{"paper_id":"5a44deaf-3120-48c9-b88d-5ada44aed818","body_text":"Mosleh et al. \nMiddle East Fertility Society Journal           (2024) 29:49  \nhttps://doi.org/10.1186/s43043-024-00207-4\nREVIEW Open Access\n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nMiddle East Fertility\nSociety Journal\nRole of neuropeptides in patients \nwith endometriosis: a literature review\nHamidreza Mosleh1, Sedighe Hosseini2, Nazanin Hajizadeh2, Leila Majdi2, Marziyeh Ajdary3,4* and \nZahra Shams Mofarahe1* \nAbstract \nBackground This article provides an overview of the role of neuropeptides in endometriosis.\nMain body.\nWhile the pathogenesis of endometriosis is not discovered exactly yet, researchers have explored endocrine, parac-\nrine, and immunological influences to better understand the disease. Neuropeptides, which play a significant role \nin regulating communication among endometrial cells, have been extensively studied and found to have effects \non neurons and other somatic cells. The interplay between neuropeptides, pain, and the immune response suggests \nthat neuropeptides may play a significant role in the development and progression of endometriosis.\nConclusion We investigate the role of nerve fibers and neuropeptides, estrogen and estrogen receptors, and new \nbiomarkers in promoting inflammation and pain in endometriosis. Further research should focus on the roles \nand therapeutic potential of neuropeptides in endometriosis.\nKeywords Neuropeptides, Endometriosis, Pain, Inflammation\nBackground\nEndometriosis is a long-term gynecological condi -\ntion characterized by the existence of tissue similar to \nthe endometrium outside the uterus. It impacts around \n5–10% of women of reproductive age worldwide [1]. The \nmost prevalent symptoms of endometriosis, regardless of \nlesion location, are infertility and pain [2]. Patients often \nexperience chronic pain throughout their reproductive \nyears [3].\nRecent research has indicated that endometrio -\nsis lesions undergo various cellular transformations, \nincluding fibroblast-to-myofibroblast transdifferentia -\ntion (FMT), fibrosis epithelial-mesenchymal transition \n(EMT), and smooth muscle metaplasia (SMM) [4]. These \nchanges lead to the formation of glands, stromal cells, and \ndense fibrotic tissues. Induction of pain in this context is \nattributed to the interaction of nerve fibers and cytokine-\nreleasing inflammatory cells such as macrophages, which \ninduce a neurogenic inflammatory pathway [5].\nThe precise pathogenesis of endometriosis remains \nincompletely understood [6]. However, the endome -\ntrium in women with endometriosis displays specific \nbiochemical differences in comparison to those without \nthe condition [7]. Researchers have explored endocrine \nand paracrine influences, as well as immunological fac -\ntors, in order to better understand the disease. A range of \ngrowth factors, gene expression patterns, immune cells, \ncytokines, neuropeptides, and hormones present in the \n*Correspondence:\nMarziyeh Ajdary\najdari.m@iums.ac.ir\nZahra Shams Mofarahe\nz_shams@sbmu.ac.ir\n1 Department of Biology and Anatomical Sciences, School of Medicine, \nShahid Beheshti University of Medical Sciences, Tehran, Iran\n2 Preventative Gynecology Research Center, Shahid Beheshti University \nof Medical Sciences, Tehran, Iran\n3 Endometriosis Research Center, Iran University of Medical Sciences, \nTehran, Iran\n4 Reproductive Sciences and Technology Research Center, Department \nof Anatomy, Iran University of Medical Sciences, Tehran, Iran\n\nPage 2 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nectopic (abnormal) and eutopic (normal) endometrium \nare involved in the pathophysiology of endometriosis [8].\nThe human endometrium possesses secretory proper -\nties and exhibits the characteristics of a neuroendocrine \norgan. Neuropeptides, which are small peptide molecules \nconsisting of 3 to 100 amino acids, play a significant role \nin regulating communication among endometrial stro -\nmal and epithelial cells, as well as interactions between \nendometrial and myometrial cells [9]. These neuropep -\ntides have been thoroughly researched, and their impacts \nare well-documented [10].