Abstract
Male reproduction is a complex biological process, and male factor infertility is increasingly recognized as a biomarker for overall male health. Emerging data suggest associations between male reproduction and medical disease (genetic, infectious, chronic comorbid conditions), psychological disease, environmental exposures, dietary habits, medications and substances of abuse, and even socioeconomic factors. There is also evidence that a diagnosis of male fertility is associated with future disease risk including cancer, metabolic disease and mortality. As such, there is a growing view that the male fertility evaluation is an opportunity to improve a man's health beyond his immediate reproductive goals, and also highlights the necessity of a multidisciplinary approach.
Key words
Introduction
Infertility, the inability to successfully conceive after 12 months of regular unprotected sexual intercourse, affects approximately 15% of couples (
Thoma et al., 2013
) . About 7% of men worldwide are diagnosed with male factor infertility, which is contributory in 30–50% of couples undergoing fertility evaluations (- Thoma M.E.
- McLain A.C.
- Louis J.F.
- King R.B.
- Trumble A.C.
- Sundaram R.
- Buck Louis G.M.
Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach.
Fertil. Steril. 2013; 99 (e1https://doi.org/): 1324-1331https://doi.org/10.1016/j.fertnstert.2012.11.037
Brugh and Lipshultz, 2004
). As sperm counts decline globally, male infertility has become a public health issue in addition to a men's health issue, and the likelihood that both urologists and other physicians will encounter a patient with abnormal semen parameters in the future will increase (- Brugh V.M.
- Lipshultz L.I.
Male factor infertility: evaluation and management.
Med. Clin. North Am. 2004; 88 (https://doi.org/): 367-385https://doi.org/10.1016/S0025-7125(03)00150-0
Levine et al., 2017
).There is a growing body of literature highlighting male infertility as a possible biomarker for current and future health (
Kasman et al., 2020
). Indeed, an Italian group reported a higher burden of medical comorbidities among infertile compared with fertile men (- Kasman 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 (https://doi.org/): 469-477https://doi.org/10.1016/j.fertnstert.2020.01.002
Salonia et al., 2009
). Moreover, as the severity of comorbidities increases, semen quality declines (Eisenberg et al., 2015a
; Ventimiglia et al., 2015
). Thus, a man being evaluated for a history of an abnormal semen analysis may therefore benefit not just from fertility counselling, but also from a comprehensive assessment of his health as a whole including lifestyle counselling, chronic disease prevention and management, and health maintenance. Some authors have suggested that routine scrotal imaging will identify pathology not detected with physical examination alone (Jequier et al., 2014
). Treatment of medical comorbidities can also lead to improvements in semen quality (Shiraishi and Matsuyama, 2018
).- Shiraishi K.
- Matsuyama H.
Effects of medical comorbidity on male infertility and comorbidity treatment on spermatogenesis.
Fertil. Steril. 2018; 110 (e2https://doi.org/): 1006-1011https://doi.org/10.1016/j.fertnstert.2018.07.002
Reproductive clinicians’ roles and responsibilities in the arena of men's health are evolving as interdisciplinary care is increasingly being emphasized, and a clinician seeing an infertile or subfertile man can improve not only the male patient's reproductive outlook, but also his current and future health. The purpose of this review is to present an integrated overview of the existing literature regarding male fertility as a marker for health (as assessed by genetics, health, exposures and lifestyle), both current and future.
Genetics
Of the 25,000 genes in the human genome, approximately 10% are related to reproduction (
Matzuk and Lamb, 2008
). However, it is highly likely that these genes have overlapping pathways with those in multiple other cell types and organ systems, which may explain why many underlying genetic defects lead to clinical phenotypes that include infertility as only one of many symptoms.Klinefelter syndrome is the most common chromosomal anomaly in males, with well-defined clinical sequelae (
Salzano et al., 2018
). Around 85% of men with Klinefelter syndrome have a 47,XXY karyotype, and up to 15% are azoospermic (Salzano et al., 2018
; Van Assche et al., 1996
). These patients typically present with hypergonadotrophic hypogonadism due to primary testicular failure, and consequently most will require surgical sperm retrieval and assisted reproductive technologies to conceive biological offspring. Practices regarding fertility preservation and hormone replacement in adolescent boys with Klinefelter syndrome vary widely according to survey data (Zganjar et al., 2020
).- Zganjar A.
- Nangia A.
- Sokol R.
- Ryabets A.
- Samplaski M.K.
Fertility in Adolescents With Klinefelter Syndrome: A Survey of Current Clinical Practice.
J. Clin. Endocrinol. Metab. 2020; 105 (https://doi.org/)https://doi.org/10.1210/clinem/dgz044
The implications of Klinefelter syndrome extend beyond reproduction into other organ systems. Klinefelter syndrome patients are at higher risk of insulin resistance and diabetes, cardiovascular disease, thromboembolism and dyslipidaemia (
Calogero et al., 2017
; - Calogero A.E.
- Giagulli V.A.
- Mongioì L.M.
- Triggiani V.
- Radicioni A.F.
- Jannini E.A.
- Pasquali D.
- Klinefelter ItaliaN Group (KING)
Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders.
J. Endocrinol. Invest. 2017; 40 (https://doi.org/): 705-712https://doi.org/10.1007/s40618-017-0619-9
Salzano et al., 2018
, Salzano et al., 2016
). Klinefelter syndrome patients have an increased risk of cancers including breast cancer and haematological malignancies (- Salzano A.
- Arcopinto M.
- Marra A.M.
- Bobbio E.
- Esposito D.
- Accardo G.
- Giallauria F.
- Bossone E.
- Vigorito C.
- Lenzi A.
- Pasquali D.
- Isidori A.M.
- Cittadini A.
Management of endocrine disease: Klinefelter syndrome, cardiovascular system, and thromboembolic disease: Review of literature and clinical perspectives.
Ji et al., 2016
). Klinefelter syndrome patients have other urological concerns including hypogonadism that often requires testosterone supplementation, and sexual dysfunction (Akinsal et al., 2017
; - Akinsal E.C.
- Baydilli N.
- Imamoglu H.
- Ekmekcioglu O.
Three cases of Klinefelter's syndrome with unilateral absence of vas deferens.
Andrologia. 2017; 49 (https://doi.org/)https://doi.org/10.1111/and.12844
El Bardisi et al., 2017
). Optimal management of Klinefelter syndrome patients may require multidisciplinary specialty care that urological consultation takes place within.- El Bardisi H.
- Majzoub A.
- Al Said S.
- Alnawasra H.
- Dabbous Z.
- Arafa M.
Sexual dysfunction in Klinefelter's syndrome patients.
Andrologia. 2017; 49 (https://doi.org/)https://doi.org/10.1111/and.12670
Another well-known cause of male infertility is congenital bilateral absence of the vas deferens (CBAVD), which causes obstructive azoospermia. Because this congenital condition is strongly associated with cystic fibrosis, genetic testing for transmembrane conductance regulator (CFTR) gene mutations are an important component of male infertility evaluation in patients with specific causes of obstructive azoospermia (
de Souza et al., 2018
). Animal models have confirmed that known CFTR gene mutations lead to obstructive azoospermia (Y.-Y. Wang et al., 2017a
a) and new CFTR mutations continue to be discovered in men with obstructive azoospermia who have undergone whole exon sequencing (Feng et al., 2019
; - Feng J.
- Wu X.
- Zhang Yanan
- Yang X.
- Ma G.
- Chen S.
- Luo S.
- Zhang Yan
A novel mutation (-195C>A) in the promoter region of CFTR gene is associated with Chinese Congenital Bilateral Absence of Vas Deferens (CBAVD).
Gene. 2019; 719 (https://doi.org/)144007https://doi.org/10.1016/j.gene.2019.144007
Yang et al., 2015
). In men with CBAVD without an identifiable mutation in the CFTR gene, a genetic anomaly in the gene is still assumed, and partner screening for CFTR carrier status is necessary before using the affected male's spermatozoa in fertility treatments (- Yang X.
- Sun Q.
- Yuan P.
- Liang H.
- Wu X.
- Lai L.
- Zhang Y.
Novel mutations and polymorphisms in the CFTR gene associated with three subtypes of congenital absence of vas deferens.
