Role of neuropeptides in patients with endometriosis: a literature review

Background This article provides an overview of the role of neuropeptides in endometriosis. Main body. While the pathogenesis of endometriosis is not discovered exactly yet, researchers have explored endocrine, parac- rine, and immunological influences to better understand the disease. Neuropeptides, which play a significant role in regulating communication among endometrial cells, have been extensively studied and found to have effects on neurons and other somatic cells. The interplay between neuropeptides, pain, and the immune response suggests that neuropeptides may play a significant role in the development and progression of endometriosis.

We investigate the role of nerve fibers and neuropeptides, estrogen and estrogen receptors, and new biomarkers in promoting inflammation and pain in endometriosis. Further research should focus on the roles and therapeutic potential of neuropeptides in endometriosis.

Neuropeptides, Endometriosis, Pain, Inflammation

Endometriosis is a long-term gynecological condi - tion characterized by the existence of tissue similar to the endometrium outside the uterus. It impacts around 5–10% of women of reproductive age worldwide [1]. The most prevalent symptoms of endometriosis, regardless of lesion location, are infertility and pain [2]. Patients often experience chronic pain throughout their reproductive years [3]. Recent research has indicated that endometrio - sis lesions undergo various cellular transformations, including fibroblast-to-myofibroblast transdifferentia - tion (FMT), fibrosis epithelial-mesenchymal transition (EMT), and smooth muscle metaplasia (SMM) [4]. These changes lead to the formation of glands, stromal cells, and dense fibrotic tissues. Induction of pain in this context is attributed to the interaction of nerve fibers and cytokine- releasing inflammatory cells such as macrophages, which induce a neurogenic inflammatory pathway [5]. The precise pathogenesis of endometriosis remains incompletely understood [6]. However, the endome - trium in women with endometriosis displays specific biochemical differences in comparison to those without the condition [7]. Researchers have explored endocrine and paracrine influences, as well as immunological fac - tors, in order to better understand the disease. A range of growth factors, gene expression patterns, immune cells, cytokines, neuropeptides, and hormones present in the *Correspondence: Marziyeh Ajdary [email protected] Zahra Shams Mofarahe [email protected] 1 Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 Preventative Gynecology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran 3 Endometriosis Research Center, Iran University of Medical Sciences, Tehran, Iran 4 Reproductive Sciences and Technology Research Center, Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran Page 2 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 ectopic (abnormal) and eutopic (normal) endometrium are involved in the pathophysiology of endometriosis [8]. The human endometrium possesses secretory proper - ties and exhibits the characteristics of a neuroendocrine organ. Neuropeptides, which are small peptide molecules consisting of 3 to 100 amino acids, play a significant role in regulating communication among endometrial stro - mal and epithelial cells, as well as interactions between endometrial and myometrial cells [9]. These neuropep - tides have been thoroughly researched, and their impacts are well-documented [10]. Neuropeptides act locally or at a distance depending on the presence of specific receptors. They can affect neu - rons as well as other somatic cells indicating a wide range of effects [11]. Moreover, neuropeptides not only serve as targets for research and treatment but also hold potential as diagnostic markers, aiding in the understanding of the etiology and pathogenesis of various disorders [10]. It is becoming increasingly clear that the immune response and pain are interconnected and have common mechanisms. Nerve activation releases neuropeptides, which subsequently facilitate the recruitment and acti - vation of leukocytes, a phenomenon known as neuro - genic inflammation [12]. Similarly, when leukocytes are attracted to the area of nerve injury, they release factors that induce pain, including chemokines, lipid mediators, cytokines, growth factors, and neuropeptides, which play a role in pain production [13]. The interaction between pain-enhancing cytokines and pro-inflammatory neuro - peptides establishes a positive feedback loop that perpet - uates both inflammation and pain. This phenomenon is known as neuropathic pain [14]. The pathophysiology of pain linked to endometriosis involves inflammatory and hormonal changes, as well as alterations in brain signaling pathways [15]. Given that pain and inflammation are hallmark symptoms of endo - metriosis, and considering the role of neuropeptides in pain and inflammation in various body systems, based on evidence, neuropeptides are associated with the progres - sion and development of endometriosis. The present arti- cle provides an overview of the effect of neuropeptides on endometriosis (Fig. 1).

