Autoimmunity and Inflammaging in Male Infertility

Abstract

Male factors contribute, alone or in combination with female-related ones, to approximately 40–50% of infertility in couples. Within the spectrum of male infertility, growing evidence indicates that autoimmune mechanisms and chronic inflammation can impair spermatogenesis, sperm function, and reproductive outcomes. The disruption of the testicular immune privilege, blood-testis barrier dysfunction, local inflammatory pathways, and antisperm antibodies represent the best-characterized immune-mediated mechanisms, although their clinical relevance varies and several mechanistic observations remain derived from preclinical models. Systemic autoimmune and chronic inflammatory diseases may also affect male reproductive function through inflammatory cytokines, endocrine dysregulation of the hypothalamic-pituitary-gonadal axis, sexual dysfunction, and treatment-related gonadotoxicity. Emerging data also implicate the gut-testis axis and age-associated low-grade inflammation (inflammaging) as potential contributors to testicular immune remodeling, oxidative stress, and declining reproductive function. This narrative review is intended to encompass disease-specific available reviews and synthesize original research, clinical studies, and systematic reviews published mainly between 2010 and 2026. We distinguish established clinical evidence from experimental or hypothesis-generating data and discuss implications for fertility preservation, assisted reproduction, and individualized management. Integrating reproductive immunology with the clinical evaluation of male infertility may improve risk stratification while avoiding overinterpretation of still-limited immune biomarkers and therapeutic evidence.

Introduction

Infertility is clinically defined as the inability to conceive spontaneously after 12 months of regular, unprotected sexual intercourse, and affects 8–17% of couples worldwide, thus constituting a significant public health concern, with substantial medical, psychosocial, and socioeconomic burdens [1, 2]. While well-established etiological factors remain central to infertility pathogenesis, an increasing body of evidence suggests that in numerous cases the immune system dysregulation plays a role in determining reproductive competence [3]. Issues in reproductive medicine have been predominantly perceived as primarily affecting women until recently, when this paradigm has been gradually changing with the growing recognition of the male contribution to infertility [4]. According to the most recent literature, men account for 20–30% of infertility cases with one single cause and contribute in combination with other factors, such as ovulatory disorders or tubal pathology in an additional 20–30%, resulting in an overall involvement in approximately 40–50% of infertile couples [4–6]. Importantly, the impaired semen quality may also affect reproductive outcomes beyond fertilization, as increased sperm DNA fragmentation, oxidative stress, and chromosomal abnormalities have been associated with recurrent pregnancy loss and early embryonic developmental failure [7, 8].

Male infertility can be broadly classified depending on the congenital, acquired, and idiopathic causes. Congenital causes include genetic abnormalities, such as Klinefelter syndrome, Y-chromosome microdeletions, and congenital bilateral absence of the vas deferens associated with cystic fibrosis gene mutations, as well as cryptorchidism and other anatomical anomalies. Acquired causes encompass conditions such as varicocele, testicular trauma, testicular torsion, and urogenital infections (including prostatitis, epididymitis, and orchitis), as well as exposure to environmental toxins, medications, radiotherapy, chemotherapy, and sexual dysfunctions, such as erectile or ejaculatory disorders [6–9]. Besides these known factors, idiopathic infertility remains and accounts for approximately 30–50% of cases, as no specific underlying cause can be identified [10–12]. This large proportion of unexplained cases has prompted increasing research interest in the field of male reproductive immunology, suggesting that immune-mediated mechanisms may represent an underrecognized contributor to infertility [13].

Autoimmune diseases manifest a striking female predominance, and reproductive research in autoimmunity has consequently focused largely on women, including studies addressing ovarian reserve, pregnancy, maternal–fetal outcomes, and reproductive manifestations of systemic autoimmune disease [14–19]. This marked female-to-male ratio, as high as 10 to 1, is largely attributed to sex-dependent immune dimorphism, driven by hormonal and genetic factors. In particular, estrogens appear to enhance adaptive immune responses, favoring Th2 and Th17 pathways and influencing immune tolerance mechanisms. X-chromosome-related effects, including the high density of immune-related genes mapping on sex chromosomes and the incomplete X-chromosome inactivation or the X chromosome monosomy, may also contribute to heightened immune reactivity and increased susceptibility to autoimmunity in females [20–25]. However, a growing body of research is highlighting the importance of immune and autoimmune mechanisms in male reproductive health [13]. It has been observed that immune-mediated mechanisms may contribute to male infertility through several pathogenic pathways, including the production of anti-sperm antibodies (ASA), testicular inflammatory processes, and disruption of the blood–testis barrier (BTB), all of which can adversely affect spermatogenesis, sperm function, and sperm–oocyte interaction [13, 26]. Moreover, systemic inflammation and autoimmune diseases may indirectly impair male reproductive function through chronic inflammatory activity, dysregulation of endocrine homeostasis, particularly involving the hypothalamic–pituitary–gonadal (HPG) axis, as well as through the use of therapeutic regimens with potential gonadotoxic effects [27–30]. By integrating evidence from reproductive immunology and systemic autoimmunity, this review highlights current knowledge gaps and discusses potential implications for future research and clinical management of immune-related male infertility.

Literature Search

We report a narrative synthesis of the available evidence on the relationship between autoimmune mechanisms, chronic inflammation, inflammaging, and male infertility. The aim of this review is not to unite reviews limited to diseases but to provide a critical discussion of clinically relevant immune-mediated conditions and mechanisms that can affect male reproductive function and to support clinical decision-making. A literature search was performed in PubMed, Scopus, and Web of Science, focusing on studies published between 2010 and 2026, while earlier landmark studies were retained when directly relevant. The update specifically considered recent systematic reviews, large epidemiological studies, and Mendelian-randomization analyses published in 2024–2025 when available. Search terms included combinations of male infertility, reproductive immunology, autoimmunity, autoimmune diseases, antisperm antibodies, immune-mediated infertility, systemic lupus erythematosus, testicular autoimmunity, inflammation, rheumatic disease, connective tissue diseases, gut microbiota, inflammaging, and assisted reproductive technology. Original research articles, clinical trials, cohort and case-control studies, systematic reviews, and meta-analyses were considered; editorials and non-English publications were excluded. Case reports including fewer than five patients and conference abstracts were generally excluded; selected emerging reports were retained only when they provided uniquely relevant mechanistic or hypothesis-generating evidence and were explicitly interpreted as preliminary. The final literature search/update was conducted on 1 July 2026. Because this work was conceived as a narrative review rather than a prospectively registered systematic review, database-specific record counts were not prospectively retained, and a PRISMA flow diagram cannot be reconstructed reliably. No formal risk-of-bias instrument was prospectively applied, and no quantitative meta-analysis was undertaken because the review question spans heterogeneous diseases, exposures, study designs, and reproductive outcomes.

Evidence Appraisal and Hierarchy of Evidence

For narrative interpretation, the evidence was grouped qualitatively by study design. Systematic reviews, meta-analyses, clinical guidelines, and large population-based studies were prioritized for epidemiological and clinical conclusions; prospective cohorts and randomized clinical trials were considered the strongest primary clinical evidence when available; retrospective cohorts, case-control studies, cross-sectional studies, and small case series were interpreted as associative evidence; and animal or in vitro experiments were used to support mechanistic plausibility rather than direct clinical inference. Mendelian-randomization studies were treated as hypothesis-strengthening genetic evidence but not as substitutes for interventional trials. This hierarchy was applied consistently throughout the review to distinguish established clinical observations from preclinical or hypothesis-generating mechanisms.

Literature Review

Breakdown of Testicular Immune Privilege

Local Immune-Mediated Mechanisms of Male Infertility

The testis is recognized as an immune-privileged organ, a status that safeguards developing germ cells from systemic immune responses. This privilege is primarily maintained by the BTB, a specialized structure formed by tight junctions between Sertoli cells, together with the broader immunoregulatory contribution of Leydig cells, peritubular cells, and resident immune cells within the testicular microenvironment [31, 32]. The BTB establishes both physical and immunological compartmentalization within the seminiferous tubules, thereby isolating post-meiotic germ cells from systemic immune surveillance. This protection is critical because many sperm-specific antigens are expressed only after puberty and are not presented during the establishment of central immune tolerance, which may render them recognizable as non-self by the immune system [33, 34].

