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Histopathology of human orchitis of different etiology and mouse experimental autoimmune orchitis. (A) Human testis: acute bacterial orchitis (epididymo-orchitis) with massive infiltration of both the interstitium and seminiferous tubules (ST) with inflammatory cells, including numerous neutrophils. The architecture of affected ST is largely disrupted, whereas adjacent ST show hypospermatogenesis; interstitial edema and enlarged venous blood vessel (BV) (Periodic acid-Schiff stain, objective ×10). (B) Sequelae of mumps orchitis with persistent focal inflammation in human testis: Dense peritubular lymphocytic infiltrate involving the lamina propria as well as adjacent blood vessels (1), tubular atrophy resulting in complete hyalinization ('tubular shadows'; 2, 3), and interstitial fibrosis (3). The adjacent seminiferous tubules show hypospermatogenesis; note the 'flattened' epithelium with a complete loss of the adluminal compartment in some tubules (4); (hematoxylin-eosin staining, objective ×10). (C) Higher magnification of area 1 in (B); note the characteristic meshwork pattern of the affected lamina propria; the germinal epithelium is largely disrupted, with only a few germ cells remaining (hematoxylin-eosin stain, objective ×40). (D) Human testis: subacute granulomatous orchitis with residual structures of ST containing inflammatory cells (hematoxylin and eosin stain, objective ×40). (E) Characteristic histopathology of mouse experimental autoimmune orchitis (EAO) showing destruction of testicular morphology with reduced size of ST, loss of germ cells and presence of dense peritubular and interstitial inflammatory infiltrates (marked by asterisk; hematoxylin stain, objective ×20). (F) Mouse EAO, higher magnification (hematoxylin stain, objective ×40) of selected area in (E). (A-D) From Schuppe and Bergmann (2013); reprinted with permission of Springer Nature (License number: 4282971349118).
Source publication
Background:
Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in...
Contexts in source publication
Context 1
... shown by adoptive transfer experiments, CD4+ T cells play a cru- cial role in the induction of EAO ( Mahi-Brown et al., 1987). Analysis of testicular inflammatory infiltrates revealed increased numbers of several T cell subsets, macrophages, dendritic cells (DC) and mast cells in EAO in the rat (Fig. 3 and Table III). During the onset of rat EAO, a dramatic increase in CD4+ and CD8+ T effector cell num- bers producing pro-inflammatory cytokines (TNF, interferon-γ, IL-17), which are commonly associated with inflammatory and auto- immune responses, was observed (Table III). In contrast, in the chronic phase of the disease, the CD8+ T cell subset was predomin- ant, suggesting its involvement in the progression of the inflammatory process ( Guazzone et al., 2009). Interestingly, in our mouse model of EAO, highly elevated numbers of CD4+ T cells, while reduced num- bers of CD8+ T cells were detected, confirmed by a higher ratio of CD4+/CD8+ T cells in the testis. Moreover, a new population of double positive CD4+CD8+ T cells was identified in mouse EAO testis, previously identified in different organs with autoimmune disor- ders ( Nicolas et al., 2017a). Although, the increased accumulation of various immunoregulatory T cell subtypes, such as CD4+CD25 +Foxp3+, CD4+Foxp3+ and CD8+Foxp3+ T cells, has been reported in chronically inflamed rat testes, these cells were not able to suppress inflammatory responses generated by the effector T cells during the onset of EAO ( Guazzone et al., 2009;Fijak et al., 2011). Interestingly, supplementation of the reduced testosterone levels in EAO animals caused an expansion of T reg cells leading to increased representation of these cells within the CD4+ T cell subset, while simultaneously inhibiting the synthesis of pro-inflammatory mediators MCP-1, TNF and anti-inflammatory IL-10 ( Fijak et al., 2011). Further studies confirmed a direct influence of testosterone on the expansion of T reg cells mediated by interaction of the androgen receptor with the transcription factor Foxp3, which is the master regulator of T reg cell function Walecki et al., ...
Context 2
... histopathology of post-infectious or non-infectious human orchi- tis, as well as focal inflammatory lesions encountered in testicular biopsies from infertile patients with post-infectious testicular failure or 'mixed atrophy' of spermatogenesis of unknown origin, intri- guingly resemble those developing in rodent EAO (Suominen and Soderstrom, 1982;Schuppe et al., 2008) (Fig. 3B, C and E, F; Tables III and IV). The predominantly peritubular localization of lymphocytes and characteristic morphological changes of the seminiferous tubules such as 'aspermatogenesis' support the concept that concomitant activation of autoreactive T cells is involved in inflammatory disorders of the human testis (Table III and Fig. 3). In early clinical experiments, delayed-type hypersensitivity reactions to sonicates prepared from human spermatozoa could be elicited in patients with mumps orchi- tis ( Andrada et al., 1977). Moreover, immunization with testis hom- ogenate in CFA performed before orchidectomy for treatment of prostate carcinoma led to testicular lesions characteristic of EAO in two of four patients tested ( Mancini et al., 1965). Testicular biopsies revealed focal interstitial infiltrates with mononuclear cells, thicken- ing of the lamina propria, and depopulation of the seminiferous epi- thelium. Comparable to rodent models, progressive tubular atrophy eventually results in a Sertoli cell-only syndrome and/or complete hyalinization of seminiferous tubules ( Schuppe et al., 2008;Naito et al., 2012b;Aslani et al., ...