A thorough literature review was carried out to assess the role of neuropeptides in endometriosis patients. The review process employed a systematic approach to guar - antee the inclusion of pertinent and high-quality studies. Search strategy The Scopus, PubMed, and Web of Science databases were searched. The search covered all articles published up until April 2024. Keywords used in the search included combinations of terms such as “neuropeptides, ” “endo - metriosis, ” “pain, ” “inflammation, ” “pathophysiology, ” and “treatment. ” Boolean operators (AND, OR) were used to refine the search and ensure the inclusion of stud - ies specifically addressing the role of neuropeptides in endometriosis. Inclusion and exclusion criteria To identify relevant papers, certain exclusion and inclu - sion criteria were established. The inclusion criteria were as follows: • Original research articles, reviews, and meta-analy - ses focusing on neuropeptides in the context of endo- metriosis. • Studies published in English. • Studies involving human subjects or animal models relevant to endometriosis. • Articles that provided clear data on the effect of neu - ropeptides on the pathogenesis, symptoms, or treat - ment of endometriosis. Exclusion criteria included: • Studies not directly related to neuropeptides or endo- metriosis. • Non-peer-reviewed articles, conference abstracts, and editorials. • Articles published in languages other than English. • Studies with insufficient or inconclusive data regard - ing neuropeptides and their role in endometriosis. Study selection and data extraction Following the initial search, duplicates were eliminated, and the abstracts and titles of the remaining papers were screened and their full texts were subsequently reviewed to assess eligibility considering the established exclusion and inclusion criteria. Data from the chosen studies were extracted, including details on study design, population, key findings related to neuropeptides, and their implica - tions for endometriosis. Quality assessment The quality of the papers was evaluated by standardized criteria, taking into account factors such as methodology, study design, sample size, and the clarity of the reported findings. Studies that met the quality standards were incorporated into the final review. Menstruation involves an inflammatory process marked by elevated levels of various tissue-resident immune cells. The intricate interplay between uterine stromal cells and these resident immune cells regulates Page 3 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 the production and secretion of chemokines, pro-inflam - matory cytokines, and prostaglandins (PGs), culminating in localized vasoconstriction [16]. Anatomical anoma - lies, obstructions, and any other causes for a retrograde flow of menstrual materials can implant endometrial tis - sue remnants into the peritoneal cavity [17]. The endo - metriosis existence in women is also linked to a rise in both the number and activity of macrophages, as well as the humoral immune response. However, cell-medi - ated responses such as natural killer cell cytotoxicity are decreased in this condition [18]. During lesion formation, recruited inflammatory cells release various proinflammatory factors. M1 mac - rophages, contributing to the early stages of injury and pro-inflammatory responses, produce cytokines and chemokines, fostering myoblast proliferation. In patients with endometriosis, peritoneal macrophages exhibit heightened NF-κB activation and increased expres - sion of IL-1β, IL-6, IL-8, TNF-α, and TGF-β, fostering an appropriate microenvironment for endometrial cell attachment, invasion, and angiogenesis [19]. Besides, endometrial tissue hypoxia in the peritoneal environ - ment upregulates the generation of hypoxia-induci - ble factor-1α (HIF-1α). This can enhance VEGF levels enhancing vascular endothelial cell production. COX-2 plays a role in connecting angiogenesis in endometriotic tissue to inflammation. COX-2 promotes the genera - tion of prostaglandin E2 (PGE2) and VEGF and activates MMP-1, 2, and 9, thereby remodeling the extracellular matrix and facilitating angiogenesis [20, 21]. Angiogen - esis occurs within the initiation phase (< 3 days post- disease onset), and supports the growth, implantation, Fig. 1 Role of neuropeptides in inducing the endometriosis Page 4 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 survival, and migration of endometriotic lesions. Addi - tionally, robust angiogenesis creates favorable conditions for nerve-ending growth, which causes pain symptoms attributed to endometriosis [22, 23]. Prostaglandins play a crucial role as mediators of chronic inflammation [24]. Increased levels of PGF2α and PGE2 in patients with endometriosis are positively associated with the severity of vaginal hyperalgesia. PGs interact with cytokines, amplifying cytokine actions on inflammatory cells and influencing their pathogenic conversion through gene expression regulation. This enhancement occurs through the induction of relevant cytokine receptors and collaboration with cytokines at the transcriptional level to activate NF-κB, which results in the expression of genes associated with inflammation. This signaling pathway boosts the expression of various genes induced by NF-κB, including chemokines, which facilitate the ongoing infiltration of neutrophils and mac- rophages, thereby intensifying chronic inflammation [25]. Additionally, PGE2, PGF2α, glycodelin, TGF-β, and TNF-α cause the induction of pain related to endome - triosis [26]. After subsiding the initial inflammatory response of M1 macrophages, M2 macrophages become the domi - nant subtype of macrophages in endometriotic lesions. These macrophages secrete growth factors anti- and inflammatory cytokines playing a crucial role in the growth of ectopic endometrial tissues and their repair and remodeling [27–29]. In the peritoneal fluid (PF) of endometriosis patients, there is a significant increase in both activated mast cells and mast cells. These cells are capable of produc - ing costimulatory molecules, growth factors, and a range of pro- and anti-inflammatory mediators. Notably, mast cells also play a role in neuropathic pain by directly sen - sitizing/activating primary nociceptive neurons through mediators such as histamine, leukotrienes, prostaglan - dins, IL-1, IL-8, serotonin, and nerve growth factor (NGF). They can also indirectly contribute by recruiting leukocytes that release Pain-causing mediators [27, 30]. Elevated IL-8 in endometriotic lesions acts as an auto - crine regulator, stimulating cell proliferation and causing angiogenesis, recruitment of neutrophils, and contrib - uting to the shift from acute to chronic inflammation. Neutrophils themselves release IL-8 and IL-17, fur - ther reinforcing this vicious cycle [19]. In a synergistic manner, cell adhesion, TGF-β1, and pro-inflammatory cytokines (TNF-α or IL-1β) elevate the