In addition to its structural function, the testicular microenvironment actively promotes local immune tolerance. Recent studies have advanced our understanding of the immunological mechanisms affecting male reproductive health, emphasizing the central role of regulatory T cells (Tregs) in maintaining tolerance to sperm antigens. Sertoli cells secrete various immunomodulatory factors, including anti-inflammatory cytokines and regulatory molecules such as transforming growth factor-β (TGF-β), which suppress local immune activation and help sustain immune privilege. Furthermore, testicular macrophages and other resident immune cells generally exhibit a tolerogenic phenotype, thereby supporting the immunoregulatory environment necessary for normal spermatogenesis [32–35].

Experimental models demonstrate that depletion of Tregs leads to severe autoimmune orchitis, characterized by infiltration of immune cells, including CD4 + T cells, monocytes, and macrophages, and by the production of ASA, which impair sperm function and reduce fertility [36, 37]. Sertoli cells also contribute to maintaining this immunoregulatory environment through retinoic acid signaling. Specifically, 9-cis-retinoic acid modulates the immunological function of Sertoli cells by influencing Treg differentiation and suppressing autoreactive lymphocytes. Despite these promising experimental data, no clinical studies in humans have yet evaluated the pharmacological modulation of Treg function or retinoic acid signaling as a therapeutic approach for autoimmune-mediated male infertility. Current evidence derives exclusively from preclinical models and cellular co-culture systems, in which manipulation of these pathways showed partial protection against immune-mediated testicular damage. Therefore, although targeting these immunoregulatory axes may represent a potentially innovative strategy, their clinical translation remains entirely experimental, and no standardized therapeutic protocols are currently available [36–38].

Inflammatory mechanisms disrupting testicular homeostasis may originate from both local and systemic triggers. Locally, infections of the male genital tract, tissue injury, oxidative stress, or disruption of the blood–testis barrier may expose normally sequestered germ cell antigens to the immune system, thereby promoting immune activation. Systemically, autoimmune diseases, metabolic inflammation, and alterations in the gut or genital microbiota may contribute to a pro-inflammatory milieu capable of affecting the testicular microenvironment. Once initiated, these processes can activate innate immune pathways, promote cytokine release, and impair Sertoli cell function, Leydig cell steroidogenesis, and spermatogenesis [31–38].

Beyond adaptive immune tolerance, innate immune cells also play a pivotal role in testicular homeostasis. Chronic orchitis can be driven by dysregulated natural killer T (NKT) cells, which normally mediate immune surveillance. This can result in damage to the seminiferous epithelium and disruption of spermatogenesis [39]. A similar process occurs when the NLRP3 inflammasome is overactivated, for example after local ischemia, leading to excessive secretion of pro-inflammatory cytokines such as IL-1β and IL-18. This, in turn, promotes germ cell apoptosis and infertility. As suggested by preclinical studies, inhibiting inflammasome activity has the potential to reduce these effects, representing a novel therapeutic target [40–42].

Inflammatory processes that disrupt testicular immune homeostasis may arise from systemic as well as microenvironmental factors. The gut–testis axis has emerged as a framework linking intestinal microbial composition, microbial metabolites, systemic immune activation, endocrine signaling, and testicular function [43–45]. Experimental data support several interconnected pathways rather than a single linear mechanism. Dysbiosis may reduce beneficial short-chain fatty acid signaling and increase exposure to microbial products, thereby favoring macrophage activation, pathogenic Th17 responses, and systemic cytokine production [43–45].

In inflammatory models, NF-κB signaling can provide a priming signal for NLRP3 inflammasome activation, while mitochondrial dysfunction and reactive oxygen species (ROS) can provide amplification signals; subsequent caspase-1 activation and release of IL-1β and IL-18 may reinforce local inflammation, germ cell injury, and disruption of Sertoli cell barrier function [40–45]. ROS can, in turn, activate additional NF-κB- and inflammasome-dependent signaling, creating a self-amplifying inflammatory–oxidative loop. Importantly, the complete sequence of this cascade has not been demonstrated as a single continuous pathway in human male infertility and should therefore be regarded as a mechanistic framework derived largely from experimental evidence.

Human genetic data provide complementary, but indirect, support, as bidirectional Mendelian randomization studies have reported associations between specific gut microbial taxa, inflammatory cytokine profiles, and male infertility-related phenotypes [46, 47]. A 2025 report further suggested that altered butyrate-dependent macrophage PPAR-γ signaling may link dysbiosis to testicular inflammation [48]; these findings require independent clinical validation.

Metabolic inflammation provides an additional bridge between dysbiosis and inflammaging. Obesity and insulin resistance are characterized by chronic low-grade cytokine and oxidative signaling that can converge on NF-κB/NLRP3 pathways, impair Leydig cell steroidogenesis, weaken blood–testis barrier integrity, and adversely affect spermatogenesis [49]. Thus, microbiota-related inflammation, metabolic inflammation, and age-related inflammaging are biologically distinct processes that can converge on shared downstream pathways involving oxidative stress, innate immune activation, and testicular dysfunction. Abnormal angiogenesis may represent another local amplifier: in experimental autoimmune orchitis, excessive VEGF-A-driven angiogenesis facilitates immune cell infiltration, whereas anti-angiogenic treatment reduces vascular expansion and inflammatory severity [50].

Anti-Sperm Antibodies

Disruption of the BTB can compromise immunological balance and expose sperm antigens to the systemic immune system. Such disruption may occur as a result of testicular trauma, urogenital infections, including orchitis and epididymitis, varicocele, or surgical procedures such as vasectomy, testicular biopsy, orchiopexy, varicocelectomy, or surgery for testicular torsion. Under these conditions, previously sequestered sperm antigens may trigger an immune response, leading to the production of ASA [34, 51, 52]. Among these factors, vasectomy represents one of the most extensively documented conditions associated with the development of ASA and has been widely used as a model to study immune responses against sperm antigens [51].

ASA can impair male fertility through multiple mechanisms (Fig. 1). They may bind to different regions of the spermatozoon, particularly the tail, thereby reducing sperm motility and hindering sperm migration through cervical mucus [34, 52]. In addition, ASA can interfere with key functional processes required for fertilization, including sperm capacitation and the acrosome reaction, partly through disruption of intracellular signaling pathways such as tyrosine phosphorylation, which are essential for penetration of the zona pellucida [34, 53, 54]. Furthermore, antibodies directed against sperm surface proteins involved in sperm–oocyte fusion, such as IZUMO1 and members of the ADAM protein family, may directly inhibit fertilization [55–57]. Beyond their direct effects on sperm function, ASA have also been associated with increased oxidative stress and sperm DNA fragmentation, both of which may further compromise sperm quality and reproductive potential [57]. In particular, the presence of anti-ODF2 autoantibodies has been associated with significantly increased sperm DNA fragmentation and apoptotic activity in men with oligozoospermia or azoospermia, suggesting that specific ASA may contribute to genomic damage by activating caspases and apoptotic signaling pathways [58].

Fig. 1.

Mechanisms by which anti-sperm antibodies (ASA) impair sperm function and male fertility. (a) ASA bound to the sperm flagellum physically hinder sperm progression through cervical mucus by cross-linking adjacent spermatozoa and reducing the amplitude and coordination of flagellar beating, thereby preventing sperm migration toward the upper female reproductive tract. (b) ASA interfere with the sperm capacitation cascade by blocking key membrane events, including cholesterol efflux, HCO3-/Na+ cotransporter activity, and bicarbonate-mediated activation of soluble adenylyl cyclase (sAC). Reduced cyclic adenosine monophosphate (cAMP) production leads to impaired protein kinase A (PKA) activation, diminished protein tyrosine phosphorylation, and suppression of RAS signaling, collectively preventing the acquisition of fertilizing capacity. (c) ASA sterically block sperm-zona pellucida (ZP) interaction by occupying ZP-binding receptors on the sperm surface and preventing IZUMO sperm-egg fusion 1 (IZUMO1)-Juno-mediated gamete fusion, thus abolishing sperm penetration of the oocyte. (d) ASA promote sperm DNA fragmentation and apoptosis through multiple converging pathways: direct binding to outer dense fiber protein 2 (ODF2) may dysregulate its expression and activate a caspase cascade, while ASA-associated immune-cell recruitment can amplify local reactive oxygen species (ROS) production and mitochondrial injury. Dashed arrows indicate indirect or hypothetical interactions; solid T-bars indicate inhibition; solid arrows indicate activation or stimulation; X symbols denote steric blockade of receptor-ligand or receptor-mediated binding