Context 3
... histopathology of post-infectious or non-infectious human orchi- tis, as well as focal inflammatory lesions encountered in testicular biopsies from infertile patients with post-infectious testicular failure or 'mixed atrophy' of spermatogenesis of unknown origin, intri- guingly resemble those developing in rodent EAO (Suominen and Soderstrom, 1982;Schuppe et al., 2008) (Fig. 3B, C and E, F; Tables III and IV). The predominantly peritubular localization of lymphocytes and characteristic morphological changes of the seminiferous tubules such as 'aspermatogenesis' support the concept that concomitant activation of autoreactive T cells is involved in inflammatory disorders of the human testis (Table III and Fig. 3). In early clinical experiments, delayed-type hypersensitivity reactions to sonicates prepared from human spermatozoa could be elicited in patients with mumps orchi- tis ( Andrada et al., 1977). Moreover, immunization with testis hom- ogenate in CFA performed before orchidectomy for treatment of prostate carcinoma led to testicular lesions characteristic of EAO in two of four patients tested ( Mancini et al., 1965). Testicular biopsies revealed focal interstitial infiltrates with mononuclear cells, thicken- ing of the lamina propria, and depopulation of the seminiferous epi- thelium. Comparable to rodent models, progressive tubular atrophy eventually results in a Sertoli cell-only syndrome and/or complete hyalinization of seminiferous tubules ( Schuppe et al., 2008;Naito et al., 2012b;Aslani et al., ...
Context 4
... it is a matter of major concern that the course of epi- didymitis remains unpredictable despite adequate antimicrobial ther- apy. After 3 months, ~20% of patients still have an epididymal infiltrate on palpation or ultrasound ( Weidner et al., 1990;Eickhoff et al., 1999;Pilatz et al., 2015b). Moreover, given the fact that up to 60% of all cases involve the testis as well (Desai et al., 1986;Kaver et al., 1990;Pilatz et al., 2013), a direct or indirect negative impact on spermatogenesis can be hypothesized. Indeed, two studies report testicular damage and subsequent infertility after acute unilateral epi- didymitis (Dietz, 1960;Osegbe, 1991). Whereas the histopathology of acute bacterial epididymo-orchitis is characterized by oedema and massive infiltration of predominantly neutrophils into both the inter- stitial compartment and seminiferous tubules (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3A), testicular biopsy spe- cimens obtained from two patients during follow-up confirmed the development of severe hypospermatogenesis with seminiferous tubules showing 'aspermatogenesis' (loss of the adluminal compart- ment), thickened lamina propria, and interstitial fibrosis in both ipsi- and contralateral testes (Osegbe, 1991) (Table III). Increased FSH levels support the histopathological findings of testicular failure. On the other hand, a recent study on 90 patients suffering unilateral epi- didymitis showed no reduction in testicular volume after the acute phase compared with the healthy contralateral side ( Pilatz et al., 2013). Thus, in addition to loss of testicular function, inflammatory obstruction of the epididymal duct has to be considered as an under- lying cause of persistent oligo-or azoospermia (Fig. ...
Context 5
... early studies dealing with testicular biopsies obtained from infertile men, inflammatory infiltrates have been reported in 4.8-16.6% of cases ( Hofmann and Kuvert, 1979;Suominen and Soderstrom, 1982;Jahnukainen et al., 1995). A systematic re-examination of tissue speci- mens obtained from asymptomatic patients with impaired fertility, i.e. non-obstructive azoospermia, showed immune cell infiltrates in the interstitial compartment in ~30% of cases ( Schuppe et al., 2001) (Table IV). The infiltrates, graded as sparse to dense, mainly com- prised lymphocytes and showed a peritubular localization distributed in a focal or multifocal pattern. In addition, the degree of lymphocytic infiltration was correlated with characteristic signs of tubular damage, such as partial or complete loss of germinal epithelium, thickening of the lamina propria and complete tubular fibrosis ( Schuppe and Bergmann, 2013) (Fig. 3B and C). Despite the patchy distribution of the lesions, testicular inflammatory reactions are associated with significantly reduced testicular volume and score counts for spermatogenesis, when inflammation represents the primary disorder (Table III). Serum FSH levels are not markedly increased in these cases compared to patients with testicular obstruction and preserved spermatogenesis. In patients with other testicular disorders, the occurrence of peritubular lympho- cytic infiltrates is closely correlated with the degree of tubular damage, i.e. impairment of spermatogenesis. With regard to the high overall prevalence of inflammatory lesions, induction of deleterious immune responses in the testis is probably not restricted to infectious agents, but a wide spectrum of etiological factors should be considered ( Schuppe and Meinhardt, 2005) (Table ...
Context 6
... EAO models offer an adequate in vivo system to study the complexity of interactions of testicular cell types (germ cells, somatic cells, immune cells) in context of the endocrine environment, which can heavily influence the immune response (Figs 3, 4 and Table III). Particularly the early stages of EAO development closely reflect the lesions seen in focal inflammatory infiltrates that are frequently observed in testicular biopsies of patients with 'mixed atrophy' of spermatogenesis. This is also the stage where experimental therapies, such as new biologicals modulating cytokine action, can be explored. The development of EAO in rodents, with progressively later stages of tubular atrophy, strong immune cell infiltration, hyalinization and loss of germ cells leading to Sertoli cell-only syndrome mirrors only a minority of cases found in men. Although the structure of the immune system in mice and human is similar, some discrepancies in both innate and adaptive immunity response are observed (reviewed in ( Mestas and Hughes, 2004). Therefore, it is important to consider the possibility that the pathological reactions occurring in a mouse testis may not reflect precisely the mechanisms playing a role in a human ...
Context 7
... elevated levels of pro-inflammatory mediators and lead to spermatogenic disruption and, eventually, loss of the adluminal com- partment of the seminiferous epithelium (aspermatogenesis) (Fig. 3 and Table III). Moreover, impairment of adherens and gap junction proteins in the seminiferous tubules contributes to germ cell slough- ing (Table III) (Perez et al., 2011(Perez et al., , 2014). Germ cell apoptosis in EAO is mediated by the involvement of Fas/FasL, TNF/TNF recep- tor 1, IL-6/IL-6 receptor and the Bax/Bcl-2 (BCL2-associated X/B- cell lymphoma 2) system ( Theas et al., 2003Theas et al., , 2006Rival et al., 2006b). Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules (Doncel et al., 1989;Lustig et al., 1993;Tung and Teuscher, 1995;Perez et al., 2012;Nicolas et al., 2017a) (Fig. 3E and F). In severe forms of the disease, granuloma formation has been observed (Fig. 3 and Table ...
