The endometrium showcases a sophisticated interplay among a network of cells, manifesting as a meticulously orchestrated phase encompassing proliferation, differentiation, and menstrual shedding (31, 32). The formation of cytokines, the expression of cytokine receptors, and the modulation of endometrial functions by these factors underscore the pivotal role of cytokines in operating at endocrine, paracrine and autocrine levels within the endometrium. Increasingly, there is compelling evidence pointing to the participation of immune cells and inflammatory mediators in the development of endometriosis (33). In our study, IL-17A and IL-17R were identified in endometrium and adenomyosis, and the fold change levels of IL-17A and IL-17R were both significantly higher in adenomyosis than in endometrium, implicating that IL-17 system functions as a local immunomodulatory factor in adenomyosis.
In endometriosis patients, various active substances, including cytokines, growth factors, hormones, and oxidative stress parameters, have been identified at different stages of the disease (34). An analysis revealed that the primary contributors to inflammation in endometriotic women were cytokines produced by macrophages (35). IL-17A has been noted to function as a chemotactic agent for macrophages via its receptor, IL-17RA, and can also trigger M2 macrophage polarization in endometriotic patients (36). Additionally, the researchers suggest that IL-17A plays a role in recruiting macrophages (37), and M2 macrophages have indeed been demonstrated to facilitate extracellular matrix remodeling and neovascularization, closely linked to the development of endometriosis (38–40). The heightened production of tumor necrosis factor, triggered by activated macrophages, along with the effect of IL-17 on endometrial cells, hastens the formation of endometriosis, often leading to unexplained pelvic pain and infertility. Moreover, recent research indicated that increased IL-17 levels in PF from patients with endometriosis-associated infertility might stimulate peritoneal macrophages to produce nitric oxide synthase 2 (NOS2) and nitric oxide (NO), which can have detrimental effects on both men’s and women’s reproductive systems (41). Therefore, elevated levels of IL-17 are associated with infertility in endometriosis.
As the research delves deeper into cytokines and endometriosis, there is increased reporting and wider confirmation of elevated IL-17 levels in endometriosis, particularly during the early stages of the disease (37, 42). Zhang and colleagues were the first to demonstrate elevated IL-17 levels in the PF of endometriotic individuals. Furthermore, they found a relationship between the IL-17 concentration in PF and the advancement of the illness. Specifically, the IL-17 concentrations in PF were notably elevated in individuals with minimal/mild endometriosis compared to those without endometriosis and individuals with moderate/severe endometriosis. Additionally, their research indicated that the IL-17 concentration in PF was linked to infertility associated with endometriosis (43). Salmeri et al. proposed that this observation could be explained by the notion that the inflammation appears to diminish in more advanced stages of endometriosis (44). Furthermore, other studies have shown heightened levels of IL-17A in both the PF and plasma of endometriotic patients compared to controls, along with the production of IL-17A by lesions of endometriosis (37, 42, 45). One research reported that they observed IL-17A levels increased comparably in both follicular fluid and serum in cases where infertility and endometriosis coexisted (46). Another study showed that cells positive for IL-17A were localized around the vasculature and in the stroma in both endometrium and endometriotic tissues from endometriotic patients (47). Additionally, one research found a higher percentage of Th17 cells in PF compared to the blood in endometriotic women. The result of this research also revealed in the PF of severe endometriosis, the Th17 cell percentage was higher compared to early-stage (I/II) endometriosis (48). Considering the facts mentioned above, it's apparent that in women with endometriosis, the IL-17 level commonly rises, often observed in both blood and PF samples.
Histologically, adenomyosis is characterized by ectopic endometrial tissue within the myometrium. Despite extensive research, its underlying causes remain unclear, with many aspects of its development still unknown. One identified mechanism contributing to adenomyosis is the heightened ability of certain endometrial cells to invade the myometrial tissue. Additionally, both local and systemic immune responses have been linked to the onset and maintenance of the condition. Immune system involvement coincides with hormonal irregularities and activation of the epithelial to mesenchymal transition pathway, facilitating the migration of endometrial cells (5). Exploring the IL-17 system may offer novel perspectives on the pathogenesis of adenomyosis. In a prior study, they concluded that regulated by cytokines and estrogen, IL-17 secretion increases, either stemming from Th17 differentiation or stromal cells of endometrium. IL-17 then enhances the development, proliferation, and ectopic invasion, promoting immune evasion and endometriotic development by inducing and recruiting the M2 macrophage differentiation (36). In conjunction with our results, the IL-17 system might participate in the formation of ectopic endometriotic lesions.
Nevertheless, this study also has several limitations. Methodologically, this study is disadvantaged by an inability to completely control for selection and confounding biases. Despite being the first published study reporting on expression of IL-17 system in adenomyosis, the number of patients with adenomyosis was small. Therefore, this population was not generally representative. Furthermore, the study design limited our ability to infer causality between IL-17 system and adenomyosis.