Reproduction as a window for health in men
2023; Elsevier BV; Volume: 120; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2023.01.014
ISSN1556-5653
AutoresFederico Belladelli, Wade Muncey, Michael L. Eisenberg,
Tópico(s)Demographic Trends and Gender Preferences
ResumoMale factor infertility is widely considered a harbinger for a man’s general health. Failure of reproduction often accompanies other underlying processes, with growing evidence suggesting that a diagnosis of infertility increases the likelihood of developing future cardiac, metabolic, and oncologic diseases. The goal of this review is to provide a comprehensive overview of the research on male fertility as a marker for current and future health. A multidisciplinary approach is essential, and there is growing consensus that the male fertility evaluation offers an opportunity to better men's wellness beyond their immediate reproductive ambitions. Male factor infertility is widely considered a harbinger for a man’s general health. Failure of reproduction often accompanies other underlying processes, with growing evidence suggesting that a diagnosis of infertility increases the likelihood of developing future cardiac, metabolic, and oncologic diseases. The goal of this review is to provide a comprehensive overview of the research on male fertility as a marker for current and future health. A multidisciplinary approach is essential, and there is growing consensus that the male fertility evaluation offers an opportunity to better men's wellness beyond their immediate reproductive ambitions. After 1 year of unprotected intercourse, 15% of couples are unable to conceive a child (1Thoma M.E. McLain A.C. Louis J.F. King R.B. Trumble A.C. Sundaram R. et al.Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach.Fertil Steril. 2013; 99: 1324-1331.e1Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar). Male factor infertility is estimated to affect 7% of males globally, and it contributes to 30%–50% of couples with infertility (2Brugh 3rd, V.M. Lipshultz L.I. Male factor infertility: evaluation and management.Med Clin North Am. 2004; 88: 367-385Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). Moreover, more than 1% of all men are azoospermic (3Vander Borght M. Wyns C. Fertility and infertility: definition and epidemiology.Clin Biochem. 2018; 62: 2-10Crossref PubMed Scopus (857) Google Scholar). There is concern that the numbers may increase because it has been observed that sperm counts have fallen worldwide (4Levine H. Jørgensen N. Martino-Andrade A. Mendiola J. Weksler-Derri D. Mindlis I. et al.Temporal trends in sperm count: a systematic review and meta-regression analysis.Hum Reprod Update. 2017; 23: 646-659Crossref PubMed Scopus (735) Google Scholar). A growing body of literature has identified male factor infertility as a potential biomarker for both present and future health (5Kasman A.M. Del Giudice F. Eisenberg M.L. New insights to guide patient care: the bidirectional relationship between male infertility and male health.Fertil Steril. 2020; 113: 469-477Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Del Giudice F. Kasman A.M. Ferro M. Sciarra A. De Berardinis E. Belladelli F. et al.Clinical correlation among male infertility and overall male health: a systematic review of the literature.Investig Clin Urol. 2020; 61: 355-371Crossref PubMed Scopus (45) Google Scholar) (Fig. 1). In fact, an Italian study found that males with infertility had more medical comorbidities than fertile men (7Salonia A. Matloob R. Gallina A. Abdollah F. Saccà A. Briganti A. et al.Are infertile men less healthy than fertile men? Results of a prospective case-control survey.Eur Urol. 2009; 56: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Additionally, semen quality decreases as a man’s medical comorbidities increase (8Eisenberg M.L. Li S. Behr B. Pera R.R. Cullen M.R. Relationship between semen production and medical comorbidity.Fertil Steril. 2015; 103: 66-71Abstract Full Text Full Text PDF PubMed Google Scholar, 9Ventimiglia E. Capogrosso P. Boeri L. Serino A. Colicchia M. Ippolito S. et al.Infertility as a proxy of general male health: results of a cross-sectional survey.Fertil Steril. 