients with comparisons to their fertility parameters before and after weight loss using paired t test and chi-square tests. The mean BMI was significantly higher in group 1, before weight loss (33.18 kg/m2 ), than in group 2, after weight loss (30.43 kg/m2 ). Overall, 53.3% of men had DFI <20% while 43.8% had a DFI between 20% and 40%, and 2.9% of men had DFI >40%. The mean DFI of participants was higher before weight loss (20.2%) and had improved significantly after weight loss (17.5%) (p = <.001). The weight loss had significant positive correlation with percentage of DFI. There was a significant improvement in morphology after weight loss (p = <.05). In one of the largest cohorts of male fertility and obesity, DFI and morphology demonstrated significant relationship with adiposity, possibly contributing to subfertility in this population.

Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta-analysis.

Men with a body mass index (BMI) of 30 or over are more likely to have reduced fertility and fecundity rates. This systematic review and meta-analysis evaluated the effect of male BMI on IVF and intracytoplasmic sperm injection (ICSI) outcome. An electronic search for published literature was conducted in MEDLINE and EMBASE between 1966 and November 2016. Outcome measures were clinical pregnancy rates (CPR) and live birth rates (LBR) per IVF or ICSI cycle. Eleven studies were identified, including 14,372 cycles; nine reported CPR and seven reported LBR. Pooling of data from those studies revealed that raised male BMI was associated with a significant reduction in CPR (OR 0.78, 95% CI 0.63 to 0.98, P = 0.03) and LBR (OR 0.88, 95% CI 0.82 to 0.95, P = 0.001) per IVF-ICSI treatment cycle. Male BMI could be an important factor influencing IVF-ICSI outcome. More robust studies are needed to confirm this conclusion using standardized methods for measuring male BMI, adhering to the World Health Organization definitions of BMI categories, accounting for female BMI, IVF and ICSI cycle characteristics, including the number of embryos transferred and embryo quality, and use the live birth rate per cycle as primary outcome.

Metabolic phenotype of male obesity-related secondary hypogonadism pre-replacement and post-replacement therapy with intra-muscular testosterone undecanoate therapy.

AIM: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU). METHODS: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD). RESULTS: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR). CONCLUSION: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition.

Obesity and reduced fertility of men.

OBJECTIVE: Description of the relationship between the overweight man and the reduction of his reproductive potential. DESIGN: Review article. SETTING: Center of Assisted Reproduction Sanus, Jihlava. METHODS: Approximately 15% of couples are trying to get pregnant unsuccessfully. In order to better assess the possible causes of this failure, it is vital to take into consideration the influence of owerweight and/or obesity in both men and women. Reduction of the reproductive potential of obese men occurs due to changes in hormonal levels regulating spermatogenesis, increased temperatures in the testicles, environmental toxins accumulated in adipose tissue, increased levels of oxidative stress as well as a higher incidence of erectile dysfunction. The likelihood of pregnancy is reduced even in the case of assisted reproduction methods. CONCLUSION: Obesity or overweight causes reduced fertility of men and often significantly prolongs the time required to achieve pregnancy. Prior to applying treatment for infertility, we assess all possibilities to increase the reproductive potential of overweight men. Significant weight loss in obese men results in regulated hormonal levels, moreover, in most cases, this leads to improved spermiogram parameters with increasing chances of getting pregnant.

Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis.