VEGF and IL-8 expression in endometrial stromal cells through the p38/ERK1/2 signaling pathways [23]. Moreover, neutro - phils in the abdominal cavity of endometriosis patients secrete VEGF and enhance the growth of lesions. This collective action of neutrophils and secreted IL-8 and IL-17 contributes to endometriosis pathogenesis, poten - tially transitioning from acute to chronic inflammation [19, 31]. Nervous system response further increases peritoneal inflammation Following the onset of endometriosis, various inflam - matory cells are attracted to the lesion as a result of inflammatory processes initiated by endometrial debris [32]. Subsequently, chemokines, several cytokines (IL- 1β, TGF-β, IL-8, IL-6, TNF-α, etc.), and inflammatory mediators such as NGF and brain-derived neurotrophic factor (BDNF) are released [26, 33, 34]. NGF is a protein that is essential for the growth, maintenance, and sur - vival of specific nerve cells, particularly sensory neurons. It is produced by inflammatory cells, with its produc - tion being stimulated by cytokines like TNF-α and IL-1β. Importantly, the expression of NGF and its receptor, TrkA, significantly increases, within the endometriotic epithelium and stroma [35–37]. The signaling pathway activated by NGF-TrkA is implicated in chronic pain and neuroinflammation [38]. NGF promotes the expression of SP and CGRP , which in turn contribute to the prolif - eration of nociceptors and an increase in the number of sensory neurons. Concurrently, under the influence of NGF and BDNF, there is an elevation in the total nerve fiber density. Ultimately, the escalated levels of BDNF and NGF culminate in the persistence of inflammatory pain [39, 40]. In this context, NGF causes the stimulation of mast cell degranulation. The perpetuation of persistent inflammation is intricately linked to the sustained acti - vation of MCs, leading to the release of IL-4, IL-6, and prostaglandins [41], which in turn, activate NF-κB, facili - tating the expression of genes associated with inflamma - tion [25]. BDNF is a distinct neurotrophin, which exerts regula - tory effects on cell proliferation, viability, and specializa - tion across various neuronal subclasses [42]. BDNF plays a crucial role in facilitating the transition from acute to chronic pain states [43]. Elevated levels of BDNF can be detected in both plasma and PF samples from women with endometriosis compared to those who do not have the condition. Notably, IL-1β further stimulates BDNF production through an IL-1 receptor-dependent pathway that is mediated by JNK and NF-κB [25, 44]. The raised up BDNF level promotes the growth, survival, and differ - entiation of various neuron types [33, 42]. These compo- nents contribute to inflammation development, fostering hurtful pain in the nervous system [45]. Women in the advanced stages of endometriosis tend to show a higher density of nerve fibers in the lower uterine myometrium compared to those without the condition [46]. Various neurotransmitters and neural Page 5 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 proteins, including transforming growth factor β1 (TGF- β1), CGRP, neurofilament, SP , and vesicular monoam - ine transporter (VMAT), are found in the nerve fibers within endometriotic lesions. Specifically, the endome - trium functional layer contained sensory C fibers that expressed higher levels of vasoactive intestinal substance P (SP ), neuropeptide Y (NPY ), polypeptide (VIP), and calcitonin gene-related peptide (CGRP). The endome - trium basal layer exhibited sensory C fibers, sensory Ad fibers, and adrenergic fibers. The myometrium dis - played sensory C, adrenergic, and cholinergic fibers in both women with/ without endometriosis. However, sensory C fibers were exclusively found in the endome - trium functional layer in women with endometriosis[7]. In different human and animal studies, it has been dem - onstrated that the balance in the distribution of sensory and sympathetic neurons has been changed to the favor of sensory neurons about 20-folds compared to the phys - iological conditions. It is of high importance because of the unique secretory profile of each type of nerve fiber and the influence of secreted neurotransmitters on the immune cells and inflammatory processes [31]. The con - tinuous activation of sensory nerve fibers induces the secretion of proinflammatory neuropeptides, like CGRP and SP , in proximity to endometrial lesions [47]. These neuropeptides are released because the abnormal endo - metrial tissue can produce inflammatory molecules like prostaglandins and cytokines, which irritate and activate sensory nerves surrounding the lesions. Endometrial implants provoke a local immune response, leading to chronic inflammation [48]. This inflammation sensitizes nerve fibers, prompting them to release neuropeptides. These neuropeptides contribute to neurogenic inflam - mation by promoting vasodilation, increasing vascular permeability, and recruiting immune cells, which further aggravates inflammation around the lesions [49]. Addi - tionally, the activation of sensory afferent nerves and pro- inflammatory neuropeptide release may trigger mast cell recruitment, leading to the release of proinflammatory cytokines, including PGE2, NGF, TNF, and interleukins, like IL-1β and IL-8. This inflammatory response further stimulates locally circulating mast cells and macrophages [50, 51]. The increase in the ratio of sensory nerves to sympathetic nerve fibers is also indicative of the transi - tion from acute to chronic inflammation [52, 53]. Sensory nerves play are linked to the fibrogenesis and development of endometriosis. SP released from sen - sory cells has been shown to activate signaling pathways that promote EMT , FMT, and the conversion of stro - mal cells into smooth muscle cells (SMCs) within endo - metriotic lesions, ultimately causing fibrosis [54]. In a mouse model, sensory nerve fibers have been identified as facilitators of fibrogenesis in endometriotic lesions. Additionally, CGRP and SP function as vasodilators and promote M2 polarization, activating signaling path - ways that lead to platelet extravasation and aggregation. TGF-β1 protein concentrations are notably elevated in the nerve fibers of peritoneal endometriosis lesions in comparison to the peritoneum of patients with no endo - metriosis [55]. These lesions are recognized as being hyper-innervated due to neurogenesis prompted by neu - rotrophins released from the lesions and possibly from platelets. These neurotrophins appear to promote the production of sensory neurons over sympathetic neu - rons. Research has indicated that sensory denervation has a more pronounced effect on reducing the weight of endometriotic lesions and alleviating hyperalgesia than sympathetic denervation. Both sympathetic and sensory denervation decrease immunoreactivity to proliferation and fibrosis markers, with sensory denervation exhibiting more