\nNeuropeptides act locally or at a distance depending on \nthe presence of specific receptors. They can affect neu -\nrons as well as other somatic cells indicating a wide range \nof effects [11]. Moreover, neuropeptides not only serve as \ntargets for research and treatment but also hold potential \nas diagnostic markers, aiding in the understanding of the \netiology and pathogenesis of various disorders [10].\nIt is becoming increasingly clear that the immune \nresponse and pain are interconnected and have common \nmechanisms. Nerve activation releases neuropeptides, \nwhich subsequently facilitate the recruitment and acti -\nvation of leukocytes, a phenomenon known as neuro -\ngenic inflammation [12]. Similarly, when leukocytes are \nattracted to the area of nerve injury, they release factors \nthat induce pain, including chemokines, lipid mediators, \ncytokines, growth factors, and neuropeptides, which play \na role in pain production [13]. The interaction between \npain-enhancing cytokines and pro-inflammatory neuro -\npeptides establishes a positive feedback loop that perpet -\nuates both inflammation and pain. This phenomenon is \nknown as neuropathic pain [14].\nThe pathophysiology of pain linked to endometriosis \ninvolves inflammatory and hormonal changes, as well as \nalterations in brain signaling pathways [15]. Given that \npain and inflammation are hallmark symptoms of endo -\nmetriosis, and considering the role of neuropeptides in \npain and inflammation in various body systems, based on \nevidence, neuropeptides are associated with the progres -\nsion and development of endometriosis. The present arti-\ncle provides an overview of the effect of neuropeptides \non endometriosis (Fig. 1).\nMethods\nA thorough literature review was carried out to assess \nthe role of neuropeptides in endometriosis patients. The \nreview process employed a systematic approach to guar -\nantee the inclusion of pertinent and high-quality studies.\nSearch strategy\nThe Scopus, PubMed, and Web of Science databases were \nsearched. The search covered all articles published up \nuntil April 2024. Keywords used in the search included \ncombinations of terms such as “neuropeptides, ” “endo -\nmetriosis, ” “pain, ” “inflammation, ” “pathophysiology, ” and \n“treatment. ” Boolean operators (AND, OR) were used \nto refine the search and ensure the inclusion of stud -\nies specifically addressing the role of neuropeptides in \nendometriosis.\nInclusion and exclusion criteria\nTo identify relevant papers, certain exclusion and inclu -\nsion criteria were established. The inclusion criteria were \nas follows:\n• Original research articles, reviews, and meta-analy -\nses focusing on neuropeptides in the context of endo-\nmetriosis.\n• Studies published in English.\n• Studies involving human subjects or animal models \nrelevant to endometriosis.\n• Articles that provided clear data on the effect of neu -\nropeptides on the pathogenesis, symptoms, or treat -\nment of endometriosis.\nExclusion criteria included:\n• Studies not directly related to neuropeptides or endo-\nmetriosis.\n• Non-peer-reviewed articles, conference abstracts, \nand editorials.\n• Articles published in languages other than English.\n• Studies with insufficient or inconclusive data regard -\ning neuropeptides and their role in endometriosis.\nStudy selection and data extraction\nFollowing the initial search, duplicates were eliminated, \nand the abstracts and titles of the remaining papers were \nscreened and their full texts were subsequently reviewed \nto assess eligibility considering the established exclusion \nand inclusion criteria. Data from the chosen studies were \nextracted, including details on study design, population, \nkey findings related to neuropeptides, and their implica -\ntions for endometriosis.\nQuality assessment\nThe quality of the papers was evaluated by standardized \ncriteria, taking into account factors such as methodology, \nstudy design, sample size, and the clarity of the reported \nfindings. Studies that met the quality standards were \nincorporated into the final review.\nMenstruation involves an inflammatory process \nmarked by elevated levels of various tissue-resident \nimmune cells. The intricate interplay between uterine \nstromal cells and these resident immune cells regulates \n\nPage 3 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nthe production and secretion of chemokines, pro-inflam -\nmatory cytokines, and prostaglandins (PGs), culminating \nin localized vasoconstriction [16]. Anatomical anoma -\nlies, obstructions, and any other causes for a retrograde \nflow of menstrual materials can implant endometrial tis -\nsue remnants into the peritoneal cavity [17]. The endo -\nmetriosis existence in women is also linked to a rise in \nboth the number and activity of macrophages, as well \nas the humoral immune response. However, cell-medi -\nated responses such as natural killer cell cytotoxicity are \ndecreased in this condition [18].