Health risks associated with infertility and non-obstructive azoospermia

Abstract

Non-obstructive azoospermia is a common condition associated with significant health risks, including increased mortality, cancer, and chronic diseases such as metabolic and cardiovascular disorders. This review aims to highlight the potential health challenges faced by men with this condition compared to fertile counterparts. Through a comprehensive bibliographic search on PubMed, using the following algorithm: (“infertility, male” [MeSH Terms] OR “azoospermia” [MeSH Terms]) AND (“mortality” [MeSH Terms] OR “neoplasms” [MeSH Terms] OR “chronic disease” [MeSH Terms] OR “diabetes mellitus” [MeSH Terms] OR “heart diseases” [MeSH Terms]), we analyzed existing literature to explore the associations between infertility, specifically azoospermia, and adverse health outcomes. Findings indicate that infertile men are at a higher risk of death, various cancers (particularly testicular cancer), metabolic syndrome, diabetes, hypogonadism, and cardiovascular disease. Although research specifically addressing azoospermia is limited, available studies support the notion that men with this condition may experience heightened health vulnerabilities. Given these risks, it is imperative for healthcare professionals, especially urologists, to conduct thorough health assessments for men diagnosed with azoospermia. Informing patients of these potential health issues and integrating comprehensive evaluations into their care can facilitate early detection and intervention for life-threatening conditions. Ultimately, men with azoospermia should receive ongoing monitoring to address their specific health concerns, thus improving their long-term health outcomes.

INTRODUCTION

Azoospermia, defined as the absence of sperm in the ejaculate on two successive spermograms,1 affects 1% of all men and up to 15% of men consulting for infertility.2 The most common situation leading to azoospermia, accounting for 50%–92% of cases depending on the study, is secretory azoospermia, commonly known as non-obstructive azoospermia (NOA).3,4,5 This situation corresponds to a heterogeneous group characterized by various impairments of spermatogenesis. Although underlying genetic abnormalities, such as Klinefelter syndrome or Y chromosome microdeletions, are detected in around 20% of cases,3,4,6 and that other non-genetic causes (varicocele, undescended testes, testicular torsion, orchitis, gonadotoxic effects of drugs, and pretesticular causes) can sometimes be identified, the etiology of testicular dysfunction leading to NOA remains unknown in many patients.5

For a long time, the attention and efforts of reproductive medicine professionals were focused on the results of assisted reproductive techniques (ART), especially when the man has NOA. This is a situation where the results in terms of births are less favorable than those in other groups of infertile patients. However, more and more attention is being paid to other health risks of men with NOA. For example, a recent international consensus in 2021 entitled “Partnership for Priority Setting in Infertility” brought together 179 health professionals, 153 people with fertility problems, and 56 others from 40 countries, to identify the top 10 research priorities for future infertility research. A modified nominal group technique was used to prioritize the top 10 research uncertainties for each area. Of the 10 priorities for male infertility, one was “What are the comorbidities associated with infertility?” and the related question “What are the health risks for these men?”7

Several studies have suggested that male fertility may be a potential biomarker for future health, evoking genetic, epigenetic, developmental, and environmental mechanisms.8,9,10,11,12,13 Here, we review the data concerning the additional health risks of infertile men and more specifically among those with NOA.

This is a narrative review on the associations of health risks with infertility and azoospermia. A bibliographic search was performed on PubMed, using the following algorithm: “azoospermia” [MeSH Terms] AND (“mortality” [MeSH Terms] OR “neoplasms” [MeSH Terms] OR “chronic disease” [MeSH Terms] OR “diabetes mellitus” [MeSH Terms] OR “heart diseases” [MeSH Terms]).

Of the 155 articles identified, 9 articles corresponded to the field of research. Consequently, we search all infertile men (“infertility, male” [MeSH Terms]), and to all health problems (“health” [MeSH Terms]). This search identified 244 references, from which we extracted 56 references that make up the bibliography of this review.