significant effects [4]. Additionally, there is a strong association between neuropeptide-Y (NPY ) sympathetic nerves present in the inferior hypogastric plexus and the neoangiogenesis necessary for endometriosis develop - ment. Possover et al. found significantly higher amounts of NPY sympathetic nerves in endometriosis-infiltrated tissue compared to “non-involved” genital tissue which could contribute to induce pain [56]. Notably, the abun - dance of nerve fibers seems to be influenced by the location of endometriosis, with a higher concentration observed in instances of deep infiltrating endometriosis [57]. Endometriotic lesions secrete a variety of proinflam - matory cytokines that activate transcription factors like NF-κB, which promotes the expression of neurotro - phins, such as NGF and BDNF. Neurotrophins bind to Trk receptors (e.g., TrkA for NGF, TrkB for BDNF) and p75 neurotrophin receptors on sensory nerve fibers [58]. Neurotrophin binding to Trk receptors activates the Ras-Raf-MEK-ERK signaling cascade, which causes the phosphorylation and activation of ERK (MAPK/ ERK Pathway), which translocates to the nucleus and promotes the transcription of genes linked to neuronal growth and differentiation. As a result, the nerve fibers in and around the endometriotic lesions undergo neurogen- esis, contributing to hyper-innervation [59]. Trk receptor activation also triggers the PI3K/Akt signaling pathway, which is linked to cell survival and the enhanced innerva- tion of endometriotic lesions [60]. Neurotrophins not only promote nerve growth but also contribute to neurogenic inflammation. Sensory nerves stimulated by neurotrophins can release neuro - peptides like SP and calcitonin CGRP , which enhance inflammation, vascular permeability, and immune cell recruitment, creating a cycle of inflammation, nerve acti - vation, and pain [61]. The production of neurotrophins Page 6 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 by endometriotic lesions is part of a positive feedback loop, where increased neurogenesis leads to enhanced nerve sensitization and inflammation. The neurogenic inflammation in turn triggers further neurotrophin release, promoting more nerve growth and contributing to the chronic nature of endometriosis [57]. Pain in endometriosis In endometriosis, normal autonomic equilibrium of parasympathetic and sympathetic activity is disturbed. Decreased parasympathetic control as well as increased sympathetic activity causes an increase in nociceptive input, thereby facilitating the transmission of painful stimuli [62]. Following local tissue injury or inflammation, nocicep - tors may undergo an enhanced sensitivity to pain, a phe - nomenon attributed to the neuroplasticity of peripheral sensory nerves. This pain sensitization process encom - passes a lowered threshold for activation of peripheral sensory neurons and an enhanced responsiveness [27]. The pain associated with endometriosis is not solely determined by the quantity and arrangement of nerves, but also by the presence of specific neurotrophic factors, notably BDNF and NGF. NGF, in particular, induces the production of SP and CGRP by activating TrkA receptors and initiating intracellular signaling pathways (MAPK/ ERK and PI3K/Akt), leading to increased expression and release of these neuropeptides, both of which are neu - ropeptides intricately involved in modulating the trans - mission of pain signals. Additionally, NGF facilitates the proliferation of nociceptors, enhances the population of sensory neurons, and is involved in sustaining inflam - matory pain over time [40, 63]. In the context of endo - metriosis, there is a notable elevation in NGF expression within invasive lesions in comparison to noninvasive lesions [37]. NGF not only is involved in promoting neu - ronal development and survival but also exerts its effects on the peripheral nociceptor terminal, notably through the interaction of NGF with the TrkA receptor [64]. NGF can undergo retrograde transport to the nocicep - tor nucleus, where it enhances the expression of nocicep- tive proteins such as TRPV1, and the Nav1 voltage-gated sodium channel subunit [65, 66]. In animal models of endometriosis, there was observed an increase in the expression of TRPV1 in the dorsal root ganglion [67]. Furthermore, elevated levels of TRPV1 in individuals with endometriosis were highly correlated with pain [68, 69]. Besides, NGF trigger mast cell degranulation and increase secretion of prostaglandin, which are considered one of the main mediators of chronic inflammation and directly generate pain. Furthermore, prostaglandins have the capability to stimulate nerve endings, triggering pain sensation and the release of additional pain-inducing agents, including NGF, histamine, serotonin, and pros - tanoids, either from adjacent cells or afferent nerves and induce a vicious cycle with the output of pain [27]. Nerve injury-induced protein 1 (Ninj1) is another key contributor to neurite outgrowth and pain sensation. It has been indicated that in endometriosis, proinflam - matory cytokines such as IL-1β elevate Ninj1 mRNA expression in endometriotic stromal cells. This suggests that Ninj1, induced by inflammation within endometri - otic sites, could contribute to the development of pain by facilitating neuroinflammation, immune cell recruit - ment, and interactions between nerves and endometrial lesions [70]. Ninj1 is upregulated in response to pro - inflammatory cytokines, including TNF-α and IL-1β, which are abundant in the inflammatory environment of endometriosis. Ninj1 facilitates cell adhesion between sensory nerves and immune cells such as macrophages and T-cells, promoting neuro-immune crosstalk [57]. NF-κB and MAPK/ERK signaling pathways are activated in nerve fibers, leading to the production of proinflam - matory mediators and neuropeptides like SP and CGRP [71]. Immune cell recruitment and nerve sensitization occur, enhancing neurogenic inflammation and pain per- ception. Finally, chronic pelvic pain is maintained by the continued sensitization of nerve endings and the hyper- innervation of endometriotic lesions [72]. Beyond its involvement in neurogenesis, Ninj1 has been implicated in promoting angiogenesis, modulating p53-dependent cell survival and senescence, and mediat - ing leukocyte migration, thus exacerbating inflammation. These multifaceted properties of Ninj1 are pivotal in the pathogenesis of endometriosis, suggesting its potential impact not only on pain symptoms but also on the pro - gression of the disease itself [70]. The role of estrogen in pain and neuroinflammation in endometriosis Endometriosis lesions consist of specific cells, which exhibit different responses to estrogen and progester - one [73]. The significant effect of estrogen on facilitating communication between immune cells, like mast cells, and macrophages and nerve fibers in endometriosis has been demonstrated [74]. Macrophages as a crucial