\nDuring lesion formation, recruited inflammatory \ncells release various proinflammatory factors. M1 mac -\nrophages, contributing to the early stages of injury and \npro-inflammatory responses, produce cytokines and \nchemokines, fostering myoblast proliferation. In patients \nwith endometriosis, peritoneal macrophages exhibit \nheightened NF-κB activation and increased expres -\nsion of IL-1β, IL-6, IL-8, TNF-α, and TGF-β, fostering \nan appropriate microenvironment for endometrial cell \nattachment, invasion, and angiogenesis [19]. Besides, \nendometrial tissue hypoxia in the peritoneal environ -\nment upregulates the generation of hypoxia-induci -\nble factor-1α (HIF-1α). This can enhance VEGF levels \nenhancing vascular endothelial cell production. COX-2 \nplays a role in connecting angiogenesis in endometriotic \ntissue to inflammation. COX-2 promotes the genera -\ntion of prostaglandin E2 (PGE2) and VEGF and activates \nMMP-1, 2, and 9, thereby remodeling the extracellular \nmatrix and facilitating angiogenesis [20, 21]. Angiogen -\nesis occurs within the initiation phase (< 3 days post-\ndisease onset), and supports the growth, implantation, \nFig. 1 Role of neuropeptides in inducing the endometriosis\n\nPage 4 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nsurvival, and migration of endometriotic lesions. Addi -\ntionally, robust angiogenesis creates favorable conditions \nfor nerve-ending growth, which causes pain symptoms \nattributed to endometriosis [22, 23].\nProstaglandins play a crucial role as mediators of \nchronic inflammation [24]. Increased levels of PGF2α \nand PGE2 in patients with endometriosis are positively \nassociated with the severity of vaginal hyperalgesia. PGs \ninteract with cytokines, amplifying cytokine actions \non inflammatory cells and influencing their pathogenic \nconversion through gene expression regulation. This \nenhancement occurs through the induction of relevant \ncytokine receptors and collaboration with cytokines at \nthe transcriptional level to activate NF-κB, which results \nin the expression of genes associated with inflammation. \nThis signaling pathway boosts the expression of various \ngenes induced by NF-κB, including chemokines, which \nfacilitate the ongoing infiltration of neutrophils and mac-\nrophages, thereby intensifying chronic inflammation \n[25]. Additionally, PGE2, PGF2α, glycodelin, TGF-β, and \nTNF-α cause the induction of pain related to endome -\ntriosis [26].\nAfter subsiding the initial inflammatory response of \nM1 macrophages, M2 macrophages become the domi -\nnant subtype of macrophages in endometriotic lesions. \nThese macrophages secrete growth factors anti- and \ninflammatory cytokines playing a crucial role in the \ngrowth of ectopic endometrial tissues and their repair \nand remodeling [27–29].\nIn the peritoneal fluid (PF) of endometriosis patients, \nthere is a significant increase in both activated mast \ncells and mast cells. These cells are capable of produc -\ning costimulatory molecules, growth factors, and a range \nof pro- and anti-inflammatory mediators. Notably, mast \ncells also play a role in neuropathic pain by directly sen -\nsitizing/activating primary nociceptive neurons through \nmediators such as histamine, leukotrienes, prostaglan -\ndins, IL-1, IL-8, serotonin, and nerve growth factor \n(NGF). They can also indirectly contribute by recruiting \nleukocytes that release Pain-causing mediators [27, 30].\nElevated IL-8 in endometriotic lesions acts as an auto -\ncrine regulator, stimulating cell proliferation and causing \nangiogenesis, recruitment of neutrophils, and contrib -\nuting to the shift from acute to chronic inflammation. \nNeutrophils themselves release IL-8 and IL-17, fur -\nther reinforcing this vicious cycle [19]. In a synergistic \nmanner, cell adhesion, TGF-β1, and pro-inflammatory \ncytokines (TNF-α or IL-1β) elevate the VEGF and IL-8 \nexpression in endometrial stromal cells through the \np38/ERK1/2 signaling pathways [23]. Moreover, neutro -\nphils in the abdominal cavity of endometriosis patients \nsecrete VEGF and enhance the growth of lesions. This \ncollective action of neutrophils and secreted IL-8 and \nIL-17 contributes to endometriosis pathogenesis, poten -\ntially transitioning from acute to chronic inflammation \n[19, 31].