MORTALITY

The first study to compare the risk of death in infertile and fertile men was a German cohort of 601 men who underwent a semen analysis as part of an andrological evaluation.14 This study revealed a possible association between oligospermia and mortality, but only among men born between 1892 and 1931. The significance of these results was therefore limited. A Swedish study also pointed to an association between increased mortality and male infertility.15 The data from Denmark and the USA reinforced these findings.16,17 From a Danish cohort of 43 277 men, Jensen et al.16 observed an inverse relationship between sperm concentration, motility, and morphology on the one hand and mortality on the other hand. However, none of these men suffered from azoospermia.16 Eisenberg et al.17 examined a cohort of 11 935 men evaluated for infertility in Texas and California, USA. The authors also found a higher risk of death in men as sperm quality deteriorated further. However, these early works had not investigated the link between excess mortality and azoospermia.

A Danish study has clarified this point, based on a nationwide prospective cohort study of almost 400 000 men who had received infertility treatment.18 The authors confirmed that men who had undergone fertility treatment had an increased risk of death (hazard ratio [HR]: 1.27, 95% confidence interval [CI]: 1.12–1.44) compared with fathers who had not undergone fertility treatment, but this excess risk was only significant in men with azoospermia (HR: 3.32, 95% CI: 2.02–5.40).18 In men with oligospermia, there was a nonsignificant trend. The authors were able to specify the causes of death and noted that most deaths were of biological causes, with cancer being the most frequent reason, which is rather surprising, given that these were fairly young patients. However, two limitations should be noted. This was a Scandinavian study, and Denmark is known to have one of the highest incidences of testicular cancer in the world.19,20,21 On the other hand, 8% of patients included in the azoospermia group actually had aspermia, a condition often linked to neurogenic damage that may be associated with mutilating surgery or physical disability. The authors’ hypothesis of common underlying etiologies for azoospermia and risk of death should therefore be interpreted with caution.

A North American case–control study of 134 796 infertile men and 242 282 controls from the Claim database (Optum Clinformatics Data Mart) queried between 2003 and 2017, also showed that men with azoospermia had a significantly higher risk of death (HR: 2.01, 95% CI: 1.60–2.53) than controls.22 The probability of survival at 30 years was 91.0% (95% CI: 89.6%–92.4%) for infertile men versus 95.9% (95% CI: 95.3%–96.4%) for fertile men (P < 0.001).

Surprisingly, the risk of death was unaffected by the exclusion of cardiovascular and malignant diseases, leading the authors to suggest that the excess risk of death in azoospermic men was unrelated to comorbidities. However, one of the weaknesses of this study was poor follow-up. In addition, certain confounding factors (notably socioeconomic status, level of education, deaths due to accidents, suicides, and violent deaths) were not available in the database.

Klinefelter syndrome is the most common genetic cause of NOA, accounting for approximately 17% of azoospermia cases.3 This group of men is known to have frequent cardiovascular and cardiometabolic comorbidities.23,24,25 Two cohorts of Klinefelter syndrome patients in Denmark and the UK showed a significant increase in mortality and morbidity from various causes.24 Mortality appeared to be increased by 50% (HR: 1.4), corresponding to a median loss of about 2 years. The risk of being admitted to a hospital for any diagnosis was 70% higher than that for a man in the same age group. The underlying reason for the deteriorating health status of people with Klinefelter syndrome appears to be multimodal, combining genetic, hormonal, and socioeconomic factors.24

CANCER

The link between male infertility and subsequent cancer diagnosis has been explored in numerous articles. Cohort studies in Europe and the USA suggested that infertility is a risk factor for testicular cancer. A multicenter study of infertile couples in California (USA) found increased rates of testicular and prostate cancer in infertile men.26 However, the azoospermic men could not be identified among infertile men. A bidirectional association between testicular cancer and male infertility is widely described in the literature27,28,29 and in particular the case of azoospermia.30 Infertility can result from testicular tumor31 and, conversely, poor sperm quality is in itself a risk factor of the subsequent development of testicular cancer.32 This association is supported by common precancerous lesions and etiopathology.33 Skakkebæk et al.34 hypothesized that testicular dysgenesis syndrome results from disturbances during fetal life that interfere with normal testicular development, leading to defective sperm production and higher rates of testicular cancer in adults.