2015; 104: 48-55Abstract Full Text Full Text PDF PubMed Google Scholar). As a result, a man who is seeking reproductive treatment may also benefit from an evaluation of his overall health because improvements in health can also manifest as an increase in semen quality (10Shiraishi K. Matsuyama H. Effects of medical comorbidity on male infertility and comorbidity treatment on spermatogenesis.Fertil Steril. 2018; 110: 1006-1011.e2Abstract Full Text Full Text PDF PubMed Google Scholar). The goal of the current review is to provide a comprehensive overview of the research on male fertility as a marker for current and long-term health and explore potential etiologies of the association, including genetics, exposures, and lifestyle. Numerous studies have shown that men with infertility are more likely to be diagnosed with testicular cancer (11Jacobsen R. Bostofte E. Engholm G. Hansen J. Olsen J.H. Skakkebaek N.E. et al.Risk of testicular cancer in men with abnormal semen characteristics: cohort study.BMJ. 2000; 321: 789-792Crossref PubMed Google Scholar, 12Walsh T.J. Croughan M.S. Schembri M. Chan J.M. Turek P.J. Increased risk of testicular germ cell cancer among infertile men.Arch Intern Med. 2009; 169: 351-356Crossref PubMed Scopus (179) Google Scholar, 13Hanson H.A. Anderson R.E. Aston K.I. Carrell D.T. Smith K.R. Hotaling J.M. Subfertility increases risk of testicular cancer: evidence from population-based semen samples.Fertil Steril. 2016; 105: 322-328.e1Abstract Full Text Full Text PDF PubMed Google Scholar) (Table 1). Genomic instability causes both spermatogenic failure and an increased risk of malignant transformation within germ cells, and deoxyribonucleic acid (DNA) repair deficiencies within germ cells have been hypothesized as a mechanism linking the 2 disorders (26Maduro M.R. Casella R. Kim E. Lévy N. Niederberger C. Lipshultz L.I. et al.Microsatellite instability and defects in mismatch repair proteins: a new aetiology for Sertoli cell-only syndrome.Mol Hum Reprod. 2003; 9: 61-68Crossref PubMed Scopus (41) Google Scholar, 27Nudell D. Castillo M. Turek P.J. Pera R.R. Increased frequency of mutations in DNA from infertile men with meiotic arrest.Hum Reprod. 2000; 15: 1289-1294Crossref PubMed Google Scholar). Prostate cancer development has also been connected to male factor infertility (15Walsh T.J. Schembri M. Turek P.J. Chan J.M. Carroll P.R. Smith J.F. et al.Increased risk of high-grade prostate cancer among infertile men.Cancer. 2010; 116: 2140-2147PubMed Google Scholar).Table 1Summary of original studies regarding male fertility and future health.CancerCancer typeAssociated male factor variableRiskEvidence typeEvidence qualityaReferencesAll cancersInfertility diagnosisHR, 1.49Retrospective insurance claimsModerateEisenberg et al. (14Eisenberg M.L. Li S. Brooks J.D. Cullen M.R. Baker L.C. Increased risk of cancer in infertile men: analysis of U.S. claims data.J Urol. 2015; 193: 1596-1601Crossref PubMed Scopus (116) Google Scholar)Testicular cancerSemen analysisStandardized incidence ratio, 1.6; HR, 3.3Population based, registryLowJacobsen et al. (11Jacobsen R. Bostofte E. Engholm G. Hansen J. Olsen J.H. Skakkebaek N.E. et al.Risk of testicular cancer in men with abnormal semen characteristics: cohort study.BMJ. 2000; 321: 789-792Crossref PubMed Google Scholar), Hanson et al. (13Hanson H.A. Anderson R.E. Aston K.I. Carrell D.T. Smith K.R. Hotaling J.M. Subfertility increases risk of testicular cancer: evidence from population-based semen samples.Fertil Steril. 2016; 105: 322-328.e1Abstract Full Text Full Text PDF PubMed Google Scholar)Testicular cancerInfertility diagnosisStandardized incidence ratio, 1.3; HR, 1.99Clinical cohort, registryHighWalsh et al. (12Walsh T.J. Croughan M.S. Schembri M. Chan J.M. Turek P.J. Increased risk of testicular germ cell cancer among infertile men.Arch Intern Med. 2009; 169: 351-356Crossref PubMed Scopus (179) Google Scholar), Eisenberg et al. (14Eisenberg M.L. Li S. Brooks J.D. Cullen M.R. Baker L.C. Increased risk of cancer in infertile men: analysis of U.S. claims data.J Urol. 2015; 193: 1596-1601Crossref PubMed Scopus (116) Google Scholar)Prostate cancerInfertility diagnosisHR, 2.6Clinical cohort, registryLowWalsh et al. (15Walsh T.J. Schembri M. Turek P.J. Chan J.M. Carroll P.R. Smith J.F. et al.Increased risk of high-grade prostate cancer among infertile men.Cancer. 