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World J Mens Health. 2024 Oct;42(4):681-693. English.
Published online Mar 05, 2024.
https://doi.org/10.5534/wjmh.230270
Copyright © 2024 Korean Society for Sexual Medicine and Andrology
Review Article

The Role of Cells and Cytokines in Male Infertility Induced by Orchitis

Ying Xu, Wanyi Chen, Xiaoyu Wu, Kai Zhao, Chunyan Liu, and Huiping Zhang
    • Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Correspondence to: Chunyan Liu. Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Air Road, Wuhan, 430030, China. Tel/Fax: +86-27-8369-2651, Email: lchy2019@hust.edu.cn
    Correspondence to: Huiping Zhang. Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Air Road, Wuhan, 430030, China. Tel/Fax: +86-27-8369-2651, Email: zhpmed@126.com
Received September 22, 2023; Revised November 05, 2023; Accepted November 19, 2023.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

AbstractINTRODUCTIONCLASSIFICATION AND EPIDEMIOLOGY OF ORCHITISDIAGNOSIS AND TREATMENT OF ORCHITISTHE ROLE OF CELLS IN ORCHITISCYTOKINES IN ORCHITISCONCLUSION AND FUTURE PERSPECTIVESNotesAcknowledgementsReferences

Abstract

Recent studies on male infertility reveal a growing worry: more infertile men are dealing with inflammation in the testis. Analyzing testicular biopsies from infertile men highlights a significant presence of inflammation. This connection, supported by clinical and pathological evidence, emphasizes that testicular inflammation hampers sperm production, leading to lasting declines in sperm count and quality. However, the exact reasons behind male infertility due to orchitis, a type of testicular inflammation, are still uncertain. Understanding these fundamental aspects of molecular signals and cellular mechanisms in testicular inflammation is crucial. Our review delves into recent literature with a dual objective: elucidating potential mechanisms involving immune cells, non-immune cells, and cytokines that link orchitis to male infertility, while also paving the way for precise interventions and solutions to address the challenges of male infertility.

Keywords
Cytokines; Infertility, male; Inflammation; Orchitis; Reproductive health

Infertility is a common issue affecting 8% to 12% of couples globally. Of these couples, half identify male factors as either the primary or contributing cause [1], with male urogenital tract infections, particularly orchitis, emerging as a significant factor [2, 3, 4, 5, 6]. In testicular biopsies, inflammation is frequently observed in infertile men [7].

Orchitis can take two forms: acute with noticeable symptoms or chronic without apparent symptoms [3, 8, 9]. The acute variant is primarily associated with viral infections and is characterized by rare isolated cases, while the more prevalent secondary orchitis is frequently caused by ascending bacterial genital-urinary tract infections [10, 11]. Among young, sexually active men, the percentage of asymptomatic infection may be even higher [12]. It’s important to note that testis epithelium lacks regenerative capabilities, which means that infections in these organs, along with their resulting inflammatory effects, often lead to permanent damage [13]. The immune response initiates the migration of immune cells to the infection site to eradicate it. Throughout this process, various cells and cytokines play a vital role in influencing the health of the testes [5].

Within modern medicine, a substantial concern lies in understanding the connection between inflammation and infertility [14]. Whether it presents acutely or as a chronic condition, this issue warrants serious attention. Unfortunately, the exploration of mechanisms leading to inflammation in human testicles is greatly hindered by the scarcity of available tissue specimens [15]. This review is dedicated to examining the functions of immune cells as well as other somatic cells in the context of orchitis.

Compared to testis under normal condition (Fig. 1), orchitis may arise from an infectious source, typically caused by bacteria or viruses, while other cases may be non-infectious, often triggered by autoimmunity.

Fig. 1
Environment of the normal adult testis.