\nNervous system response further increases peritoneal \ninflammation\nFollowing the onset of endometriosis, various inflam -\nmatory cells are attracted to the lesion as a result of \ninflammatory processes initiated by endometrial debris \n[32]. Subsequently, chemokines, several cytokines (IL-\n1β, TGF-β, IL-8, IL-6, TNF-α, etc.), and inflammatory \nmediators such as NGF and brain-derived neurotrophic \nfactor (BDNF) are released [26, 33, 34]. NGF is a protein \nthat is essential for the growth, maintenance, and sur -\nvival of specific nerve cells, particularly sensory neurons. \nIt is produced by inflammatory cells, with its produc -\ntion being stimulated by cytokines like TNF-α and IL-1β. \nImportantly, the expression of NGF and its receptor, \nTrkA, significantly increases, within the endometriotic \nepithelium and stroma [35–37]. The signaling pathway \nactivated by NGF-TrkA is implicated in chronic pain and \nneuroinflammation [38]. NGF promotes the expression \nof SP and CGRP , which in turn contribute to the prolif -\neration of nociceptors and an increase in the number of \nsensory neurons. Concurrently, under the influence of \nNGF and BDNF, there is an elevation in the total nerve \nfiber density. Ultimately, the escalated levels of BDNF \nand NGF culminate in the persistence of inflammatory \npain [39, 40]. In this context, NGF causes the stimulation \nof mast cell degranulation. The perpetuation of persistent \ninflammation is intricately linked to the sustained acti -\nvation of MCs, leading to the release of IL-4, IL-6, and \nprostaglandins [41], which in turn, activate NF-κB, facili -\ntating the expression of genes associated with inflamma -\ntion [25].\nBDNF is a distinct neurotrophin, which exerts regula -\ntory effects on cell proliferation, viability, and specializa -\ntion across various neuronal subclasses [42]. BDNF plays \na crucial role in facilitating the transition from acute to \nchronic pain states [43]. Elevated levels of BDNF can be \ndetected in both plasma and PF samples from women \nwith endometriosis compared to those who do not have \nthe condition. Notably, IL-1β further stimulates BDNF \nproduction through an IL-1 receptor-dependent pathway \nthat is mediated by JNK and NF-κB [25, 44]. The raised \nup BDNF level promotes the growth, survival, and differ -\nentiation of various neuron types [33, 42]. These compo-\nnents contribute to inflammation development, fostering \nhurtful pain in the nervous system [45].\nWomen in the advanced stages of endometriosis tend \nto show a higher density of nerve fibers in the lower \nuterine myometrium compared to those without the \ncondition [46]. Various neurotransmitters and neural \n\nPage 5 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nproteins, including transforming growth factor β1 (TGF-\nβ1), CGRP, neurofilament, SP , and vesicular monoam -\nine transporter (VMAT), are found in the nerve fibers \nwithin endometriotic lesions. Specifically, the endome -\ntrium functional layer contained sensory C fibers that \nexpressed higher levels of vasoactive intestinal substance \nP (SP ), neuropeptide Y (NPY ), polypeptide (VIP), and \ncalcitonin gene-related peptide (CGRP). The endome -\ntrium basal layer exhibited sensory C fibers, sensory \nAd fibers, and adrenergic fibers. The myometrium dis -\nplayed sensory C, adrenergic, and cholinergic fibers in \nboth women with/ without endometriosis. However, \nsensory C fibers were exclusively found in the endome -\ntrium functional layer in women with endometriosis[7]. \nIn different human and animal studies, it has been dem -\nonstrated that the balance in the distribution of sensory \nand sympathetic neurons has been changed to the favor \nof sensory neurons about 20-folds compared to the phys -\niological conditions. It is of high importance because of \nthe unique secretory profile of each type of nerve fiber \nand the influence of secreted neurotransmitters on the \nimmune cells and inflammatory processes [31]. The con -\ntinuous activation of sensory nerve fibers induces the \nsecretion