A recent meta-analysis showed not only an increased risk of diagnosis of testicular cancer (relative risk [RR]: 1.86, 95% CI: 1.41–2.45, P < 0.001) but also of melanoma (RR: 1.30, 95% CI: 1.08–1.56, P = 0.006) and prostate cancer (RR: 1.66, 95% CI: 1.06–2.61, P < 0.001) in infertile men.35 However, azoospermic men were not analyzed separately in most studies.

A recent Japanese study confirmed a higher risk of testicular cancer in azoospermic men.36 More generally, a Texas cohort (USA) of 2238 men evaluated at an andrology clinic between 1989 and 2009 was analyzed to determine whether men with azoospermia had a higher risk of future cancer diagnosis. A total of 451 men had azoospermia and 1787 were not azoospermic. The mean age at the time of infertility assessment was 35.7 years. Compared with the general population, azoospermic men were 2.9 times more likely to develop cancer than the general Texas population (standardized incidence rate [SIR]: 2.9, 95% CI: 1.4–5.4), whereas in infertile men without azoospermia, there was only a trend toward a higher cancer rate (SIR: 1.4, 95% CI: 0.9–2.2). In fact, the cancer risk for an azoospermic man was similar to that of a man of 10 years older.37 Interestingly, most cancers identified in this study were clinically important and life-threatening. Indeed, given the young age at diagnosis (mean: 35.8 years), even clinically insignificant prostate cancers should be considered clinically significant in the long run. A problem with the study design was that azoospermia etiology was available in only about a quarter (101 out of 451) of cases. A possible “contamination” of the NOA group by obstructive azoospermia cannot be excluded.

Walsh et al.38 reported a 2.6-fold increased risk of high-grade prostate cancer in men with male infertility. A case–control study in the USA revealed a trend toward an association between male infertility and breast cancer.39

The lifetime risk of developing cancer for these men may be very significant and far greater than 3.5% reported by Eisenberg et al.37 Thus, men with a history of severe male infertility warrant long-term observation and earlier screening of potential cancers.

CHRONIC DISEASES

While there is growing interest in the association between male infertility and future health, the main focus has been on the risk of cancer and less on the risk of chronic nonmalignant diseases. Several cross-sectional studies have shown that already at the time of infertility diagnosis, men are in poorer health than their fertile peers, suggesting that men’s reproductive and somatic health are closely linked.40,41,42 A case–control study including 344 consecutive infertile men and 293 consecutive fertile men of comparable age showed that infertile men had a significantly higher rate of comorbidities than fertile controls (Charlson comorbidity index [CCI]: 0.33 vs 0.14, 95% CI: 0.08–0.29, P < 0.001). Linear regression analyses showed that CCI increased linearly with age (β: 0.196, P < 0.001) and body mass index (BMI; β: 0.161, P < 0.001).40 A prospective study assessed the risk of chronic nonmalignant diseases in infertile men and found a 30% increase in risk, including diabetes.41

METABOLIC SYNDROME

Metabolic syndrome is defined as a set of risk factors for cardiovascular disease and type 2 diabetes, which are often assessed and managed together. Although there are different definitions of metabolic syndrome, all of them include insulin resistance, high blood pressure, obesity, and atherogenic dyslipidemia (high triglycerides and low high-density lipoprotein [HDL] cholesterol).

Using the Malmö Preventive Project cohort of over 22 000 men, Elenkov et al.43 observed that infertile men had a worse metabolic profile than fertile men at initial examination, with an increased risk of elevated triglycerides (odds ratio [OR]: 1.24, 95% CI: 1.10–1.42), elevated fasting blood glucose (OR: 1.23, 95% CI: 1.05–1.43), and hypertension (OR: 1.28, 95% CI: 1.14–1.45).