1. Infectious orchitis

Information gathered from male outpatient clinics indicates that the prevalence of male infertility attributed to infections varies between 6% and 15% [16, 17]. The predominant source of inflammatory conditions in the reproductive tracts of males can be primarily attributed to sexually transmitted bacteria or common urinary pathogens, leading to ascending tubular infections [18].

2. Autoimmune orchitis

Autoimmune orchitis, a variant of non-infectious orchitis, arises when the immune system launches an assault on the testicles, leading to inflammation and the generation of specific anti-sperm antibodies (ASA) [19]. Primary autoimmune orchitis, which involves autoantibodies binding to sperm surfaces, is observed in the serum or seminal plasma of 5%–12% of male partners experiencing infertility [20, 21]. This distinct form of organ-specific ailment can be classified into two categories: primary and secondary autoimmune orchitis, depending on clinical indicators and the presence or absence of recognized systemic disorders [22].

1. Infectious orchitis

Infectious orchitis typically arises following a local or systemic infection, leading to symptoms like testicular pain, redness, and swelling [22]. Managing infections and inflammation in the male reproductive system primarily relies on pharmaceutical approaches such as antibiotics and anti-inflammatory (M2) medications [23, 24] with surgical interventions being rarely necessary [25, 26]. Nevertheless, even when suitable anti-infective and microbiological treatments are administered in the initial stage of the condition, they may not completely resolve persistent inflammatory processes and significant complications in reproductive health outcomes [7]. For patients displaying manifestations of persistent infection and pertinent microbial discoveries and the administration of antibiotics may be employed following the same guidelines as for acute infection. Nevertheless, it’s crucial to highlight that antibiotics can have adverse effects on spermatogenesis and sperm parameters, leading to the accumulation of genetic mutations in germ cells and compromising the completeness of the blood-testicular barrier, which normally shields against biotoxins [27].

2. Autoimmune orchitis

Autoimmune orchitis can be categorized into two primary types: primary and secondary. Primary autoimmune orchitis is distinguished by the existence of ASA without any accompanying signs of systemic disease. In contrast, secondary autoimmune orchitis is identified by the presence of orchitis and/or testicular vasculitis, which are linked to systemic autoimmune disorders [28]. Autoimmune orchitis is often asymptomatic and may hinder specific diagnosis [22]. Detecting this condition early is crucial for effective management [29]. However, the diagnosis typically necessitates an invasive biopsy procedure [18]. The absence of non-invasive diagnostic tools further complicates the identification of silent asymptomatic testicular inflammation in humans, posing a significant obstacle to effective treatment [30]. Nonetheless, there is promise in the identification of antitesticular antibodies, as these specific antibodies may be produced during instances of chronic testicular inflammation [22]. Prior research has demonstrated some success in halting the progression of experimental autoimmune orchitis (EAO), employing various methods such as depleting testicular macrophages (TMs) [31], blocking pro-inflammatory (M1) substances [32] or administrating testosterone [33].

1. Immune cells

Testicular immune cells, primarily including macrophages, T cells, dendritic cells (DCs), and mast cells (MCs), play an essential role in preserving the testes’ physiological environment [34, 35]. However, studies have revealed that approximately 30% of asymptomatic patients with impaired fertility exhibit immune cell infiltration in the interstitial space [36]. In the EAO model, immune cells infiltrate the interstitial tissue, resulting in the generation of autoantibodies targeting testicular antigens and the production of M1 mediators, and an imbalance in steroidogenesis, resulting in decreased serum testosterone levels [30].

