Infectious, inflammatory and ‘autoimmune’ male factor infertility: how do rodent models inform clinical practice?

Fijak, Monika; Pilatz, Adrian; Hedger, Mark P.; Nicolas, Nour; Bhushan, Sudhanshu; Michel, Vera; Tung, Kenneth S. K.; Schuppe, Hans‐Christian; Meinhardt, Andreas

doi:10.1093/humupd/dmy009

Cited by 210 publications

(208 citation statements)

References 278 publications

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“…Inflammatory conditions and microbial infections in the male genital tract account for almost 15.0% of male infertility reasons in developed countries (Fijak et al, ), and this ratio can be much higher in undeveloped countries (Ekwere, ). Orchitis and epididymitis are more likely to contribute to male infertility than inflammatory conditions in seminal vesicle glands and prostate (Schuppe et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Expression profile of Toll‐like receptor 4 in rat testis and epididymis throughout postnatal development

et al. 2020

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Toll‐like receptors (TLRs) belonging to pattern recognition receptors are involved in maintaining testicular and epididymal immune homeostasis. The purpose of the current study was to investigate TLR4 expression in rat testis and epididymis throughout postnatal development. Weak staining was detected in peritubular myoid cells and immature Sertoli cells while no staining was observed in gonocytes during prepubertal period. However, TLR4 expression began to appear in spermatocytes in pubertal period and gradually increased in spermatids. An intense staining was observed in steps 5–19 spermatids in post pubertal and mature periods. Similarly, TLR4 expression in the testes steadily increased from pubertal period to mature period. Puberty also caused a significant increase in TLR4 expression in epididymis. TLR4 expression in cauda epididymis was lower as compared to those of other epididymal segments. The majority of epididymal epithelial cells exhibited apical TLR4 expression, whereas basal cells showed intense intracytoplasmic immunoreaction. We detected an intense staining in epididymal smooth muscle cells. The expression levels of TLR4 showed dynamic changes in both spermatogenic cells, and entire testicular and epididymal tissues during postnatal development. These results suggest that TLR4 expression contributes not only to inflammation but also to the development of spermatogenic cells.

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Section: Introductionmentioning

confidence: 99%

“…developed countries (Fijak et al, 2018), and this ratio can be much higher in undeveloped countries (Ekwere, 1995). Orchitis and epididymitis are more likely to contribute to male infertility than inflammatory conditions in seminal vesicle glands and prostate (Schuppe et al, 2008).…”

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confidence: 99%

Expression profile of Toll‐like receptor 4 in rat testis and epididymis throughout postnatal development

et al. 2020

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“…Clinical data and research results indicate that an abnormal systemic and local immune status associated with infection and inflammation can inhibit spermatogenesis within the testes and lead to male infertility. [3][4][5] The incidence of male infertility due to infection ranges from 6% to 15% in different reports 6 ; however, the underlying mechanism has not been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Identification of programmed cell death 1 and its ligand in the testicular tissue of mice

Wang

Duan

et al. 2019

American J Rep Immunol

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Problem This study aims to determine the expression and localization of programmed cell death 1 (PD‐1) and programmed cell death 1 ligand 1 (PD‐L1) in the testes of mice at different developmental stages. Method of study By means of RT‐qPCR, Western blot and immunofluorescence, the expression and localization of PD‐1 and PD‐L1 were detected in the testicular tissues of mice at different postnatal times: P7, P14, P21, P28, P35, and adulthood. Meanwhile, the level of soluble PD‐L1 (sPD‐L1) was evaluated by ELISA in the testicular interstitial fluid (IF) of the adult mice, culture supernatants of TM4 cell lines (Sertoli cells lines), and primary Sertoli cells at P14. Results Pd‐1 mRNA levels were unexpectedly low. From P7 to P21, there was limited PD‐1 protein detected while PD‐1 was evident at P28 and afterward at significantly higher levels than at P14 and P21 (P < 0.05). Despite being found in the interstitial area at P7, P14, and P21, PD‐1 was also detected in the germ cells of the seminiferous tubules after P28. Pd‐l1 mRNA exhibited age‐related changes, peaking at P21, while PD‐L1 protein was constitutively expressed at any stage, specifically localized in the nucleus of Sertoli cells. Moreover, the level of sPD‐L1 in IF was significantly higher than that in the culture supernatants of both TM4 and primary Sertoli cells at P14. Conclusions PD‐1 and PD‐L1 were present in the testicular tissue of adult mice. The expression and localization of PD‐1 fluctuated with age, and PD‐1 was mainly localized to advanced germ cells, suggesting that it may play a role in spermiogenesis. PD‐L1 was constitutively expressed in the nucleus of Sertoli cells, which could secrete sPD‐L1 into the testicular interstitial space and thus may be involved in testicular immune privilege.