BACKGROUND: Sexual dimorphism manifests noticeably in obesity-associated gonadal dysfunction. In women, obesity is associated with androgen excess disorders, mostly the polycystic ovary syndrome (PCOS), whereas androgen deficiency is frequently present in obese men in what has been termed as male obesity-associated secondary hypogonadism (MOSH). Obesity-associated gonadal dysfunction, consisting of PCOS in women and MOSH in men, is a frequent finding in patients with severe obesity and it may be ameliorated or even resolve with marked weight loss, especially after bariatric surgery. OBJECTIVE AND RATIONALE: We aimed to obtain an estimation of the prevalence of obesity-associated gonadal dysfunction among women and men presenting with severe obesity and to evaluate the response to bariatric surgery in terms of resolution and/or improvement of this condition and changes in circulating sex hormone concentrations. SEARCH METHODS: We searched PubMed and EMBASE for articles published up to June 2016. After deleting duplicates, the abstract of 757 articles were analyzed. We subsequently excluded 712 articles leaving 45 studies for full-text assessment of eligibility. Of these, 16 articles were excluded. Hence, 29 studies were included in the quantitative synthesis and in the different meta-analyses. Quality of the studies was assessed using the Quality index for prevalence studies and the Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group available from the National Heart, Lung and Blood Institute. For meta-analyses including more than 10 studies, we used funnel and Doi plots to estimate publication bias. OUTCOMES: In severely obese patients submitted to bariatric surgery, obesity-associated gonadal dysfunction was very prevalent: PCOS was present in 36% (95CI 22-50) of women and MOSH was present in 64% (95CI 50-77) of men. After bariatric surgery, resolution of PCOS was found in 96% (95CI 89-100) of affected women and resolution of MOSH occurred in 87% (95CI 76-95) of affected men. Sex hormone-binding globulin concentrations increased after bariatric surgery in women (22 pmol/l, 95CI 2-47) and in men (22 pmol/l, 95CI 19-26) and serum estradiol concentrations decreased in women (-104 pmol/l, 95CI -171 to -39) and to a lesser extent in men (-22 pmol/l, 95CI -38 to -7). On the contrary, sex-specific changes were observed in serum androgen concentrations: for example, total testosterone concentration increased in men (8.1 nmol/l, 95CI 6-11) but decreased in women (-0.7 nmol/l, 95CI -0.9 to -0.5). The latter was accompanied by resolution of hirsutism in 53% (95CI 29-76), and of menstrual dysfunction in 96% (95CI 88-100), of women showing these symptoms before surgery. WIDER IMPLICATIONS: Obesity-associated gonadal dysfunction is among the most prevalent comorbidities in patients with severe obesity and should be ruled out routinely during their initial diagnostic workup. Considering the excellent response regarding both PCOS and MOSH, bariatric surgery should be offered to severely obese patients presenting with obesity-associated gonadal dysfunction.

The imbalance of sex-hormones related to depressive symptoms in obese men.

Obese men may present hypogonadothrofic hypogonadism, mainly related to higher insulinemia and aromatase activity. Our objectives were to evaluate the relationship of sex-hormones profiles and frequency of depressive symptoms in 43 obese men, in a cross-sectional study. They had 19-60 years, and body mass index 30-50 kg/m(2). LH, total and free testosterone (TT and FT), estradiol (E2), sex hormone binding globulin, estradiol/total testosterone ratio (E2/T) were analyzed. Depressive symptoms were evaluated by "beck depression inventory" (BDI), and significant depression was considered if BDI ≥ 16.Thirty-four (80%) presented low TT levels, but only 4 (14%) had low free testosterone and hypogonadism symptoms; 12 of 43 (28%) presented increased E2. Forty five (56%) presented depressive symptoms, but 16 (28% of the 45) had significant depression. BDI correlated positively with E2 (r = 0.407; p = 0.001) and E2/T (r = 0.473; p = 0.001), but not TT or FT. Patients with significant depressive showed higher levels of estradiol (136 ± 48 versus 103 ± 48 pg/ml, p = 0.02) and E2/T (16.0 ± 9.9 versus 9.8 ± 4.6; p = 0.002) (mean ± SD).In conclusion, obese men may present relatively excess of estradiol and deficiency in testosterone, leading to an imbalance between these two hormones. The greater this imbalance, the more depressive symptoms had our patients.

Androgen and Estrogen Shifts in Men Before and After Bariatric Surgery and Links to Vitamins and Trace Elements.