1) Macrophages

TMs constitute the primary subset of immune cells [37]. They primarily undergo polarization into two specific forms: M1 and M2. When an infection or inflammation reaches a point where it affects organs, macrophages initially adopt the M1 phenotype, releasing cytokines like tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12, IL-1β, and IL-23 in response to the stimulus [38, 39, 40]. If the M1 phase persists, it can result in tissue damage, Therefore, M2 macrophages play a crucial role by secreting significant amounts of IL-10 as well as transforming growth factor-beta (TGF-β), which act to dampen inflammation, facilitate tissue repair, contribute to remodeling, promote angiogenesis, and maintain internal homeostasis [41, 42]. These M2 macrophages are predominantly located near peritubular myocyte cells on the seminiferous tubules’ surface and adjacent to Leydig cells (Lc) in the testicular interstitium [43, 44, 45]. Our previous studies have demonstrated that in uropathogenic Escherichia coli (UPEC)-induced orchitis in rats, the inflammatory mediator NLRP3 becomes activated within TMs, leading to the significant production of IL-1β and the inhibition of normal testosterone synthesis [40]. This, in turn, has significant consequences, ultimately leading to infertility.

In the context of orchitis, the heightened expression of TNF triggers Sertoli cells to secrete increased levels of activin A and CCL2. This, in turn, attracts macrophages expressing CCR2 to the site of damage, where they infiltrate the inflamed testicular tissue, assuming a M1 and pro-fibrotic phenotype [46]. The nitric oxide (NO)-nitric oxide synthase system is closely associated with testicular inflammation and the compromise of testicular function. NO, primarily released by TMs, can foster oxidative stress, inflict damage on seminiferous tubules, and interfere with Lc function [47]. Recently, it was discovered in the macrophages of bull testes infected with Besnoitia besnoiti that mitogen-activated protein kinase (MAPK), cell apoptosis, and interferon (IFN)-α pathway were regulated (Fig. 2) [48].

Fig. 2
The role of testicular macrophages in male infertility caused by orchitis. In the event of testicular infection or autoimmune conditions, testicular macrophages become activated, predominantly adopting the M1 phenotype. This activation involves the activation of relevant receptors such as NLRP3, leading to the release of inflammatory mediators including TNF-α, IL-1β, and so forth. This process disrupts the BTB, resulting in oxidative stress within germ cells and subsequent impairment of spermatogenic function. Activation of NLRP3 on macrophages, coupled with NO release, promotes oxidative stress in interstitial cells, thereby causing a reduction in testosterone production. These processes likely involve cell apoptosis, the MAPK pathway, and the IFN-α pathway. In contrast, M2 macrophages can counteract inflammatory responses by secreting M2 factors. Melatonin has been shown to ameliorate these adverse effects by inhibiting the p38 MAPK pathway. TNF-α: tumor necrosis factor-alpha, IL: interleukin, BTB: blood–testis barrier, NO: nitric oxide, MAPK: mitogen-activated protein kinase, IFN-α: interferon-alpha, TGF-β: transforming growth factor-beta.

Nevertheless, melatonin exhibits the ability to inhibit the M1 cytokine secretion by TM by inhibiting the p38 MAPK pathway, concurrently promoting testosterone secretion in Lc [49].

2) T cells

It is imperative to emphasize that testicular inflammation primarily arises due to immune responses orchestrated by T cells [29]. In cases of chronic orchitis that ultimately result in infertility, T-lymphocytic infiltration was identified in more than half of the cases [50, 51].

T cells can be categorized into two primary types: αβ T cells and γδ T cells. The former mainly includes CD4+ T cells (helper T cells, Th) as well as CD8+ T cells (cytotoxic T cells), as well as memory T cells and regulatory T (Treg) cells (Fig. 3) [52]. The receptors of the latter are γδ T cell receptors, distinct from the typical αβ T cell receptors [53, 54].

Fig. 3
The roles of T cells in orchitis. Th: CD4+ T (helper T), Treg: regulatory T, IFN-γ: interferon-gamma, IL: interleukin, TGF-β: transforming growth factor-beta.

In the context of inflammation, infection, or injury affecting the testicles, T cells can generate M1 cytokines. This, in turn, may disrupt the integrity of the blood-testis barrier, facilitating the production of ASA and, consequently, impairing sperm viability [22].