con - tributor in the endometriosis pathophysiology affect lesion proliferation and vascularization. They are often located around nerve fibers within endometriosis lesions. It has been elucidated a bidirectional interaction between nerves and macrophages in endometriosis, which is mediated by estradiol, a ligand produced in lesions due to the overexpression of steroidogenic enzymes like aro - matase [75]. Estradiol facilitates an elevation in chemokine ligand 2 (Ccl-2) production via nerve fibers. This increase in Page 7 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 Table 1 The mechanisms, their descriptions, and the associated signaling pathways that are influenced by estradiol in endometriosis Mechanism Description Signaling Pathways Promotes growth of endometriotic lesions [87] Estradiol promoting lesion growth ERK/MAPK pathway: Activated by estrogen binding to estrogen recep- tors (ER-α, ER-β) to promote cell growth Local production of estradiol [88] Endometriotic lesions produce estradiol locally via overexpression of aromatase, creating a positive feedback loop for growth Aromatase signaling: Increased expression of aromatase converts androgens to estradiol locally Enhances inflammation [89] Estradiol increases proinflammatory cytokine release, sustaining chronic inflammation NF-κB signaling: Activated by estradiol to increase the production of proinflammatory cytokines Stimulates angiogenesis [90] Estradiol promotes the formation of new blood vessels by upregulating VEGF VEGF/ERK pathway: Estradiol stimulates VEGF production, which drives angiogenesis through the ERK pathway Modulates immune function [91] Estradiol alters immune responses, reducing NK cell activity and pro- moting macrophage-mediated inflammation ER signaling in immune cells: Estrogen influences immune cell activity and cytokine release Enhances nerve growth and sensitization [92] Estradiol promotes nerve growth (via NGF) and sensitizes sensory nerves, increasing pain perception in endometriotic lesions NGF/TrkA pathway: Estradiol upregulates NGF, activating nerve growth through TrkA signaling Contributes to progesterone resistance [93] Estradiol contributes to progesterone resistance, reducing the inhibi- tory effect of progesterone on lesion growth PI3K/Akt pathway: Estradiol-mediated signaling leads to reduced responsiveness to progesterone Therapeutic target [94–96] Treatments such as aromatase inhibitors, GnRH agonists, and SERMs target estradiol to inhibit lesion growth and inflammation ER signaling: Therapeutics aim to block estrogen receptor activation or inhibit estrogen production Page 8 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 Ccl-2 attracts macrophages, which subsequently exhibit heightened expression of BDNF and neurotrophin-3 (Nt- 3), thereby inducing neurotrophic effects on nerves [75]. The estrogen-induced activation of mast cells can lead to the NGF release and sensitization of dorsal root ganglion cells [76]. Activating mast cells can also result in the pro - gression of neuropathic pain by recruiting leukocytes, which secrete pain-inducing mediators [77]. Estrogen plays a central role in endometriosis progression by bind- ing to different estrogen receptors (ER ) present in the disease. The specific action of estrogen on endometriosis depends on the type and distribution of these receptors [78]. For instance, elevated ERβ expression and increased ERα expression in endometriotic lesions are key factors in estrogen action [79]. Cross-talk between ERα and interleukin (IL6) pathways has also been implicated in promoting the early initiation of endometriosis [80]. In the context of neuroinflammation and pain associ - ated with endometriosis, it is recognized that the dis - ease is dependent on estrogen. Estrogen stimulates the chemokine secretion from peripheral nerves, which leads to the macrophage recruitment and polarization in endometriotic tissue. These macrophages, then are involved in the expression of NGF, contributing to an imbalance in neurogenesis in an estrogen-dependent pat- tern [81]. The coexistence of macrophages and nerves under estrogen influence creates a novel neuro-immune communication [74]. Inflammatory cytokines released by macrophages continuously activate peripheral nerve nociceptors, resulting in neuroinflammation by releas - ing inflammatory neurotransmitters. This estrogen-regu- lated neuro-immune interaction can sensitize peripheral nerves and cause neuropathic pain due to endometriosis [36]. Macrophages are the main producers of chemokines pro-inflammatory and cytokines in this condition. Fur - thermore, both ERβ and ERα are significantly overex - pressed in macrophages linked to endometriosis[82]. There is evidence suggesting that estrogen also influ - ences alterations in nerve fiber patterns. Specifically, estrogen has been observed to inhibit the outgrowth of sympathetic nerve fibers by regulating the synthesis of BDNF [83]. Furthermore, in environments with elevated concentrations of estrogen, heightened levels of NGF tend to facilitate the growth of sensory nerve fibers while concurrently inhibiting the outgrowth of mature sym - pathetic ganglia. Consequently, estrogen plays a crucial role in regulating aberrant innervation within the female reproductive system [84, 85]. Notably, progesterone has been shown to reverse estrogen effects on sympathetic nerve fibers, suggesting its efficacy as a pain-relieving therapeutic agent for endometriotic patients [86]. We summarized the role of estrogen in endometriosis in Table 1. The contribution of neuropeptides to endometriosis In endometriosis, intense pain episodes frequently occur during menstruation. The dysregulation of inflammatory signaling pathways and the release of neurotransmitters, particularly CGRP, are associated with the onset of acute pain episodes[97]. The increased expression of neuropeptides and neuro - trophins is a significant contributor to the development of hypersensitivity in endometriosis. Some studies have shown elevated levels of the neurotransmitter TAC1 which encodes the neuropeptide substance P in endo - metriosis lesions. Pro-inflammatory cytokines (TNF-α and IL-1β) are able to stimulate the expression of TAC1 in surrounding neurons and immune cells, leading to increased Substance P levels. Substance P , in turn, can further promote inflammation by recruiting immune cells like macrophages and mast cells, creating a vicious cycle [98]. Also, the presence of more nerves in the lesions can increase the local production and release of TAC1-encoded neuropeptides. Elevated levels of TAC1 and SP can promote the formation of new blood vessels, supporting lesion growth and persistence [99]. SP has been immunolocalized to these lesions suggesting hyper - sensitization of nerves within the peritoneal lining of women with pain and shedding light on the mechanisms underlying chronic hypersensitivity [100]. Additionally, neuropeptide hormones