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

Abstract

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 adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans.

Objective and rationale: This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions.

Search methods: An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: 'infection' and/or 'inflammation' and 'testis' and/or 'epididymis', 'infection' and/or 'inflammation' and 'male genital tract', 'male infertility', 'orchitis', 'epididymitis', 'experimental autoimmune' and 'orchitis' or 'epididymitis' or 'epididymo-orchitis', antisperm antibodies', 'vasectomy'. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team.

Outcomes: There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with 'mixed atrophy' of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response.

Wider implications: This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.

Figure 1

Immune environment of the normal adult testis and epididymis. BC, basal cell; BM, basement membrane; BTB, blood–testis barrier; DC, dendritic cell; GC, germ cell; LC, Leydig cell; M, macrophage; MC, mast cell; NC, narrow and clear cell; PC, principal cell; PTC, peritubular cell; SC, Sertoli cell; SMC, smooth muscle cell; TC, T cell; TM, testicular macrophage; IL, interleukin; MHC, major histocompatibility complex; IDO, indoleamine 2,3-dioxygenase.

Figure 2

Pathogen spectrum in patients with acute epididymitis. (A) In patients without antimicrobial pretreatment (n = 157) bacterial pathogens can be identified in 88% of cases. (B) In patients with antimicrobial pretreatment (n = 90) a pathogen detection is only possible in ~54% of cases.

Figure 3

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).

Figure 4

Histopathology of human ‘chronic’ epididymitis and a mouse epididymitis model. Seven days post infection with uropathogenic E. coli (UPEC) fibrotic transformation, epithelial degeneration and ductal obstruction (yellow line) are visible in mice (B) comparable to the histopathology observed in ‘chronic’ epididymitis in men (A) (azan staining; from Michel et al. (2016)). Reprinted with permissions from Wiley and Sons (license number: 3973511270642).

Figure 5

Lessons learned from animal models of testicular and epididymal infection and inflammation. BC, basal cell; BM, basement membrane; BTB, blood–testis barrier; DC, dendritic cell; ECM, extracellular matrix; GC, germ cell; IL, interleukin; LC, Leydig cell; M, macrophage; MC, mast cell; MCP, monocyte chemotactic protein; N, neutrophils; NC, narrow and clear cell; NO, nitric oxide; PC, principal cell; PTC, peritubular cell; SC, Sertoli cell; SMC, smooth muscle cell; TC, T cell; TM, testicular macrophage; TNF, tumor necrosis factor; T_reg, regulatory T cell.