Context 8
... elevated levels of pro-inflammatory mediators and lead to spermatogenic disruption and, eventually, loss of the adluminal com- partment of the seminiferous epithelium (aspermatogenesis) (Fig. 3 and Table III). Moreover, impairment of adherens and gap junction proteins in the seminiferous tubules contributes to germ cell slough- ing (Table III) (Perez et al., 2011(Perez et al., , 2014). Germ cell apoptosis in EAO is mediated by the involvement of Fas/FasL, TNF/TNF recep- tor 1, IL-6/IL-6 receptor and the Bax/Bcl-2 (BCL2-associated X/B- cell lymphoma 2) system ( Theas et al., 2003Theas et al., , 2006Rival et al., 2006b). Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules (Doncel et al., 1989;Lustig et al., 1993;Tung and Teuscher, 1995;Perez et al., 2012;Nicolas et al., 2017a) (Fig. 3E and F). In severe forms of the disease, granuloma formation has been observed (Fig. 3 and Table ...
Context 9
... elevated levels of pro-inflammatory mediators and lead to spermatogenic disruption and, eventually, loss of the adluminal com- partment of the seminiferous epithelium (aspermatogenesis) (Fig. 3 and Table III). Moreover, impairment of adherens and gap junction proteins in the seminiferous tubules contributes to germ cell slough- ing (Table III) (Perez et al., 2011(Perez et al., , 2014). Germ cell apoptosis in EAO is mediated by the involvement of Fas/FasL, TNF/TNF recep- tor 1, IL-6/IL-6 receptor and the Bax/Bcl-2 (BCL2-associated X/B- cell lymphoma 2) system ( Theas et al., 2003Theas et al., , 2006Rival et al., 2006b). Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules (Doncel et al., 1989;Lustig et al., 1993;Tung and Teuscher, 1995;Perez et al., 2012;Nicolas et al., 2017a) (Fig. 3E and F). In severe forms of the disease, granuloma formation has been observed (Fig. 3 and Table ...
Context 10
... viral orchitis is characterized by multifocal peri- vascular as well as peri-and intratubular infiltrates with neutrophils, lymphocytes, plasma cells and macrophages. Affected seminiferous tubules show degeneration of the germinal epithelium sparing few spermatogonia and the Sertoli cells; concomitant thickening of the lamina propria may result in complete hyalinization and fibrosis of the tubules (Mikuz and Damjanov, 1982) (Fig. 3B and C). This pattern of tubular damage has also been described as 'mixed atrophy' (Sigg and Hedinger, 1981;Bergmann, 2006). Notably, persistent chronic inflam- matory reactions following acute orchitis are characterized by focal or multifocal peritubular lymphocytic infiltrates (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3C and Table III). Leydig cells in the interstitial compartment show little evidence of damage in most viral orchitis ...
Context 11
... viral orchitis is characterized by multifocal peri- vascular as well as peri-and intratubular infiltrates with neutrophils, lymphocytes, plasma cells and macrophages. Affected seminiferous tubules show degeneration of the germinal epithelium sparing few spermatogonia and the Sertoli cells; concomitant thickening of the lamina propria may result in complete hyalinization and fibrosis of the tubules (Mikuz and Damjanov, 1982) (Fig. 3B and C). This pattern of tubular damage has also been described as 'mixed atrophy' (Sigg and Hedinger, 1981;Bergmann, 2006). Notably, persistent chronic inflam- matory reactions following acute orchitis are characterized by focal or multifocal peritubular lymphocytic infiltrates (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3C and Table III). Leydig cells in the interstitial compartment show little evidence of damage in most viral orchitis ...
Context 12
... predominantly granulomatous, chronic orchitis occurs as a mani- festation of tuberculosis, syphilis, lepromatous leprosy, or brucellosis (Mikuz and Damjanov, 1982;Schuppe et al., 2008;Schuppe and Bergmann, 2013) (Fig. 3D). In pre-pubertal boys, epididymo-orchitis may complicate bacterial infections, such as pneumonia, by haema- togenous dissemination of the pathogen (Greenfield, ...
Context 13
... infertility after acute unilateral epididymitis (Dietz, 1960;Osegbe, 1991). Whereas the histopathology of acute bacterial epididymo-orchitis is characterized by oedema and massive infiltration of predominantly neutrophils into both the interstitial compartment and seminiferous tubules (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3A), testicular biopsy specimens obtained from two patients during follow-up confirmed the development of severe hypospermatogenesis with seminiferous tubules showing 'aspermatogenesis' (loss of the adluminal compartment), thickened lamina propria, and interstitial fibrosis in both ipsiand contralateral testes (Osegbe, 1991) (Table III). ...
Context 14
... intratubular infiltrates with neutrophils, lymphocytes, plasma cells and macrophages. Affected seminiferous tubules show degeneration of the germinal epithelium sparing few spermatogonia and the Sertoli cells; concomitant thickening of the lamina propria may result in complete hyalinization and fibrosis of the tubules (Mikuz and Damjanov, 1982) (Fig. 3B and C). This pattern of tubular damage has also been described as 'mixed atrophy' (Sigg and Hedinger, 1981;Bergmann, 2006). Notably, persistent chronic inflammatory reactions following acute orchitis are characterized by focal or multifocal peritubular lymphocytic infiltrates (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3C and ...
Context 15
... 1982) (Fig. 3B and C). This pattern of tubular damage has also been described as 'mixed atrophy' (Sigg and Hedinger, 1981;Bergmann, 2006). Notably, persistent chronic inflammatory reactions following acute orchitis are characterized by focal or multifocal peritubular lymphocytic infiltrates (Mikuz and Damjanov, 1982;Schuppe and Bergmann, 2013) (Fig. 3C and Table III). Leydig cells in the interstitial compartment show little evidence of damage in most viral orchitis ...