such as neurotrophin-3 (NT-3) and nerve growth factor (NGF), released from peritoneal lesions, promote the growth of nerve fibers in and around endometriotic lesions, which contributes to adhesions and pain [101]. Neurotrophic factors, including NGF, are crucial for neural sprouting and hypertrophy, which may lead to an increased density of nerves in endometriosis. NGF can lower the activation threshold of certain noci - ceptors and trigger the release of pain-related neuropep - tides, resulting in hyperalgesia [102]. Neuropeptides and neurotransmitters seem to have important roles in the development and symptoms of conditions like endometriosis and adenomyosis. Phoe - nixin, referred to as PNX-14, is a newly identified neu - ropeptide [103]. In both in  vitro and in  vivo preclinical studies, Phoenixin has demonstrated beneficial effects by reducing inflammation and oxidative stress. This posi - tions Phoenixin as a promising candidate for the develop- ment of new anti-inflammatory medications, especially for treating endometriosis [104]. Phoenixin, known as PNX-14, functions as a neuropep - tide that regulates the hypothalamic-pituitary–gonadal (HPG) axis and reproductive functions. Research has shown that the Phoenixin precursor protein and its receptor are present in the human endometrium, with reduced levels of PNX-14 noted in cases of endome - triosis. Decreased PNX-14 levels are associated with an Page 9 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 increased LH/FSH ratio and higher 17β-estradiol levels in endometriosis with ovarian involvement. This suggests a potential role for PNX-14 in addressing endometrial epithelial dysfunction and implies its potential effective - ness in treating endometriosis [105, 106]. Kisspeptin, another neuropeptide, is associated with regulating the hypothalamic-pituitary–gonadal (HPG) axis and reproductive functions [107]. Studies have explored the connection between dysregulations of the KISS1/KISS1R system and issues such as infertility, pre - mature ovarian failure, and abnormal puberty onset, but clear results are yet to be established [108]. Research has also shown differential expression of Kisspeptin and its receptor in endometriosis patients which may contrib - ute to the invasiveness of this condition. This suggests a potential role of Kisspeptin in addressing endometriosis invasiveness [109]. In endometriosis, the altered expres - sion of Kisspeptin and KISS1R can affect several key path- ways, such as PI3K/AKT, ERK/MAPK, NF-κB, mTOR, and others [110, 111]. These pathways are involved in processes such as cell proliferation, inflammation, apop - tosis resistance, angiogenesis, and tissue remodeling. The precise effects of Kisspeptin signaling in endometriosis likely depend on the local hormonal and inflammatory environment, which may lead to either promotion or suppression of lesion growth and survival [112]. Akad et  al. in their study compared serum kisspeptin levels in female patients with endometriosis and infertility to those of healthy patients with regular menstruation and at least one child. They found significant differences in kisspeptin levels between the two groups. The research - ers concluded that elevated serum kisspeptin values in endometriosis patients may represent compensatory- adaptive mechanisms that help restrain the spread of endometriomas in the early stages of the disease. Thus, the KISS1/KISS1R system plays a crucial role in repro - ductive functions [3]. In contrast, Abdelkareem et  al. reported the opposite results in their study. They found significantly lower kisspeptin levels in patients with ovar - ian endometriomas compared to healthy patients. They proposed that the downregulation of KISS1 levels might contribute to the invasiveness of endometrial implanta - tion [112]. Galectin-3 contributes to the development of endo - metriosis through its involvement in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, TGF-β/SMAD, NF-κB, FAK, and ERK/MAPK [113, 114]. Galectin-3 can stabilize β-catenin via the Wnt/β- catenin signaling pathway in the cytoplasm and facili - tate its translocation to the nucleus, where it promotes the transcription of target genes associated with prolif - eration and invasion, thereby contributing to the persis - tence and dissemination of endometriotic lesions [115]. Also, Galectin-3 can activate FAK signaling, promoting the adhesion and invasive behavior of endometrial cells in ectopic sites [116]. Yamashita et al. found that galec - tin-3 in the endometrium plays a role in the develop - ment of endometriosis by enhancing the survival and engraftment of eutopic endometrial cells within the peritoneal cavity. They noted that galectin-3 was over - expressed and secreted by eutopic endometrial stromal cells in patients with endometriosis compared to those without the condition. Galectin-3 promoted the adhe - sion and migration of endometrial stromal cells, while inhibitors of galectin-3 hindered these processes. Addi - tionally, galectin-3 diminished the cytotoxicity of natu - ral killer cells against endometrial stromal cells without influencing cell proliferation [117]. Urocortin ( UCN) is a neuropeptide that is part of the corticotrophin-releasing hormone ( CRH) family, and its expression in both eutopic and ectopic human endo - metria has been extensively investigated concerning endometriosis [118]. Neuropeptides associated with endometrial stress, such as CRH and UCN , appear to exert their biological effects locally within the uterus, as both the human endometrium and myometrium express the relevant receptors, particularly endometrial CRH [119]. CRH plays a role in enhancing inflammation and pain through the CRF-R1 receptor, leading to recruit - ing immune cells and the release of inflammatory mediators [120]. UCN mainly acts through the CRF- R2 receptor, where it can promote anti-inflammatory responses, tissue protection, and cell survival [121]. Both neuropeptides influence several pathways, includ - ing the cAMP/PKA and MAPK/ERK pathways, which are involved in inflammation, immune modulation, pain, and cell survival. CRH contributes to the pro- inflammatory environment in endometriosis and pro - motes chronic pain, while UCN has a more protective role, balancing inflammation and promoting lesion sur - vival [8 , 122]. Vergetaki et  al. revealed that both CRH and UCN receptor subtypes, CRHR1b and CRHR2a, were pre - sent at endometriotic sites. Moreover, their expression was significantly higher in the eutopic endometrium of women with endometriosis compared to healthy women, observed at both the mRNA and protein levels. These

