MEN'S HEALTH PEER REVIEWED Obesity A growing issue for male

MADHUNI HERATH MB BS, BMedSci(Hons), MPH, FRACP IE-WEN SIM MB BS(Hons), BMedSci, FRACP

Obesity in men has been associated with besity is a growing health issue that causes substantial reduced fertility. The impact of paternal body morbidity and mortality. Epidemiological data mass index on fertility is multifactorial, with ­suggest an association between increasing body mass increased weight associated with endocrine index (BMI) and reduced fertility in men, with one Ostudy suggesting that a gain of 10 kg decreases male fertility dysregulation and impaired sexual desire and function. Weight loss may improve fertility by approximately 10%.1 The effect of BMI on male fertility is outcomes as well as conferring longer-term multifactorial, with increased weight associated with changes health benefits. in sex profile and impaired sexual desire and function. Some studies also suggest poorer semen parameters in over- weight men. Despite the prevalence and costs of male subfertility, there are few data regarding the fertility benefits of weight loss in men. Although weight reduction may normalise the hormone profile, the extent that this improves fertility and the time course of any improvement are unclear.

Factors Contributing to Subfertility in Obese Men Increased BMI is strongly associated with both hormonal dys- regulation and poorer sexual function in men, which can impair fertility, as outlined in the Flowchart.

Hormonal dysregulation Excess body weight has numerous effects on the reproductive First published: MedicineToday 2014; 15(1): 49-53 Updated SEPTEMBER 2020 hormone profile in men, leading to: • a relative excess of oestrogen Dr Herath is the Andrology Fellow at Monash Health, which is supported by • resultant suppression of hypothalamic secretion of Healthy Male (formerly Andrology Australia). Dr Sim is a Consultant Andrologist -gonadotrophin-releasing hormone (GnRH) at Monash Health and Monash IVF, Expert Advisor to Healthy Male, and • reduced serum levels of gonadotrophins (luteinising Consultant Endocrinologist at Monash Health, Eastern Health and Western hormone and follicle stimulating hormone)

© GETTY IMAGES/OF SCIENCE EYE. SPERM FERTILISING AN OVUM Health, Melbourne, Vic. • reduced serum levels.

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POTENTIAL EFFECTS OF INCREASED BMI ON FERTILITY IN MEN

Increased BMI in men Excessive alcohol, sedentary lifestyle

Increased Increased aromatisation Obstructive Mood Psychosocial Cardiovascular testicular of sleep apnoea disorders factors risk factors, temperature including diabetes

Hypogonadotrophic

Abnormal Reduced libido

Subfertility Abbreviation: BMI = .

Furthermore, there may be a feedback by the aromatase enzyme in adipose tis- and psychosocial factors. effect as there is a well-recognised asso- sue. In overweight men, the increased Obese men report poorer sexual desire ciation between hypogonadism and the adipose tissue mass and upregulation of and satisfaction compared with control , which itself is asso- aromatase activity lead to excess periph- subjects, which may contribute to avoid- ciated with increased weight. eral aromatisation of androgens. The ance of sexual encounters.3 Overweight resulting hyperoestrogenism exerts a individuals are more likely to have chronic Effects on testosterone negative feedback effect on hypothalamic medical comorbidities and to be of lower BMI is a strong predictor of low serum GnRH pulses, reducing stimulation of socioeconomic class with resulting finan- total testosterone concentrations in men, gonadotrophin secretion. Circulating cial or domestic problems that can reduce with a clear inverse correlation shown in oestrogens may also have a direct adverse libido. Depressive illness is also more many studies. BMI is also inversely pro- effect on testicular function. In addition, common, and correlates with both low portional to free testosterone concentra- circulating endogenous opioids are likely libido and ED. Low libido ultimately tions, suggesting an association even after to have a pathophysiological role in the results in reduced coital frequency, low- accounting for lower sex hormone bind- development of hypogonadotrophic ering fertility rates. ing globulin levels due to hypogonadism in overweight men. In addition, sexual dysfunction is an resistance.2 important contributor to subfertility, with Reduced libido and erectile the presence of ED being correlated with Effects on other reproductive dysfunction lower fertility rates in men. ED is more Although hormonal dysregulation may prevalent in men with higher BMI. Its Low serum testosterone in overweight affect semen quality, as described below, aetiology in this setting is multifactorial, men is associated with inappropriately the primary reasons for the reduced fer- including deficiency and low-to-normal levels of gonadotrophins. tility rate observed in obese men may be ­vasculogenic dysfunction. This reversible hypogonadotrophic hypo- decreased sexual desire and impaired Medical comorbidities such as the gonadism includes hyperoestrogenism sexual function. Potential contributing ­metabolic syndrome are significantly as a significant component. Androgens factors include androgen deficiency, associated with ED. Both diabetes and are converted to oestrone and oestradiol organic causes of erectile dysfunction (ED) hypertension are associated with vascular