Fertil. Steril. 2015; 104 (e1–2https://doi.org/): 1268-1275https://doi.org/10.1016/j.fertnstert.2015.07.1143
Jarow et al., 2011
). Interestingly, CFTR mutations have been found in men with oligozoospermia or non-obstructive azoospermia without CBAVD, which suggests that its impact on male reproduction is likely to be multifaceted and yet to be fully delineated (Sharma et al., 2014
). Knowing the link between cystic fibrosis and CBAVD can also encourage clinicians to refer couples to genetic counselling during reproductive planning. Clinicians caring for men with cystic fibrosis or CFTR mutations need to appreciate the reproductive consequences of these conditions when managing patients of reproductive age.Another category of known genetic causes of azoospermia and severe oligozoospermia comprises Y chromosome microdeletions, specifically those in the azoospermia factor (AZF) region (
Kuroda et al., 2020
). Identification of specific deletions (i.e. AZFa, AZFb, or AZFc) can guide clinical management. The American Urological Association's best practice statement ‘The evaluation of the azoospermic male’ suggests screening for Y microdeletions in men with sperm concentrations of less than 5 million/ml (Jarow et al., 2011
) . A study of 4000 infertile men in Portugal reported Yq microdeletions in 4.6% of patients, with a majority being associated with azoospermia rather than oligo- or cryptozoospermia (Pinho et al., 2020
). AZFc was the most common microdeletion, representing 56.8% of cases, with AZFa (4.7%) and AZFb (4.0%) being less common. There is a range of reported Y microdeletion incidences, with other studies reporting rates as high as 16.9%, with specific rates of AZFc mutations being similar (Liu et al., 2016
). The clinical relevance of the specific deletion relates to the treatment options available to these men. Those with AZFc mutations are eligible for testicular sperm extraction whereas men with AZFa or AZFb microdeletions are typically counselled towards donor spermatozoa or adoption owing to the low probability of success of sperm extraction (- Liu X.G.
- Hu H.Y.
- Guo Y.H.
- Sun Y.P.
Correlation between Y chromosome microdeletion and male infertility.
Genet. Mol. Res. 2016; 15 (https://doi.org/)https://doi.org/10.4238/gmr.15028426
Krausz and Forti, 2006
). Men with AZFc mutations have successful sperm retrieval rates of approximately 50%, with clinical pregnancy rates of 37.5% and live birth rates of 25% (Abur et al., 2019
).While Y chromosome microdeletion is part of the standard evaluation for azoospermic or cryptozoospermic male patients, recent studies suggest there are health implications beyond male fertility. These microdeletions are expressed in the stomach, brain and urinary tract as well (
Colaco and Modi, 2019
). AZFb and AZFc copy-number variations are associated with intellectual disorders, delayed development and neuropsychiatric disorders such as delayed language development or depression (- Colaco S.
- Modi D.
Consequences of Y chromosome microdeletions beyond male infertility.
J. Assist. Reprod. Genet. 2019; 36 (https://doi.org/): 1329-1337https://doi.org/10.1007/s10815-019-01492-z
Castro et al., 2017
; Colaco and Modi, 2019
).- Colaco S.
- Modi D.
Consequences of Y chromosome microdeletions beyond male infertility.
J. Assist. Reprod. Genet. 2019; 36 (https://doi.org/): 1329-1337https://doi.org/10.1007/s10815-019-01492-z
The scope of the impacts of genetics continues to evolve. DNA mismatch repair (MMR) mechanisms are important to maintain the integrity of spermatozoa DNA and play an important role in spermatogenesis (
Feitsma et al., 2007
). Defects in MMR-related genes such as MLH1, MLH3, PMS2, MSH4 and MSH5 have measurable effects in humans, manifesting as severe oligozoospermia or non-obstructive azoospermia (Terribas et al., 2010
). MMR mutations have also been found in individuals with Lynch syndrome (Stupart et al., 2015
), but are not part of the standard evaluation of infertile males at this time. As the genetic underpinnings of spermatogenesis evolve, this will possibly expand the scope of genetic screening in men presenting with infertility.Infections
Infectious aetiologies of male infertility range from testicular insults to widespread systemic illnesses, with mechanisms of injury ranging from inflammation to vasculitis, endocrine disruption or direct tissue damage. In addition, systemic infections can also lead to febrile illness, which can impair spermatogenesis directly. Infections may occur at the site of the testicle or distally in the spermatic tract such as the prostate or urethra. Sexually transmitted infections (STI) are sometimes asymptomatic in men, but are known to cause infertility.
One of the classic infectious causes of male infertility is mumps orchitis, which was much more common before a vaccine became available in 1988. The virus is an RNA virus of the paramyxovirus genus that is spread from human reservoirs by direct contact and airborne droplets (
Masarani et al., 2006
). Mouse models have shown that the mumps virus impairs spermatogenesis by targeting Sertoli cells and disrupting the blood–testis barrier by impairing junctional protein function (Wu et al., 2019
). Histopathological studies have also shown that direct viral infection of tissues can lead to lymphocytic invasion progressing to eventual hyalinization and direct damage to the seminiferous tubules (Gall, 1947
). In an early study by Bartek and colleagues of 298 cases of mumps orchitis between 1951 and 1970, abnormal ejaculates were seen even after 3 years of unilateral orchitis in a quarter of adults and almost 40% of adolescents (Barták, 1973
). Persistent public concerns over the repeatedly disproven link between the measles, mumps and rubella vaccine and autism unfortunately continue to lead to decreased vaccine uptake, and to a subsequent resurgence of mumps along with its complications. Vaccines should continue to be emphasized as part of routine adolescent male health and prevention, and parents should continue to be educated regarding the widely proven benefits of vaccination.Human immunodeficiency virus (HIV) can be found in the semen in infected men, and when it progresses to acquired immunodeficiency syndrome, it can cause hypogonadism and testicular dysfunction due to direct testicular damage (
Liu et al., 2018
). However, as antiretroviral therapy has improved and HIV-positive status has transitioned to being a chronic disease, Pilatz and co-workers found that 25% of men on antiretroviral therapy had semen parameters below the fifth percentile of the 2010 World Health Organization criteria (Pilatz et al., 2014
).Human papillomavirus (HPV), one of the most common STI in both women and men, is associated with male infertility, with the prevalence of HPV DNA within the semen of infertile men estimated to be approximately 16% (
Laprise et al., 2014
). Infertile men with HPV DNA detected in semen had lower motility, lower normal morphology and higher DNA fragmentation indexes (Boeri et al., 2019b
; Moghimi et al., 2019
). Women inseminated with spermatozoa containing HPV DNA had a four-fold decrease in clinical pregnancies compared with women inseminated with spermatozoa that were HPV-negative (Depuydt et al., 2019
).- Depuydt C.E.
- Donders G.G.G.
- Verstraete L.
- Vanden Broeck D.
- Beert J.F.A.
- Salembier G.
- Bosmans E.
- Ombelet W.
Infectious human papillomavirus virions in semen reduce clinical pregnancy rates in women undergoing intrauterine insemination.
Fertil. Steril. 2019; 111 (https://doi.org/): 1135-1144https://doi.org/10.1016/j.fertnstert.2019.02.002
The implications of other infections are less clear. Chlamydia trachomatis is an STI that is only symptomatic in up to 50% of men, and its DNA has been detected in fresh testicular biopsy samples from infertile men, suggesting a possible role in spermatogenesis disruption (
Bryan et al., 2019
).The coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has also led to concerns of direct virally mediated testicular damage through reports of viral DNA in semen (which has been debated in the literature) and scrotal pain/orchitis (
Li et al., 2020
; - Li D.
- Jin M.
- Bao P.
- Zhao W.
- Zhang S.
Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019.
JAMA Netw. open. 2020; 3 (https://doi.org/)e208292https://doi.org/10.1001/jamanetworkopen.2020.8292
Pan et al., 2020
). Other reports suggested that the severity of systemic illness and febrile presentation of disease led to reported impairments in semen quality after infection (- Pan F.
- Xiao X.
- Guo J.
- Song Y.
- Li H.
- Patel D.P.
- Spivak A.M.
- Alukal J.P.
- Zhang X.
- Xiong C.
- Li P.S.
- Hotaling J.M.
No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019.
Fertil. Steril. 2020; 113 (https://doi.org/): 1135-1139https://doi.org/10.1016/j.fertnstert.2020.04.024
Holtmann et al., 2020
). To date, the association between infection with SARS-CoV-2 and testicular function remains uncertain.- Holtmann N.
- Edimiris P.
- Andree M.
- Doehmen C.
- Baston-Buest D.
- Adams O.
- Kruessel J.-S.
- Bielfeld A.P.
Assessment of SARS-CoV-2 in human semen-a cohort study.