Diagnosis and Management Strategies

Given the potential impact of ASA on sperm function and fertilization, their clinical detection has been investigated as a possible diagnostic tool in the evaluation of immune-mediated male infertility [57]. However, according to current guidelines from the American Urological Association and the American Society for Reproductive Medicine, routine ASA testing is not recommended in the initial evaluation of male infertility, mainly due to the lack of standardized diagnostic methods and the uncertain clinical significance of positive findings in many cases [59]. When ASA testing is performed, the most commonly used diagnostic techniques are the mixed antiglobulin reaction (MAR) test and the immunobead test, both of which detect antibodies bound to the surface of spermatozoa [60]. The World Health Organization includes the MAR test among the possible assessments in semen analysis; however, the thresholds defining clinical relevance remain controversial, and the interpretation of positive results often requires careful clinical correlation [61]. Moreover, the overall prevalence of clinically significant ASA-mediated infertility remains relatively low, affecting approximately 2–6% of infertile men, and its impact largely depends on the degree of autoimmunization and the specificity of the antibodies involved [60]. The lack of standardized methods for the detection, quantification, and reporting of ASA remains a significant challenge in clarifying their role in male infertility and in defining appropriate clinical management strategies. This methodological heterogeneity makes it difficult to compare findings across studies and to establish the true clinical relevance of ASA positivity [35]. Future research should therefore aim to develop more standardized and reproducible diagnostic approaches for the identification and characterization of ASA. In addition, a deeper understanding of the specific sperm antigens targeted by these autoantibodies, together with their biological functions and clinical implications, could help elucidate the mechanisms through which ASA affects male fertility and supports the development of more targeted therapeutic strategies, ultimately improving reproductive outcomes [35].

From a therapeutic perspective, assisted reproductive technologies represent the main management option when clinically relevant ASA-mediated infertility is suspected [62–65]. Intrauterine insemination (IUI) can bypass the cervical mucus barrier, but it does not eliminate antibody-related interference with capacitation, the acrosome reaction, or sperm-oocyte interaction [66]. In severe sperm autoimmunization, ICSI is commonly favored because direct injection bypasses several functional barriers imposed by ASA [35, 60–64]. However, the evidence does not support a universal assumption that ICSI is superior to conventional IVF in all ASA-positive couples. The 2011 meta-analysis by Zini et al. found no significant association between ASA positivity and pregnancy rates after IVF or ICSI [65]. In our updated search through 2026, we did not identify a more recent meta-analysis specifically comparing IVF with ICSI outcomes in ASA-positive men; therefore, this conclusion should be interpreted considering the age and heterogeneity of the available evidence rather than as a definitive treatment hierarchy. Laboratory approaches intended to reduce antibody-bound spermatozoa, including sperm washing, immunomagnetic separation, and enzymatic treatment, have been investigated, but clinical benefit remains uncertain [67]. Corticosteroids have also been used to reduce ASA production, yet inconsistent efficacy and potential adverse effects preclude routine immunosuppression for isolated ASA positivity [67, 68].

Recent advances in genomics, proteomics, and reproductive immunology may help identify specific sperm antigens and functional antibody targets, potentially improving the biological classification of ASA-mediated infertility. At present, however, these approaches remain investigational and have not produced standardized antigen-specific diagnostic or therapeutic strategies [69, 70].

Systemic Autoimmunity and Male Infertility

Central Tolerance and Male Reproductive Autoimmunity

The immunological mechanisms that regulate tolerance to self-antigens are relevant to sex differences in autoimmunity and may also influence susceptibility to reproductive autoimmunity. Among these mechanisms, the autoimmune regulator (AIRE) is a key regulator of central immune tolerance [71]. In medullary thymic epithelial cells, AIRE promotes ectopic expression of tissue-restricted antigens, facilitating deletion of high-affinity autoreactive T cells and diversion of selected clones toward the regulatory T-cell lineage [72]. Androgens provide a mechanistic link between sex hormones and this pathway. Experimental work has shown that androgen binding to the androgen receptor (AR) recruits AR to AIRE promoter regions and enhances AIRE transcription; thymic AIRE expression is consequently higher in males than in females in both murine and human observations [73]. This androgen-AR-AIRE axis may contribute to the lower prevalence of several T-cell-mediated autoimmune diseases in males by strengthening central deletion of autoreactive T cells. However, it should not be interpreted as proof that males have intrinsically stronger local testicular immune privilege: central thymic tolerance and the peripheral immune-privileged testicular microenvironment are distinct, although complementary, layers of tolerance. When AIRE function is reduced or absent, tissue-restricted antigen presentation in the thymus is impaired, allowing autoreactive lymphocytes to escape negative selection and potentially recognize reproductive antigens in peripheral tissues [71–73]. In experimental models, AIRE deficiency has been associated with sterile epididymitis, inflammatory infiltration, and impaired fertility, together with disturbances in the local ionic microenvironment of the reproductive tract [74]. Because the available experimental report does not establish a clinically validated human electrolyte biomarker, this observation should not be attributed to a specific ion. Reviews have therefore proposed that defective AIRE-mediated central tolerance may facilitate autoimmune responses against epididymal or testicular antigens, but direct disease-specific evidence in men remains limited [75, 76].

More recently, there has been growing attention on infection-associated immune dysregulation, particularly after SARS-CoV-2 infection and in long COVID. Persistent autoantibodies have been described in subsets of patients after acute infection, raising the possibility of immune cross-reactivity and chronic inflammatory effects on reproductive tissues, although direct evidence for autoantibody-mediated male infertility remains preliminary [77–79]. This distinction is clinically relevant because concerns have also been raised about COVID-19 vaccination. Available systematic reviews and meta-analyses do not show a detrimental effect of mRNA or inactivated COVID-19 vaccination on conventional semen parameters, whereas SARS-CoV-2 infection itself has been associated in several studies with transient impairment of semen quality [80, 81]. Thus, current evidence does not support extending hypotheses about post-infectious autoimmunity to vaccination-related male infertility.

Systemic Autoimmune Diseases and Male Infertility

There is no single accepted worldwide male prevalence of autoimmune diseases, because estimates vary substantially with which diseases are included and case definition/data source; current best large-scale estimates span roughly from 2% to 7.4%. A pooled estimate including 81 autoimmune diseases from a large literature-based synthesis reported an overall prevalence of autoimmune diseases of approximately 2.7% in men [82]. The largest European study, conducted on over 22 million individuals in the United Kingdom, estimated that the overall prevalence of autoimmune diseases in men is approximately 7.4% [83]. Despite the strong female predominance overall, some autoimmune conditions show a similar or even higher prevalence in the male population, including psoriasis, childhood-onset type 1 diabetes mellitus and ankylosing spondylitis [84]. Autoimmune diseases that are more frequently observed in men tend to be associated with more acute inflammatory processes and a predominantly cell-mediated immune response, often characterized by a Th1-driven profile. This response is marked by heightened activity in T lymphocytes and elevated levels of pro-inflammatory cytokines, which play a role in tissue damage through both cytotoxic and inflammatory pathways [85, 86]. This pattern conflicts with that observed in many autoimmune diseases that are more prevalent in women, particularly connective tissue diseases, which are often characterized by stronger activation of the humoral immune response and the production of autoantibodies. Overall, these differences suggest that in men, autoimmunity manifests more frequently through cell-mediated immune mechanisms and pronounced inflammatory processes, reflecting specific biologic features of male immune regulation [85, 86]. The pharmacological treatments used to manage autoimmune conditions may further influence male fertility and should be evaluated in the assessment of men wanting to conceive. The treatment of autoimmune diseases includes several classes of immunomodulatory and immunosuppressive agents, ranging from conventional therapies such as corticosteroids and cytotoxic drugs to targeted biologic agents. Although these treatments fulfill a key role in disease control, their potential effects on male reproductive function vary considerably [87]. Table 1 summarizes the main therapeutic agents used in autoimmune diseases and their reported effects on male fertility [87, 88, 90–92, 94, 99–101]. Despite efficacy in the treatment of the autoimmune disease, robust evidence demonstrating a direct improvement in reproductive outcomes is still lacking. A major limitation of the current literature is the heterogeneity of study populations, diagnostic criteria, and outcome measures, which complicates the interpretation of therapeutic efficacy [87]. Current recommendations for fertility preservation in men with systemic autoimmune diseases, particularly those who are candidates for cytotoxic or immunosuppressive therapies, include counseling regarding reproductive risks and the offer of sperm cryopreservation prior to treatment initiation. Guidelines from the American Society of Clinical Oncology recommend that sperm banking be discussed with all pubertal and postpubertal males before exposure to potentially gonadotoxic therapies, including alkylating agents and other cytotoxic drugs [91, 92].

Table 1.