Androgens and estrogens play a key role regarding sexual life and reproduction. Along with hypotestosteronemia, obese men exhibit a 2-fold increase in estradiol concentration, adversely infl uencing these parameters. Estrogens and adipokines also infl uence bone metabolism, exerting a direct effect on vitamin D, calcium homeostasis and bone health. Bariatric procedures normalize some sex hormones, and may reverse several obesity-related conditions. Estrogens levels may remain elevated postoperatively, and despite its protective effect on the skeleton, bariatric patients are more prone to fractures when compared to the general population. Multiple nutritional defi cits are common after bariatric interventions, and hypozincemia is the most likely to negatively infl uence reproductive parameters. Zinc is an essential element for normal spermatogenesis, and severe hypozincemia is associated with infertility in both sexes. Vitamin D also acts as a regulator of several enzymes involved in steroid hormone production, and its defi ciency could impair reproductive function. Few studies have addressed changes in sex hormones and in reproductive function in the male bariatric population, as they represent a minority of surgical candidates. Although obesity rates and burden are similar for both sexes, society is more lenient with the obese male. Moreover, 73 % of overweight/obese men are satisfi ed with their health, causing body weight and obesity-related health problems to increase when they opt for bariatric surgery. In the present article, we discuss shifts of sex hormones before and after bariatric surgery, surgery impact on semen quality, skeletal health and nutrients, and new research directions regarding links between vitamin D, zinc, androgens and reproduction.

Influence of Donor, Recipient, and Male Partner Body Mass index on Pregnancy Rates in Oocyte Donation Cycles.

OBJECTIVE: A high body mass index (BMI) has been shown to associate with negative reproductive outcomes. Women with high BMI have in general lower chances of getting pregnant as well as higher risk of pregnancy complications. Several studies have described in the past the relationship between high BMI and the pregnancy outcome, however, some of them have a small sample size or fail to control for variables associated with a diminished probability of pregnancy. In the present study, we aim to analyze the role of the BMI of all parties involved in oocyte donation cycles (that is: the oocyte donor, the recipient woman, and the male partner) on pregnancy outcomes. METHODS: This study includes 1092 oocyte donation cycles. Inclusion criteria were: fertilization by ICSI, frozen semen, transfer of 2 embryos at day 3 of in vitro development. For statistical analysis, BMI was divided in: low weight (<20 kg/m2), normal (20-24 kg/m2), overweight (25-29 kg/m2) and obesity (≥30 kg/m2). Quantitative and categorical variables were assessed by squared-Chi test and one-way ANOVA. The association between the BMI (recipient, oocyte donor and partner) and pregnancy rate was assessed by multivariate logistic regression. RESULTS: Laboratory outcomes and pregnancy rates do not differ among the different BMI categories of recipient, oocyte donor or partner. After adjusted analyses (for oocyte donor age, for laboratory outcomes and for age and BMI of all the parties for pregnancy outcomes), no difference was found either. CONCLUSION: In oocyte donation cycles, where donors BMI is by law mandated to be in the 18-30 range, the pregnancy rate of the oocyte recipient does not seem to be affected by the BMI of any of the parties involved.

Relation between male obesity and male infertility in a Tunisian population.

Obesity is associated with significant disturbance in the hormonal milieu that can affect the reproductive system. Male infertility affects approximately 6% of reproductive-aged men. It has been suggested that overweight men or men with obese body mass index (BMI) experience prolonged time to pregnancy, although the influence of male BMI on fertility remains understudied. We hypothesised that BMI is inversely correlated with fertility, manifested by reduced sperm concentration and varicocele. Males of mean age 32.74 ± 6.96 years with semen analyses and self-reported BMI were included (n = 98). Patient parameters analysed included age, BMI, pubertal timing, the development of varicocele, and leutinizing hormone, follicle-stimulating hormone and testosterone (n = 18). The mean age of the study population was 32.74 ± 6.96 years. The incidence of azospermia, oligozoospermia, normospermia and the development of varicocele did not vary across BMI categories. Male obesity is not associated with the incidence of sperm concentration and the development of varicocele.