Fertil. Steril. 2020; 114 (https://doi.org/): 233-238https://doi.org/10.1016/j.fertnstert.2020.05.028
A detailed sexual history is important in the workup of infertile male patients and should lead to infectious diagnostic workup and subsequent treatment if an STI is suggested.
Obesity
The obesity epidemic has been recognized as a public health crisis, and is associated with several chronic diseases including coronary artery disease, diabetes, and non-alcoholic fatty liver disease (
Heymsfield and Wadden, 2017
). The mechanism by which obesity and increased adiposity leads to these conditions is complex and unclear, with the main postulated pathways involving insulin resistance, chronic inflammation and neurohormonal activation (Rochlani et al., 2017
). Meta-analyses examining the association between body mass index (BMI) and semen parameters have reported a negative association between BMI and semen volume, total sperm count and sperm concentration (Dan - Rochlani Y.
- Pothineni N.V.
- Kovelamudi S.
- Mehta J.L.
Metabolic syndrome: pathophysiology, management, and modulation by natural compounds.
Ther. Adv. Cardiovasc. Dis. 2017; 11 (https://doi.org/): 215-225https://doi.org/10.1177/1753944717711379
Guo et al., 2017a
a; Sermondade et al., 2013
). Obesity has also been associated with azoospermia, with an odds ratio of 2.04 (95% confidence interval [CI] 1.59–2.62; - Sermondade N.
- Faure C.
- Fezeu L.
- Shayeb A.G.
- Bonde J.P.
- Jensen T.K.
- Van Wely M.
- Cao J.
- Martini A.C.
- Eskandar M.
- Chavarro J.E.
- Koloszar S.
- Twigt J.M.
- Ramlau-Hansen C.H.
- Borges E.
- Lotti F.
- Steegers-Theunissen R.P.M.
- Zorn B.
- Polotsky A.J.
- La Vignera S.
- Eskenazi B.
- Tremellen K.
- Magnusdottir E.V
- Fejes I.
- Hercberg S.
- Lévy R.
- Czernichow S.
BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.
Sermondade et al., 2013
). Unfortunately, bariatric surgery in obese men has not been shown to significantly alter semen parameters even up to 24 months of follow-up (- Sermondade N.
- Faure C.
- Fezeu L.
- Shayeb A.G.
- Bonde J.P.
- Jensen T.K.
- Van Wely M.
- Cao J.
- Martini A.C.
- Eskandar M.
- Chavarro J.E.
- Koloszar S.
- Twigt J.M.
- Ramlau-Hansen C.H.
- Borges E.
- Lotti F.
- Steegers-Theunissen R.P.M.
- Zorn B.
- Polotsky A.J.
- La Vignera S.
- Eskenazi B.
- Tremellen K.
- Magnusdottir E.V
- Fejes I.
- Hercberg S.
- Lévy R.
- Czernichow S.
BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.
Reis et al., 2012
).Psychological stress
Chronic psychological stress can lead to impairment of the hypothalamic–pituitary–gonadal (HPG) axis, which can lead to reduced testosterone, decreased prolactin and changes in growth hormone concentrations (
Nargund, 2015
). A study of 384 men surveyed with a validated work-stress questionnaire who also provided semen samples found that higher work stress was associated with greater risk of lower sperm concentration (Zou et al., 2019
). Similar effects have been seen with school stress in medical students (- Zou P.
- Sun L.
- Chen Q.
- Zhang G.
- Yang W.
- Zeng Y.
- Zhou N.
- Li Y.
- Liu J.
- Ao L.
- Cao J.
- Yang H.
Social support modifies an association between work stress and semen quality: Results from 384 Chinese male workers.
J. Psychosom. Res. 2019; 117 (https://doi.org/): 65-70https://doi.org/10.1016/j.jpsychores.2018.10.013
Eskiocak et al., 2006
). When semen samples were obtained in the 3 months before final examinations, statistically significant decreases in sperm concentration and progressive motility were seen, but these impairments recovered by the 3-month post-examination date.- Eskiocak S.
- Gozen A.S.
- Taskiran A.
- Kilic A.S.
- Eskiocak M.
- Gulen S.
Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality.
Brazilian J. Med. Biol. Res. 2006; 39 (https://doi.org/): 581-588https://doi.org/10.1590/S0100-879X2006000500003
Bhongade and colleagues measured the psychological stress levels of 70 men in infertile couples using the Hospital Anxiety and Depression Score (HADS) and found abnormal scores in 27% of participants (
Bhongade et al., 2015
). Abnormal scores were associated with lower values for total sperm count (25 versus 63 million), normal morphology (40% versus 80%) and motility (40% versus 60%) compared with individuals with normal HADS scores. The study also noted higher FSH and LH, and lower testosterone concentrations, in men with abnormal HADS scores.A similar relationship between stress and lower semen quality was found in a cohort of 1215 Danish men given the Copenhagen Psychosocial Questionnaire, a survey instrument designed to assess psychosocial factors at work, stress and the well-being of employees (
Nordkap et al., 2016
). Notably, no significant hormonal impairments were seen in the Danish cohort, suggesting that the mechanism by which psychological stress affects male fertility may not explicitly act through hormonal mechanisms.- Nordkap L.
- Jensen T.K.
- Hansen Å.M.
- Lassen T.H.
- Bang A.K.
- Joensen U.N.
- Jensen M.B.
- Skakkebæk N.E.
- Jørgensen N.
Psychological stress and testicular function: A cross-sectional study of 1,215 Danish men.
Fertil. Steril. 2016; 105 (e2https://doi.org/): 174-187https://doi.org/10.1016/j.fertnstert.2015.09.016
Oxidative stress
Reactive oxygen species (ROS) are a by-product of normal cellular metabolism. During the enzymatically controlled reduction of oxygen to produce energy, free radicals are formed (
Valko et al., 2007
) and they soon start to release unpaired electrons in different chemical reactions. As a result of this process lipids in membranes, amino acids in proteins, and carbohydrates within nucleic acids are oxidized (- Valko M.
- Leibfritz D.
- Moncol J.
- Cronin M.T.D.
- Mazur M.
- Telser J.
Free radicals and antioxidants in normal physiological functions and human disease.
Int. J. Biochem. Cell Biol. 2007; 39 (https://doi.org/): 44-84https://doi.org/10.1016/j.biocel.2006.07.001
Ochsendorf, 1999
).Free radicals in the semen are produced mainly by leukocytes and spermatocytes. In particular, cells undergoing spermatogenesis produce the majority of ROS in the semen, and this process is initiated in the earliest stages of their development (
Fisher and Aitken, 1997
). ROS have a wide range of functions in sperm cells that range from chromatin condensation, induction of apoptosis or proliferation to being involved in capacitation, the acrosome reaction, mitochondrial sheath stability and sperm motility (Aitken, 1999
). Not only has higher ROS production been observed in spermatozoa with abnormal morphology (Aziz et al., 2004
; - Aziz N.
- Saleh R.A.
- Sharma R.K.
- Lewis-Jones I.
- Esfandiari N.
- Thomas A.J.
- Agarwal A.
Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index.
Fertil. Steril. 2004; 81 (https://doi.org/): 349-354https://doi.org/10.1016/j.fertnstert.2003.06.026
Gomez et al., 1996
), but patients with normal sperm parameters who are unable to conceive also present with higher ROS concentrations in the semen (- Gomez E.
- Buckingham D.W.
- Brindle J.
- Lanzafame F.
- Irvine D.S.
- Aitken R.J.
Development of an image analysis system to monitor the retention of residual cytoplasm by human spermatozoa: correlation with biochemical markers of the cytoplasmic space, oxidative stress, and sperm function.
J. Androl. 1996; 17: 276-287
Agarwal et al., 2006
; Pasqualotto et al., 2001
).Leukocytes, to carry out their role in immune defence mechanisms, produce higher concentrations of ROS when compared with sperm cells (
Plante et al., 1994
). Because of this mechanism, an increased number of leukocytes in the semen due to infections, long abstinence from sex or varicocele can cause cellular damage. In fact, in about 10–20% of cases of infertility men present with elevated seminal leukocyte concentrations due to infections or inflammatory conditions (Henkel et al., 2006
).The potential benefit of antioxidant activity has also been investigated in human clinical settings. Pasqualotto and colleagues investigated 186 men and observed higher ROS concentrations in infertile men when compared with control participants (
Pasqualotto et al., 2000
). Seminal plasma concentrations of superoxide dismutase, a well-known antioxidant, have been positively correlated with increased sperm concentration and motility in a study comparing healthy sperm donor controls and infertile men (Murawski et al., 2007
). Preclinical studies based on mouse models demonstrate that the administration of antioxidant compounds significantly reduced sperm DNA damage and led to normal pregnancy rates (Gharagozloo et al., 2016
).- Gharagozloo P.