of proinflammatory neuropeptides, like CGRP \nand SP , in proximity to endometrial lesions [47]. These \nneuropeptides are released because the abnormal endo -\nmetrial tissue can produce inflammatory molecules like \nprostaglandins and cytokines, which irritate and activate \nsensory nerves surrounding the lesions. Endometrial \nimplants provoke a local immune response, leading to \nchronic inflammation [48]. This inflammation sensitizes \nnerve fibers, prompting them to release neuropeptides. \nThese neuropeptides contribute to neurogenic inflam -\nmation by promoting vasodilation, increasing vascular \npermeability, and recruiting immune cells, which further \naggravates inflammation around the lesions [49]. Addi -\ntionally, the activation of sensory afferent nerves and pro-\ninflammatory neuropeptide release may trigger mast cell \nrecruitment, leading to the release of proinflammatory \ncytokines, including PGE2, NGF, TNF, and interleukins, \nlike IL-1β and IL-8. This inflammatory response further \nstimulates locally circulating mast cells and macrophages \n[50, 51]. The increase in the ratio of sensory nerves to \nsympathetic nerve fibers is also indicative of the transi -\ntion from acute to chronic inflammation [52, 53].\nSensory nerves play are linked to the fibrogenesis and \ndevelopment of endometriosis. SP  released from sen -\nsory cells has been shown to activate signaling pathways \nthat promote EMT , FMT, and the conversion of stro -\nmal cells into smooth muscle cells (SMCs) within endo -\nmetriotic lesions, ultimately causing fibrosis [54]. In a \nmouse model, sensory nerve fibers have been identified \nas facilitators of fibrogenesis in endometriotic lesions. \nAdditionally, CGRP and SP  function as vasodilators and \npromote M2 polarization, activating signaling path -\nways that lead to platelet extravasation and aggregation. \nTGF-β1 protein concentrations are notably elevated in \nthe nerve fibers of peritoneal endometriosis lesions in \ncomparison to the peritoneum of patients with no endo -\nmetriosis [55]. These lesions are recognized as being \nhyper-innervated due to neurogenesis prompted by neu -\nrotrophins released from the lesions and possibly from \nplatelets. These neurotrophins appear to promote the \nproduction of sensory neurons over sympathetic neu -\nrons. Research has indicated that sensory denervation \nhas a more pronounced effect on reducing the weight of \nendometriotic lesions and alleviating hyperalgesia than \nsympathetic denervation. Both sympathetic and sensory \ndenervation decrease immunoreactivity to proliferation \nand fibrosis markers, with sensory denervation exhibiting \nmore significant effects [4]. Additionally, there is a strong \nassociation between neuropeptide-Y (NPY ) sympathetic \nnerves present in the inferior hypogastric plexus and the \nneoangiogenesis necessary for endometriosis develop -\nment. Possover et al. found significantly higher amounts \nof NPY sympathetic nerves in endometriosis-infiltrated \ntissue compared to “non-involved” genital tissue which \ncould contribute to induce pain [56]. Notably, the abun -\ndance of nerve fibers seems to be influenced by the \nlocation of endometriosis, with a higher concentration \nobserved in instances of deep infiltrating endometriosis \n[57].\nEndometriotic lesions secrete a variety of proinflam -\nmatory cytokines that activate transcription factors like \nNF-κB, which promotes the expression of neurotro -\nphins, such as NGF and BDNF. Neurotrophins bind to \nTrk receptors (e.g., TrkA for NGF, TrkB for BDNF) and \np75 neurotrophin receptors on sensory nerve fibers \n[58]. Neurotrophin binding to Trk receptors activates \nthe Ras-Raf-MEK-ERK signaling cascade, which causes \nthe phosphorylation and activation of ERK (MAPK/\nERK Pathway), which translocates to the nucleus and \npromotes the transcription of genes linked to neuronal \ngrowth and differentiation. As a result, the nerve fibers in \nand around the endometriotic lesions undergo neurogen-\nesis, contributing to hyper-innervation [59]. Trk receptor \nactivation also triggers the PI3K/Akt signaling pathway, \nwhich is linked to cell survival and the enhanced innerva-\ntion of endometriotic lesions [60].