Context 16
... predominantly granulomatous, chronic orchitis occurs as a manifestation of tuberculosis, syphilis, lepromatous leprosy, or brucellosis (Mikuz and Damjanov, 1982;Schuppe et al., 2008;Schuppe and Bergmann, 2013) (Fig. 3D). In pre-pubertal boys, epididymo-orchitis may complicate bacterial infections, such as pneumonia, by haematogenous dissemination of the pathogen (Greenfield, ...
Context 17
... and showed a peritubular localization distributed in a focal or multifocal pattern. In addition, the degree of lymphocytic infiltration was correlated with characteristic signs of tubular damage, such as partial or complete loss of germinal epithelium, thickening of the lamina propria and complete tubular fibrosis ( Schuppe and Bergmann, 2013) (Fig. 3B and C). Despite the patchy distribution of the lesions, testicular inflammatory reactions are associated with significantly reduced testicular volume and score counts for spermatogenesis, when inflammation represents the primary disorder (Table III). Serum FSH levels are not markedly increased in these cases compared to patients with ...
Context 18
... elevated levels of pro-inflammatory mediators and lead to spermatogenic disruption and, eventually, loss of the adluminal compartment of the seminiferous epithelium (aspermatogenesis) (Fig. 3 and Table III). Moreover, impairment of adherens and gap junction proteins in the seminiferous tubules contributes to germ cell sloughing (Table III) (Perez et al., 2011(Perez et al., , 2014). Germ cell apoptosis in EAO is mediated by the involvement of Fas/FasL, TNF/TNF receptor 1, IL-6/IL-6 receptor and the Bax/Bcl-2 (BCL2-associated ...
Context 19
... (BCL2-associated X/Bcell lymphoma 2) system ( Theas et al., 2003Theas et al., , 2006Rival et al., 2006b). Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules (Doncel et al., 1989;Lustig et al., 1993;Tung and Teuscher, 1995;Perez et al., 2012;Nicolas et al., 2017a) (Fig. 3E and F). In severe forms of the disease, granuloma formation has been observed (Fig. 3 and Table ...
Context 20
... 2006Rival et al., 2006b). Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules (Doncel et al., 1989;Lustig et al., 1993;Tung and Teuscher, 1995;Perez et al., 2012;Nicolas et al., 2017a) (Fig. 3E and F). In severe forms of the disease, granuloma formation has been observed (Fig. 3 and Table ...
Context 21
... shown by adoptive transfer experiments, CD4+ T cells play a crucial role in the induction of EAO ( Mahi-Brown et al., 1987). Analysis of testicular inflammatory infiltrates revealed increased numbers of several T cell subsets, macrophages, dendritic cells (DC) and mast cells in EAO in the rat (Fig. 3 and Table III). During the onset of rat EAO, a dramatic increase in CD4+ and CD8+ T effector cell numbers producing pro-inflammatory cytokines (TNF, interferon-γ, IL-17), which are commonly associated with inflammatory and autoimmune responses, was observed (Table III). In contrast, in the chronic phase of the disease, the CD8+ T cell ...
Context 22
... or non-infectious human orchitis, as well as focal inflammatory lesions encountered in testicular biopsies from infertile patients with post-infectious testicular failure or 'mixed atrophy' of spermatogenesis of unknown origin, intriguingly resemble those developing in rodent EAO (Suominen and Soderstrom, 1982;Schuppe et al., 2008) (Fig. 3B, C and E, F; Tables III and IV). The predominantly peritubular localization of lymphocytes and characteristic morphological changes of the seminiferous tubules such as 'aspermatogenesis' support the concept that concomitant activation of autoreactive T cells is involved in inflammatory disorders of the human testis (Table III and Fig. ...
Context 23
... 2008) (Fig. 3B, C and E, F; Tables III and IV). The predominantly peritubular localization of lymphocytes and characteristic morphological changes of the seminiferous tubules such as 'aspermatogenesis' support the concept that concomitant activation of autoreactive T cells is involved in inflammatory disorders of the human testis (Table III and Fig. 3). In early clinical experiments, delayed-type hypersensitivity reactions to sonicates prepared from human spermatozoa could be elicited in patients with mumps orchitis ( Andrada et al., 1977). Moreover, immunization with testis homogenate in CFA performed before orchidectomy for treatment of prostate carcinoma led to testicular lesions ...
Context 24
... EAO models offer an adequate in vivo system to study the complexity of interactions of testicular cell types (germ cells, somatic cells, immune cells) in context of the endocrine environment, which can heavily influence the immune response (Figs 3, 4 and Table III). Particularly the early stages of EAO development closely reflect the lesions seen in focal inflammatory infiltrates that are frequently observed in testicular biopsies of patients with 'mixed atrophy' of spermatogenesis. ...
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... Underlying etiologies are diverse and include congenital, genetically determined, and acquired disorders. Among the identifiable and potentially curable causes, infection and inflammation of the genital tract are the most frequent, with a 15-30% prevalence (Olesen et al., 2017;Fijak et al., 2018); however, the majority of patients who experience infertility are asymptomatic, which reduces diagnostic accuracy (Schuppe et al., 2017). Moreover, the frequency of asymptomatic testicular inflammatory reactions remains largely underestimated due to a lack of specific, non-invasive diagnostic markers (Schuppe et al., 2008;Fijak et al., 2018). ...
... Among the identifiable and potentially curable causes, infection and inflammation of the genital tract are the most frequent, with a 15-30% prevalence (Olesen et al., 2017;Fijak et al., 2018); however, the majority of patients who experience infertility are asymptomatic, which reduces diagnostic accuracy (Schuppe et al., 2017). Moreover, the frequency of asymptomatic testicular inflammatory reactions remains largely underestimated due to a lack of specific, non-invasive diagnostic markers (Schuppe et al., 2008;Fijak et al., 2018). While only 2-3% of patients evaluated for infertility report prior epididymoorchitis, the testicular biopsies from 25-30% of men with azoospermia show evidence of focal inflammatory lesions (Olesen et al., 2017;Fijak et al., 2018). ...