(1) αβ T cells

CD4+ T cells have the capacity to differentiate into various subsets, with notable examples being Th1, Th17, and Treg cells. Among these, Th1 and Th17 subsets have a substantial impact as co-effector cells in the initiation of EAO [55]. In the early stage (8–16 weeks) of EAO, IFN-γ from Th1 cells is dominant, and transferring these cells leads to early inflammation. In the later stage (>17 weeks), Th17 cells release IL-17 and dominate, causing advanced inflammation when transferred [56].

Additionally, pathological T cells have the potential to subvert the regulatory actions of Tregs, thereby tipping the balance towards an autoimmune response and worsen autoimmune orchitis [55, 57, 58]. TGF-β may be involved in the mechanism [57]. Fijak et al [33] have discovered that in the testes of EAO rats, the addition of testosterone increases both the absolute number and proportion of Treg cells within the CD4+ lymphocyte population, thereby inhibiting the progression of chronic inflammation.

Regarding CD8+ cells, there is an observed rise in the count of CD8+ T cells during the chronic phase of EAO, although the precise mechanism behind this increase remains unclear [55].

Memory T cells are both present in CD4+ or CD8+ lineage. Apart from macrophages, T cells with a memory phenotype predominate among immune cells in the testes [35]. They possess a “memory” function, allowing them to recall previously encountered antigens and mount a rapid immune response upon reencountering the same antigen, thereby enhancing the effectiveness in combating infections [59].

The quantity of tissue-resident memory T cells significantly decreased in the testis of BATF3−/− mice, which resulted in the absence of notable inflammation in the EAO model of BATF3−/− mice. This insight suggests that the buildup of tissue-resident memory T cells is crucial in perpetuating chronic autoimmune orchitis [35].

(2) γδ T cells

Inflammatory responses in both infected and autoimmune conditions lead to the infiltration of γδ and αβ T cells within the testes. αβ T cells initiate autoaggressive reactivity [60]. However, γδ T cells play a completely opposite role. They have the capacity to produce IFN-γ, TGF-β, IL-2, IL-4, and IL-10 can serve as immune regulatory cells [53]. Removing testicular γδ T cells can substantially increase the inflammatory response in both infected and autoimmune testes [60]. The γδ T cell response did not correlate with the presence of bacteria or bacterial products [61].

3) Dendritic cells

In a typical or standard scenario, DCs are primarily located in the interstitial tissue of rat testes [62]. However, the count of DCs rises in the testes of rats with EAO [62]. In control testes, DCs remain in an immature state and exhibit tolerogenic functionality. In contrast, in testes affected by EAO, there is an upregulation of the expression of IL-12 and the proliferation of T cells, indicating a shift towards a mature immunogenic state for DCs. This transition enables DCs to migrate to the testicular lymph nodes (TLN) and enhance immune reactions directed at testicular antigens [63]. The migration process initiates as testicular DCs internalize spermatic antigens from the compromised seminiferous tubules, undergo maturation triggered by immunogenic stimuli, and then proceed to the TLN via the lymphatic system [64]. As chronic testicular inflammation progresses, the population of DCs gains the ability to migrate to the LN, facilitated by the increased CCR7 expression, thereby promoting antigen-specific T cell responses [63]. Mature DCs produce bioactive IL-12p70, which, in turn, supports an inflammatory Th1 response (Fig. 4) [65, 66].

Fig. 4
The role of dendritic cells in orchitis. Under autoimmune conditions, dendritic cells carrying sperm antigens migrate to lymph nodes, thereby activating T cells to induce antigen-specific T cell responses. Th: CD4+ T (helper T), IL: interleukin, IFN-γ: interferon-gamma.