DIABETES

In a large prospective cohort study including 39 516 men identified from the Danish National In vitro Fertilization (IVF) Registry, a total of 651 (1.6%) cases of diabetes mellitus occurred during the 5.6-year follow-up period (prevalence rate: 2.9 per 1000 person-years). The risk of diabetes in men with azoospermia was 2.10 (95% CI: 1.25–3.56) and 1.44 (95% CI: 1.01–2.06) in men with oligospermia.44

Recently, a meta-analysis was carried out on 288 448 fertile men and 109 136 infertile men, with 6984 and 4598 new diagnoses of diabetes, respectively.35 The meta-analysis failed to establish an excess risk of diabetes during follow-up in infertile men (HR: 1.26, 95% CI: 0.96–1.65, P = 0.09). However, further analysis after exclusion of a study without HR data revealed a higher risk of diabetes in infertile men (HR: 1.39, 95% CI: 1.09–1.71, P = 0.008). The probability of diabetes diagnosis at 10 years was 11.5% (95% CI: 11.3%–11.7%) for infertile men versus 7.4% (95% CI: 7.3%–7.5%) for fertile men (P < 0.001) and at 30 years was 25.0% (95% CI: 21.1–26.9%) for infertile men versus 17.1% (95% CI: 16.1%–18.1%) for fertile men (P < 0.001). It should be noted that heterogeneity between the included studies was high (I² = 92.44%)35 and the results should be interpreted with caution.

One explanation for the link between male infertility and diabetes could be via insulin resistance, which, particularly when associated with obesity, is thought to be associated with impaired spermatogenesis and increased sperm DNA damage.45 As the prevalence of diabetes is associated with an overall risk of cardiovascular disease,46 it is also important to review the link between infertility and cardiovascular disease.

CARDIOVASCULAR DISEASE

Analysis of the Malmö Preventive Project cohort showed that infertile men were at higher risks of cardiovascular mortality (HR: 1.33, 95% CI: 1.18–1.49).43 The meta-analysis by Fallara et al.35 found an increased risk of cardiovascular events (HR: 1.20, 95% CI: 1.00–1.44, P = 0.049), with a probability of major cardiovascular events of 13.9% (95% CI: 13.3%–14.6%) for fertile men versus 15.7% (95% CI: 14.3%–16.9%) for infertile men (P = 0.008).

HYPOGONADISM

A Swedish study conducted between 2007 and 2014 examined over 400 000 men and used sperm donation to identify those with NOA.47 The findings revealed that men who became fathers through sperm donation had a statistically higher risk of being prescribed testosterone treatment. Specifically, they were at an increased risk compared to those who conceived naturally (HR: 18.14, 95% CI: 11.71–28.10, P < 0.001) and those who conceived by assisted reproductive technology with their own sperm (HR: 5.10, 95% CI: 3.15–8.27, P < 0.001).47

With regard to azoospermic men, a Swedish study (n = 206) revealed a 10-fold increased risk of hypogonadism in azoospermic men.48 Another cross-sectional study of 65 men with NOA undergoing testicular biopsy revealed that nearly 47% of men with NOA had hypogonadism (95% CI: 0.36–0.59).49 Compared with fertile controls, the OR for post-testicular sperm extraction (post-TESE) hypogonadism was 17 (95% CI: 6.6–45). Serum LH (P = 0.03), but not testosterone (P = 0.43), differed significantly before and after TESE. Compared with eugonadal NOA men, the OR for having deviations in lipid profile was 3.3 (95% CI: 1.3–8.8) for hypogonadal NOA men. This study confirms that NOA men present a very high risk of androgen deficiency which, even in young participants, is associated with dyslipidemia.48 It is well known that in men, insufficient androgen production is associated with numerous adverse health effects, including higher risks of metabolic syndrome49,50 and cardiovascular disease.51 A study of Bobjer et al.49 also revealed that these men had low bone mineral density what may illustrate a deep and ancient testosterone deficiency. Medical management of these men should therefore include endocrinological and metabolic assessment and follow-up after a diagnosis of infertility.