... Moreover, the frequency of asymptomatic testicular inflammatory reactions remains largely underestimated due to a lack of specific, non-invasive diagnostic markers (Schuppe et al., 2008;Fijak et al., 2018). While only 2-3% of patients evaluated for infertility report prior epididymoorchitis, the testicular biopsies from 25-30% of men with azoospermia show evidence of focal inflammatory lesions (Olesen et al., 2017;Fijak et al., 2018). Thus, men affected by 'silent' testicular inflammation likely represent a large proportion of patients with so-called idiopathic infertility; yet the etiopathogenesis of these patients remains obscure, which may limit their treatment options (Colpi et al., 2018;Fijak et al., 2018). ...
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STUDY QUESTION
Does the chemokine/chemokine receptor axis, involved in immune cell trafficking, contribute to the pathology of testicular inflammation and how does activin A modulate this network?
SUMMARY ANSWER
Testicular chemokines and their receptors (especially those essential for trafficking of monocytes) are elevated in orchitis, and activin A modulates the expression of the chemokine/chemokine receptor network to promote monocyte/macrophage and T cell infiltration into the testes, causing extensive tissue damage.
WHAT IS KNOWN ALREADY
The levels of CC motif chemokine receptor (CCR)2 and its ligand CC motif chemokine ligand (CCL)2 are increased in experimental autoimmune orchitis (EAO) compared with healthy testes, and mice deficient in CCR2 are protected from EAO-induced tissue damage. Activin A induces CCR2 expression in macrophages, promoting their migration. Moreover, there is a positive correlation between testicular activin A concentration and the severity of autoimmune orchitis. Inhibition of activin A activity by overexpression of follistatin (FST) reduces EAO-induced testicular damage.
STUDY DESIGN, SIZE, DURATION
EAO was induced in 10–12-week-old male C57BL/6J (wild-type; WT) and B6.129P2-Ccr2tm1Mae/tm1Mae (Ccr2−/−) mice (n = 6). Adjuvant (n = 6) and untreated (n = 6) age-matched control mice were also included. Testes were collected at 50 days after the first immunization with testicular homogenate in complete Freund’s adjuvant. In another experimental setup, WT mice were injected with a non-replicative recombinant adeno-associated viral vector carrying a FST315-expressing gene cassette (rAAV-FST315; n = 7–9) or an empty control vector (n = 5) 30 days prior to EAO induction. Appropriate adjuvant (n = 4–5) and untreated (n = 4–6) controls were also examined. Furthermore, human testicular biopsies exhibiting focal leukocytic infiltration and impaired spermatogenesis (n = 17) were investigated. Biopsies showing intact spermatogenesis were included as controls (n = 9). Bone-marrow-derived macrophages (BMDMs) generated from WT mice were treated with activin A (50 ng/ml) for 6 days. Activin-A-treated or untreated BMDMs were then co-cultured with purified mouse splenic T cells for two days to assess chemokine and cytokine production.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of chemokines in total testicular RNA collected from mice. Immunofluorescence staining was used to detect activin A, F4/80, and CD3 expression in mouse testes. The expression of chemokine/chemokine-receptor-encoding genes was examined in human testicular biopsies by qRT-PCR. Correlations between chemokine expression levels and either the immune cell infiltration density or the mean spermatogenesis score were analyzed. Immunofluorescence staining was used to evaluate the expression of CD68 and CCR2 in human testicular biopsies. RNA isolated from murine BMDMs was used to characterize these cells in terms of their chemokine/chemokine receptor expression levels. Conditioned media from co-cultures of BMDMs and T cells were collected to determine chemokine levels and the production of pro-inflammatory cytokines tumor necrosis factor (TNF) and interferon (IFN)-γ by T cells.
MAIN RESULTS AND THE ROLE OF CHANCE
Induction of EAO in the testes of WT mice increased the expression of chemokine receptors such as Ccr1 (P < 0.001), Ccr2 (P < 0.0001), Ccr3 (P < 0.0001), Ccr5 (P < 0.0001), CXC motif chemokine receptor (Cxcr)3 (P < 0.01), and CX3C motif chemokine receptor (Cx3cr)1 (P < 0.001), as well as that of most of their ligands. Ccr2 deficiency reversed some of the changes associated with EAO by reducing the expression of Ccr1 (P < 0.0001), Ccr3 (P < 0.0001), Ccr5 (P < 0.01), Cxcr3 (P < 0.001), and Cx3cr1 (P < 0.0001). Importantly, the biopsies showing impaired spermatogenesis and concomitant focal leukocytic infiltration exhibited higher expression of CCL2 (P < 0.01), CCR1 (P < 0.05), CCR2 (P < 0.001), and CCR5 (P < 0.001) than control biopsies with no signs of inflammation and intact spermatogenesis. The gene expression of CCR2 and its ligand CCL2 correlated positively with the immune cell infiltration density (P < 0.05) and negatively with the mean spermatogenesis score (P < 0.001). Moreover, CD68+ macrophages expressing CCR2 were present in human testes with leukocytic infiltration with evidence of tubular damage. Treatment of BMDMs, as surrogates for testicular macrophages, with activin A increased their expression of Ccr1, Ccr2, and Ccr5 while reducing their expression of Ccl2, Ccl3, Ccl4, Ccl6, Ccl7 Ccl8, and Ccl12. These findings were validated in vivo, by showing that inhibiting activin A activity by overexpressing FST in EAO mice decreased the expression of Ccr2 (P < 0.05) and Ccr5 (P < 0.001) in the testes. Interestingly, co-culturing activin-A-treated BMDMs and T cells reduced the levels of CCL2 (P < 0.05), CCL3/4 (P < 0.01), and CCL12 (P < 0.05) in the medium and attenuated the production of TNF (P < 0.05) by T cells. The majority of cells secreting activin A in EAO testes were identified as macrophages.