- Gutiérrez-Adán A.
- Champroux A.
- Noblanc A.
- Kocer A.
- Calle A.
- Pérez-Cerezales S.
- Pericuesta E.
- Polhemus A.
- Moazamian A.
- Drevet J.R.
- Aitken R.J.
A novel antioxidant formulation designed to treat male infertility associated with oxidative stress: promising preclinical evidence from animal models.
There are numerous compounds with antioxidant activity that have been investigated for their potential to improve human semen parameters thus far: arginine, carnitines, carotenoids, coenzyme Q10, N-acetylcysteine, folate, zinc, vitamins E and C, selenium, magnesium, omega fatty acids and resveratrol. A 2019 Cochrane review analysed 61 randomized controlled trials from 28 different countries evaluating various antioxidant therapies and their impacts on male fertility (
Smits et al., 2019
). The main conclusions, despite significant interstudy heterogeneity and low-quality evidence, were that antioxidant therapy improved clinical pregnancy rates compared with placebo, but no difference was seen for live birth rates. This review also found improvements in DNA fragmentation with docosahexaenoic acid (DHA), an omega fatty acid, or a vitamin C+E combination. Improvements in total sperm motility at 3 months post-supplementation were seen in N-acetylcysteine, selenium, vitamin E, or vitamin E and zinc combination studies. Total sperm concentration at 3 months post-supplementation improved in patients supplemented with carnitines, vitamin C, zinc, vitamin E, or zinc and folic acid. Two subsequent randomized clinical trials, one evaluating a commercially available antioxidant blend and one evaluating zinc and folate, did not show any improvements in live birth or semen parameters (- Smits R.M.
- Mackenzie-Proctor R.
- Yazdani A.
- Stankiewicz M.T.
- Jordan V.
- Showell M.G.
Antioxidants for male subfertility.
Cochrane Database Syst. Rev. 2019; (https://doi.org/)https://doi.org/10.1002/14651858.CD007411.pub4
Schisterman et al., 2020
; - Schisterman E.F.
- Sjaarda L.A.
- Clemons T.
- Carrell D.T.
- Perkins N.J.
- Johnstone E.
- Lamb D.
- Chaney K.
- Van Voorhis B.J.
- Ryan G.
- Summers K.
- Hotaling J.
- Robins J.
- Mills J.L.
- Mendola P.
- Chen Z.
- DeVilbiss E.A.
- Peterson C.M.
- Mumford S.L.
Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment.
Steiner et al., 2020
).- Steiner A.Z.
- Hansen K.R.
- Barnhart K.T.
- Cedars M.I.
- Legro R.S.
- Diamond M.P.
- Krawetz S.A.
- Usadi R.
- Baker V.L.
- Coward R.M.
- Huang H.
- Wild R.
- Masson P.
- Smith J.F.
- Santoro N.
- Eisenberg E.
- Zhang H.
- Reproductive Medicine Network
The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial.
Fertil. Steril. 2020; 113 (e3https://doi.org/): 552-560https://doi.org/10.1016/j.fertnstert.2019.11.008
Medications and substances
Different exogenous substances have been linked to male infertility. Some of them are pharmaceutical drugs used for comorbid diseases while others are recreational substances related to lifestyle choices.
Among the first group, abnormal semen quality has been observed in patients affected by chronic inflammatory bowel disease treated with salicylazosulfapyridine (SASP;
Tobias et al., 1982
). SASP is composed of a combination of two molecules: sulphapyridine and 5α-reductase inhibitors (5ARIs). The former has been linked to the majority of these side effects while 5-ASA is considered to be the better-tolerated moiety of the drug (Azad Khan et al., 1977
; - Azad Khan A.K.
- Piris J.
- Truelove S.C.
An experiment to determine the active therapeutic moiety of sulphasalazine.
Lancet (London, England). 1977; 2 (https://doi.org/): 892-895https://doi.org/10.1016/s0140-6736(77)90831-5
Dew et al., 1983
). In a cross-sectional study analysing 21 men treated with SASP, 86% had an abnormal semen analysis and 72% had oligozoospermia (- Dew M.J.
- Harries A.D.
- Evans B.K.
- Rhodes J.
Treatment of ulcerative colitis with oral 5-aminosalicyclic acid in patients unable to take sulphasalazine.
Lancet (London, England). 1983; 2 (https://doi.org/): 801https://doi.org/10.1016/s0140-6736(83)92341-3
Birnie et al., 1981
). Mesazaline is a well-known and effective substitute for SASP in cases of SASP-induced infertility (Kjaergaard et al., 1989
), even if the exact molecular mechanism underlying SASP's side effects are currently unknown.- Kjaergaard N.
- Christensen L.A.
- Lauritsen J.G.
- Rasmussen S.N.
- Hansen S.H.
Effects of mesalazine substitution on salicylazosulfapyridine-induced seminal abnormalities in men with ulcerative colitis.
Scand. J. Gastroenterol. 1989; 24 (https://doi.org/): 891-896https://doi.org/10.3109/00365528909089231
Another class of medications associated with semen abnormalities is the class of 5α-reductase inhibitors (5ARIs). The suspected mechanism behind the negative effects on spermatogenesis is the reduction of circulating serum concentrations of dihydrotestosterone. In particular, total sperm count is the parameter more likely to be affected by this drug class (
Drobnis and Nangia, 2017
). In one randomized study performed by Amory and co-workers investigating men with daily use of either dutasteride (0.5 mg), finasteride (5 mg) or placebo for 1 year, it was observed that use of 5ARIs led to a decreased sperm count of about 30% and motility of about 6–12%; however, most impairments were not felt to be clinically significant and most decreases recovered after approximately 6 months of discontinuation (- Drobnis E.Z.
- Nangia A.K.
5α-Reductase Inhibitors (5ARIs) and Male Reproduction.
Adv. Exp. Med. Biol. 2017; 1034 (https://doi.org/): 59-61https://doi.org/10.1007/978-3-319-69535-8_7
Amory et al., 2007
). In contrast, Overstreet and collaborators observed that among 79 men taking a lower dose of finasteride (1 mg), a dose typical for the treatment of alopecia, for 48 weeks, testosterone and gonadotrophin concentrations remained stable and semen quality was not affected, raising the possibility of a dose-dependent effect (- Amory J.K.
- Wang C.
- Swerdloff R.S.
- Anawalt B.D.
- Matsumoto A.M.
- Bremner W.J.
- Walker S.E.
- Haberer L.J.
- Clark R.V.
The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men.
J. Clin. Endocrinol. Metab. 2007; 92 (https://doi.org/): 1659-1665https://doi.org/10.1210/jc.2006-2203
Overstreet et al., 1999
).- Overstreet J.W.
- Fuh V.L.
- Gould J.
- Howards S.S.
- Lieber M.M.
- Hellstrom W.
- Shapiro S.
- Carroll P.
- Corfman R.S.
- Petrou S.
- Lewis R.
- Toth P.
- Shown T.
- Roy J.
- Jarow J.P.
- Bonilla J.
- Jacobsen C.A.
- Wang D.Z.
- Kaufman K.D.
Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men.
J. Urol. 1999; 162: 1295-1300
While hypertension itself is associated with impaired semen quality, its treatment may also lead to semen abnormalities (
Eisenberg et al., 2015a
). A retrospective study compared semen quality among men treated with different classes of antihypertensive medication (Guo et al., 2017b
). Men on beta-blockers displayed significantly lower sperm concentration, motility, total count and total motile count. In contrast, men on other classes of antihypertensive (i.e. calcium channel-blockers, angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) did not show alterations in semen quality compared with controls.The negative effects of hypogonadism on male fertility are well known, but the primary treatment, exogenous testosterone replacement therapy, is also a well-known cause of impaired spermatogenesis (
Crosnoe et al., 2013
). One worrisome trend that has been observed is that the number of men seeking medical help for fertility treated with exogenous testosterone appears to be increasing (- Crosnoe L.E.
- Grober E.
- Ohl D.
- Kim E.D.
Exogenous testosterone: a preventable cause of male infertility.