Main immunosuppressive and immunomodulatory therapies used in autoimmune diseases and their reported effects on male fertility

Drug class	Examples	Main autoimmune indications	Mechanism of action	Reported effects on male fertility	Reversibility/clinical relevance	Key References
Corticosteroids	Prednisone, methylprednisolone	Connective tissue diseases, vasculitis, myasthenia gravis, inflammatory bowel disease	Broad anti-inflammatory and immunosuppressive effects through inhibition of cytokine production and immune cell activation	No consistent direct detrimental effect on male fertility has been demonstrated. In selected cases of immune-mediated infertility, corticosteroids have been used to reduce antisperm antibodies, although the clinical benefit remains uncertain	Generally reversible; not considered directly gonadotoxic	[67, 68, 87–89]
Alkylating agents	Cyclophosphamide	Severe systemic lupus erythematosus, vasculitis, Behçet disease, severe systemic autoimmune diseases	DNA cross-linking with cytotoxic damage to rapidly dividing cells, including germ cells	Strongly associated with impaired spermatogenesis, oligozoospermia, or azoospermia, particularly with high cumulative doses	Dose-dependent; may be irreversible. Sperm cryopreservation should be discussed before treatment	[87, 89–93]
Antimetabolites/antiproliferative agents	Methotrexate	Rheumatoid arthritis, psoriasis, inflammatory bowel disease	Folate antagonism and inhibition of DNA synthesis	Human data do not show a consistent clinically important adverse effect on male fertility; isolated reports of transient semen changes exist, but persistent infertility has not been established	Usually reversible after discontinuation	[87–89, 94]
Antimetabolites/antiproliferative agents	Mycophenolate mofetil	Connective tissue diseases, systemic lupus erythematosus, vasculitis	Inhibition of inosine monophosphate dehydrogenase, with reduced T- and B-cell proliferation	Available data do not show consistent adverse effects on semen parameters or male fertility, although evidence remains limited	Probably reversible; not considered strongly gonadotoxic	[87, 88]
Thiopurines	Azathioprine, 6-mercaptopurine	Inflammatory bowel disease, connective tissue diseases, autoimmune hepatitis	Inhibition of purine synthesis and lymphocyte proliferation	No consistent negative effects on sperm parameters, fertility, or pregnancy outcomes from paternal exposure have been demonstrated	Generally considered compatible with male fertility	[87, 88, 94]
Aminosalicylates	Sulfasalazine	Inflammatory bowel disease, rheumatoid arthritis	Anti-inflammatory activity; may impair sperm maturation and function	Associated with reversible oligozoospermia, reduced sperm motility, and abnormal morphology	Reversible, usually within 2–3 months after discontinuation	[30, 87–89]
Calcineurin inhibitors	Cyclosporine, tacrolimus	Autoimmune hepatitis, myasthenia gravis, severe psoriasis, selected connective tissue diseases	Inhibition of calcineurin-dependent T-cell activation and IL-2 production	Human evidence is limited and partly conflicting; no clear major gonadotoxic effect has been consistently demonstrated	Likely reversible; clinical relevance uncertain	[87–89]
Anti-TNF biologics	Infliximab, adalimumab, etanercept, certolizumab	Inflammatory bowel disease, ankylosing spondylitis, psoriasis, psoriatic arthritis, rheumatoid arthritis	Inhibition of TNF-α-mediated inflammation	Generally reassuring safety profile. In some inflammatory diseases, semen parameters may improve when disease activity is controlled; a direct fertility-enhancing effect has not been established	Generally considered compatible with male fertility	[87, 88, 95–98]
Anti-IL biologics	Secukinumab, ustekinumab, ixekizumab	Psoriasis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease	Targeted blockade of interleukin-mediated inflammatory pathways	Limited human data; no consistent adverse effects on semen parameters have been reported	Probably reversible; evidence still limited	[87, 88]
JAK inhibitors	Tofacitinib, baricitinib, upadacitinib	Rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, selected immune-mediated diseases	Inhibition of JAK–STAT signaling pathways	Very limited data on male reproductive outcomes; no definitive conclusions can be drawn	Unknown; more evidence is needed	[87]
Colchicine	Colchicine	Behçet disease, familial Mediterranean fever, autoinflammatory disorders	Inhibition of microtubule polymerization and neutrophil activity	Possible impairment of spermatogenesis has been reported, but evidence is inconsistent and often confounded by underlying disease	Usually reversible, but clinical relevance remains uncertain	[87–89, 93]

The following sections will discuss the major autoimmune and chronic inflammatory diseases for which clinically relevant male reproductive data are available, together with treatment-related effects. Table 2 summarizes the main epidemiological and clinical evidence on the impact of these conditions on male reproductive health, including proposed pathogenic mechanisms, alterations in semen parameters and sexual function, and the potential reproductive effects of commonly used therapies. Vasculitis will be addressed separately because gonadotoxic cyclophosphamide exposure is particularly relevant to fertility preservation. Autoimmune hepatitis is retained among treatment indications in Table 1 but is not presented as a separate disease-specific fertility section because current evidence does not establish a consistent direct effect of autoimmune hepatitis itself on male fertility; the available reproductive literature is more informative for therapies such as thiopurines and calcineurin inhibitors than for disease-specific gonadal mechanisms.

Table 2.

Epidemiological and clinical impact of systemic autoimmune diseases on male fertility and sexual function

Autoimmune Disease	Prevalence	Pathogenetic Mechanism	Seminal Parameters	Effects on Sexual Life Impact	Therapies	Key References
Spondyloarthritis Ankylosing Spondylitis (AS)	0.23%	Chronic systemic inflammation, oxidative stress, hormonal alterations (increased LH/FSH, reduced testosterone), association with varicocele	Poorer sperm morphology and motility	Related to Varicocele	Anti-TNFα agents are safe and may improve semen quality and hormones by reducing inflammation	[30, 95, 96, 101–103]
Psoriasis	0.1–3%	Chronic systemic inflammation, oxidative stress, hormonal imbalance, DNA damage, dysfunction of Sertoli and Leydig cells	Alterations in sperm count, motility, and morphology	Increased risk of erectile dysfunction	Anti-TNF-alpha agents are generally considered compatible with male fertility and may improve semen quality indirectly through better inflammatory disease control; evidence for other biologics remains limited.	[87, 88, 90, 97, 98, 104–112]
Psoriatic arthritis	0.1%	Chronic systemic inflammation and oxidative stress	Increased risk of altered semen parameters	Erectile dysfunction and decreased libido	TNF inhibitors are generally considered compatible with male fertility; current evidence does not show a consistent detrimental effect of methotrexate on paternal reproductive outcomes.	[30, 87, 88, 90]
Type 1 Diabetes Mellitus	0.3–0.9%	Chronic hyperglycaemia, oxidative stress, testicular inflammation, HPG axis dysregulation, hormonal imbalance (reduced free testosterone and increased LH and PRL)	Reduced concentration, motility and viability; increased DNA fragmentation and apoptosis	Higher prevalence of erectile dysfunction and retrograde ejaculation.	Adequate glycaemic control and insulin therapy may partially improve testicular function	[113–119]
Multiple Sclerosis	0.05–0.1%	Neurological disability and psychological factors	Increased risk of altered semen parameters	High prevalence of erectile dysfunction, anejaculation, and reduced libido	Cytotoxic therapies (mitoxantrone, cyclophosphamide) may impair spermatogenesis; first-line therapies (natalizumab, ocrelizumab) are safe	[28, 120–123]
Systemic Lupus Erythematosus (SLE)	0.01%	Vascular involvement, chronic inflammation, psychological factors, hormonal impairment (elevated FSH/LH, reduced testosterone).	Reduced sperm count and quality; increased DNA fragmentation.	Increased risk of erectile dysfunction.	Cyclophosphamide causes gonadal toxicity; azathioprine, methotrexate, and mycophenolate mofetil have limited impact.	[27, 87, 89, 90, 124, 125]
Antiphospholipid syndrome	< 0.01%	Thrombotic events affecting the testicular vasculature, potentially leading to testicular infarction.	Impaired spermatogenesis.	Erectile dysfunction in some studies	Not defined	[29, 126–128]
Systemic sclerosis	0.006%	Related to vascular involvement	No significant alterations consistently documented.	High prevalence of erectile dysfunction.	Exposure to cyclophosphamide can impair spermatogenesis.	[87, 89, 99, 129, 130]
Rheumatoid Arthritis	0.12%	Chronic systemic inflammation affecting HPG axis; hormonal impairment (elevated FSH/LH, reduced testosterone)	Reduced sperm motility and count	Erectile dysfunction and decreased libido	Methotrexate and sulfasalazine may affect spermatogenesis (often reversible)	[29, 87–90, 99–101, 131]
Autoimmune Thyroiditis	TPOAb positivity 11%, Ultrasound evidence 4–5%.	Overt thyroid dysfunction alters hormones (testosterone and SHBG)	Associated with pathozoospermia and asthenozoospermia;	Modulated primarily by hormonal imbalance	Levothyroxine substitution is safe	[132–137]
Celiac Disease	0.4–0.6%.	Could impair gonadal function	Reduced motility and led to abnormal morphology in older studies; normal fertility rates in modern cohorts.	Sexual dysfunction reported in older studies.	Gluten free diet may help restore fertility	[90, 138–140]
Myasthenia gravis	0.02%	Psychosocial factors	Not reported	Erectile dysfunction and decreased libido	Acetylcholinesterase inhibitors and immunosuppressive agents are safe.	[87–89, 141, 142]
Sjögren’s disease	0.02%	Chronic inflammation and autoimmune-mediated testicular involvement.	Impaired spermatogenesis.	Not reported	Exposure to cyclophosphamide can impair spermatogenesis.	[82]
Behçet’s disease	< 0.01%	Epididymitis, epididymo-orchitis, and varicocele.	Impaired spermatogenesis.	Not reported	Exposure to cyclophosphamide can impair spermatogenesis.	[29, 87, 89, 93, 143]
Inflammatory Bowel Diseases	0.3%	Chronic systemic inflammation, increased oxidative stress; lower testosterone in severe disease	Reduced concentration, motility, and normal morphology; increased DNA fragmentation	Erectile or ejaculatory disorders	Sulfasalazine causes reversible male infertility; biologics, thiopurines, and methotrexate are generally safe	[87, 90, 144–148]
Systemic vasculitis	Disease-dependent	Systemic inflammation; reproductive risk is often dominated by treatment exposure rather than a uniform direct gonadal mechanism	Disease-specific semen data are limited; cyclophosphamide can cause oligozoospermia or azoospermia	May be affected by systemic disease burden	Sperm cryopreservation should be offered before cyclophosphamide when feasible; minimize cumulative gonadotoxic exposure	[52, 87–89, 99]

