Obesity, male infertility, and the sperm epigenome

Obesity is a growing epidemic and a common problem among reproductive-age men that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the fidelity and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and nonhuman animal data support these findings. Recent works in the burgeoning field of 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, and perhaps more importantly, conveying the impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Reproductive urologists and endocrinologists must learn to assimilate these new findings to better counsel men about the importance of paternal preconception health, a topic recently being championed by the Centers for Disease Control and Prevention. Obesity is a growing epidemic and a common problem among reproductive-age men that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the fidelity and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and nonhuman animal data support these findings. Recent works in the burgeoning field of 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, and perhaps more importantly, conveying the impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Reproductive urologists and endocrinologists must learn to assimilate these new findings to better counsel men about the importance of paternal preconception health, a topic recently being championed by the Centers for Disease Control and Prevention. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/15227-23552 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/15227-23552 Obesity, defined as a body mass index (BMI) of >30 kg/m2, is a disease approaching pandemic proportions, affecting more than 1.9 billion adults over the age of 18 years worldwide (1American Medical Association. Recognition of obesity as a disease. H-440.842. In: Public Health Policy. Annual Meeting, 2013. Available at: https://searchpf.ama-assn.org/SearchML/searchDetails.action?uri=%2FAMADoc%2FHOD.xml-0-3858.xml#. Last accesed March 12, 2017.Google Scholar, 2World Health Organization. Obesity and overweight. Fact Sheet. 2016. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/. Last accessed March 12, 2017.Google Scholar) (Fig. 1). In the United States alone, the prevalence of obese men who are of reproductive age has tripled since the 1970s and currently affects 33.9% of the population over the age of 20 years (3National Center for Health StatisticsHealth, United States, 2008, with chartbook. National Center for Health Statistics, Hyattsville, MD2009Google Scholar). The rise in obesity rates have paralleled reports of rising rates of poor sperm quality and male infertility (4Katib A. Mechanisms linking obesity to male infertility.Cent Eur J Urol. 2015; 68: 79-85Abstract Full Text Full Text PDF PubMed Google Scholar, 5Swan S.H. Elkin E.P. Fenster L. The question of declining sperm density revisited: an analysis of 101 studies published 1934–1996.Environ Health Perspect. 2000; 108: 961-966Crossref PubMed Google Scholar). With the rate of male-related infertility contributing to 45%–50% of infertile couples (6Rowe P.J. World Health OrganizationWHO manual for the standardized investigation, diagnosis, and management of the infertile male. Cambridge University Press, Cambridge, UK2000Google Scholar, 7Lamb D.J. Lipshultz L.I. Male infertility: recent advances and a look toward the future.Curr Opin Urol. 2000; 10: 359-362Crossref PubMed Scopus (0) Google Scholar), there is an enlarging body of evidence linking male infertility to obesity. Mechanisms by which obesity may affect spermatogenesis include thermal effects, hyperestrogenism, hypogonadotropic hypogonadism, diabetes mellitus, sexual dysfunction, and sperm epigenetic perturbations. In addition to the immediate effects that obesity has on the father, there is evidence that negative effects may be transmitted to the offspring via genetic and epigenetic alterations of germ cell DNA (8Fullston T. Ohlsson Teague E.M. Palmer N.O. DeBlasio M.J. Mitchell M. Corbett M. et al.Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content.FASEB J. 2013; 27: 4226-4243Crossref PubMed Scopus (119) Google Scholar, 9McPherson N.O. Fullston T. Bakos H.W. Setchell B.P. Lane M. Obese father’s metabolic state, adiposity, and reproductive capacity indicate son’s reproductive health.Fertil Steril. 2014; 101: 865-873Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 10Soubry A. Schildkraut J.M. Murtha A. Wang F. Huang Z. Bernal A. et al.Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.BMC Med. 2013; 11: 29Crossref PubMed Scopus (91) Google Scholar). The objective of the present review is to explore the epidemiology and pathophysiology of obesity-induced male infertility with an emphasis on the role of epigenetics. The negative effects of obesity on semen parameters and androgen profiles have been well established; however, population-based epidemiologic evidence was not available until a decade ago. In 2006, Sallmen et al. (11Sallmen M. Sandler D.P. Hoppin J.A. Blair A. Baird D.D. Reduced fertility among overweight and obese men.Epidemiology. 2006; 17: 520-523Crossref PubMed Scopus (138) Google Scholar) described a group of 20,620 families in Iowa and North Carolina. They illustrated a dose-response relationship between BMI and male infertility, with worsening male fertility for every 3-point increase in BMI >25 kg/m2, with an odds ratio (OR) of 1.12 (95% confidence interval [CI] 1.01–1.25). These findings were confirmed in later studies across the globe, including in Danish (12Ramlau-Hansen C.H. Thulstrup A.M. Nohr E.A. Bonde J.P. Sorensen T.I. Olsen J. Subfecundity in overweight and obese couples.Hum Reprod. 2007; 22: 1634-1637Crossref PubMed Scopus (169) Google Scholar) and Norwegian (13Nguyen R.H. Wilcox A.J. Skjaerven R. Baird D.D. Men’s body mass index and infertility.Hum Reprod. 2007; 22: 2488-2493Crossref PubMed Scopus (127) Google Scholar) cohorts that showed an association between obesity and male infertility with ORs of 1.53 (95% CI 1.32–1.77) and 1.36 (95% CI 1.32–1.77), respectively (12Ramlau-Hansen C.H. Thulstrup A.M. Nohr E.A. Bonde J.P. Sorensen T.I. Olsen J. Subfecundity in overweight and obese couples.Hum Reprod. 2007; 22: 1634-1637Crossref PubMed Scopus (169) Google Scholar, 13Nguyen R.H. Wilcox A.J. Skjaerven R. Baird D.D. Men’s body mass index and infertility.Hum Reprod. 2007; 22: 2488-2493Crossref PubMed Scopus (127) Google Scholar, 14Stewart T.M. Liu D.Y. Garrett C. Brown E.H. Baker H.W. Recruitment bias in studies of semen and other factors affecting pregnancy rates in fertile men.Hum Reprod. 2009; 24: 2401-2408Crossref PubMed Scopus (0) Google Scholar, 15Jensen T.K. Andersson A.M. Jorgensen N. Andersen A.G. Carlsen E. Petersen J.H. et al.Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.Fertil Steril. 2004; 82: 863-870Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 16Kort H.I. Massey J.B. Elsner C.W. Mitchell-Leef D. Shapiro D.B. Witt M.A. et al.Impact of body mass index values on sperm quantity and quality.J Androl. 2006; 27: 450-452Crossref PubMed Scopus (227) Google Scholar, 17Aggerholm A.S. Thulstrup A.M. Toft G. Ramlau-Hansen C.H. Bonde J.P. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile?.Fertil Steril. 2008; 90: 619-626Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Martini A.C. Tissera A. Estofan D. Molina R.I. Mangeaud A. de Cuneo M.F. et al.Overweight and seminal quality: a study of 794 patients.Fertil Steril. 2010; 94: 1739-1743Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Bieniek J.M. Kashanian J.A. Deibert C.M. Grober E.D. Lo K.C. Brannigan R.E. et al.Influence of increasing body mass index on semen and reproductive hormonal parameters in a multi-institutional cohort of subfertile men.Fertil Steril. 