Transl. Androl. Urol. 2013; 2 (https://doi.org/): 106-113https://doi.org/10.3978/j.issn.2223-4683.2013.06.01
Kolettis et al., 2015
). After discontinuation of exogenous testosterone therapy, normal spermatogenesis is not always guaranteed. In a study of 66 men at 12 months after cessation of testosterone therapy and treatment with human chorionic gonadotrophin or selective oestrogen receptor modulators, only 70% of men recovered spermatogenesis. Age and duration of therapy were associated with likelihood of recovery. In addition, azoospermic men had a lower rate of recovery when compared with cryptozoospermic men (Kohn et al., 2017
).- Kohn T.P.
- Louis M.R.
- Pickett S.M.
- Lindgren M.C.
- Kohn J.R.
- Pastuszak A.W.
- Lipshultz L.I.
Age and duration of testosterone therapy predict time to return of sperm count after human chorionic gonadotropin therapy.
Fertil. Steril. 2017; 107 (e1https://doi.org/): 351-357https://doi.org/10.1016/j.fertnstert.2016.10.004
Among recreational substances that are known to affect semen parameters, alcohol plays a prominent role. A recent meta-analysis described how occasional alcohol intake is not considered to be a major risk factor, but daily use has been consistently linked to different sperm abnormalities including decreased semen volume and worse sperm morphology (
Ricci et al., 2017a
). Moreover, Bai and colleagues, in a study investigating 776 infertile men, observed that those reporting heavy alcohol consumption had a higher risk of abnormal sperm concentrations (- Ricci E.
- Al Beitawi S.
- Cipriani S.
- Candiani M.
- Chiaffarino F.
- Viganò P.
- Noli S.
- Parazzini F.
Semen quality and alcohol intake: a systematic review and meta-analysis.
Reprod. Biomed. Online. 2017; 34 (https://doi.org/): 38-47https://doi.org/10.1016/j.rbmo.2016.09.012
Bai et al., 2020
). These findings are additionally supported by Boeri and co-workers’ study of 189 infertile men, which found that heavy alcohol consumption led to worse semen quality than abstinence or moderate consumption (- Bai S.
- Wan Y.
- Zong L.
- Li W.
- Xu X.
- Zhao Y.
- Hu X.
- Zuo Y.
- Xu B.
- Tong X.
- Guo T.
Association of Alcohol Intake and Semen Parameters in Men With Primary and Secondary Infertility: A Cross-Sectional Study.
Front. Physiol. 2020; 11 (https://doi.org/)https://doi.org/10.3389/fphys.2020.566625
Boeri et al., 2019a
).Caffeine intake has also been extensively investigated in the context of men's reproductive function. A systematic review by Ricci and colleagues collected evidence suggesting that caffeine intake may negatively affect sperm DNA integrity without affecting semen analysis parameters such as semen volume, concentration, motility or morphology (
Ricci et al., 2017b
). Karmon and co-workers investigated caffeine intake in the context of IVF outcomes. It was observed that males consuming more than 272 mg/day of caffeine had a lower adjusted live birth rate when compared with couples in which the male partner consumed less than 99 mg/day of caffeine (19% versus 55%) (- Ricci E.
- Viganò P.
- Cipriani S.
- Somigliana E.
- Chiaffarino F.
- Bulfoni A.
- Parazzini F.
Coffee and caffeine intake and male infertility: A systematic review.
Nutr. J. 2017; 16 (https://doi.org/)https://doi.org/10.1186/s12937-017-0257-2
Karmon et al., 2017
).Cigarette smoking has also been identified as a risk factor for semen abnormalities. A recent meta-analysis and systematic review observed that both sperm count and morphology are negatively affected by smoking (
Bundhun et al., 2019
). Boeri and colleagues confirmed these associations by identifying worse seminal parameters in heavy smokers when compared with moderate smokers and non-smokers (Boeri et al., 2019a
). Similarly, in a study of 160 men, Tawadrus and collaborators observed a negative association between daily cigarettes and sperm DNA fragmentation (Tawadrous et al., 2011
).When investigating the aetiology of male infertility, a history of illicit substances is a consideration. As many illicit drug consumers are males of reproductive age, the importance of obtaining an accurate and comprehensive reproductive health history has grown. To date, the substances analysed in most studies are marijuana, opioid narcotics, methamphetamines, cocaine and anabolic-androgenic steroids (AAS) (
Fronczak et al., 2012
). Opioids are known to act on the HPG axis and to act as an inhibitor of gonadotrophin-releasing hormone (Böttcher et al., 2017
). In a study of patients on long-term intrathecal opioids, it was observed by Abs and colleagues that almost every male patient reported decreased libido, erectile dysfunction and significantly lower testosterone and LH concentrations (- Böttcher B.
- Seeber B.
- Leyendecker G.
- Wildt L.
Impact of the opioid system on the reproductive axis.
Fertil. Steril. 2017; 108 (https://doi.org/): 207-213https://doi.org/10.1016/j.fertnstert.2017.06.009
Abs et al., 2000
). Moreover, Farag and co-workers found that individuals who abused tramadol, a centrally acting analgesic with weak opioid agonist properties, had statistically lower sperm progressive motility and concentration, and lower testosterone concentrations (- Abs R.
- Verhelst J.
- Maeyaert J.
- Van Buyten J.P.
- Opsomer F.
- Adriaensen H.
- Verlooy J.
- Van Havenbergh T.
- Smet M.
- Van Acker K.
Endocrine consequences of long-term intrathecal administration of opioids.
J. Clin. Endocrinol. Metab. 2000; 85 (https://doi.org/): 2215-2222https://doi.org/10.1210/jcem.85.6.6615
Farag et al., 2018
).Regarding methamphetamine, an animal study demonstrated that this drug harms the normal morphology and progressive motility of sperm cells (
Sabour et al., 2017
). To the current authors’ knowledge, analogous clinical studies on methamphetamines are currently lacking. Cocaine's relation to male fertility has been thoroughly investigated. In a study published in 1990, it was observed that cocaine use resulted in lower semen parameters. Moreover, duration of abuse longer than 5 years was associated with lower sperm motility, lower sperm concentration and a lower percentage of normal morphology (Bracken et al., 1990
). AAS use has risen in recent years, especially in athletes and recreational users. A systematic review and meta-analysis observed a higher incidence of hypogonadism in AAS users even after discontinuation of the substance (Christou et al., 2017
).As legalization of cannabis spreads, the association between cannabis use and male fertility increases in importance but currently the literature is limited. Gundersen and colleagues examined 1215 military conscripts in Denmark and observed a negative association between cannabis use and sperm concentration and total sperm count (
Gundersen et al., 2015
). However, in a recent meta-analysis of 4014 men (1158 cannabis users and 2856 non-users), no association between cannabis use and semen abnormalities was identified (Belladelli et al., 2021
).Diet
In general, good dietary habits have demonstrated consistent benefits on semen quality. The Mediterranean diet, characterized by high vegetable, fruit, legume and whole-grain intake with a low amount of saturated fatty acids and meat intake, has been shown to be associated with a lower risk of abnormal sperm concentration, motility and total sperm count (
Karayiannis et al., 2016
). In fact, healthy dietary patterns that generally limit processed foods and that are rich in foods high in saturated fats, fruit, vegetables, poultry, seafood and skimmed milk have repeatedly been linked to better semen parameters in several meta-analyses (- Karayiannis D.
- Kontogianni M.D.
- Mendorou C.
- Douka L.
- Mastrominas M.
- Yiannakouris N.
Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility.
Hum. Reprod. 2016; (https://doi.org/)https://doi.org/10.1093/humrep/dew288
Giahi et al., 2016
; Y. Li et al., 2011a
a; - Li D.-K.
- Zhou Z.
- Miao M.
- He Y.
- Wang J.
- Ferber J.
- Herrinton L.J.
- Gao E.
- Yuan W.
Urine bisphenol-A (BPA) level in relation to semen quality.
Fertil. Steril. 2011; 95 (e1–4https://doi.org/): 625-630https://doi.org/10.1016/j.fertnstert.2010.09.026
Salas-Huetos et al., 2017
).It is known that fatty acids are an integral component of the sperm cell membrane, and they play a critical role in fertilization events such as capacitation and the acrosome reaction (
Flesch and Gadella, 2000
). Spermatozoa have higher concentrations of polyunsaturated fatty acids (PUFA), especially DHA, than other tissues or cells in the body. Because PUFA are not endogenously synthesized by humans, they must be obtained by dietary means. It has been shown that diets high in fish oils, which are rich in omega-3 PUFA, are associated with normal morphology, normal concentration and higher sperm motility (- Flesch F.M.
- Gadella B.M.
Dynamics of the mammalian sperm plasma membrane in the process of fertilization.