Rheumatoid arthritis. The prevalence of rheumatoid arthritis (RA) is approximately 120 cases per 100,000, with a global female-to-male ratio of about 2.5:1 [100]. RA has been associated with an increased risk of male infertility through several interrelated mechanisms. Chronic systemic inflammation plays a central role and may negatively affect the hypothalamic–pituitary–gonadal axis, leading to hormonal alterations that can impair reproductive function. In particular, men with RA exhibit elevated levels of FSH and LH, together with reduced testosterone levels, suggesting a degree of testicular dysfunction and altered spermatogenesis [29, 131]. Alterations in semen parameters have also been described in men with RA. These include reduced sperm motility and decreased sperm count, although such abnormalities appear to occur less frequently compared with other rheumatic diseases [29]. Sexual dysfunction also contributes significantly to reduced fertility in these patients, being around 3 times higher than among men without RA. Erectile dysfunction and decreased libido are common and may be related to chronic pain, fatigue, psychological distress, vascular impairment, and the systemic inflammatory state associated with the disease. Interestingly, this association appears stronger in males younger than 45 years than in those older and in patients with longer disease duration [131]. In addition to disease-related factors, pharmacological treatments used in RA may influence male reproductive function. Treatment of RA may harm sexual function, causing reduced sexual desire and depressed mood. Drugs such as methotrexate and sulfasalazine have been reported to affect spermatogenesis in some patients [90]. Despite that, the effect is reversible, and discontinuation of these drugs is not recommended in male patients planning to conceive. Similarly, anti-TNF, anti-IL6, and anti-CD20 biologic drugs can be continued. On the other hand, insufficient data are available for other biologics such as JAK inhibitors [88].

Spondyloarthritis. Spondyloarthritis (SpA) is a group of chronic inflammatory diseases that mainly affect axial parts of the skeleton, resulting in persistent inflammatory back pain and stiffness, as well as peripheral arthritis. The disease typically begins before the age of 40 [102, 103] and the axial involvement is more common and severe in men, with a prevalence of approximately 0.23% and a male-to-female ratio of 2–3:1 [102, 103]. The relationship between SpA and male infertility is still debated. Researchers continue to investigate the possible links between these two conditions. Available epidemiological data do not consistently show a higher prevalence of infertility among men with SpA compared to the general population. However, several disease-related mechanisms could potentially influence male reproductive function. Chronic systemic inflammation may impair testicular physiology through pro-inflammatory cytokines and oxidative stress. This can negatively affect spermatogenesis and sperm motility. Some studies have reported hormonal alterations. These include elevated FSH and LH levels, as well as reduced testosterone levels, particularly in patients with higher disease activity [102, 103]. In addition, varicocele appears to occur more frequently in men with ankylosing spondylitis. This condition has been associated with poorer sperm morphology and may contribute to subfertility [95]. Among SpA treatments, sulfasalazine is associated with reversible impairment of semen parameters, including reduced sperm count, motility and morphology, whereas current evidence suggests that anti-TNFα therapies do not adversely affect semen quality. These therapies may even help normalize hormonal parameters [30, 96] although, overall, a clear increase in infertility has not been consistently established.

Psoriasis and psoriatic arthritis. Skin psoriasis affects approximately 3% of men in the United States, with a prevalence similar to what is observed in women. Globally, prevalence varies widely depending on geographic region and ethnicity, ranging from about 0.1% in some Asian populations to 1.5–3% in Northern Europe and Scandinavia [104, 105]. Current evidence suggests that psoriasis may adversely affect male reproductive and sexual health, likely through systemic inflammation, hormonal alterations, and associated psychosocial factors [90, 106–109]. Epidemiological and case-control studies have reported impaired semen quality and a higher burden of sexual dysfunction in men with psoriasis [107–109]. Psoriasis has been associated with alterations in semen parameters, including sperm count, motility, and morphology [107], as well as an increased risk of erectile dysfunction [108, 109].

Sexual dysfunction is relatively common among men with psoriasis, although reported prevalence varies considerably among studies [108–110]. Sperm alterations have also been associated with ultrasound evidence of accessory gland inflammation and increased levels of inflammatory markers, including soluble urokinase plasminogen activator receptor (suPAR), in seminal fluid [107]. Hormonal disturbances, including alterations in testosterone and estradiol levels, may further contribute to gonadal dysfunction [111, 112]. Chronic inflammation associated with psoriasis may negatively affect male reproductive function [90, 106, 107].

The severity and clinical activity of psoriasis may correlate with reproductive abnormalities. Higher disease activity has been associated with impaired semen parameters and inflammatory changes in the male genital tract [107], whereas alterations in sex hormones have also been correlated with the Psoriasis Area and Severity Index (PASI) [112]. Pro-inflammatory and immunometabolic pathways have been proposed to link psoriasis with abnormal sperm phenotypes through inflammatory mediators, oxidative stress, and metabolic alterations [90, 106, 107]. Mendelian-randomization analyses also suggest a possible causal relationship between psoriasis and male reproductive abnormalities, although the identified inflammatory and metabolic mediators require further biological and clinical validation [106].

Similar to skin disease, in psoriatic arthritis fertility may be influenced by both disease-related and treatment-related factors. Chronic systemic inflammation may adversely affect male reproductive function, although disease-specific semen data in psoriatic arthritis remain limited [30, 90]. Most commonly used therapies, including TNF inhibitors and methotrexate, have not demonstrated a consistent detrimental effect on paternal reproductive outcomes [87, 88, 90]. Studies in men with psoriasis receiving TNF-α inhibitors have generally shown reassuring reproductive safety and, in some cohorts, improvement in semen parameters or hormonal profiles after control of systemic inflammation [97, 98]. Consequently, anti-TNFα therapy appears compatible with male fertility, although a direct fertility-enhancing effect has not been established [87, 88, 97, 98]. Data remain substantially more limited for other targeted biologic agents, including IL-17- and IL-23-directed therapies [87, 88, 90].