4) Mast cells

MC originate from hematopoietic progenitor cells that express the CD34 surface marker and undergo initial differentiation occurring within the bone marrow. They subsequently migrate to specific organs, a process influenced by estrogen. In individuals with normal spermatogenesis, MCs are typically observed around blood vessels in Leydig [67]. Under normal physiological conditions, the testicular MC population remains small. However, during inflammatory activation, MCs undergo significant differentiation, resulting in a marked increase in their numbers in the testicles of individuals with testicular atrophy and infertility [62, 68]. MC tryptase can activate proteinase-activated receptor-2 (PAR2) found on peritubular cells, leading to acute testicular inflammation (Fig. 5). This pathogenic mechanism may also contribute to autoimmune orchitis [69]. A study by Moreno et al [70] showed that ketotifen fumarate reduced testicular inflammation and MC infiltrates in EAO models. It’s important to note that current research on MCs in the context of orchitis is limited, with most studies primarily focusing on fibrosis [69, 71, 72].

Fig. 5
The role of mast cells in orchitis. In cases of infection or autoimmunity, the number of mast cells increases tenfold. Mast cells undergo degranulation, releasing proteases that activate PAR2 on surrounding cells. This activation leads to the release of TGF-β2 and MCP-1, resulting in the disruption of the seminiferous tubules and peritubular fibrosis. PAR2: protease-activated receptor-2, TGF-β2: transforming growth factor-beta 2, MAPK: mitogen-activated protein kinase.

2. Role of other testicular cells in orchitis

1) Leydig cell

Lc, situated in the interstitial space between seminiferous tubules within the testis, are responsible for producing approximately 95% of testosterone in males. This hormone is crucial for male sexual differentiation, spermatogenesis, and the maintenance of secondary male sexual characteristics [73]. These cells make up the majority of cells in the testicular interstitium, are responsible for initiating innate immunity by activating toll-like receptors (TLRs). In mice, Lc express several TLRs, with TLR3 and TLR4 being the most highly expressed. These receptors can be activated by their agonists, namely polyinositol: polycytidylate and lipopolysaccharide (LPS). Upon activation, they induce the production of inflammatory cytokines such as IL-6, IL-1β, IFN-α, IFN-β, and TNF-α [74, 75, 76]. Fijak et al [33] found that testosterone directly inhibits the production of TNF-α, IL-6, and MCP-1 induced by LPS in vitro. When high doses of recombinant IL-18 were introduced to the Lc line, emulating the levels typically seen in inflammation, FADD mRNA, Fas protein and TNF-α mRNA were upregulated. These changes promoted the cleavage of caspase-3 and caspase-8, ultimately inducing apoptosis of Lc line [77]. Recently, research has discovered that the type 1 parathyroid hormone receptor (PTH1R) and its agonists, PTH and PTHrP (parathyroid hormone-related protein), are present in Lc within the testes (Fig. 6).

Fig. 6
The role of Sertoli cells and Leydig cells in orchitis. Sertoli cells closely adhere to neighboring supporting cells, forming the BTB, effectively shielding germ cells from immune system attacks. In inflammatory conditions, TLRs in Sertoli cells and Leydig cells are activated, leading to the production of various pro-inflammatory molecules and the degradation of the CAR, thus resulting in disruption of BTB integrity, Leydig cells apoptosis and less testosterone production. The activation of PTH1R on Leydig cells can inhibit the aforementioned inflammatory response. TLR: Toll-like receptor, PTH1R: type 1 parathyroid hormone receptor, IL: interleukin, TNF-α: tumor necrosis factor-alpha, BTB: blood-testis barrier, IFN-γ: interferon-gamma, CAR: coxsackievirus and adenovirus receptor.

Inflammation induced by mumps virus or LPS downregulates PTH1R through Gq and β-arrestin-1 pathway in the testes. Targeting PTH1R may have therapeutic effects on testicular inflammation [78].