Biochim. Biophys. Acta. 2000; 1469 (https://doi.org/): 197-235https://doi.org/10.1016/s0304-4157(00)00018-6
Safarinejad, 2011
; Tavilani et al., 2007
). A randomized controlled trial of healthy men consuming Western-style diets showed that those given supplementation with walnut, a source of plant-based omega-3 PUFA, showed improvements in sperm motility and morphology compared with the control group (- Tavilani H.
- Doosti M.
- Nourmohammadi I.
- Mahjub H.
- Vaisiraygani A.
- Salimi S.
- Hosseinipanah S.M.
Lipid composition of spermatozoa in normozoospermic and asthenozoospermic males.
Prostaglandins. Leukot. Essent. Fatty Acids. 2007; 77 (https://doi.org/): 45-50https://doi.org/10.1016/j.plefa.2007.07.001
Robbins et al., 2012
). Conversely, diets rich in saturated and trans fatty acids, often linked to commercially processed and fried foods, are often detrimental to sperm quality. Attaman and colleagues evaluated the dietary and semen data from 99 men presenting to a fertility clinic and found that saturated fats were associated with lower total sperm count and lower sperm concentrations (Attaman et al., 2012
).Soy-derived products contain isoflavones, which have mild oestrogenic effects that can bind to oestrogen receptors (
Thomas and Dong, 2006
). While animal models have demonstrated a potential link between isoflavone intake and smaller testicular size (- Thomas P.
- Dong J.
Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: A potential novel mechanism of endocrine disruption.
J. Steroid Biochem. Mol. Biol. 2006; 102 (https://doi.org/): 175-179https://doi.org/10.1016/j.jsbmb.2006.09.017
Atanassova et al., 2000
), there is inconclusive evidence regarding the relationships between soy intake and male fertility in humans. Song and collaborators reported that dietary isoflavone intake was associated with lower sperm DNA damage and higher sperm count among 48 men with abnormal semen parameters (- Atanassova N.
- McKinnell C.
- Turner K.J.
- Walker M.
- Fisher J.S.
- Morley M.
- Millar M.R.
- Groome N.P.
- Sharpe R.M.
Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship, to adult testis size and fertility: Evidence for stimulatory effects of low estrogen levels.
Song et al., 2006
). However, other studies have reported no benefits of isoflavone dietary supplementation (Mitchell et al., 2001
), while one Chinese study of 609 men with male infertility reported an inverse relationship between urinary isoflavone concentration and sperm concentration, and motility (Xia et al., 2013
).The evidence suggests that a healthier diet, beyond having the benefits of increased life expectancy and reduced risk of developing chronic diseases, has beneficial impacts on male fertility. The management of infertile men can benefit from an assessment of dietary practices, and may pose an opportunity for nutrition education and possibly referral for professional dietetic consultation.
Environment and pollution
Environmental factors can also impact male fertility by way of exposures to pollutants. Air pollution may be associated with increased concentrations of carbon monoxide, sulphur dioxide, ozone and particulate matter. Particulate matter in air is particularly concerning due to the presence of trace elements and potential endocrine disruptors (
Mi et al., 2001
). Ambient air pollution has been linked to conditions from chronic cardiopulmonary diseases to mortality (- Mi H.H.
- Lee W.J.
- Tsai P.J.
- Chen C.B.
A comparison on the emission of polycyclic aromatic hydrocarbons and their corresponding carcinogenic potencies from a vehicle engine using leaded and lead-free gasoline.
Environ. Health Perspect. 2001; 109 (https://doi.org/): 1285-1290https://doi.org/10.1289/ehp.011091285
Pope, 2007
). Unsurprisingly, exposure to air pollution has been linked to impairments in semen parameters as well. Hammoud and colleagues reviewed 1699 semen analyses of men presenting for artificial insemination and correlated the results with particulate air pollution levels over a 5-year period. They found that when indices of air pollution levels were elevated, sperm motility was decreased 2–3 months after exposure, suggesting a deleterious effect on spermatogenesis (Hammoud et al., 2010
). A study of Czech Republic citizens residing in areas with higher concentrations of sulphur coal usage for industry and home heating purposes found a significant increase in sperm DNA damage when air pollution levels were at their highest (- Hammoud A.
- Carrell D.T.
- Gibson M.
- Sanderson M.
- Parker-Jones K.
- Peterson C.M.
Decreased sperm motility is associated with air pollution in Salt Lake City.
Fertil. Steril. 2010; 93 (https://doi.org/): 1875-1879https://doi.org/10.1016/j.fertnstert.2008.12.089
Rubes et al., 2005
). Interestingly, neither study identified a significant difference in sperm counts.Bisphenol A (BPA) is a potent endocrine disrupter that has had pervasive usage as a raw material for the manufacture of consumer products ranging from canned goods to plastic containers (
Huang et al., 2012
). BPA exposure within the USA is widespread: urine samples from the 2003–2004 and 2011–2012 National Health and Nutrition Examination Surveys (NHANES) reported that 90% of surveyed urine samples contained detectable concentrations of BPA (Calafat et al., 2008
; Vandenberg et al., 2007
). In-vitro and animal studies have shown that BPA has both a pro-oestrogenic effect by interacting with oestrogen receptors, and an anti-androgen effect by acting as an androgen receptor antagonist (Kuiper et al., 1998
; Wang et al., 2017b
). Several animal studies have demonstrated that doses of BPA even below the lowest observed adverse level of less than 50 mg/kg have been associated with decreased sperm counts, decreased motility and increased sperm DNA damage (- Wang Y.-Y.
- Lin Y.-H.
- Wu Y.-N.
- Chen Y.-L.
- Lin Y.-C.
- Cheng C.-Y.
- Chiang H.-S.
Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
PLoS Genet. 2017; 13 (https://doi.org/)e1006715https://doi.org/10.1371/journal.pgen.1006715
Chitra et al., 2003
; Qiu et al., 2013
; Tiwari and Vanage, 2013
).Studies in humans are increasingly finding associations between elevated BPA concentrations and impaired semen parameters. Li and co-workers studied 218 men in China with and without workplace exposure to BPA and found that increasing urine BPA concentrations were associated with decreased sperm concentration, decreased total sperm count and decreased motility. There was no impact on semen volume or sperm morphology (D.-K.
Li et al., 2011b
). Within the USA, the Longitudinal Investigation of Fertility and the Environment (LIFE) study enrolled 501 reproductive-age men from Michigan and Texas who were part of couples recruited upon discontinuing contraception with the intent to become pregnant. Urinary BPA concentration among these participants was negatively associated only with DNA fragmentation, but not other parameters (- Li Y.
- Lin H.
- Li Yafei
- Cao J.
Association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses.
Fertil. Steril. 2011; 95 (https://doi.org/): 116-123https://doi.org/10.1016/j.fertnstert.2010.06.031
Goldstone et al., 2015
). When the reproductive outcomes of those couples were analysed, higher paternal urinary BPA concentrations were not associated with an increased time to pregnancy (Buck Louis et al., 2014
). A study from Massachusetts General Hospital of a cohort of subfertile couples undergoing fertility treatments did not find any association of paternal urinary BPA concentration with embryo quality or live birth rate among 218 couples undergoing intrauterine insemination and/or IVF cycles (- Buck Louis G.M.
- Sundaram R.
- Sweeney A.M.
- Schisterman E.F.
- Maisog J.
- Kannan K.
Urinary bisphenol A, phthalates, and couple fecundity: The Longitudinal Investigation of Fertility and the Environment (LIFE) Study.
Fertil. Steril. 2014; 101 (https://doi.org/): 1359-1366https://doi.org/10.1016/j.fertnstert.2014.01.022
Dodge et al., 2015
). All of the above-mentioned studies were investigating adult exposures to BPA, and none has assessed the potential effects of exposures either prenatally or during peripubertal time frames.Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of organic molecules consisting of fluorinated hydrocarbon chains and are commonly used in consumer cookware manufacturing for their non-stick properties. PFAS are also used in several other industries including automotive, aerospace and construction. PFAS include perfluooctane sulfonate (PFOS) and perfluorooctanoic acid, the most common forms found in human and environmental studies. Due to the strength of the fluorine–carbon bond, these chemicals do not degrade in the environment and are referred to in the media as ‘forever chemicals’ (
Pelch et al., 2019
). Animal studies have demonstrated that mice exposed to high doses of PFOS had lower serum testosterone and epididymal sperm concentrations (- Pelch K.E.
- Reade A.
- Wolffe T.A.M.
- Kwiatkowski C.F.
PFAS health effects database: Protocol for a systematic evidence map.