Systemic Lupus Erythematosus. Systemic lupus erythematosus (SLE) is predominantly a disease of women, with a female-to-male ratio of approximately 9:1 [149]. However, when it occurs in males, it may present with more severe clinical manifestations [124]. Men with SLE have been reported to exhibit an increased risk of sexual dysfunction, particularly erectile dysfunction, with an OR of 7.4 versus controls. This may be related to vascular involvement, chronic inflammation, psychological factors, and the overall burden of the systemic disease [27]. In addition, endocrine alterations have been described, including elevated levels of FSH and LH, suggesting a degree of testicular dysfunction and impaired spermatogenesis [27]. Testicular hypofunction and reduced testosterone levels have been reported more frequently in men with SLE compared with the general population, further supporting the presence of endocrine and reproductive alterations associated with the disease [124]. Semen abnormalities have also been reported in male patients with SLE. These may include reduced sperm count and impaired sperm quality, potentially reflecting both systemic inflammatory processes and immune-mediated mechanisms affecting the male reproductive tract. Further, increased sperm DNA fragmentation has been documented in some patients, which may negatively affect fertility even in the absence of significant alterations in conventional semen parameters [27, 125]. Pharmacological treatments used in SLE may further contribute to reproductive impairment. In particular, cyclophosphamide is well recognized to cause dose-dependent gonadotoxicity and may lead to prolonged or irreversible impairment of spermatogenesis. The risk of persistent oligozoospermia or azoospermia increases with cumulative exposure, but reproductive recovery varies according to age at exposure, treatment regimen, concomitant gonadotoxic therapies, and duration of follow-up. A cumulative dose of ≥ 4,000 mg/m² has been associated with a high risk of permanent azoospermia, whereas doses < 4,000 mg/m² are associated with a lower risk of infertility [88, 91]; however, a single cumulative-dose threshold should not be interpreted as uniformly predictive of permanent azoospermia. Further, mice models have shown male-mediated teratogenicity, but the few data on pregnancy outcome in humans do not allow firm conclusions to be drawn. Male patients should be counselled about fertility preservation before starting treatment. Specifically, sperm cryopreservation should be discussed and offered before treatment begins and, when feasible, cyclophosphamide should be discontinued at least 3 months before attempting conception. In contrast, other immunosuppressive therapies commonly used in SLE, including azathioprine, methotrexate, and mycophenolate mofetil, appear to have a more limited impact on male fertility and can be continued during attempts at conception [86–88, 90, 91, 94, 99].

Antiphospholipid antibody syndrome. As for SLE, the prevalence of antiphospholipid syndrome (APS) is around 50 per 100,000 in females and 10 per 100,000 in males [126]. The relationship between APS and male infertility remains unclear and insufficiently defined. Some papers suggest that antiphospholipid antibodies may contribute to male reproductive dysfunction by inducing thrombotic events in the testicular vasculature, potentially leading to testicular infarction and impaired spermatogenesis. However, evidence is limited to isolated cases, and population studies have not consistently confirmed an association [127, 128].

Systemic sclerosis and inflammatory myositis. The prevalence of systemic sclerosis in male patients is significantly lower than in females, with a female-to-male ratio ranging between 5:1 and 8:1 [129]. In men, this disease is characterized by a high prevalence of sexual dysfunction, particularly erectile dysfunction, which may significantly compromise reproductive capacity [130]. A cross-sectional study has reported a prevalence of erectile dysfunction of up to 88%, often with moderate to severe severity and strongly associated with disease duration, disease severity, and increasing age [129, 130]. However, systematic data on the prevalence of male infertility specifically in systemic sclerosis are lacking, and no studies have consistently documented significant alterations in semen parameters in affected men. There is no clear evidence of a consistent impairment of male fertility in inflammatory myositis. Chronic inflammation and oxidative stress associated with inflammatory myopathies may, in theory, affect reproductive function, although this association has not been confirmed by specific clinical studies. However, cytotoxic therapies used in the treatment of connective tissue diseases, particularly cyclophosphamide, may result in gonadal toxicity and impaired spermatogenesis. Therefore, the fertility preservation strategies described for patients with SLE also apply to these individuals [89].

Sjögren’s disease. The prevalence of male infertility in Sjögren’s disease has not been systematically quantified. Although chronic inflammation and autoimmune-mediated testicular involvement may impair reproductive function, the impact of the disease on male fertility remains unclear and warrants further investigation [82].

Behçet disease. Current evidence does not indicate an increased risk of male infertility in patients with Behçet’s disease [143]. Although urogenital manifestations such as epididymitis, epididymo-orchitis, and varicocele may occur more frequently in affected men and could theoretically impact testicular function, impaired fertility has mainly been reported in cases exposed to gonadotoxic treatments, particularly cyclophosphamide [93, 113].

Systemic vasculitis. Disease-specific data on male infertility are heterogeneous across the vasculitides, but reproductive counseling is particularly important because cyclophosphamide remains a treatment option for severe organ- or life-threatening disease. The major established reproductive risk is treatment-related rather than a uniform direct effect of vasculitis on spermatogenesis. Cyclophosphamide can damage spermatogonial stem cells and may cause persistent oligozoospermia or azoospermia in a dose-dependent manner; therefore, sperm cryopreservation should be offered before treatment whenever feasible, and conception should generally be deferred until recovery after exposure [87, 88, 90, 99]. Where disease control can be achieved with non-gonadotoxic regimens, minimizing cumulative cyclophosphamide exposure is an important reproductive consideration. These data also explain why vasculitis appears among the indications in Table 1 despite the limited disease-specific semen literature.

Type 1 diabetes mellitus. Type 1 diabetes mellitus (T1DM) is a relatively common autoimmune disease, with a global prevalence between 0.3% and 0.9% in adults. Epidemiological studies indicate a modest male predominance, particularly after puberty, with reported male-to-female ratios ranging from approximately 1.3:1 to 2:1 [114]. Current evidence suggests that T1DM represents an independent risk factor for male infertility, through a combination of metabolic, inflammatory, and endocrine mechanisms [114]. T1DM has been associated with impaired male reproductive function, as supported by clinical, epidemiological, and experimental evidence [114–117]. Both human and animal studies have reported alterations in semen quality in men with T1DM, including reduced sperm concentration, motility, and viability, together with increased sperm DNA fragmentation and apoptosis. Several pathophysiological mechanisms have been proposed to explain these alterations, including chronic hyperglycemia, oxidative stress, testicular inflammation mediated by cytokines such as TNF-α and the NLRP3 inflammasome, and disruption of steroidogenesis. In addition, damage to Leydig cells and dysregulation of the hypothalamic–pituitary–gonadal axis may further contribute to gonadal dysfunction [118, 119]. Clinically, men with T1DM may also exhibit hormonal alterations, such as reduced free testosterone and increased LH and prolactin levels, as well as a higher prevalence of sexual dysfunction, including erectile dysfunction and retrograde ejaculation [114, 115]. Although adequate glycemic control and insulin therapy may partially improve testicular function, fertility parameters are not always fully restored [117, 119].

Myasthenia gravis. Direct disease-specific evidence on male fertility in myasthenia gravis is limited. Affected men may experience sexual dysfunction, including erectile dysfunction and decreased libido, which appears to be associated mainly with age, psychological factors, and disease-related burden rather than with a demonstrated direct impairment of spermatogenesis [141]. Conventional treatment includes acetylcholinesterase inhibitors and, when required, immunosuppressive therapies [142]. The reproductive safety of immunosuppressive treatment is drug-dependent; most commonly used non-cytotoxic agents are generally considered compatible with paternal conception, whereas gonadotoxic agents such as cyclophosphamide require specific fertility counseling [87–89].

Multiple sclerosis. Multiple sclerosis is an autoimmune disease that mainly affects females and, according to the most recent epidemiological data, the prevalence in men is significantly lower than in women, with a female-to-male ratio of approximately 3:1 worldwide. The prevalence in the male population generally ranges between 50 and 100 cases per 100,000 individuals [120, 121]. The relationship between multiple sclerosis and male infertility is complex and multifactorial. Male fertility may be impaired mainly as a consequence of sexual dysfunction such as erectile dysfunction, anejaculation, and reduced libido and, to a lesser extent, through direct alterations in semen parameters. Sexual dysfunction is common in patients with multiple sclerosis, with a reported prevalence ranging from 35% to 72%, and is associated with both neurological disability and psychological conditions such as depression [122]. Recent genetic studies and Mendelian randomization analyses imply a possible causal relationship between multiple sclerosis and sperm abnormalities, indicating an increased risk of altered semen parameters in male patients [123]. Some medications used in the treatment of multiple sclerosis, particularly cytotoxic therapies such as mitoxantrone and cyclophosphamide, may impair spermatogenesis, other therapies such as natalizumab and ocrelizumab have not shown negative effects on male fertility [122].