2010; 116: 2140-2147PubMed Google Scholar)Prostate cancerUse of ARTHR, 1.64Population based, registryModerateAl-Jebari et al. (16Al-Jebari Y. Elenkov A. Wirestrand E. Schütz I. Giwercman A. Lundberg Giwercman Y. Risk of prostate cancer for men fathering through assisted reproduction: nationwide population based register study.BMJ. 2019; 366: l5214Crossref PubMed Scopus (22) Google Scholar)Breast cancerUndescended testisOR, 11.6Clinical cohortVery lowThomas et al. (17Thomas D.B. Jimenez L.M. McTiernan A. Rosenblatt K. Stalsberg H. Stemhagen A. et al.Breast cancer in men: risk factors with hormonal implications.Am J Epidemiol. 1992; 135: 734-748Crossref PubMed Scopus (0) Google Scholar)Cardiovascular diseasesDisease typeAssociated male factor variableRiskEvidence typeEvidence qualityaBalshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6.All CVDsInfertility diagnosisHR, 1.47Population based, insurance claimsModerateChen et al. (18Chen P.C. Chen Y.J. Yang C.C. Lin T.T. Huang C.C. Chung C.H. et al.Male infertility increases the risk of cardiovascular diseases: a nationwide population-based cohort study in Taiwan.World J Mens Health. 2022; 40: 490-500Crossref PubMed Scopus (4) Google Scholar)Ischemic heart diseaseInfertility diagnosisHR, 1.34Retrospective insurance claimsModerateKasman et al. (19Kasman A.M. Li S. Luke B. Sutcliffe A.G. Pacey A.A. Eisenberg M.L. Male infertility and future cardiometabolic health: does the association vary by sociodemographic factors?.Urology. 2019; 133: 121-128Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar)StrokeInfertility diagnosisaaHR, 1.11Population based, registryVery lowSkåra et al. (20Skåra K.H. Åsvold B.O. Hernáez Á. Fraser A. Rich-Edwards J.W. Farland L.V. et al.Risk of cardiovascular disease in women and men with subfertility: the Trøndelag Health Study.Fertil Steril. 2022; 118: 537-547Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar)CVD mortalityNo. of offspringHR, 1.17Prospective cohortHighEisenberg et al. (21Eisenberg M.L. Park Y. Hollenbeck A.R. Lipshultz L.I. Schatzkin A. Pletcher M.J. Fatherhood and the risk of cardiovascular mortality in the NIH-AARP Diet and Health Study.Hum Reprod. 2011; 26: 3479-3485Crossref PubMed Scopus (49) Google Scholar)Other diseasesDisease typeAssociated male factor variableRiskEvidence typeEvidence qualityaBalshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6.DiabetesInfertility diagnosisHR, 1.1–2.12Retrospective insurance claims; population based, registryHighKasman et al. (19Kasman A.M. Li S. Luke B. Sutcliffe A.G. Pacey A.A. Eisenberg M.L. Male infertility and future cardiometabolic health: does the association vary by sociodemographic factors?.Urology. 2019; 133: 121-128Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar), Glazer et al. (22Glazer C.H. Bonde J.P. Giwercman A. Vassard D. Pinborg A. Schmidt L. et al.Risk of diabetes according to male factor infertility: a register-based cohort study.Hum Reprod. 2017; 32: 1474-1481Crossref PubMed Scopus (54) Google Scholar), Bungum et al. (23Bungum A.B. Glazer C.H. Bonde J.P. Nilsson P.M. Giwercman A. Søgaard Tøttenborg S. Risk of metabolic disorders in childless men: a population-based cohort study.BMJ Open. 2018; 8e020293Crossref PubMed Scopus (14) Google Scholar)MetSInfertility diagnosisHR, 1.22Population based, registryModerateBungum et al. (23Bungum A.B. Glazer C.H. Bonde J.P. Nilsson P.M. Giwercman A. Søgaard Tøttenborg S. Risk of metabolic disorders in childless men: a population-based cohort study.BMJ Open. 2018; 8e020293Crossref PubMed Scopus (14) Google Scholar)All immune disordersInfertility diagnosisHR, 3.11Retrospective insurance claimsModerateBrubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar)Rheumatoid arthritisInfertility diagnosisHR, 1.29Retrospective insurance claimsModerateBrubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar)PsoriasisInfertility diagnosisHR, 1.28Retrospective insurance claimsModerateBrubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar)Multiple sclerosisInfertility diagnosisHR, 1.61–1.91Retrospective insurance claims; population based, registryModerateBrubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar), Glazer et al. (25Glazer C.H. Tøttenborg S.S. Giwercman A. Bräuner E.V. Eisenberg M.L. Vassard D. et al.Male factor infertility and risk of multiple sclerosis: a register-based cohort study.Mult Scler. 