2) Sertoli cell

Sertoli cells’ exclusive presence in the seminiferous tubules’ lumen enables them to establish direct contact with spermatogenic cells. Moreover, they closely adhere to adjacent Sertoli cells to create the blood-testis barrier (BTB), which effectively provide a protective shield for germ cells to keep them separate from the immune system and nurtures a supportive biochemical milieu for their growth and development [79, 80, 81]. Several TLRs have been detected within Sertoli cells and can be activated to produce a diverse range of M1 substances like TNF-α, IL-6, IL-1β, as well as type I IFNs (α and β) [82]. Inflammatory cytokines stimulate oxidative stress within Sertoli cells and destroy the integrity of BTB, which was proved in orchitis caused by Brucellosis [83], EAO rats [84]. Study found that inflammatory cytokines like IFN-γ and TNF-α promote Coxsackievirus and adenovirus receptor (CAR) which is a cell adhesion molecule expressed on the surface of Sertoli cells protein degradation and repress CAR gene transcription, leading to disrupted BTB and testicular inflammation (Fig. 6) [85].

1. Pro-inflammatory cytokines

1) TNF-α

TNF-α in the testis is generated by TMs, round spermatids, pachytene spermatocytes [86] and Sertoli cells [87]. In conditions of inflammation, M1 macrophages in the testis can produce elevated levels of TNF-α. Excessive TNF-α production can have several detrimental effects, including the potential to disrupt Lc function, influence germ cell apoptosis, and compromise the integrity of the BTB. This disruption can create an environment where bacterial cells come into contact with cytotoxic inflammatory cytokines, ultimately hampering spermatogenesis in the long term [38, 39]. Stimulating TMs with polyinosinic-polycytidylic acid or LPS activates the AP-1, MAPK, and CREB signaling pathways, consequently triggering the generation of M1 substances like TNF-α [88]. TNF-α is also involved in germ cell apoptosis, interacting with local factors like Fas-FasL, and it participates in inhibiting Lc steroid production in the context of EAO [89, 90, 91]. Yule and Tung [92] have reported that the administration of a TNF neutralizing antibody can counteract the effects of EAO.

2) IL-1, IL-6, and IL-17

IL-1 is a proinflammatory cytokine with important roles in innate immunity. It comprises two distinct agonist proteins, namely IL-1α and IL-1β [93, 94]. Cells within the adult mammalian testis consistently produce IL-1α [94, 95] along with its counterpart, the IL-1 receptor antagonist (IL-1Ra) [96]. However, under normal physiological conditions, IL-1β is notably absent, and the presence of its transcripts in the testis is barely detectable [93, 94]. In inflammatory conditions, IL-1β molecules are predominantly present in the interstitial compartment and are secreted by TMs [45] and Sertoli cells [97]. In a rat orchitis model induced by UPEC infection, the expression of PK2 in TMs leads to an elevation in CaSR levels, enhancing IL-1β secretion by activating the NLRP3 inflammasome pathway [40, 45]. In the ureaplasma urealyticum-induced model, the expression of IL-1α and IL-6 is significantly increased, playing an M1 role [98].

As M1 factors, IL-6 and IL-17 are upregulated in testicular inflammation. Sertoli cells constitute an important source of IL-6 within the testis [98]. IL-1 generated by Sertoli cells in response to LPS or residual bodies stimulates the production of IL-6 via the lipoxygenase pathway [97]. An increase number of IL-17+CD4 T cells was observed in EAO rat models [63].

3) IFN-γ

Th1 cells serve as the primary cellular source of IFN-γ, and IFN-γ expression is up-regulated in EAO models [56]. Although somewhat controversial, most research findings are in alignment concerning the involvement of p38 MAPK in both IFN-γ production and Th1 differentiation [99]. Signaling through histamine receptor H1 (H1R) may result in p38 MAPK activation in CD4+ T cells via classical or alternative pathways, ultimately leading to the production of IFN-γ [100].

2. Anti-inflammatory cytokines

1) IL-10

An expression of IL-10 in DCs isolated from the testes were observed in EAO rat models [63]. In initial validation using single-cell RNA sequencing and the Human Protein Atlas (HPA) online database, elevated levels of IL-10 expression were detected in TMs from nonobstructive azoospermia patients, indicating a weakened inflammatory response [101]. The elevated expression of IL-10 may be due to its negative regulatory role in inflammation condition.