LARGE SCALE DATA
N/A.
LIMITATIONS, REASONS FOR CAUTION
BMDMs were used as surrogates for testicular macrophages. Hence, results obtained from the in vitro experiments might not be fully representative of the situation in the testes in vivo. Moreover, since total RNA was extracted from the testicular tissue to examine chemokine expression, the contributions of individual cell types as producers of specific chemokines may have been overlooked.
WIDER IMPLICATIONS OF THE FINDINGS
Our data indicate that macrophages are implicated in the development and progression of testicular inflammation by expressing CCR2 and activin A, which ultimately remodel the chemokine/chemokine receptor network and recruit other immune cells to the site of inflammation. Consequently, inhibition of CCR2 or activin A could serve as a potential therapeutic strategy for reducing testicular inflammation.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the International Research Training Group in ‘Molecular pathogenesis on male reproductive disorders’, a collaboration between Justus Liebig University (Giessen) and Monash University (Melbourne) (GRK1871/1-2) funded by the Deutsche Forschungsgemeinschaft and Monash University, a National Health and Medical Research Council of Australia Ideas Grant (1184867), and the Victorian Government’s Operational Infrastructure Support Programme. The authors declare no competing financial interests.
... Under physiological conditions, immune cells are essential for maintaining the "immune privilege" within the testis. Macrophages are normally the most abundant immune cells in the adult testis, displaying an anti-inflammatory phenotype, including anergy to inflammatory stimuli, with a phenotype shaped by the local microenvironment [12,13]. Present in small numbers, antigen-presenting dendritic cells (DC) and regulatory T lymphocytes (Treg) are important for the induction of systemic tolerance to developing germ cell antigens [13,14]. ...
... Macrophages are normally the most abundant immune cells in the adult testis, displaying an anti-inflammatory phenotype, including anergy to inflammatory stimuli, with a phenotype shaped by the local microenvironment [12,13]. Present in small numbers, antigen-presenting dendritic cells (DC) and regulatory T lymphocytes (Treg) are important for the induction of systemic tolerance to developing germ cell antigens [13,14]. The physiological milieu is also determined by a combination of immunoregulatory and immunosuppressive factors, including cytokines such as TGF-β and interleukin (IL)-10, activin A, and androgens, provided by resident immune cells and somatic Sertoli, Leydig, and peritubular cells [11,15]. ...
... The physiological milieu is also determined by a combination of immunoregulatory and immunosuppressive factors, including cytokines such as TGF-β and interleukin (IL)-10, activin A, and androgens, provided by resident immune cells and somatic Sertoli, Leydig, and peritubular cells [11,15]. This delicate milieu can be disrupted by pathogens such as bacteria and viruses, as well as by the presence of neoplastic germ cells [10,13]. ...
Background
Immune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown.
Methods
Human testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes.
Results
Profound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma.
Conclusion
Despite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients’ prognosis, and as putative targets for personalized immunotherapy.
... Experimental models of infertility associated with chronic inflammation, such as experimental autoimmune orchitis (EAO), are relevant as they provide a valuable tool to study how processes are initiated and progress, as suggested by Naito et al. (2012) [4] and Fijak et al. (2018) [5]. In EAO, inflammatory agents (nitric oxide, TNFα, IL6, IFNγ, and others) produced by infiltrating lymphomonocytes alter spermatogenesis, primarily targeting germ cells and Sertoli cells and also disrupting testosterone production via Leydig cells [6]. ...
... Experimental models of infertility associated with chronic inflammation, such as experimental autoimmune orchitis (EAO), are relevant as they provide a valuable tool to study how processes are initiated and progress, as suggested by Naito et al. (2012) [4] and Fijak et al. (2018) [5]. In EAO, inflammatory agents (nitric oxide, TNFα, IL6, IFNγ, and others) produced by infiltrating lymphomonocytes alter spermatogenesis, primarily targeting germ cells and Sertoli cells and also disrupting testosterone production via Leydig cells [6]. ...
Experimental autoimmune orchitis (EAO) is a well-established rodent model of organ-specific autoimmunity associated with infertility in which the testis immunohistopathology has been extensively studied. In contrast, analysis of testis biopsies from infertile patients associated with inflammation has been more limited. In this work, testicular biopsies from patients with idiopathic non-obstructive azoospermia diagnosed with hypospermatogenesis (HypoSp) [mild: n = 9, and severe: n = 11], with obstructive azoospermia and complete Sp (spermatogenesis) (control group, C, n = 9), and from Sertoli cell-only syndrome (SCOS, n = 9) were analyzed for the presence of immune cells, spermatogonia and Sertoli cell (SCs) alterations, and reproductive hormones levels. These parameters were compared with those obtained in rats with EAO. The presence of increased CD45+ cells in the seminiferous tubules (STs) wall and lumen in severe HypoSp is associated with increased numbers of apoptotic meiotic germ cells and decreased populations of undifferentiated and differentiated spermatogonia. The SCs showed an immature profile with the highest expression of AMH in patients with SCOS and severe HypoSp. In SCOS patients, the amount of SCs/ST and Ki67+ SCs/ST increased and correlated with high serum FSH levels and CD45+ cells. In the severe phase of EAO, immune cell infiltration and apoptosis of meiotic germ cells increased and the number of undifferentiated and differentiated spermatogonia was lowest, as previously reported. Here, we found that orchitis leads to reduced sperm number, viability, and motility. SCs were mature (AMH-) but increased in number, with Ki67+ observed in severely damaged STs and associated with the highest levels of FSH and inflammatory cells. Our findings demonstrate that in a scenario where a chronic inflammatory process is underway, FSH levels, immune cell infiltration, and immature phenotypes of SCs are associated with severe changes in spermatogenesis, leading to azoospermia. Furthermore, AMH and Ki67 expression in SCs is a distinctive marker of severe alterations of STs in human orchitis.