2018; 24: 1835-1842Crossref PubMed Scopus (22) Google Scholar)Grave’s diseaseInfertility diagnosisHR, 1.46Retrospective insurance claimsModerateBrubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar)aaHR = age-adjusted hazard ratio; ART = assisted reproductive technology; CVD = cardiovascular disease; HR = hazard ratio; MetS = metabolic syndrome; OR = odds ratio.a Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. Open table in a new tab aaHR = age-adjusted hazard ratio; ART = assisted reproductive technology; CVD = cardiovascular disease; HR = hazard ratio; MetS = metabolic syndrome; OR = odds ratio. Additionally, it has been discovered that men who needed in vitro fertilization (IVF) had a higher risk of prostate cancer than men who conceived naturally (16Al-Jebari Y. Elenkov A. Wirestrand E. Schütz I. Giwercman A. Lundberg Giwercman Y. Risk of prostate cancer for men fathering through assisted reproduction: nationwide population based register study.BMJ. 2019; 366: l5214Crossref PubMed Scopus (22) Google Scholar). The impact of male factor infertility and relative risk of testicular or prostate cancer have recently been updated by a systematic review and meta-analysis by Del Giudice et al. (28Del Giudice F. Kasman A.M. De Berardinis E. Busetto G.M. Belladelli F. Eisenberg M.L. Association between male infertility and male-specific malignancies: systematic review and meta-analysis of population-based retrospective cohort studies.Fertil Steril. 2020; 114: 984-996Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Men with subinfertility and infertility had an approximately twofold higher risk of both malignancies, which was statistically significant. Importantly, the absolute risk of cancer remained low (1% for either malignancy), despite the fact that the relative risk was pertinent and meaningful (29Laukhtina E. Mori K. Pradere B. Shariat S.F. Association between male infertility and prostate cancer: a systematic review and meta-analysis.Curr Opin Urol. 2021; 31: 346-353Crossref PubMed Scopus (1) Google Scholar). Finally, there is evidence that poor spermatogenesis may increase the risk of developing any type of cancer. Eisenberg et al. (14Eisenberg M.L. Li S. Brooks J.D. Cullen M.R. Baker L.C. Increased risk of cancer in infertile men: analysis of U.S. claims data.J Urol. 2015; 193: 1596-1601Crossref PubMed Scopus (116) Google Scholar) discovered a greater frequency of all tumors in men with infertility than in fertile controls in an investigation of US insurance claims data from 2001 to 2009 (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.37–1.63). Malignancies, including non-Hodgkin lymphoma, were also included in the cancer risk in addition to genitourinary cancers. In addition, the risk seems to be higher among men with azoospermia than among males with oligozoospermia (30Eisenberg M.L. Betts P. Herder D. Lamb D.J. Lipshultz L.I. Increased cancer risk and azoospermia.Fertil Steril. 2013; 100: e12Abstract Full Text Full Text PDF PubMed Google Scholar). Another study investigated breast cancer in men using data from men recruited from the United States from 1983 to 1986. One of the strongest risk factors for breast cancer was undescended testes, which was also linked to orchiectomy, orchitis, testicular injury, late puberty, and infertility. The risk of breast cancer declined as the number of children increased (17Thomas D.B. Jimenez L.M. McTiernan A. Rosenblatt K. Stalsberg H. Stemhagen A. et al.Breast cancer in men: risk factors with hormonal implications.Am J Epidemiol. 1992; 135: 734-748Crossref PubMed Scopus (0) Google Scholar). Another study investigated the risk of cancer in relatives of men with suboptimal semen analysis. First-degree relatives had a 52% increased risk of testicular cancer compared with controls. Moreover, first- and second-degree relatives of men with azoospermia had a significantly increased risk of thyroid cancer (31Anderson R.E. Hanson H.A. Patel D.P. Johnstone E. Aston K.I. Carrell D.T. et al.Cancer risk in first- and second-degree relatives of men with poor semen quality.Fertil Steril. 