2) TGF-β

TGF-β is primarily released by Sertoli cells, spermatocytes, and round spermatids within the seminiferous epithelium. Its receptor is present on both Sertoli cells and germ cells [102]. TGF-β family includes TGF-β1, TGF-β2, and TGF-β3 three different members. TGF-β1 is the most important member in physiological repair and collagen accumulation during inflammation and fibrosis [103]. It helps maintain a balance between M1 and M2 effects by limiting the growth of immune precursor cells [104]. The role of TGF-β in Sertoli cells, both in vivo and in vitro, tends to lean towards being a negative regulator of immune responses [98]. However, there is limited research on TGF-β in orchitis, and its role in this disease needs to be further explored (Table 1) [45, 53, 63, 86, 89, 97, 98, 102, 105, 106, 107, 108, 109, 110].

Table 1
Summary of cytokines reported in testis in human and animal models of orchitis

To translate the current understanding of orchitis mechanisms into clinical treatment, it is imperative to gain further insight into the roles of cells and cytokines in the testis under both physiological and pathological conditions and to implement targeted interventions.

While previous research has focused on the functions of individual immune cells in testicular inflammation or the impact of cytokines in orchitis, a comprehensive review examining the intricate interplay among immune cells, non-immune cells, and cytokines in testicular inflammation is notably absent. This paper aims to fill this gap by conducting a comprehensive literature review in these areas.

In this review, we have elucidated the roles and mechanisms of immune and non-immune cells, as well as cytokines within the testicle in orchitis-induced male infertility up to the present. The process involves both of them, which exert significant influence by modulating receptor expression on various cell types and affecting the secretion of relevant cytokines. These factors, in turn, impact sperm production and quality, trigger immune responses, and reduce testosterone levels. The complexity of this process underscores the critical importance of orchitis treatment and management in addressing male infertility issues.

In the future, continued research and exploration in this field hold the promise of uncovering novel therapeutic avenues, enabling us to develop precise interventions that target the intricate web of interactions within the testicle. These endeavors have the potential to not only mitigate the devastating impact of orchitis on male fertility but also open new horizons for tailored clinical approaches, offering hope to individuals grappling with reproductive challenges.

AbstractINTRODUCTIONCLASSIFICATION AND EPIDEMIOLOGY OF ORCHITISDIAGNOSIS AND TREATMENT OF ORCHITISTHE ROLE OF CELLS IN ORCHITISCYTOKINES IN ORCHITISCONCLUSION AND FUTURE PERSPECTIVESNotesAcknowledgementsReferences
Notes

Conflict of Interest:The authors have nothing to disclose.

Funding:This work is supported by The State Key Laboratory Program (ZD202201).

Author Contribution:

  • Conceptualization: YX.

  • Funding acquisition: HZ.

  • Supervision: HZ.

  • Validation: YX, CL, HZ.

  • Writing – original draft: YX.

  • Writing – review & editing: YX, CL, HZ, WC, XW, KZ.

We sincerely appreciate the invaluable support provided by Jiangsu Liansheng Medical Equipment Co., Ltd. and all the coauthors’ cooperation during the whole process.

AbstractINTRODUCTIONCLASSIFICATION AND EPIDEMIOLOGY OF ORCHITISDIAGNOSIS AND TREATMENT OF ORCHITISTHE ROLE OF CELLS IN ORCHITISCYTOKINES IN ORCHITISCONCLUSION AND FUTURE PERSPECTIVESNotesAcknowledgementsReferences

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Publication Types
Review
MeSH Terms
Biopsy
Cytokines
Cytokines*
Humans
Infertility, Male*
Inflammation
Male
Orchitis*
Reproductive Health*
Spermatozoa
Sperm Count
Testis
Metrics
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