indicate that CRH and UCN may play an immu - noregulatory role in endometriotic sites, potentially influencing reproductive processes such as decidualiza - tion and implantation in women with endometriosis [8]. Vergetaki et al. propose that Galectin-1 may play a sig - nificant role in the pathology of endometriosis and the infertility issues experienced by affected women. Galec - tin-1 is regulated by UCN and CRH and could contribute Page 10 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 to the immune imbalance that characterizes endometrio- sis [123]. Additionally, a decrease in CRH-R1 mRNA expression has been noted in endometriosis, indicating a disruption in the local CRH/Ucn/CRH-R1 pathway, which may be linked to the reduced fertility associated with this condi - tion [122]. Key regulatory factors, such as CRH and UCN , have been investigated for their involvement in endometri - osis-related inflammation. Modulating these factors, like using CRH-R2 antagonists, could potentially be a new treatment approach for endometriosis-related pain. Plasma Urocortin-1 level evaluation has also shown promise as a noninvasive diagnostic test for endometrio - sis. [2, 124]. Studies suggest that neuropeptide receptors including SP, CGRP, and noradrenaline receptors, along with the neurotransmitter acetylcholine, may influence the devel - opment and progression of adenomyosis. In contrast, vagus nerve-derived neurotransmitter acetylcholine may stall the progression of adenomyosis [125]. NPSR1 (Neuropeptide S receptor 1) plays a role in regulating inflammation, pain, and immune responses in endometriosis [126]. Inflammation modulation is achieved through the cAMP/PKA and calcium sign - aling pathways, affecting immune cells and reducing or enhancing inflammatory cytokine production. The MAPK/ERK and NF-κB pathways activated by NPSR1 cause the survival and proliferation of ectopic endome - trial cells, as well as the chronic inflammation seen in endometriotic lesions [99, 127]. In a study by Tapmeier et al., NPSR1 has been explored as a therapeutic option for endometriosis. Increased NPSR1 gene expression has been observed in leukocytes and monocytes of the PF in endometriosis patients, along with enhanced expression of inflammatory cytokines. Inhibition of the NPSR1 gene may help reduce chronic inflammation and alleviate pain in endometriosis patients [128]. Novel strategies for the treatment of endometriosis Surgical Intervention is the first available treatment approach, which involves excising or ablating endometri- otic lesions, with hysterectomy considered in some cases. It is important to note that surgery aims to remove all lesions, but response rates vary, and recurrence is com - mon [62]. Non-hormonal therapeutics constitute the second treatment strategy. Non-hormonal options, such as NSAIDs and opioids target inflammation and allevi - ate pain [62]. Newer agents of this group precisely tar - get inflammatory factors that promote angiogenesis and neuroangiogenesis. These agents have shown promising effects for the treatment of pain in the context of endo - metriosis [57]. Resveratrol, a natural phenolic compound, is emerging as a potential therapeutic option for prevent - ing and treating endometriosis. Its primary mechanism of action is attributed to its anti-inflammatory effects. Resveratrol works by inhibiting the synthesis of prosta - glandins (PGs) through the suppression of cyclooxyge - nase (COX) enzyme synthesis and inhibits activating immune cells and pro-inflammatory cytokines [129]. Moreover, reactive oxygen species (ROS) lead to the oxidative modification of proteins, and elevated levels of protein oxidative stress markers are observed in the peritoneal fluid of women with endometriosis [130]. The use of oral antioxidants, such as vitamin E and vita - min C, targeting oxidized proteins, has shown a signifi - cant reduction in reported chronic pain in women with endometriosis compared to a placebo [62]. Another anti- inflammatory drug, which has been shown to contribute to pain alleviation in endometriosis, is sulforaphane. It effectively relieved pain in sciatic endometriosis by inhib- iting ectopic endometrial tissue growth, reducing VEGF levels, and decreasing pro-inflammatory cytokines (IL6, IL-1β, TNF-α) in preclinical studies. Sulforaphane also influenced key regulatory proteins (DOX2, INOS, Keap1, Nrf2) associated with inflammation [131]. The third type of endometriosis treatment is based on the application of hormonal therapeutic agents. GnRH agonists, aromatase inhibitors, and oral contraceptives are hormonal treatments that suppress pain symptoms by inhibiting estrogen and regulating menstrual cycles [62]. These medical treatments mimic some conditions in which women experience relief from endometriosis symptoms such as pregnancy, breastfeeding, or meno - pause [ 31]. Selective estrogen receptor modulators such as raloxifene have shown potential for treating chronic pelvic pain in endometriosis patients. They decreased the production of nitric oxide (NO), IL-1β, and IL-6 and exhibited anti-inflammatory effects by reducing M1 monocytes, macrophage density, and NF-κB response [81]. Notably, because of the variability of lesions in endometriosis, hormonal therapy for endometriosis may not be effective in some cases, with some not requiring estrogens for growth and others being progesterone- resistant [73]. The diverse nature of endometriosis, with 40% of women experiencing noncyclical pelvic pain, implies that focusing solely on surgery, anti-inflammatory, or hormonal treatments may miss specific patients. Exploring alternatives, such as modulating ion chan - nels and targeting pain receptors could offer a new, non-hormonal treatment for those with chronic pelvic pain [132]. For instance, targeting the EP4 receptor rep - resents a promising strategy for inhibiting endometrial cell proliferation, regulating anti-inflammatory activity, and alleviating inflammatory pain. The presence of the Page 11 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 Table 2 Treatment strategies for endometriosis Treatment type Description Examples/agents Mechanism of action Non-hormonal therapeutics Target inflammation, alleviate pain. promoting angiogenesis and neuroangiogenesis NSAIDs, opioids, Resveratrol, oral antioxidants (e.g., vitamin E, vitamin C), sulforaphane Inhibition of prostaglandin synthesis, suppression of cyclooxygenase (COX) production, reduction of VEGF and pro-inflammatory cytokines, antioxidant effects, modulation of regulatory proteins associated with inflammation Hormonal therapeutic agents Suppress pain symptoms by inhibiting estrogen and regulating menstrual cycles GnRH agonists, aromatase inhibitors, oral contra- ceptives, selective estrogen receptor modulators (e.g., raloxifene) Inhibition of estrogen, reduction of NO, IL-1β, IL-6, anti-inflammatory effects, modulation of monocytes and macrophages, regulation of endometrial cell proliferation Neuromodulation and receptor targeting Target neuropeptides, nerve pathways, and spe- cific receptors for pain reduction Drugs blocking SP and CGRP receptors, cannabi- noid receptor type 1 (CB1R) activation, selective estrogen receptor modulators (SERMs), NPSR1 antagonists (e.g., SHA 