... Understanding these events is relevant because (i) well-controlled TLR activation is crucial to activate defense mechanisms against pathogens and to promote tissue repair, (ii) disturbances in TLR signaling pathways are associated with loss of immune homeostasis and, consequently, tissue damage and disease progression, and (iii) the long-term consequences of infectious epididymitis hinge on the magnitude of the host's immune response. [35][36][37] Thus, we employed different models of epididymitis in mice to investigate the expression and regulation of genes involved in TLR-associated signaling pathways as a potential regulatory mechanism in the regionspecific epididymal immune responses to infectious or inflammatory stimuli. ...
Background
Region‐specific immune environments in the epididymis influence the immune responses to uropathogenic Escherichia coli (UPEC) infection, a relevant cause of epididymitis in men. Toll‐like receptors (TLRs) are essential to orchestrate immune responses against bacterial infections. The epididymis displays region‐specific inflammatory responses to bacterial‐derived TLR agonists, such as lipopolysaccharide (LPS; TLR4 agonist) and lipoteichoic acid (LTA; TLR2/TLR6 agonist), suggesting that TLR‐associated signaling pathways could influence the magnitude of inflammatory responses in epididymitis.
Objectives
To investigate the expression and regulation of key genes associated with TLR4 and TLR2/TLR6 signaling pathways during epididymitis induced by UPEC, LPS, and LTA in mice.
Material and methods
Epididymitis was induced in mice using UPEC, ultrapure LPS, or LTA, injected into the interstitial space of the initial segment or the lumen of the vas deferens close to the cauda epididymidis. Samples were harvested after 1, 5, and 10 days for UPEC‐treated animals and 6 and 24 h for LPS‐/LTA‐treated animals. Ex vivo epididymitis was induced by incubating epididymal regions from naive mice with LPS or LTA. RT‐qPCR and Western blot assays were conducted.
Results
UPEC infection up‐regulated Tlr2 , Tlr4 , and Tlr6 transcripts and their associated signaling molecules Cd14 , Ticam1 , and Traf6 in the cauda epididymidis but not in the initial segment. In these epididymal regions, LPS and LTA differentially modulated Tlr2 , Tlr4 , Tlr6 , Cd14 , Myd88 , Ticam1 , Traf3 , and Traf6 expression levels. NFKB and AP1 activation was required for LPS‐ and LTA‐induced up‐regulation of TLR‐associated signaling transcripts in the cauda epididymidis and initial segment, respectively.
Conclusion
The dynamic modulation of TLR4 and TLR2/TLR6 signaling pathways gene expression during epididymitis indicates bacterial‐derived antigens elicit an increased tissue sensitivity to combat microbial infection in a spatial manner in the epididymis. Differential activation of TLR‐associated signaling pathways may contribute to fine‐tuning inflammatory responses along the epididymis.
... This finding indicates that inflammation has been induced. Male infertility is well recognized to be brought on by the unchecked production of pro-inflammatory cytokines in the testes, such as IL-1b and TNF-a, which are damaging to spermatogenesis [65]. At 21 and 28 days in the current study, aflatoxin treatment caused a substantial elevation of TNF-gene expression. ...
Background
Camel milk and silymarin have many different beneficial effects on several animal species. Meanwhile, Aflatoxins are mycotoxins with extraordinary potency that pose major health risks to several animal species. Additionally, it has been documented that aflatoxins harm the reproductive systems of a variety of domestic animals. The present design aimed to investigate the impact of aflatoxin B1 (AFB1) on rat body weight and reproductive organs and the ameliorative effects of camel milk and silymarin through measured serum testosterone, testes pathology, and gene expression of tumor necrosis factor (TNF-α), luteinizing hormone receptor (LHR), and steroidogenic acute regulatory protein (StAR) in the testes. A total of sixty mature male Wister white rats, each weighing an average of 83.67 ± 0.21 g, were used. There were six groups created from the rats. Each division had ten rats. The groups were the control (without any treatment), CM (1 ml of camel milk/kg body weight orally), S (20 mg silymarin/kg b. wt. suspension, orally), A (1.4 mg aflatoxin/kg diet), ACM (aflatoxin plus camel milk), and AS (aflatoxin plus silymarin).
Results
The results indicated the positive effects of camel milk and silymarin on growth, reproductive organs, and gene expression of TNF-α, LHR, and StAR with normal testicular architecture. Also, the negative effect of AFB1 on the rat’s body weight and reproductive organs, as indicated by low body weight and testosterone concentration, was confirmed by the results of histopathology and gene expression. However, these negative effects were ameliorated by the ingestion of camel milk and silymarin.
Conclusion
In conclusion, camel milk and silymarin could mitigate the negative effect of AFB1 on rat body weight and reproductive organs.
... 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]. ...
... 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]. ...
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.
... Notably, Leydig cells have been confirmed to stimulate the activity and proliferation of DCs, neutrophils, and NK cells, which are critical for resolving inflammation [11]. In addition to testosterone, corticosterone present in the interstitial fluid can induce macrophage polarization toward the M2 phenotype, contributing to the establishment of an immunosuppressive testicular microenvironment and ameliorating UPECinduced orchitis [12]. This review discusses the roles of diverse immune cells in infection-induced orchitis, elucidates their functions, and introduces potential therapeutic strategies for epididymo-orchitis. ...
... Spermatogenic disorders can be caused by excessive immune responses. Our previous study found that corticosterone can maintain the immunosuppressive phenotype of testicular macrophages during infection by strengthening the adenosine monophosphate-activated protein (AMP)-activated protein kinase pathway, thereby reducing damage by the inflammatory response in the testis [12]. UPEC infection can activate the TLR4-myd88 pathway, promote activin A expression, and induce fibrosis of the male reproductive system [33]. ...