2 MedicineToday ❙ Collection: Obesity Awareness SEPTEMBER 2020 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2020. dysfunction, and diabetes may also lead TABLE. FERTILITY ASSESSMENT OF OVERWEIGHT MEN to neuropathic complications. Further- more, obstructive sleep apnoea (OSA) is History more common in obese men and is strongly independently linked with both Risk factors for male • Previous history of infertility ED and androgen deficiency. • Family history of infertility • Genital trauma or infection (e.g. orchitis) Reduced sperm quality • Cryptorchidism, testicular tumours Effect of BMI on semen parameters • Previous inguinal or pelvic surgery The relationship between BMI and sub- • Previous chemotherapy or radiotherapy fertility is not completely explained by • Occupational or environmental toxin exposure obesity-associated sexual dysfunction • Current medications and reduced frequency of intercourse. • Tobacco, alcohol, anabolic steroid use Changes with increased BMI, including hormonal imbalance and increased tes- Symptoms of androgen • Decreased sexual desire deficiency ticular ­temperature, may impair semen • Decreased sexual function parameters. • Reduced sense of wellbeing, energy, mood A recent systematic review and Comorbidities • History of cardiovascular disease, stroke meta-analysis demonstrated an associa- • Diabetes mellitus, dyslipidaemia, hypertension tion between increased BMI and modest • Obstructive sleep apnoea decreases in sperm motility, sperm mor- phology and concentration,4 whereas Physical examination earlier reviews have failed to establish this General examination • Height, weight, waist circumference 7 correlation. The association between BMI • Blood pressure and sperm DNA fragmentation has also been investigated. DNA fragmentation Genital examination • Testicular volume may correlate with poorer sperm quality • Epididymis, vas deferens and integrity, and consequently be asso- • Signs of androgen deficiency ciated with reduced fertility and an • Secondary sexual characteristics increased incidence of subsequent mis- • Gynaecomastia carriage. Although some studies have • Hair distribution demonstrated increased fragmentation in men with severe obesity,5,6 other studies Investigations have not reliably reproduced these find- Reproductive and other • Total and calculated free testosterone and SHBG levels 5,6,8 ings. Additionally, mouse models sug- hormones • FSH, LH and prolactin levels; thyroid function tests gest that paternal obesity may have met- abolic sequelae and lead to subfertility and Semen analysis • Sperm concentration, motility, morphology other metabolic effects in offspring Cardiovascular risk • Diabetes screen 9 through epigenetic effects. • Lipid profile