68) Reduction of pain via neuropeptide receptor blocking, modulation of nerve pathways, inhibition of neuroinflammatory pathways Page 12 of 16Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 EP4 receptor in sensory nociceptive nerve fibers sug - gests that human PGE2 receptor subtype 4 antagonists could offer a new treatment option for endometrio - sis [19, 133]. Additionally, treatments such as activat - ing cannabinoid receptor type 1 (CB1R), expressed by nerves in endometrial lesions, show promise in reduc - ing endometriosis-associated hyperalgesia [134]. Researchers indicate that Δ9-tetrahydrocannabinol (THC) can alleviate mechanical hypersensitivity and pain, inhibiting the proliferation of the cyst and restor - ing function [135]. Furthermore, Coexisting nerve pathways linking the female reproductive tract, bladder, and colon contribute to co-morbidities through cross- organ sensitization. Animal models of chronic pain conditions, such as irritable bowel syndrome (IBS), demonstrate successful pain modulation by targeting peripheral pathways. This approach holds potential for future chronic pelvic pain management in endo - metriosis [136, 137]. Also, Selective estrogen receptor modulators (SERMs ), which have both agonistic and antagonistic effects on ER, offer potential treatment strategies for endometriosis [138]. Medications that can suppress neurogenic inflamma - tion, and thus the release of neuropeptides, may have a role in managing endometriosis [31]. Drugs that block the receptors for neuropeptides, such as SP and CGRP , may help reduce pain associated with endometrio - sis. Antagonism of SP and CGRP receptors, stalls the development and fibrogenesis of endometriotic lesions through EMT, FMT, and transdifferentiation to SMC [54]. Compounds that block the activity of NPSR1, such as specific antagonists (SHA 68), could potentially reducing pain and inflammation. Inhibition of NPSR1 signaling may also impact neuroinflammatory path - ways [ 128]. It’s important to note that while research into neuropeptides and endometriosis is ongoing, these treatment options are still under investigation and may not be widely available or approved for use in clinical practice [139]. We summarized the key points of this section in Table 2 .

and future perspective In conclusion, the data presented in this article highlight the significant involvement of the nervous system, neu - ropeptides, and estrogen in the pathogenesis of endome - triosis. Understanding these molecular mechanisms can aid in the development of targeted therapies for manag - ing inflammation, pain, and disease progression in endo - metriosis patients. Further studies are essential to fully explain the complex interplay across the neuropeptide, and endometriosis, and to explore potential therapeutic intervention.

Variability across studies: The research included in this review shows significant variability in terms of study design, participant characteristics, and methodologies. This inconsistency makes it difficult to draw firm con - clusions and may reduce the applicability of the results to broader populations. Limited scope of research: Although the role of neuropeptides in endometriosis is increasingly recognized, the current body of research is relatively limited. Many of the studies are prelimi - nary or involve small sample sizes, which could affect the strength of their conclusions. Animal models: A sig - nificant proportion of the studies on neuropeptides and endometriosis are based on animal models. While these models provide valuable insights, they may not fully rep - licate the complex pathophysiology of endometriosis in humans. Therefore, caution is warranted when extrapo - lating these findings to clinical practice. Absence of longi- tudinal research: Most of the studies examined are either cross-sectional or short-term, offering only a brief view of neuropeptide involvement at a particular moment. Longitudinal research is needed to explore the ongoing changes in neuropeptide levels and how these affect the progression and treatment of endometriosis. Publication bias: The potential for publication bias cannot be over - looked. Studies reporting positive outcomes are more likely to be published, which may create a biased under - standing of the role neuropeptides play in endometriosis. Future directions Clinical trials: Future research should prioritize well- made clinical trials to explore the therapeutic potential of targeting neuropeptides in endometriosis. Such stud - ies should focus on assessing the efficacy and safety of neuropeptide-based treatments in diverse patient popu - lations. Longitudinal and large-scale studies: There is a need for large-scale research and longitudinal studies to better understand the temporal relationship between neuropeptide expression and the clinical manifestations of endometriosis. These studies would help clarify what is the neuropeptides’ role in the development of the dis - ease and their potential as biomarkers for diagnosis and prognosis. Molecular mechanisms: Further studies are essential to elucidate the precise molecular mechanisms by which neuropeptides contribute to the pathogenesis of endometriosis. Understanding these mechanisms may reveal novel therapeutic targets and improve the man - agement of the disease. Integration with other pathways: Investigating how neuropeptides interact with other signaling pathways involved in endometriosis, such as immune responses and hormonal regulation, could iden - tify synergistic therapeutic approaches. Personalized Page 13 of 16 Mosleh et al. Middle East Fertility Society Journal (2024) 29:49 medicine: Future studies should explore the potential for personalized medicine approaches that take into account individual variations in neuropeptide expression and response to treatment. This could pave the way for more personalized and effective treatment options for individ - uals with endometriosis.

We are most grateful to Shahid Beheshti and Iran University of Medical Sci- ences for conducting this research. Authors’ contributions All authors reviewed and approved the final manuscript. MA and ZS were responsible for study design, drafting the protocol, resolving conflicts, and approving the final manuscript version. HM conducted database searches, screened and selected studies, performed data analysis, and approved the final manuscript. SH contributed by writing the manuscript, extracting data, and approving the final manuscript. NH and LM took part in study design, protocol writing, conflict resolution, and approving the final version of the manuscript. Funding NA. Data availability NA. Ethics approval and consent to participate. NA. Consent for publication All authors consent to the publication of this study. Competing interests The authors declare that they have no competing interests. Received: 18 June 2024 Accepted: 18 October 2024

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