DISCUSSION

One of the main factors limiting this association between infertility and worsening somatic health is the poor understanding of the molecular features that link infertility to comorbidities and cancers throughout life. As up to 25% of the male genome is involved in reproduction, it is likely that other nonreproductive processes may also be affected.9 Indeed, an in-depth study has already shown that various etiologies of infertility share particular genes and molecular pathways with a number of other pathologies, including various cancers.52

In addition, the number of genetic abnormalities identified in NOA is increasing thanks to advancements in whole-genome amplification and next-generation sequencing.4 Azoospermic males frequently have severely altered recombination frequencies and genomic instability, including copy number variations.53 This susceptibility to DNA damage affects not only spermatogenesis but also the general health status of these men, which is corroborated by the higher percentage of deaths in infertile men.53 Alongside genetic causes, it is very likely that men with NOA are at higher risks of hypogonadism and metabolic syndrome. Recent studies show that enzymes involved in the lipid oxidation process may be implicated.54

Whatever the cause, the health risks faced by infertile men, and in particular those with azoospermia, deserve to be explored in greater depth. However, the current situation is that most infertile men, with or without azoospermia, have not been adequately assessed.

A recent committee editorial to the UK Parliament by Dr. Ralf Henkel entitled “The importance of male fertility as a proxy of general health” stated that “the system in the UK is clearly failing men.”55 While many women’s health programs are available and advocated, there is virtually no education and support for men. According to this editorial, “If a couple is not conceiving, the referral pathway is first to the general practitioner who is referring the couple to the reproductive medicine specialist, who is a gynecologist and is also heading a fertility clinic.” According to Dr. Ralf Henkel’s experience, neither a general practitioner nor a gynecologist is adequately qualified to properly diagnose and treat male reproductive problems. Dr. Ralf Henkel further notes that underlying or concomitant general health issues, such as cardiovascular problems, may go undetected. This oversight could lead to even higher treatment costs at a later stage.55 Male fertility assessment should be seen as an opportunity to implement a genuine men’s health policy that goes far beyond the question of fertility.

Given that infertile men have a higher risk of dying from cancer, a higher rate of cardiovascular disease, and a reduced life expectancy, and that men are not usually seen by a qualified andrology/men’s health specialist, the proposals made by Dr. Ralf Henkel to the UK Parliament55 are as follows.

Educating boys about their health, fertility, and the consequences of infertility is crucial for fostering awareness from a young age. To enhance early detection, it is essential to provide better fertility screening by andrologists or urologists specialized in male infertility. A comprehensive assessment of men’s lifestyles in relation to their fertility should also be prioritized. Additionally, conducting regular health checks for male-related diseases, including hormone testing and hormone replacement therapy, can help mitigate the impact of testosterone decline and promote long-term health. Establishing men’s health centers, as suggested in the USA, could further support these initiatives by creating dedicated spaces for education, screening, and treatment, ultimately improving men’s overall health outcomes.56

CONCLUSIONS

Over the past decade, growing evidence has highlighted an alarming association between male infertility (notably NOA) and poor somatic health, with substantial evidence of increased incidence of oncological disease, cardiovascular disease, and metabolic disorders. This paradigm could open a new window for a crucial health reform in which the infertile phenotype could serve as a biomarker of potential pathological conditions. Since men are not subjected to regular screening programs like women, fertility assessment is a great opportunity to identify men who may be at increased risk, in order to initiate appropriate preventive actions. This underlines the crucial importance of male assessment by an expert with a comprehensive understanding of men’s health and confirms the role of urologist not only to provide sperm extracted from the testicle but also for the proper diagnosis and treatment of the potential conditions other than infertility.

AUTHOR CONTRIBUTIONS

EH prepared the evidence and manuscript. PKFC prepared the manuscript. Both authors read and approved the final manuscript.

COMPETING INTERESTS

Both authors declare no competing interests.