2016; 106: 1070-1075Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). A complete review of these studies is presented in Table 1.Table 1Epidemiologic studies on male infertility.StudynLocationDesignVariables studiedAssociation with male BMIStudies on association between BMI and male infertility Sallmen et al. 2006 11Sallmen M. Sandler D.P. Hoppin J.A. Blair A. Baird D.D. Reduced fertility among overweight and obese men.Epidemiology. 2006; 17: 520-523Crossref PubMed Scopus (138) Google Scholar1,329United StatesSecondary analysis of data from the Agricultural Health Study on couples with a certified pesticide applicator and spouseInfertility (defined as not conceiving a pregnancy after ≥12 mo of unprotected intercourse)Adjusted for female BMI, male and female ages, smoking status, alcohol use, and exposure to solvents and pesticides:1. OR for infertility 1.12 (95% CI 1.01–1.25).2. Positive dose-effect relationship, with maximal effect in the BMI 32–43 kg/m2 group and a plateau beyond that. Ramlau-Hansen et al. 2007 12Ramlau-Hansen C.H. Thulstrup A.M. Nohr E.A. Bonde J.P. Sorensen T.I. Olsen J. Subfecundity in overweight and obese couples.Hum Reprod. 2007; 22: 1634-1637Crossref PubMed Scopus (169) Google Scholar47,835DenmarkProspective study: Danish Birth Cohort of couples from 1996 to 2002Subfecundity (time to pregnancy)Adjusted for the partner's BMI:1. OR 1.18 (95% CI 1.10–1.27) in overweight men.2. OR 1.53 (95% CI 1.32–1.77) in obese men. Nguyen et al. 2007 13Nguyen R.H. Wilcox A.J. Skjaerven R. Baird D.D. Men’s body mass index and infertility.Hum Reprod. 2007; 22: 2488-2493Crossref PubMed Scopus (127) Google Scholar26,303NorwayRetrospective study: Norwegian Mother and Child Cohort Study on pregnancies from 1999 to 2005Subfecundity (time to pregnancy)Adjusted for partner's BMI, coital frequency, and the ages and smoking habits of both partners:1. OR 1.20 (95% CI 1.04–1.38) in overweight men.2. OR 1.36 (95% CI 1.13–1.63) in obese men, with a plateauing effect over a BMI of 32 kg/m2. Stewart et al. 2009 14Stewart T.M. Liu D.Y. Garrett C. Brown E.H. Baker H.W. Recruitment bias in studies of semen and other factors affecting pregnancy rates in fertile men.Hum Reprod. 2009; 24: 2401-2408Crossref PubMed Scopus (0) Google Scholar225AustraliaCross-sectional study. Initiated by WHO on male partners of women who conceived naturally1. Time to pregnancy2. Semen analysis3. Hormone profile4. Physical exam to rule out local causes for infertility1. Obesity was significantly related to reduced total sperm count (mean 324 vs. 231 million; P<.05).2. Obese men (BMI >30 kg/m2) had significantly lower T, SHBG, and inhibin but not FSH.Studies on association between BMI and sperm parameters ± hormone profile Jensen et al. 2004 15Jensen T.K. Andersson A.M. Jorgensen N. Andersen A.G. Carlsen E. Petersen J.H. et al.Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.Fertil Steril. 2004; 82: 863-870Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar1,558DenmarkProspective study on military recruits from 1996 to 19981. Semen analysis2. Hormone profile3. Physical exam to rule out local causes for infertility and to measure testis size1. BMI >25 kg/m2 had a reduction in sperm concentration of 21.6% (95% CI 4.0%–39.4%) and reduced total sperm count of 23.9% (95% CI 4.7%–43.2%). Nonsignificant reduction in sperm count. Testis size, semen volume, and percentage of motile spermatozoa were not affected by high BMI.2. Decreased serum T, SHBG, and inhibin B. E2 demonstrated a positive relationship. Kort et al. 2006 16Kort H.I. Massey J.B. Elsner C.W. Mitchell-Leef D. Shapiro D.B. Witt M.A. et al.Impact of body mass index values on sperm quantity and quality.J Androl. 2006; 27: 450-452Crossref PubMed Scopus (227) Google Scholar520United StatesProspective study on normal healthy menSemen parameters, including sperm chromatin integrity (DNA fragmentation index [DFI])1. Significant decrease in sperm motility: normal BMI 18.6 × 106 cells; overweight 3.6 × 106 cells; obese 0.7 × 106 cells.2. Significant increase in DFI: normal BMI 19.9% (±1.96%); overweight 25.8% (±2.23%); obese 27.0% (±3.16%). Aggerholm et al. 2008 17Aggerholm A.S. Thulstrup A.M. Toft G. Ramlau-Hansen C.H. Bonde J.P. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile?.Fertil Steril. 2008; 90: 619-626Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar1,989EuropeProspective study on men aged 18–69 y. Data from five previous population-based environmental studies of semen quality were combined into one database.1. Semen analysis2. Hormone profile1. Overweight group had slightly lower sperm concentration (56 × 106 per mL; 95% CI 52–60) compared with normal-BMI group (59 × 106 per mL; 95% CI 55–63) and lower total sperm count (154 × 106; 95% CI 142–168) compared with normal-BMI group (168 × 106; 95% CI 157–180). Obese men had higher sperm density (68 × 106 per mL; 95% CI 58–78) and total sperm count (190 × 106; 95% CI 161–223) than the reference group of normal-weight men. None of these differences were statistically significant.2. Decreased T and inhibin (25%–32% lower) in obese men. E2 concentration 6% higher in obese men. Martini et al. 2010 18Martini A.C. Tissera A. Estofan D. Molina R.I. Mangeaud A. de Cuneo M.F. et al.Overweight and seminal quality: a study of 794 patients.Fertil Steril. 2010; 94: 1739-1743Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar794ArgentinaProspective study on male partners of infertile couples from 2006 to 20071. Semen analysis2. Seminal hormone and biochemical profile1. Decreased sperm motility in the high-BMI group. Percentage of sperm motility: normal BMI 51.4% (95% CI 50.2%–52.6%); overweight 50.2% (95% CI 49.2%–51.2%); obese 46.6% (95% CI 44.9%–48.3%).2. No association between BMI and sperm concentration.3. No significant differences were detected in seminal T levels between groups. Bieniek et al. 2016 19Bieniek J.M. Kashanian J.A. Deibert C.M. Grober E.D. Lo K.C. Brannigan R.E. et al.Influence of increasing body mass index on semen and reproductive hormonal parameters in a multi-institutional cohort of subfertile men.Fertil Steril. 2016; 106: 1070-1075Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar4,440North AmericaProspective multicenter study from 2002 to 20141. Semen analysis2. Hormone profile1. BMI had weak but significant negative correlations with ejaculate volume (r = −0.04), sperm concentration (r = −0.08), motility (r = −0.07), and morphology (r = −0.04).2. Rates of azoospermia and oligospermia were also more prevalent among obese (12.7% and 31.7%, respectively) compared with normal-weight (9.8% and 24.5%) men.3. Testosterone had a significant negative correlation, with BMI. E2 demonstrated a positive relationship.4. Neither FSH nor LH demonstrated significant correlations with BMI.Note: BMI = body mass index; CI = confidence interval; OR = odds ratio; WHO = World Health Organization. Open table in a new tab Note: BMI = body mass index; CI = confidence interval; OR = odds ratio; WHO = World Health Organization. Obesity-related health deficits include increased risks of diabetes mellitus, cardiovascular disease, epigenetic alterations, and certain malignancies (20Twig G. Yaniv G. Levine H. Leiba A. Goldberger N. Derazne E. et al.Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood.N Engl J Med. 2016; 374: 2430-2440Crossref PubMed Google Scholar, 21Lauby-Secretan B. Scoccianti C. Loomis D. Grosse Y. Bianchini F. Straif K. et al.Body fatness and cancer—viewpoint of the IARC Working Group.N Engl J Med. 2016; 375: 794-798Crossref PubMed Scopus (0) Google Scholar, 22Ozanne S.E. Epigenetic signatures of obesity.N Engl J Med. 2015; 372: 973-974Crossref PubMed Scopus (0) Google Scholar). Obese men are also at greater risk of developing hypogonadism, impaired spermatogenesis, and erectile dysfunction (23Lamm S. Chidakel A. Bansal R. Obesity and Hypogonadism.Urol Clin North Am. 2016; 43: 239-245Abstract Full Text Full Text PDF PubMed Google Scholar, 24Dandona P. Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity.J Clin Endocrinol Metab. 2011; 96: 2643-2651Crossref PubMed Scopus (0) Google Scholar, 25Vermeulen A. Kaufman J.M. Deslypere J.P. Thomas G. Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men.J Clin Endocrinol Metab. 1993; 76: 1140-1146Crossref PubMed Scopus (0) Google Scholar, 26MacDonald A.A. Herbison G.P. Showell M. Farquhar C.M. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.Hum Reprod Update. 2010; 16: 293-311Crossref PubMed Scopus (179) Google Scholar). All of these factors are potential contributors to increased rates of male infertility in these patients. Normal intratesticular testosterone levels are a prerequisite for normal spermatogenesis (27O’Shaughnessy P.J. Verhoeven G. de Gendt K. Monteiro A. Abel M.H. Direct action through the Sertoli cells is essential for androgen stimulation of spermatogenesis.Endocrinology. 2010; 151: 2343-2348Crossref PubMed Scopus (0) Google Scholar). Currently, our understanding of the hypothalamic-pituitary-gonadal (HPG) axis constitutes the core of our understanding of male reproduction. However, recent evidence has indicated that a number of “neohormones,” which include leptin (28Munzberg H. Myers Jr., M.G. Molecular and anatomical determinants of central leptin resistance.Nat Neurosci. 2005; 8: 566-570Crossref PubMed Scopus (345) Google Scholar, 29Farooqi I.S. O’Rahilly S. Leptin: a pivotal regulator of human energy homeostasis.Am J Clin Nutr. 2009; 89: 980S-984SCrossref PubMed Scopus (183) Google Scholar) and kisspeptin (30Clarke H. Dhillo W.S. Jayasena C.N. Comprehensive review on kisspeptin and its role in reproductive disorders.Endocrinol Metab (Seoul). 2015; 30: 124-141Crossref PubMed Scopus (10) Google Scholar), may also impact this axis. Furthermore, many of the comorbidities of obesity, such as diabetes (24Dandona P. Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity.J Clin Endocrinol Metab. 2011; 96: 2643-2651Crossref PubMed Scopus (0) Google Scholar) and sleep apnea (31Luboshitzky R. Lavie L. Shen-Orr Z. Herer P. Altered luteinizing hormone and testosterone secretion in middle-aged obese men with obstructive sleep apnea.Obes Res. 2005; 13: 780-786Crossref PubMed Google Scholar, 32Axelsson J. Ingre M. Akerstedt T. Holmback U. Effects of acutely displaced sleep on testosterone.J Clin Endocrinol Metab. 2005; 90: 4530-4535Crossref PubMed Scopus (0) Google Scholar, 33Boyar R.M. Rosenfeld R.S. Kapen S. Finkelstein J.W. Roffwarg H.P. Weitzman E.D. et al.Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep.J Clin Invest. 1974; 54: 609-618Crossref PubMed Google Scholar, 34Schiavi R.C. White D. Mandeli J. Pituitary-gonadal function during sleep in healthy aging men.Psychoneuroendocrinology. 1992; 17: 599-609Abstract Full Text PDF PubMed Scopus (0) Google Scholar), exacerbate these endocrine derangements. Below, we discuss in more detail the HPG axis, the effect of obesity on the HPG axis, and how these neohormones effect these pathways. Testosterone levels measured within the testicle are found to be 25–125-fold greater than levels in serum (35Comhaire F.H. Vermeulen A. Testosterone concentration in the fluids of seminiferous tubules, the interstitium and the rete testis of the rat.J Endocrinol. 1976; 70: 229-235Crossref PubMed Google Scholar, 36Turner T.T. Jones C.E. Howards S.S. Ewing L.L. Zegeye B. Gunsalus G.L. On the androgen microenvironment of maturing spermatozoa.Endocrinology. 1984; 115: 1925-1932Crossref PubMed Google Scholar, 37Awoniyi C.A. Santulli R. Sprando R.L. Ewing L.L. Zirkin B.R. Restoration of advanced spermatogenic cells in the experimentally regressed rat testis: quantitative relationship to testosterone concentration within the testis.Endocrinology. 1989; 124: 1217-1223Crossref PubMed Google Scholar, 38Maddocks S. Hargreave T.B. Reddie K. Fraser H.M. Kerr J.B. Sharpe R.M. Intratesticular hormone levels and the route of secretion of hormones from the testis of the rat, guinea pig, monkey and human.Int J Androl. 