Effect of BMI on assisted reproductive Other • Liver function tests (to exclude nonalcoholic fatty liver disease) technology outcomes • Sleep study (if symptoms of obstructive sleep apnoea) With the increasing use of assisted repro- ductive technology, the impact of paternal ABBREVIATIONS: FSH = follicle stimulating hormone; LH = luteinising hormone; SHBG = sex hormone binding BMI on their outcomes is pertinent. globulin. Increased paternal BMI has been associ- ated with reduced chemical and clinical on implantation and pregnancy rates, Lifestyle and environmental factors pregnancy rates, as well as lower live-birth there have also been suggestions that A range of potentially remediable lifestyle rates.8,10,11 This may be a result of sperm paternal obesity may have an impact on factors can affect fertility and should be dysfunction that is not detectable by blastocyst development, possibly as a con- addressed in all men with subfertility. standard analysis. In addition to effects sequence of sperm DNA damage. Some of these factors, such as a sedentary

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cannabis may activate cannabinoid recep- and depression should also be considered PRACTICE POINTS REGARDING MALE OBESITY AND FERTILITY tors located on sperm and the paraven- in all overweight men. tricular nucleus of the hypothalamus. The initial assessment of a couple with • Epidemiological data suggest an These receptors are believed to be respon- subfertility by a GP can expedite their association between increasing sible for regulating sperm motility, and evaluation and ensure they are referred paternal BMI and poorer fertility sexual and erectile function, respectively. to an appropriate specialist, such as an outcomes. Although cannabis use has been linked endocrinologist and/or a gynaecologist • The pathophysiology of subfertility in with abnormal sperm motility and specialising in assisted reproductive the obese man is multifactorial, impaired fertility in male mice,14 human technology. including endocrine dysregulation, reduced sexual desire and function, studies are limited. In vitro studies as well as the effects of demonstrate a dose-dependent negative Treatment comorbidities and lifestyle choices. effect on sperm motility and function, There are limited data regarding the • Evaluation of subfertility in obese whereas the impact on sexual function is fertility outcomes of interventions in men should encompass a standard less conclusive, with some studies report- obese men. Nevertheless, a patient con- fertility assessment, with a particular ing enhanced sexual pleasure with can- sultation about fertility is an opportunity focus on identifying obesity- associated comorbidities and lifestyle nabis use, but others report impaired for a GP to establish a therapeutic rela- 15 factors. erectile function. tionship with the patient and to promote • Although weight loss may improve lifestyle modifications and weight loss hormonal profile, sexual desire and management of overweight men that will have long-term cardiovascular sexual function, improved fertility with subfertility benefits. These include tobacco cessa- outcomes have not been shown. Patient assessment tion, avoidance of excessive alcohol and • Consider the longer term benefits of Assessment of overweight men with sub- promotion of moderate exercise. Iden- weight loss and lifestyle modification fertility should include a basic fertility tified comorbidities, such as diabetes, on cardiovascular health and comorbidities such as diabetes and assessment to ensure that other causes dyslipidaemia and OSA, should also be 16 obstructive sleep apnoea. of male subfertility are not overlooked. treated. Treatment of OSA with contin- The potential contribution of female uous positive airway pressure (CPAP) factors must also be considered. A male has been shown to increase testosterone lifestyle, are associated with obesity. fertility assessment tool developed by levels. Sedentary lifestyle. Prolonged sitting, in Healthy Male is available for free down- combination with increased lower abdom- load at www.healthymale.org.au/health-­ Weight loss inal and scrotal fat deposition, might professionals/clinical-resources/patient- Weight loss can reverse the hormonal adversely affect sperm production by assessment-tools. Points to cover in a abnormalities seen in overweight men, increasing testicular temperature. fertility assessment of overweight men while also improving comorbidities such Tobacco. Tobacco use has a modest are summarised in the Table. as OSA.17 Biochemical changes that cor- dose–dependent effect on sperm quality, In addition to the basic fertility assess- relate with weight loss include increases with lower sperm concentration and ment, evaluation of overweight men in serum testosterone and sex hormone poorer sperm motility.12 and morphology should focus on identifying obesity-­ binding globulin levels and decreases in seen in smokers.13 Furthermore, smoking associated comorbidities and lifestyle oestradiol levels. Nonsurgical approaches may decrease the success rate of assisted factors that may play a significant role in to weight loss include low-calorie diets, reproductive technologies, including in the aetiology of subfertility as well as increased physical exercise and some- vitro fertilisation and intracytoplasmic confer significant cardiovascular risk. times pharmacological therapy to help sperm injection. Sperm -isolated from Cardiovascular assessment should maintenance of weight loss. Bariatric smokers have poorer function and higher include inquiring about -erectile dys- surgery allows greater and more sus- DNA fragmentation, suggesting a direct function, measuring blood pressure and tained weight loss. Reduced BMI in men detrimental effect of tobacco on sperm screening for diabetes and dyslipidaemia. after bariatric surgery has been shown DNA. These outcomes may be reversible The importance of ED as an independent to improve their sexual desire and satis- within a year of tobacco cessation. risk factor for metabolic syndrome and faction, as well as erectile function.18 Alcohol. Heavy alcohol use may be asso- ­cardiovascular disease is increasingly There is emerging evidence to suggest ciated with hypogonadism, poorer sperm being recognised, with ED representing a beneficial effect of weight loss through quality and sexual dysfunction. a surrogate biomarker for endothelial lifestyle modification on sperm param- Cannabis. It has been suggested that dysfunction and atherosclerosis. OSA eters including DNA fragmentation.19