2016; 106: 731-738Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). The same group also investigated the incidence of any childhood cancer among siblings and cousins of males who underwent semen analysis compared with fertile, age-matched controls in children ( 10 years, men without children are more likely than men with 2 or more children to pass away from CVD (21Eisenberg M.L. Park Y. Hollenbeck A.R. Lipshultz L.I. Schatzkin A. Pletcher M.J. Fatherhood and the risk of cardiovascular mortality in the NIH-AARP Diet and Health Study.Hum Reprod. 2011; 26: 3479-3485Crossref PubMed Scopus (49) Google Scholar). Although childlessness is an imperfect marker of fertility, the investigators implied that infertility may increase a man’s risk of CVD. Thus, recognizing the emerging evidence of male factor infertility as a marker for future CVD is crucial when starting preventative health care measures after an infertility diagnosis because heart disease is the leading cause of death in the United States. Male factor infertility is linked to higher mortality and future comorbid illnesses, even after adjusting for variables, such as smoking status and body mass index (BMI) (34Batty G.D. Mortensen L.H. Shipley M.J. Semen quality and risk factors for mortality.Epidemiology. 2019; 30: e19-e21Crossref PubMed Scopus (0) Google Scholar). This was demonstrated in a study of 43,000 males with infertility where an inverse connection between semen parameters and death was clearly noted (35Jensen T.K. Jacobsen R. Christensen K. Nielsen N.C. Bostofte E. Good semen quality and life expectancy: a cohort study of 43,277 men.Am J Epidemiol. 2009; 170: 559-565Crossref PubMed Scopus (211) Google Scholar). Glazer et al. (36Glazer C.H. Eisenberg M.L. Tøttenborg S.S. Giwercman A. Flachs E.M. Bräuner E.V. et al.Male factor infertility and risk of death: a nationwide record-linkage study.Hum Reprod. 2019; 34: 2266-2273PubMed Google Scholar) demonstrated a similar relationship while raising the possibility that males with azoospermia may be at the greatest risk. Eisenberg et al. (37Eisenberg M.L. Li S. Behr B. Cullen M.R. Galusha D. Lamb D.J. et al.Semen quality, infertility and mortality in the USA.Hum Reprod. 2014; 29: 1567-1574Crossref PubMed Scopus (157) Google Scholar) revealed that even after controlling for baseline health, which may be compromised in men with infertility, the heightened risk of mortality associated with poor semen quality persisted. Del Giudice et al. (38Del Giudice F. Kasman A.M. Li S. Belladelli F. Ferro M. de Cobelli O. et al.Increased mortality among men diagnosed with impaired fertility: analysis of US claims data.Urology. 2021; 147: 143-149Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) confirmed these findings in a recent US insurance claims–based database analysis from 2003 to 2017. They found that not only was the diagnosis of male factor infertility associated with a higher risk of all-cause mortality (HR, 1.42; 95% CI, 1.27–1.60), but also the odds of dying were significantly increased with increased severity of the spermatogenesis impairment, particularly in the subgroup with azoospermia (38Del Giudice F. Kasman A.M. Li S. Belladelli F. Ferro M. de Cobelli O. et al.Increased mortality among men diagnosed with impaired fertility: analysis of US claims data.Urology. 2021; 147: 143-149Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In a recent systematic review and meta-analysis, the same team of writers showed that all studies on this topic showed the same tendency (39Del Giudice F. Kasman A.M. Chen T. De Berardinis E. Busetto G.M. Sciarra A. et al.The association between mortality and male infertility: systematic review and meta-analysis.Urology. 2021; 154: 148-157Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Although males with infertility were shown to have a significant relative risk of dying, the overall absolute risk was determined to be minimal (risk difference, 0.33%; 95% CI, 0.19%–0.47%). Male factor infertility is frequently linked to metabolic conditions including diabetes mellitus and metabolic syndrome, where insulin resistance plays an important role in pathogenicity. Using data from 39,516 men who had undergone fertility treatment identified from the Danish National IVF Registry, Glazer et al. (22Glazer C.H. Bonde J.P. Giwercman A. Vassard D. Pinborg A. Schmidt L. et al.Risk of diabetes according to male factor infertility: a register-based cohort study.Hum Reprod. 