Epididymitis or epididymo-orchitis is a common urological condition in males characterized by scrotal pain, swelling, and potential urinary symptoms. Although antibiotics can eliminate the causative pathogens, persistent inflammation may compromise spermatogenesis and steroidogenesis. The testis, an immune-privileged organ, possesses a specialized immune microenvironment that shields germ cells (GCs) from autoimmune attacks and orchestrates immune defenses against pathogens. This review focuses on the complex interplay between immune cells, including macrophages, dendritic cells (DCs), mast cells (MCs), and T cell subsets, in the testis. The roles of these immune cells in infection-induced orchitis were deliberated upon, emphasizing their involvement in inflammation and immune tolerance. Furthermore, the implications of testicular fibrosis and its effect on male infertility are discussed, emphasizing the role of MCs in tissue remodeling. The objective of this review is to expand comprehension of male reproductive health and foster the identification of potential therapeutic targets for epididymo-orchitis.
... This is because viruses can induce cells to produce a large amount of interferon and express a variety of antiviral proteins, which play a significant role in the testicles' resistance to viral infections (Le Tortorec et al. 2020). BTB, which protects germ cells located in the seminiferous tubules from immune cells in the interstitium, and the immune protective functions of Sertoli cells, which may contribute to immune privilege, are additional mechanisms that safeguard the testes (Fijak et al. 2018). Moreover, Leydig cells, being the most abundant cell in the testicular interstitium, secrete numerous cytokines that have a crucial role in the natural immune response of the testes and the maintenance of the immune immunity state, primarily by regulating the proliferation and differentiation of various cells (Shen et al. 2021). ...
... One of the leading causes of male infertility is the destruction of the immune immunity mechanism of the testicles, which can be caused by viral or bacterial infection, stress, or genetic factors (Gan et al. 2023;Tsetsarkin et al. 2018;Yu et al. 2022). Orchitis and epididymitis are key factors contributing to male infertility, accounting for up to 15% of male fertility disorders (Fijak et al. 2018;Punab et al. 2017). When orchitis occurs, it disrupts the immune immunity status of the testicles, leading to a disordered homeostasis of the testicular microenvironment. ...
The male reproductive system has a standard immune response regulatory mechanism, However, a variety of external stimuli, including viruses, bacteria, heat, and medications can damage the testicles and cause orchitis and epididymitis. It has been shown that various RNA viruses are more likely to infect the testis than DNA viruses, inducing orchitis and impairing testicular function. It was found that local injection of the viral RNA analog poly(I:C) into the testes markedly disrupted the structure of the seminiferous tubules, accompanied by apoptosis and inflammation. Poly(I:C) mainly inhibited the expression of testosterone synthesis-associated proteins, STAR and MGARP, and affected the synthesis and metabolism of amino acids and lipids in the testis. This led to the disruption of the metabolite levels in the testis of mice, thus affecting the normal spermatogenesis process. The present study analyzed the acute inflammatory response of the testis to viral infection using a multi-omics approach. It provides insights into how RNA virus infection impairs testicular function and offers a theoretical basis for future studies on immune homeostasis and responses under stress conditions in male reproduction.
... Infertility affects~15% couples of childbearing age worldwide, and approximately half of the cases are attributed to male infertility. Infection, autoimmunity, and inflammation of the reproductive tract have been reported as etiological factors affecting male fertility (Fijak et al, 2018). Approximately 6−15% cases of male infertility is related to infection and inflammation of the urogenital tract (Fijak et al, 2018). ...
... Infection, autoimmunity, and inflammation of the reproductive tract have been reported as etiological factors affecting male fertility (Fijak et al, 2018). Approximately 6−15% cases of male infertility is related to infection and inflammation of the urogenital tract (Fijak et al, 2018). Uropathogenic Escherichia coli (UPEC) has been identified as the predominant etiological pathogen of genitourinary infections and can be isolated from 50 to 95% patients with genitourinary infections (Wiles et al, 2008). ...
... GSDMD was highly activated in the testes of mice with UPEC-induced acute orchitis UPEC infection can induce epididymo-orchitis in mice, and the epididymis is known to be vulnerable to bacterial infection and concomitant inflammation (Fijak et al, 2018;Klein et al, 2020;Klein et al, 2019;Michel et al, 2016). However, few studies have investigated the direct effects of UPEC on the testes. ...
Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD’s role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis.
... Activated NF-κB shifts from the cytosol into the nucleus and increases the transcription of inflammatory mediators, IL-1β, IL-6, TNF-α, and COX-2 (Akaras et al., 2023). It is reported that inflammation is detrimental to the male reproductive system as it impairs sperm motility and spermatogenesis, thereby affecting the overall spermatogenic and testicular dynamics (Hedger, 2011;Fijak et al., 2018). Summing up, AFB 1 -induced inflammation is mediated through the activation of the NF-κB pathway, resulting in increased levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and COX-2. ...
Polycystic ovarian syndrome (PCOS) is the most prevalent metabolic and endocrine disorder that affects women globally. This research was planned to evaluate the curative effects of nobiletin (NOB) on biochemical, metabolic , androgenic as well as histological parameters of PCOS induced rats. 24 female albino rats were divided into 4 equal groups: Group-I served as control. Group-II was treated with letrozole (1 mg/kg) (dissolved in 0.5 % CMC) for 21 days, for the induction of PCOs. Group III received letrozole (1 mg/kg) and metformin (2 mg/100 g) for 21 days. Group-IV received letrozole 1 mg/kg and NOB 10 mg/kg for 21 days. Testosterone, estradiol, progesterone, triglycerides, antioxidants (CAT, SOD, GSR, GPx, GST, GSH,), reactive oxygen species, thio-barbituric acid reactive substances, glucose, cholesterol level (HDL-C, LDL-C, VLDL-C, Non-HDL-C) as well as histopathological analysis of ovaries were performed. However, nobiletin treatment demonstrated beneficial effects by lowering testosterone levels, glucose levels, cysts, and improving estradiol and progesterone level as well as number of follicles and corpus luteum in PCOS rats. Furthermore, dysregulated lipid as well as anti-oxidant profiles in PCOS rats were reverted to the normal level. The current investigation demonstrated that NOB shows the ability to mitigate the irregularities associated with PCOS.