Environ. Int. 2019; 130 (https://doi.org/)104851https://doi.org/10.1016/j.envint.2019.05.045
Wan et al., 2011
), but these scenarios may not be correlative to real-world human exposures. The mechanisms by which PFAS may impact fertility are thought to be by an alteration of steroidogenesis pathways (Biegel et al., 1995
). PFAS have been found in human blood as well as semen, leading to concerns of potential impacts on male fertility (Olsen et al., 2012
; Raymer et al., 2012
). However, human studies have not shown a clear link between PFAS exposure and abnormal semen parameters. A meta-analysis by Bach and collaborators reviewed 16 studies that investigated potential associations between male PFAS exposure and reproductive hormones, semen parameters or time to pregnancy, but no consistent relationships were found (Bach et al., 2016
).- Bach C.C.
- Vested A.
- Jørgensen K.T.
- Bonde J.P.E.
- Henriksen T.B.
- Toft G.
Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review.
Crit. Rev. Toxicol. 2016; 46 (https://doi.org/): 735-755https://doi.org/10.1080/10408444.2016.1182117
Phthalates
Phthalates are a category of synthetic chemical additives often used as plasticizers in consumer products ranging from food packaging materials to personal hygiene products such as shampoos (
Guo et al., 2014
). A majority of human exposure is related to dietary ingestion from contaminated food and beverage products. Exposure to phthalates is pervasive: a 2004 NHANES study of 2540 urine samples from the 1999–2000 cycle found detectable phthalate metabolites in over 75% of samples (Silva et al., 2004
). Phthalates have been found in human blood, sweat and breast milk as well, reinforcing the ubiquity of exposure (Genuis et al., 2012
).- Genuis S.J.
- Beesoon S.
- Lobo R.A.
- Birkholz D.
Human elimination of phthalate compounds: blood, urine, and sweat (BUS) study.
ScientificWorldJournal. 2012; 2012 (https://doi.org/)615068https://doi.org/10.1100/2012/615068
Phthalates and their metabolites have been shown to have hormone-disrupting properties and are associated with increased serum oestradiol concentrations (
Fong et al., 2015
). A 2006 study of 463 males from subfertile couples demonstrated a dose–response between phthalate urinary concentrations and sperm motility and concentration (Hauser et al., 2006
). A 2014 study of 589 spouses of pregnant women similarly demonstrated an inverse relationship between serum concentrations of phthalates and testosterone concentrations, semen volume and total sperm count (- Hauser R.
- Meeker J.D.
- Duty S.
- Silva M.J.
- Calafat A.M.
Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites.
Epidemiology. 2006; 17 (https://doi.org/): 682-691https://doi.org/10.1097/01.ede.0000235996.89953.d7
Specht et al., 2014
). Similarly, in-utero exposure to phthalates has been associated with anogenital distance, a marker for masculinization, semen quality and serum testosterone (Bornehag et al., 2015
; Eisenberg et al., 2012
, Eisenberg et al., 2011
; Mendiola et al., 2011
; Swan et al., 2015
, Swan et al., 2005
).Pesticides
Pesticides can enter the body either through direct skin contact or inhalation with occupational exposures such as those working in the agricultural industry, or through dietary consumption, which is the more common mechanism for the vast majority of people. Historically, the pesticide with the most well-documented link to male infertility is 1,2-dibromo-3-chloropropane (DBCP), a soil fumigant and nematocidal agent used in the USA from 1955 until 1977, after which its use was suspended in the USA over health concerns (
Babich et al., 1981
). An initial 1977 study of DBCP factory workers revealed that 14 out of 25 men had azoospermia or oligozoospermia, a finding that was only present in men who had worked more than 3 months at the factory (- Babich H.
- Davis D.L.
- Stotzky G.
Dibromochloropropane (DBCP): A review.
Sci. Total Environ. 1981; 17 (https://doi.org/): 207-221https://doi.org/10.1016/0048-9697(81)90062-0
Whorton et al., 1977
). Other pesticides such as ethylene dibromide, malathion and paraquat have also been implicated in decreasing sperm counts of workers who are exposed to them (- Whorton D.
- Krauss R.M.
- Marshall S.
- Milby T.H.
Infertility in male pesticide workers.
Lancet (London, England). 1977; 2 (https://doi.org/): 1259-1261https://doi.org/10.1016/s0140-6736(77)92665-4
Hossain et al., 2010
; Ratcliffe et al., 1987
).For the average consumer who does not have occupational exposure to pesticides, dietary intake of pesticide residues in fruit and vegetables has also been implicated in impacting spermatogenesis. Within the Environment and Reproductive Health (EARTH) study, which is a prospective cohort of couples at an academic fertility centre, the intake of high pesticide residue fruit and vegetables was associated with worse semen quality: men in the highest quartile of ingestion of those foods had a 49% lower total sperm count and 32% lower normal morphologies (
Chiu et al., 2015
). A study using the same EARTH cohort demonstrated that the intake of low to moderate pesticide residue fruits and vegetables was associated with higher total sperm counts (Chiu et al., 2016
). High or low pesticide residue status did not have any statistical impact on reproductive hormone concentrations.Male fertility and future health
The mechanisms to explain the link between male infertility as a marker for a man's future health are the focus of active investigations. Interrelated variables related to genetic, epigenetic, hormonal and environmental factors are postulated to be involved (
Choy and Eisenberg, 2018
).- Choy J.T.
- Eisenberg M.L.
Male infertility as a window to health.
Fertil. Steril. 2018; 110 (https://doi.org/): 810-814https://doi.org/10.1016/j.fertnstert.2018.08.015
Hypogonadism
A well-functioning hypothalamic–pituitary axis is necessary for physiological spermatogenesis. Infertile male populations are at higher risk of having coexisting testosterone deficiencies (
Bobjer et al., 2016
; Yang et al., 2012
). As part of the routine evaluation of infertile men, screening for endocrinopathies including testosterone deficiency should be routine (- Yang B.
- Sun H.
- Wan Y.
- Wang H.
- Qin W.
- Yang L.
- Zhao H.
- Yuan J.
- Yao B.
Associations between testosterone, bone mineral density, vitamin D and semen quality in fertile and infertile Chinese men.
Int. J. Androl. 2012; 35 (https://doi.org/): 783-792https://doi.org/10.1111/j.1365-2605.2012.01287.x
Practice Committee of the American Society for Reproductive Medicine 2015
) and may uncover otherwise undiagnosed hypogonadism. Testosterone plays a key role not only in reproductive health, but also in overall health by influencing metabolism, mood and cardiovascular and bone health (Practice Committee of the American Society for Reproductive Medicine
Diagnostic evaluation of the infertile male: a committee opinion.
Diagnostic evaluation of the infertile male: a committee opinion.
Fertil. Steril. 2015; 103 (https://doi.org/): e18-e25https://doi.org/10.1016/j.fertnstert.2014.12.103
Mulhall et al., 2018
). Diagnosing and treating hypogonadism may lead to improvements in the affected systems.Cardiovascular disease, hypertension, diabetes
Multiple cohort studies have found that a male infertility diagnosis is significantly associated with an increased risk of comorbidities closely tied to cardiovascular health. Using insurance claims data, Eisenberg and colleagues found that men diagnosed with infertility were more likely to develop incident ischaemic heart disease and diabetes in the years after an infertility evaluation (
Eisenberg et al., 2016
). Importantly, the association holds even when accounting for sociodemographic data (- Eisenberg M.L.
- Li S.
- Cullen M.R.
- Baker L.C.
Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data.