1993; 16: 272-278Crossref PubMed Scopus (0) Google Scholar, 39Jarow J.P. Chen H. Rosner T.W. Trentacoste S. Zirkin B.R. Assessment of the androgen environment within the human testis: minimally invasive method to obtain intratesticular fluid.J Androl. 2001; 22: 640-645PubMed Google Scholar). The physiologic need for elevated intratesticular levels is not completely understood; however, levels >70 nmol/L have been shown to be required for normal spermatogenesis (40Zirkin B.R. Santulli R. Awoniyi C.A. Ewing L.L. Maintenance of advanced spermatogenic cells in the adult rat testis: quantitative relationship to testosterone concentration within the testis.Endocrinology. 1989; 124: 3043-3049Crossref PubMed Google Scholar). Thus, even a small decrease of the systemic testosterone levels can reflect a major reduction of the intratesticular levels. GnRH is produced by the hypothalamus in a pulsatile manner and stimulates LH and FSH. Normally, LH is produced by the pituitary gland and acts to induce steroidogenesis of testosterone by the Leydig cells. Once testosterone diffuses out of the Leydig cells, it is bound by proteins in circulation, mainly SHBG, and is then metabolized to estrogen by aromatase (41Kim H.H. Schlegel P.N. Endocrine manipulation in male infertility.Urol Clin North Am. 2008; 35: 303-318Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). FSH, while not strictly required for spermatogenesis in humans, does augment Sertoli cell function, making it a core component of optimal testicular function (42Levallet J. Pakarinen P. Huhtaniemi I.T. Follicle-stimulating hormone ligand and receptor mutations, and gonadal dysfunction.Arch Med Res. 1999; 30: 486-494Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Hypogonadism in obesity can be mediated by both reduced pulse amplitude of the cyclical secretion of LH from the pituitary as well as decreased response to LH by the testis (25Vermeulen A. Kaufman J.M. Deslypere J.P. Thomas G. Attenuated luteinizing hormone (LH) pulse amplitude but normal LH pulse frequency, and its relation to plasma androgens in hypogonadism of obese men.J Clin Endocrinol Metab. 1993; 76: 1140-1146Crossref PubMed Scopus (0) Google Scholar). Reductions in SHBG, FSH, and inhibin B and elevated E2, via increased aromatization of testosterone to E2 peripherally, are also commonly seen (17Aggerholm A.S. Thulstrup A.M. Toft G. Ramlau-Hansen C.H. Bonde J.P. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile?.Fertil Steril. 2008; 90: 619-626Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Ramlau-Hansen C.H. Hansen M. Jensen C.R. Olsen J. Bonde J.P. Thulstrup A.M. Semen quality and reproductive hormones according to birthweight and body mass index in childhood and adult life: two decades of follow-up.Fertil Steril. 2010; 94: 610-618Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Paasch U. Grunewald S. Kratzsch J. Glander H.J. Obesity and age affect male fertility potential.Fertil Steril. 2010; 94: 2898-2901Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 45Chavarro J.E. Toth T.L. Wright D.L. Meeker J.D. Hauser R. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.Fertil Steril. 2010; 93: 2222-2231Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). All of these changes result in reductions in the throughput and fidelity of human spermatogenic function and, possibly, alter the sperm epigenome (46Soubry A. Guo L. Huang Z. Hoyo C. Romanus S. Price T. et al.Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study.Clin Epigenetics. 2016; 8: 51Crossref PubMed Scopus (3) Google Scholar). In addition to perturbations by these standard pathways, obesity is associated with dysregulation of a number of “neohormones” which act to further disrupt the male endocrine axis (28Munzberg H. Myers Jr., M.G. Molecular and anatomical determinants of central leptin resistance.Nat Neurosci. 