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“…Urogenital infections and inflammation are accepted as significant aetiologic factors in male infertility (Fijak et al, ; Gimenes et al, ; Jungwirth et al, ; Weng et al, ). Although the available data are extremely heterogeneous, between 6% and 44% of all male cases with infertility are reported to be of infectious/inflammatory origin (Ahmed, Bello, Mbibu, Maitama, & Kalayi, ; Bayasgalan, Naranbat, Radnaabazar, Lhagvasuren, & Rowe, ; Comhaire, De Kretser, Farley, & Rowe, ).…”

Section: Introductionmentioning

confidence: 99%

“…As the diagnosis is primarily based on abnormalities in the ejaculate, organ‐specific attribution of infectious/inflammatory signs remains difficult (Schuppe et al, ). Thus, patient categorisation using MAGI criteria does not necessarily reflect testicular or epididymal inflammation and its sequelae (Fijak et al, ).…”

Section: Introductionmentioning

confidence: 99%

High prevalence of urogenital infection/inflammation in patients with azoospermia does not impede surgical sperm retrieval

et al. 2019

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Considering infection/inflammation to be an important risk factor in male infertility, the aim of this study was to make a comprehensive evaluation of the prevalence of urogenital tract infection/inflammation and its potential impact on sperm retrieval in azoospermic patients. In this prospective study, 71 patients with azoospermia were subjected to an extensive andrological workup including comprehensive microbiological diagnostics (2-glass test, semen, testicular swab and testicular tissue analysis) and testicular biopsy/testicular sperm extraction (TESE). Medical history suggested urogenital tract infection/inflammation in 7% of patients, 11% harboured STIs, 14% showed significant bacteriospermia, 15% had seminal inflammation, 17% fulfilled the MAGI definition, and 27% had relevant pathogens. At the testicular level, 1 patient had a swab positive for bacteria, no viruses were detected, tissue specimens never indicated pathogens, whereas histopathology revealed focal immune cell infiltrates in 23% of samples. Testicular sperm retrieval rate was 100% in obstructive and 46% in nonobstructive azoospermia. None of the infection/inflammation-related variables was associated with the success of sperm retrieval or inflammatory lesions in the testis. The high prevalence of urogenital infection/inflammation among azoospermic men underpins their role as significant aetiologic factors in male infertility.However, this observation does not refer to the chances of sperm retrieval at the time of surgery/TESE. K E Y W O R D Sazoospermia, genital tract inflammation, infertility, male accessory gland infection, TESE 2 of 10 | PILATZ eT AL.

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Infectious, inflammatory and ‘autoimmune’ male factor infertility: how do rodent models inform clinical practice?

Cited by 210 publications

References 278 publications

Expression profile of Toll‐like receptor 4 in rat testis and epididymis throughout postnatal development

Expression profile of Toll‐like receptor 4 in rat testis and epididymis throughout postnatal development

Identification of programmed cell death 1 and its ligand in the testicular tissue of mice

High prevalence of urogenital infection/inflammation in patients with azoospermia does not impede surgical sperm retrieval

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