2017; 32: 1474-1481Crossref PubMed Scopus (54) Google Scholar) investigated whether male factor infertility was associated with an increased risk of developing diabetes. The adjusted HRs for males with oligospermia, azoospermia, and aspermia were 1.44 (95% CI, 1.01–2.06), 2.10 (95% CI, 1.25–3.56), and 3.20 (95% CI, 1.00–10.31), respectively, when examining the impact of specific causes of male factor infertility (22Glazer C.H. Bonde J.P. Giwercman A. Vassard D. Pinborg A. Schmidt L. et al.Risk of diabetes according to male factor infertility: a register-based cohort study.Hum Reprod. 2017; 32: 1474-1481Crossref PubMed Scopus (54) Google Scholar). Similarly, another study investigated the childless men’s risk of developing metabolic disorders. Childless men had higher odds ratios (ORs) for metabolic syndrome (1.22) and diabetes (2.12) than fathers (23Bungum A.B. Glazer C.H. Bonde J.P. Nilsson P.M. Giwercman A. Søgaard Tøttenborg S. Risk of metabolic disorders in childless men: a population-based cohort study.BMJ Open. 2018; 8e020293Crossref PubMed Scopus (14) Google Scholar). Next, emerging data suggest that male factor infertility is also associated with incident autoimmune disorders. Brubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar) used data from a US insurance claims database to examine the risk of common immune disorders developing in the population of men with infertility. Men with infertility had a higher risk of developing rheumatoid arthritis than age-matched controls (HR, 1.29) and vasectomized males (HR, 1.56). Additionally, a higher risk was observed in men with general immunological diseases (including systemic lupus erythematosus) than that in males who had vasectomies (HR, 3.11) and age-matched controls (HR, 2.12). Examining the development of psoriasis revealed a similar increased risk for men with infertility. In addition, males with infertility had a higher risk of developing thyroiditis and Grave’s disease (HR, 1.46) (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar). The incidence of multiple sclerosis (MS) is associated with patient sex, likely because of the influence of gonadal hormones. Linking data from the Danish National IVF Registry and Danish Multiple Sclerosis Registry, Glazer et al. (25Glazer C.H. Tøttenborg S.S. Giwercman A. Bräuner E.V. Eisenberg M.L. Vassard D. et al.Male factor infertility and risk of multiple sclerosis: a register-based cohort study.Mult Scler. 2018; 24: 1835-1842Crossref PubMed Scopus (22) Google Scholar) examined the association between male factor infertility and MS. Indeed, men with male factor infertility had a greater chance of having a previous diagnosis of MS (HR, 1.28) and developing incident MS (OR, 1.61) (25Glazer C.H. Tøttenborg S.S. Giwercman A. Bräuner E.V. Eisenberg M.L. Vassard D. et al.Male factor infertility and risk of multiple sclerosis: a register-based cohort study.Mult Scler. 2018; 24: 1835-1842Crossref PubMed Scopus (22) Google Scholar). Brubaker et al. (24Brubaker W.D. Li S. Baker L.C. Eisenberg M.L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data.Andrology. 2018; 6: 94-98Crossref PubMed Scopus (44) Google Scholar) also identified an increased risk of MS (HR, 1.91). Although the etiologies are unknown, several plausibly hypotheses have been posited to explain the association between male factor infertility and later health. Genetics, development, and lifestyle and health are the primary classifications. Genetic abnormalities may be implicated in 15%–30% of cases of male factor infertility, with over 2,000 genes alone devoted to spermatogenesis (40Shamsi M.B. Kumar K. Dada R. Genetic and epigenetic factors: role in male infertility.Indian J Urol. 2011; 27: 110-120Crossref PubMed Scopus (0) Google Scholar, 41Gibson G. Hints of hidden heritability in GWAS.Na
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