4 MedicineToday ❙ Collection: Obesity Awareness SEPTEMBER 2020 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2020. The impact of bariatric surgery is less been shown to improve the hormone pro- pregnancy after ART is decreased in IVF but not clear, with some studies demonstrating file and is linked with improved sexual in ICSI cycles. J Assist Reprod Genet 2010; 27: reduced sperm defragmentation follow- function. Importantly, a consultation 539-544. ing surgery, whereas others have observed about fertility provides a rare opportunity 11. Campbell JM, Lane M, Owens JA, Bakos HW. decreased or no impact on sperm con- for GPs to engage with obese men about Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic centration and/or motility.20,21 their weight, lifestyle choices and cardio- review and meta-analysis. Reproductive Importantly, the effects of paternal vascular health. Practice points regarding biomedicine online 2015; 31: 593-604. obesity on spermatogenesis are likely to male obesity and fertility are summarised 12. Vine MF. Smoking and male reproduction: a be at most modest, with most male sub- in the Box. MT review. Int J Andrology 1996; 19: 323-337. fertility and significant sperm defects Bundhun PK, Janoo G, Bhurtu A, et al. Tobacco References being a result of intrinsic disorders of smoking and semen quality in infertile males: a 1. Sallmen M, Sandler DP, Hoppin JA, Blair A, Baird spermatogenesis rather than solely attrib- systematic review and meta-analysis. BMC public DD. Reduced fertility among overweight and obese utable to BMI. It would thus be remiss health 2019; 19: 36. men. Epidemiology 2006; 17: 520-523. 14. Banerjee A, Singh A, Srivastava P, Turner H, to overstate the effects of overweight on 2. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Krishna A. Effects of chronic bhang (cannabis) fertility and to rely exclusively on weight Association of bioavailable, free, and total administration on the reproductive system of male loss as a cure for subfertility in obese testosterone with : influence of mice. Birth Defects Res B Dev Reprod Toxicol men. sex hormone-binding globulin and body fat. 2011; 92: 195-205. Diabetes Care 2004; 27: 861-868. Rajanahally S, Raheem O, Rogers M, et al. The 3. Dallal RM, Chernoff A, O’Leary MP, Smith JA, Other treatments relationship between cannabis and male infertility, Braverman JD, Quebbemann BB. Sexual Although weight loss improves the hor- sexual health, and neoplasm: a systematic review. dysfunction is common in the morbidly obese male mone profile, there are few data regarding Andrology 2019; 7: 139-147. and improves after gastric bypass surgery. J Am therapies that directly target endocrine 16. McLachlan RI, Kovacs G, Cook R. The role of Coll Surg 2008; 207:859-864. abnormalities in obese men. Aromatase the GP in managing male infertility. Med Today 4. Salas-Huetos A, Maghsoumi-Norouzabad L, inhibitors might potentially correct oes- 2010; 11(10): 16-26. James ER, Carrell DT, Aston KI, Jenkins TG, et al. 17. Camacho EM, Huhtaniemi IT, O’Neill TW, et al; trogen excess and ameliorate hypogon- Male adiposity, sperm parameters and EMAS Group. Age-associated changes in -hypo- adotrophic hypogonadism, but