Autoimmune thyroiditis. Although less common than in women, autoimmune thyroiditis remains relatively frequent in men, with epidemiological studies reporting thyroid autoantibody positivity in approximately 11% of adult males and ultrasound evidence of autoimmune thyroiditis in about 4–5% [132]. The relationship between autoimmune thyroiditis and male infertility remains a subject of debate. Current evidence suggests that the presence of thyroid autoantibodies, particularly anti-thyroid peroxidase antibodies, may be associated with alterations in semen parameters, including pathozoospermia and asthenozoospermia [133, 134]. However, a clear and consistent impact on overall male fertility has not been firmly established. Thyroid dysfunction itself, including both hypothyroidism and hyperthyroidism, is known to negatively affect male reproductive function by impairing spermatogenesis, reducing sperm motility, and altering hormonal balance, particularly testosterone and sex hormone-binding globulin levels [135, 136]. In contrast, autoimmune thyroiditis in the absence of clinically significant thyroid dysfunction appears to have a more limited effect on male fertility [137].

Celiac disease. Celiac disease has a prevalence of approximately 0.4–0.6% in men, lower than in women, but still clinically relevant and often underdiagnosed [138]. The association between celiac disease and male infertility appears to be weak. Old studies have reported that untreated celiac disease may be associated with alterations in male reproductive function, including impaired gonadal function, sexual dysfunction, and abnormalities in semen parameters such as reduced sperm motility and abnormal morphology [139]. However, large population-based studies have not demonstrated a higher prevalence of infertility among men with celiac disease compared with the general population. In fact, men with a confirmed diagnosis of celiac disease generally show normal fertility rates when compared with healthy controls [140].

Inflammatory bowel diseases. Men with inflammatory bowel diseases (IBD) appear to have slightly reduced fertility compared with the general population, with epidemiological studies reporting a modest but statistically significant decrease in birth rates and progression to subsequent paternity [144]. The reduction in reproductive outcomes reported in men with IBD is more pronounced in patients with active disease and may also be influenced by treatment burden, abdominal or pelvic surgery, and sexual dysfunction, including erectile or ejaculatory disorders [144, 145]. Semen quality may also be impaired, particularly in patients with active or severe disease. Studies have reported reduced sperm concentration, motility, and normal morphology, together with increased oxidative stress and sperm DNA fragmentation [146, 147]. Greater disease severity has specifically been associated with poorer semen parameters and lower testosterone levels, supporting a relationship between inflammatory disease burden and impaired male reproductive function [146]. Treatment-related effects are drug-specific also in IBD. Sulfasalazine is associated with reversible impairment of spermatogenesis, whereas paternal exposure to biologic agents, thiopurines, and methotrexate has not been associated with clinically relevant adverse effects on semen parameters, fertility, or pregnancy outcomes [87, 94, 148]. The adverse effects of sulfasalazine on semen quality are generally reversible after discontinuation, with recovery typically occurring within approximately three months [87, 148].

Chronic Inflammation and Inflammaging as Distinct but Convergent Pathways in Male Infertility

Autoimmunity, chronic inflammation, and inflammaging overlap biologically but should not be considered interchangeable. Autoimmunity is characterized by loss of tolerance to self-antigens and adaptive immune responses directed against specific tissues or molecular targets [150]. Chronic inflammation is a broader state that may occur with autoimmune disease, infection, obesity, metabolic disease, or other persistent stimuli. Inflammaging refers specifically to the age-associated, low-grade, systemic inflammatory state that develops in parallel with immunosenescence and does not require classical autoantigen-specific autoimmunity [151]. These processes can nevertheless converge on the male reproductive system through shared downstream mechanisms, including oxidative stress, inflammatory signaling, altered immune-cell phenotypes, impaired Sertoli-cell barrier function, Leydig-cell dysfunction, and disruption of endocrine homeostasis [49, 151, 152]. This distinction is important clinically: treatment of a defined autoimmune disease aims primarily at disease control and prevention of therapy-related gonadotoxicity, whereas no established fertility-directed immunomodulatory treatment currently exists for inflammaging itself.

Ageing is accompanied by inflammatory and cellular remodeling of the testicular microenvironment. Ageing testes show alterations in germ cells, Sertoli cells, Leydig cells, and the surrounding niche, together with inflammatory and senescence-associated changes that may impair spermatogenic support and blood-testis barrier integrity [49, 152]. Exposure of normally sequestered germ-cell antigens could theoretically facilitate secondary immune activation, but this should be distinguished from primary autoimmune orchitis. More broadly, age-related immune dysregulation and persistent low-grade inflammation support the concept of reproductive immunosenescence [151, 152].

Inflammation and oxidative stress can reinforce one another. Persistent inflammatory signaling can increase reactive oxygen species, whereas oxidative stress may activate additional inflammatory pathways, including NF-kappaB and inflammasome-dependent responses [40–42, 49]. This feed-forward interaction may promote oxidative and mitochondrial damage and thereby compromise sperm and testicular function [49, 152]. Leydig cells are particularly relevant because inflammatory and metabolic stress may impair steroidogenic function [49, 152]. Clinically, late-onset hypogonadism and symptomatic androgen deficiency become increasingly relevant with advancing age [153]. Reduced androgenic support may in turn adversely affect Sertoli-cell function and spermatogenic efficiency [152]. Multi-omics and single-cell studies of ageing testes have identified transcriptional, epigenetic, metabolic, and proteomic alterations affecting both germ-cell and somatic compartments, supporting a model in which reproductive ageing reflects intrinsic cellular ageing together with deterioration of the testicular niche [152].

Metabolic inflammation may accelerate this process. Obesity, insulin resistance, and type 2 diabetes are associated with chronic low-grade systemic inflammation and with dysregulation of inflammatory and nutrient-sensing pathways, including NF-kappaB, mTOR, HIF-1alpha, AMPK, and SIRT1, thereby promoting oxidative and metabolic stress and potentially impairing steroidogenic and spermatogenic function [49]. Importantly, these mechanisms are not specific to autoimmunity and should be interpreted as convergent inflammatory pathways. In men with established autoimmune disease, ageing, metabolic comorbidity, persistent disease activity, and exposure to gonadotoxic therapy may therefore accumulate rather than represent a single unified mechanism [87, 90, 151, 152].

Human evidence directly connecting immunosenescence with infertility is still emerging. Immunophenotyping studies have identified T-cell exhaustion and senescence-associated signatures in specific forms of male infertility, supporting an association between reproductive dysfunction and immune-ageing phenotypes [154]. These observations should currently be regarded as mechanistic and hypothesis-generating rather than diagnostic: these immune-ageing signatures have not yet been validated for routine infertility assessment, and prospective studies are required to determine whether they predict reproductive outcomes or treatment response [154].

In patients with chronic autoimmune diseases, disease-related inflammation, ageing, comorbidities, and potentially gonadotoxic treatments may create a cumulative reproductive burden (Fig. 2). Male fertility should therefore be considered within an age-sensitive framework that separates disease-specific autoimmunity from broader chronic inflammation and inflammaging while recognizing their convergent effects on oxidative stress, endocrine function, immune regulation, and testicular homeostasis [49, 87, 90, 151–154].

Fig. 2.

Overview of the mechanisms linking chronic systemic inflammation to male reproductive impairment. Ageing, metabolic disorders, chronic diseases, and adverse lifestyle factors promote a state of persistent low-grade systemic inflammation. Pro-inflammatory mediators can suppress hypothalamic gonadotropin-releasing hormone (GnRH) secretion, thereby reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) output and impairing downstream testicular steroidogenesis. In parallel, inflammatory cytokines directly compromise Leydig and Sertoli cell function, disrupt blood-testis barrier (BTB) integrity, and contribute to immune dysregulation within the testicular microenvironment. These processes converge on a self-sustaining oxidative-inflammatory loop involving nuclear factor kappa B (NF-κB) and inflammasome signaling: cytokine-driven reactive oxygen species (ROS) generation activates NF-κB and inflammasome pathways, which further enhance inflammatory mediator release and ROS production. Persistent oxidative and inflammatory stress damages sperm membranes, structural components, and DNA, leading to abnormal morphology, reduced motility, increased sperm DNA fragmentation, and ultimately impaired fertilizing capacity. GnRH gonadotropin-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, BTB blood-testis barrier, ROS reactive oxygen species, NF-κB nuclear factor kappa B “Icons from BioIcons (bioicons.com), licensed under CC0.” and “Adapted from SMART (Servier Medical Art), CC BY 3.0.”