2005; 8: 566-570Crossref PubMed Scopus (345) Google Scholar, 29Farooqi I.S. O’Rahilly S. Leptin: a pivotal regulator of human energy homeostasis.Am J Clin Nutr. 2009; 89: 980S-984SCrossref PubMed Scopus (183) Google Scholar, 30Clarke H. Dhillo W.S. Jayasena C.N. Comprehensive review on kisspeptin and its role in reproductive disorders.Endocrinol Metab (Seoul). 2015; 30: 124-141Crossref PubMed Scopus (10) Google Scholar). Under normal physiologic control, adipocytes release leptin, increasing release of kisspeptin from KISS neurons. This acts to increase the release of GnRH from the hypothalamus, elevating FSH and LH secretion from the anterior pituitary, which in turn increases testicular testosterone biosynthesis. Obesity induces changes via multiple pathways in the HPG axis that lead to hypogonadotropic hyperestrogenic hypoandrogenism (Fig. 2). Obese men have increased adipocyte-related aromatization of testosterone into E2 and estrone (47Kley H.K. Deselaers T. Peerenboom H. Kruskemper H.L. Enhanced conversion of androstenedione to estrogens in obese males.J Clin Endocrinol Metab. 1980; 51: 1128-1132Crossref PubMed Google Scholar). These increased levels of E2 and estrone down-regulate the release of kisspeptin from KISS neurons and decrease the activity of the HPG axis (48Gautier A. Bonnet F. Dubois S. Massart C. Grosheny C. Bachelot A. et al.Associations between visceral adipose tissue, inflammation and sex steroid concentrations in men.Clin Endocrinol (Oxf). 2013; 78: 373-378Crossref PubMed Scopus (27) Google Scholar, 49George J.T. Millar R.P. Anderson R.A. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes.Neuroendocrinology. 2010; 91: 302-307Crossref PubMed Scopus (0) Google Scholar). In addition to aromatization of testosterone, adipocytes also produce a hormone called leptin, a critical factor in regulating energy homeostasis (50Brennan A.M. Mantzoros C.S. Drug insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications.Nat Clin Pract Endocrinol Metab. 2006; 2: 318-327Crossref PubMed Scopus (0) Google Scholar). Mutations in the leptin gene or leptin receptor leads to increased food intake and decreased energy expenditure. However, in obese individuals without mutations in the leptin gene or receptor, leptin levels are chronically elevated, leading to “leptin resistance” (51Considine R.V. Considine E.L. Williams C.J. Nyce M.R. Magosin S.A. Bauer T.L. et al.Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.J Clin Invest. 1995; 95: 2986-2988Crossref PubMed Google Scholar). This resistance is seen centrally in the hypothalamus, where leptin is unable to stimulate the HPG axis in these leptin-resistant men, leading to decreased testosterone levels (28Munzberg H. Myers Jr., M.G. Molecular and anatomical determinants of central leptin resistance.Nat Neurosci. 2005; 8: 566-570Crossref PubMed Scopus (345) Google Scholar, 29Farooqi I.S. O’Rahilly S. Leptin: a pivotal regulator of human energy homeostasis.Am J Clin Nutr. 2009; 89: 980S-984SCrossref PubMed Scopus (183) Google Scholar). Diabetes is associated with obesity and can negatively affect the androgenic axis. The prevalence of diabetes in the obese population is significant, with 3.4% of the American population affected by both conditions (52Mokdad A.H. Ford E.S. Bowman B.A. Dietz W.H. Vinicor F. Bales V.S. et al.Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.JAMA. 2003; 289: 76-79Crossref PubMed Scopus (3405) Google Scholar). The obese man with diabetes exhibits both central and peripheral insulin resistance, leading to reduction of SHBG synthesis by the liver. The reduction of SHBG allows for a greater fraction of testosterone to remain free, which magnifies the negative feedback effect of E2 through aromatization (52Mokdad A.H. Ford E.S. Bowman B.A. Dietz W.H. Vinicor F. Bales V.S. et al.Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.JAMA. 2003; 289: 76-79Crossref PubMed Scopus (3405) Google Scholar)