this reproductive hormones: An updated systematic thalamic-pituitary-testicular function in -middle- intervention has not been well studied review and collaborative meta-analysis. Obesity aged and older men are modified by weight change in obese men, and these drugs are not Reviews. Published online 23 July 2020. and lifestyle factors: longitudinal results from the 5. Chavarro JE, Toth TL, Wright DL, Meeker JD, approved for this indication. Notably, European Male Ageing Study. Eur J Endocrinol Hauser R. Body mass index in relation to semen even in the presence of hypogonadism, 2013; 168: 445-455. quality, sperm DNA integrity, and serum exogenous androgens should not be pre- 18. Dallal RM, Chernoff A, O’Leary MP, Smith JA, reproductive hormone levels among men attending scribed in obese men seeking fertility Braverman JD, Quebbemann BB. Sexual an infertility clinic. Fertil Steril 2010; 93: 2222-2231. because of their contraceptive action. dysfunction is common in the morbidly obese male 6. Hammoud AO, Wilde N, Gibson M, Parks A, Other potential therapies include the and improves after gastric bypass surgery. J Am Carrell DT, Meikle AW. Male obesity and alteration use of phosphodiesterase inhibitors to Coll Surg 2008; 207: 859-864. in sperm parameters. Fertil Steril 2008; 90: 19. Mir J, Franken D, Andrabi SW, Ashraf M, Rao K. improve erectile function. Scrotal lipec- 2222-2225. Impact of weight loss on sperm DNA integrity in tomy to remove accumulated fat has 7. MacDonald AA, Herbison GP, Showell M, obese men. Andrologia 2018; 50: e12957. been advocated to reduce scrotal Farquhar CM. The impact of body mass index 20. Calderón B, Huerta L, Galindo J, et al. Lack of temperature. on semen parameters and reproductive hormones improvement of sperm characteristics in obese in human males: a systematic review with males after obesity surgery despite the beneficial meta-analysis. Hum Reprod Update 2010; 16: Conclusion changes observed in reproductive hormones. Obes 293-311. Male obesity is a significant health issue Surg 2019; 29: 2045-2050. 8. Oliveira JBA, Petersen CG, Mauri AL, et al. and is associated with decreased fertility. 21. Wood GJA, Tiseo BC, Paluello DV, et al. Association between body mass index and sperm The association is likely to involve multiple Bariatric surgery impact on reproductive hormones, quality and sperm DNA integrity. A large population factors, including endocrine dysregula- semen analysis, and sperm dna fragmentation in study. Andrologia 2018; 50: e12889. tion, reduced sexual desire and function, men with severe obesity: prospective study. Obes 9. Soubry A, Guo L, Huang Z, et al. Obesity-related Surg 2020. doi: 10.1007/s11695-020-04851- comorbidities such as OSA, and subopti- DNA methylation at imprinted genes in human 3. Online ahead of print. mal semen parameters. Although there sperm: Results from the TIEGER study. Clinical are limited data demonstrating the direct Epigenetics 2016; 8: 51. benefits of weight loss on semen param- 10. Keltz J, Zapantis A, Jindal SK, Lieman HJ, eters and sperm quality, weight loss has Santoro N, Polotsky AJ. Overweight men: clinical COMPETING INTERESTS: None.

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