Fertil. Steril. 2016; 105 (https://doi.org/): 629-636https://doi.org/10.1016/j.fertnstert.2015.11.011
Kasman et al., 2019
). In addition, infertile men are more likely to have hypertension and prediabetes as well (Boeri et al., 2019c
; Cazzaniga et al., 2020
). With heart disease being the leading cause of death in the USA, appreciating the growing evidence of male infertility as a marker for future cardiovascular disease is important in initiating preventative healthcare measures upon the diagnosis of infertility.Cancer risk
There is a well-described relationship between infertility and testicular cancer. Several studies have demonstrated an increased risk of testicular cancer among infertile men (
Hanson et al., 2016
; - Hanson 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 (e1https://doi.org/): 322-328https://doi.org/10.1016/j.fertnstert.2015.10.027
Jacobsen et al., 2000
; Walsh et al., 2009
). Within an infertile male population, worse semen quality has been correlated with a higher risk of testicular cancer. DNA repair defects within germ cells have been proposed as a mechanism linking the two conditions, with genomic instability leading to both spermatogenic failure and an increased risk of malignant transformation within germ cells (- Walsh 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 (https://doi.org/): 351-356https://doi.org/10.1001/archinternmed.2008.562
Maduro et al., 2003
).Male infertility has also been linked to the development of prostate cancer. Walsh and colleagues reported that male factor infertility was a risk factor for high-grade prostate cancer (
Walsh et al., 2010
). Men requiring IVF with or without intracytoplasmic sperm injection have also been found to have a higher risk of prostate cancer compared with men who conceived without assistance (Al-Jebari et al., 2019
). Recently, a systematic review and meta-analysis by Del Giudice and collaborators cumulatively provided updated evidence regarding the impact of male infertility and the relative risk of developing either testicular or prostate cancer (Del Giudice et al., 2020
). The authors were able to determine a statistically significant higher risk of both cancers among subfertile/infertile men with an almost two-fold increased risk in both diseases. Importantly, while the relative risk was relevant and significant, the absolute risk of cancer remained low (<1% for either cancer).- Del 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 (https://doi.org/): 984-996https://doi.org/10.1016/j.fertnstert.2020.04.042
Finally, there is a growing body of evidence that impaired spermatogenesis may be linked to an increased risk of any cancer diagnosis. In an analysis of US insurance claims data from 2001 to 2009, Eisenberg and co-workers found a higher incidence of all malignancies in infertile men when compared with fertile controls (hazard ratio 1.49, 95% CI 1.37–1.63;
Eisenberg et al., 2015b
). The cancer risk extended beyond genitourinary cancers and also included malignancies such as non-Hodgkin lymphoma. Moreover, the risk appears to be highest among azoospermic men compared with men with oligozoospermia (Eisenberg et al., 2013
).Autoimmune diseases
Other medical conditions linked to male fertility include a range of autoimmune disorders. A Danish study by Glazer and colleagues of 24,000 men found that those with male factor infertility were at increased risk of having multiple sclerosis (
Glazer et al., 2018
). Brubaker and co-workers’ study using the Truven Health MarketScan insurance claims database found that infertile men had a higher risk of developing a wide range of autoimmune diseases such as psoriasis, systemic lupus erythematosus, Graves disease, thyroiditis and multiple sclerosis in the years after an infertility diagnosis (Brubaker et al., 2018
).Mortality
In addition to infertile men having higher risks of comorbid conditions, male infertility is also associated with mortality. This relationship persists even after controlling for factors that themselves lead to impaired semen parameters such as smoking status and BMI (
Batty et al., 2019
). A study of 43,000 infertile men demonstrated an inverse relationship between semen parameters and mortality regardless of whether they had a history of successful paternity (Jensen et al., 2009
). Glazer and colleagues showed a similar relationship, but also suggested that the risk of death may be highest among men with azoospermia (Glazer et al., 2019
). Eisenberg and collaborators demonstrated that the elevated risk of mortality with impaired semen quality persists even when accounting for baseline health, which may be impaired in infertile men (- Glazer C.H.
- Eisenberg M.L.
- Tøttenborg S.S.
- Giwercman A.
- Flachs E.M.
- Bräuner E.V.
- Vassard D.
- Pinborg A.
- Schmidt L.
- Bonde J.P.
Male factor infertility and risk of death: a nationwide record-linkage study.
Hum. Reprod. 2019; (https://doi.org/)https://doi.org/10.1093/humrep/dez189
Eisenberg et al., 2014
).In a recent US insurance-claims based database analysis from 2003 to 2017, Del Giudice and co-workers were able to confirm these findings that not only was male infertility diagnosis linked with a higher risk of all-cause mortality (hazard ratio 1.42, 95% CI 1.27–1.60), but also the odds of death were significantly increased with increased severity of the spermatogenesis impairment, especially in the subgroup with azoospermia (hazard ratio 2.01, 95% CI 1.60–2.53;
Del Giudice et al., 2021b
). The same group of authors recently demonstrated through a systematic review and meta-analysis that the same trend was seen in all studies that focused on this topic (Del Giudice et al., 2021a
). In particular, the pooled hazard ratio for the six studies included corroborated the existence of a threshold effect with a degree of altered sperm concentration that was significant for both the oligo- and azoospermic participants screened (hazard ratio 1.31, 95% CI 1.11–1.54 and hazard ratio 2.17, 95% CI 1.55–3.04, respectively). However, while the relative risk of death among infertile men was found high, the cumulative absolute risk was low (risk difference 0.33%, 95% CI 0.19–0.47%). This interesting outcome could be explained by the existence of the so-called ‘healthy’ prospective father effect whereby healthier men may be the ones who choose to attempt to become fathers, thus resulting in a lower mortality rate compared with the general population.- Del Giudice F.
- Kasman A.M.
- Chen T.
- De Berardinis E.
- Busetto G.M.
- Sciarra A.
- Ferro M.
- Lucarelli G.
- Belladelli F.
- Salonia A.
- Eisenberg M.L.
The Association between Mortality and Male Infertility: Systematic Review and Meta-analysis.
Urology. 2021; (https://doi.org/)https://doi.org/10.1016/j.urology.2021.02.041
Psychological impacts
Beyond its clinical implications, male infertility has severe sociocultural stigmas attached to it. Across the globe including the USA and China, male fertility has been strongly linked to masculinity, while infertility is often associated with shame, impotence and weakness (
Gannon et al., 2004
; - Gannon K.
- Glover L.
- Abel P.
Masculinity, infertility, stigma and media reports.
Soc. Sci. Med. 2004; 59 (https://doi.org/): 1169-1175https://doi.org/10.1016/j.socscimed.2004.01.015
Lee and Chu, 2001
). The negative effects of psychological stress on male semen parameters were mentioned earlier, but the corollary of a diagnosis of male infertility negatively impacting mood has also been described. A 2011 Iranian survey study of 114 men diagnosed with infertility found a 43% incidence of depression regardless of economic status or relationship status (Ahmadi et al., 2011
). Similar relationships between infertility diagnosis and depression have also been found in studies in Africa and Europe (Dyer et al., 2009
; Wischmann, 2001
). A cross-sectional Finnish study of childless men with infertility reported a significantly poorer self-reported quality of life (Klemetti et al., 2010
). Understanding the risk of an infertility diagnosis leading to decreased mood in men is important because men may be more reluctant to undergo infertility counselling compared with women, but nonetheless would benefit from psychosocial support offerings (- Klemetti R.
- Raitanen J.
- Sihvo S.
- Saarni S.
- Koponen P.
Infertility, mental disorders and well-being – a nationwide survey.
Acta Obstet. Gynecol. Scand. 2010; 89 (https://doi.org/): 677-682https://doi.org/10.3109/00016341003623746
Wischmann and Thorn, 2013
).- Wischmann T.
- Thorn P.
Male infertility: what does it mean to men? New evidence from quantitative and qualitative studies.
Reprod. Biomed. Online. 2013; 27 (https://doi.org/): 236-243https://doi.org/10.1016/j.rbmo.2013.06.002
Socioeconomic impacts
Once diagnosed with infertility, male patients must come to terms with not only the medical diagnosis, but also the financial implications. While the American Society of Reproductive Medicine and the World Health Organization both classify infertility as a disease, there are very few US states that mandate insurance coverage for treatment including sperm retrieval and banking (
Dupree et al., 2016
). Infertility treatments are expensive, and a study by Elliot and colleagues surveying 111 men seeking fertility care on out-of-pocket costs found that 47% reported financial strain, and 64% had expenses exceeding $15,000 (- Dupree J.M.
- Dickey R.M.
- Lipshultz L.I.
Inequity between male and female coverage in state infertility laws.
Fertil. Steril. 2016; 105 (https://doi.org/): 1519-1522https://doi.org/10.1016/j.fertnstert.2016.02.025
Elliott et al., 2016
). Financial strain has significant impacts on health outcomes, and has been linked to a higher probability of mortality compared with individuals who do not report financial hardship (Tucker-Seeley et al., 2009
). It is important for healthcare providers to continue advocating for expanding fertility health insurance coverage through legislative advocacy on behalf of their patients.Conclusion
The management of male infertility has significantly broader implications than the immediate goal of fathering offspring. Proper evaluation of the infertile male should include a comprehensive and detailed history and physical examination, along with appropriate laboratory testing. This holistic approach can uncover underlying genetic, lifestyle and health factors that may have long-lasting ramifications for the male patients and can play a key role in initiating preventative counselling and intervention. Male fertility is becoming increasingly recognized as a biomarker for overall male health.
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