Clinical Decision Framework for Immune-Related Male Infertility

A practical approach should begin with the standard male-infertility evaluation rather than indiscriminate immune testing. First, assess conventional causes of infertility, semen parameters, reproductive hormones, medical history, medications, and sexual function. Second, consider targeted immune evaluation when clinical context raises specific suspicion: previous vasectomy or reproductive-tract surgery, testicular trauma, orchitis/epididymitis, marked sperm agglutination, or otherwise unexplained infertility may justify discussion of ASA testing, while recognizing that AUA/ASRM guidelines do not recommend ASA testing as part of the routine initial evaluation [59]. Third, refer for rheumatologic or other specialist assessment when infertility coexists with symptoms, examination findings, or laboratory abnormalities suggestive of systemic autoimmune disease rather than screening asymptomatic men with broad autoantibody panels. Fourth, before cyclophosphamide or other clearly gonadotoxic therapy, discuss fertility preservation and offer sperm cryopreservation whenever feasible [89, 90]. Finally, treatment should prioritize control of the underlying inflammatory disease with the least gonadotoxic effective regimen; ART, including IUI, IVF, or ICSI, should be selected according to the couple’s complete reproductive profile rather than immune markers alone. This framework is intended to organize current evidence and guideline principles and is not a validated prediction algorithm.

Clinical Trials and Translational Evidence

Clinical intervention data remain substantially less mature than the mechanistic literature. Randomized trials have mainly evaluated oxidative-stress or microbiota-directed strategies in men with idiopathic or male-factor infertility rather than in patients with defined autoimmune orchitis or systemic autoimmune disease. Because randomized trials specifically enrolling men with autoimmune orchitis or systemic autoimmune disease are currently lacking, the studies summarized in Table 3 were selected as representative human interventional evidence targeting oxidative-stress and microbiota-related pathways that intersect mechanistically with chronic inflammation and inflammaging. Their inclusion is intended to illustrate the translational relevance of pathway modulation rather than to provide direct evidence for the treatment of autoimmune-related male infertility. The mixed results emphasize the need to distinguish biological plausibility from demonstrated clinical benefit: a large antioxidant trial did not improve semen parameters, sperm DNA fragmentation, or live-birth outcomes, whereas smaller probiotic/synbiotic studies reported improvements in selected semen parameters and inflammatory or oxidative-stress markers [155–157]. These studies do not establish that treating systemic autoimmunity with these interventions improves fertility, and most use surrogate semen endpoints rather than live birth.

Table 3.

Representative randomized clinical trials targeting oxidative-stress and microbiota-related pathways in idiopathic or male-factor infertility: indirect translational relevance to inflammatory mechanisms. Representative randomized clinical trials of antioxidant, probiotic, and synbiotic strategies relevant to inflammatory or oxidative pathways in male infertility are summarized, including study design, clinical endpoints, principal findings, and limitations

Study	Population	Intervention	Sample size	Main endpoints	Major findings	Main limitations
NCT02421887, Steiner et al. [155]	Couples with male-factor infertility; men with abnormal semen parameters and/or DNA fragmentation	Combination antioxidant formulation vs placebo	174 randomized	Semen parameters and sperm DNA fragmentation at 3 months; pregnancy/live birth through 6 months	No significant improvement in sperm morphology, motility, DNA fragmentation, pregnancy, or live-birth outcomes; cumulative live birth 15% vs 24%.	Trial stopped after internal-pilot assessment; limited power for live birth; heterogeneous male-factor phenotypes.
IRCT20190810044500N6, Zarehoroki et al. [156]	Men with idiopathic oligoasthenoteratozoospermia	Synbiotic plus multivitamin-mineral antioxidant vs antioxidant plus placebo for 3 months	73	Semen parameters and sperm DNA fragmentation	Combination therapy improved progressive motility and DNA-fragmentation measures compared with antioxidant plus placebo.	Modest sample; no untreated placebo arm; semen surrogate endpoints; no pregnancy/live-birth endpoint.
IRCT20150420021869N5, Gholipour et al. [157]	Men with idiopathic oligoasthenoteratozoospermia	Probiotic vs antioxidant vs placebo for 3 months	110	Sperm concentration, motility, morphology, semen volume	Probiotic group showed greater improvements in concentration, motility, and morphology than placebo; some measures also favored probiotics over antioxidants.	Two-center study; surrogate semen endpoints; no live-birth endpoint; generalizability to autoimmune infertility is uncertain.

Limitations of this Review

This review has limitations inherent to its narrative design. First, study identification and selection were not conducted within a prospectively registered systematic-review protocol, creating a risk of selection bias; database-specific screening counts were not retained, and a PRISMA flow diagram cannot be reconstructed reliably. Second, much of the disease-specific literature is observational, cross-sectional, retrospective, or based on small cohorts, which limits causal inference and makes it difficult to separate effects of disease activity, comorbidity, age, sexual dysfunction, and treatment exposure. Third, studies of antisperm antibodies use heterogeneous detection methods, thresholds, sample types, and reporting standards, limiting direct comparison across cohorts and contributing to uncertainty regarding their clinical significance. Fourth, high-quality clinical evidence is particularly sparse for rare autoimmune disorders, including antiphospholipid syndrome and systemic sclerosis, for which mechanistic plausibility often exceeds the available fertility-outcome data. Fifth, vasculitis-specific fertility data are sparse, and much of the reproductive-risk discussion in systemic vasculitis is extrapolated from the broader cyclophosphamide gonadotoxicity literature shared with SLE and Behçet disease rather than from disease-specific fertility cohorts. Finally, the breadth of diseases, interventions, and reproductive endpoints precluded meaningful quantitative pooling; therefore, no meta-analysis was performed, and the strength of evidence is presented qualitatively according to study design and clinical relevance.

Conclusions

The evidence reviewed here supports immune dysregulation as a relevant but heterogeneous contributor to male reproductive dysfunction [13, 31–35]. Local breakdown of testicular immune privilege, blood-testis barrier injury, inflammatory-cell infiltration, and ASA can directly affect sperm production or function [31–35, 50–53, 55, 58], whereas systemic autoimmune diseases more often influence fertility through a combination of disease activity, endocrine disruption, sexual dysfunction, comorbidity, and treatment-related toxicity [27–30, 87, 90, 101]. The strength of evidence differs substantially across these mechanisms: ASA have direct clinical relevance [34, 35, 53, 60, 64–66], and cyclophosphamide-associated gonadotoxicity is well recognized [87, 89, 90, 93], whereas many proposed pathways involving inflammasomes, microbiota, or immune ageing remain supported predominantly by experimental, genetic, or observational data [40–48, 151–154, 158]. Autoimmunity and inflammaging should therefore be viewed as distinct processes that can converge on common downstream pathways rather than as interchangeable causes of infertility [151–154, 158].

Important knowledge gaps remain. Diagnostic methods for ASA are not fully standardized [34, 35, 59, 69], immune biomarkers have not been validated for routine infertility stratification [150, 154], prospective disease-specific cohorts are limited [27–30, 90], and interventional studies frequently focus on surrogate reproductive outcomes rather than pregnancy or live birth [34, 69, 155–157]. Clinically, evaluation should remain anchored in standard andrological assessment, with targeted immune investigation guided by history and phenotype [11, 34, 59]. Men who may receive cyclophosphamide or other gonadotoxic therapy should receive fertility counseling and sperm cryopreservation before treatment [87–91, 93]. Effective control of systemic inflammatory disease may benefit reproductive health by reducing inflammatory burden, but this should not be equated with proven fertility efficacy for every immunomodulatory agent [87, 88, 90, 99]. The emerging gut-testis and inflammaging literature provides a rationale for future mechanistic and clinical studies [43–48, 150–153, 158], but microbiome-directed or anti-inflammaging treatments cannot yet be recommended as established fertility therapies [43–48, 151–158].

Future studies should integrate reproductive phenotyping with immunology, endocrinology, and longitudinal treatment exposure, while clearly separating preclinical mechanisms from clinically validated outcomes [13, 34, 90, 150, 154]. Antigen-specific reproductive immunology may also have translational relevance beyond infertility; for example, controlled targeting of sperm antigens has been explored conceptually for immunocontraception, but this remains an experimental future direction rather than a current infertility treatment [57, 70]. Bridging reproductive medicine and immunology will be most useful when it produces reproducible biomarkers, safer fertility-preservation strategies, and interventions linked to clinically meaningful outcomes.

Author Contributions

All authors contributed to the conceptualization of the review. I.M. and F.M. wrote the first draft, V.L. prepared the figures. All authors contrib uted to critical review and revising of the manuscript. All authors reviewed and approved the final submitted manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethical Approval

Not applicable.

Competing Interests

The authors declare no competing interests.