\nNeurotrophins not only promote nerve growth but \nalso contribute to neurogenic inflammation. Sensory \nnerves stimulated by neurotrophins can release neuro -\npeptides like SP and calcitonin CGRP , which enhance \ninflammation, vascular permeability, and immune cell \nrecruitment, creating a cycle of inflammation, nerve acti -\nvation, and pain [61]. The production of neurotrophins \n\nPage 6 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nby endometriotic lesions is part of a positive feedback \nloop, where increased neurogenesis leads to enhanced \nnerve sensitization and inflammation. The neurogenic \ninflammation in turn triggers further neurotrophin \nrelease, promoting more nerve growth and contributing \nto the chronic nature of endometriosis [57].\nPain in endometriosis\nIn endometriosis, normal autonomic equilibrium of \nparasympathetic and sympathetic activity is disturbed. \nDecreased parasympathetic control as well as increased \nsympathetic activity causes an increase in nociceptive \ninput, thereby facilitating the transmission of painful \nstimuli [62].\nFollowing local tissue injury or inflammation, nocicep -\ntors may undergo an enhanced sensitivity to pain, a phe -\nnomenon attributed to the neuroplasticity of peripheral \nsensory nerves. This pain sensitization process encom -\npasses a lowered threshold for activation of peripheral \nsensory neurons and an enhanced responsiveness [27]. \nThe pain associated with endometriosis is not solely \ndetermined by the quantity and arrangement of nerves, \nbut also by the presence of specific neurotrophic factors, \nnotably BDNF and NGF. NGF, in particular, induces the \nproduction of SP and CGRP by activating TrkA receptors \nand initiating intracellular signaling pathways (MAPK/\nERK and PI3K/Akt), leading to increased expression and \nrelease of these neuropeptides, both of which are neu -\nropeptides intricately involved in modulating the trans -\nmission of pain signals. Additionally, NGF facilitates the \nproliferation of nociceptors, enhances the population of \nsensory neurons, and is involved in sustaining inflam -\nmatory pain over time [40, 63]. In the context of endo -\nmetriosis, there is a notable elevation in NGF expression \nwithin invasive lesions in comparison to noninvasive \nlesions [37]. NGF not only is involved in promoting neu -\nronal development and survival but also exerts its effects \non the peripheral nociceptor terminal, notably through \nthe interaction of NGF with the TrkA receptor [64]. \nNGF can undergo retrograde transport to the nocicep -\ntor nucleus, where it enhances the expression of nocicep-\ntive proteins such as TRPV1, and the Nav1 voltage-gated \nsodium channel subunit [65, 66]. In animal models of \nendometriosis, there was observed an increase in the \nexpression of TRPV1 in the dorsal root ganglion [67]. \nFurthermore, elevated levels of TRPV1 in individuals \nwith endometriosis were highly correlated with pain [68, \n69]. Besides, NGF trigger mast cell degranulation and \nincrease secretion of prostaglandin, which are considered \none of the main mediators of chronic inflammation and \ndirectly generate pain. Furthermore, prostaglandins have \nthe capability to stimulate nerve endings, triggering pain \nsensation and the release of additional pain-inducing \nagents, including NGF, histamine, serotonin, and pros -\ntanoids, either from adjacent cells or afferent nerves and \ninduce a vicious cycle with the output of pain [27].\nNerve injury-induced protein 1 (Ninj1) is another key \ncontributor to neurite outgrowth and pain sensation. \nIt has been indicated that in endometriosis, proinflam -\nmatory cytokines such as IL-1β elevate Ninj1 mRNA \nexpression in endometriotic stromal cells. This suggests \nthat Ninj1, induced by inflammation within endometri -\notic sites, could contribute to the development of pain \nby facilitating neuroinflammation, immune cell recruit -\nment, and interactions between nerves and endometrial \nlesions [70]. Ninj1 is upregulated in response to pro -\ninflammatory cytokines, including TNF-α and IL-1β, \nwhich are abundant in the inflammatory environment \nof endometriosis. Ninj1 facilitates cell adhesion between \nsensory nerves and immune cells such as macrophages \nand T-cells, promoting neuro-immune crosstalk [57]. \nNF-κB and MAPK/ERK signaling pathways are activated \nin nerve fibers, leading to the production of proinflam -\nmatory mediators and neuropeptides like SP and CGRP \n[71]. Immune cell recruitment and nerve sensitization \noccur, enhancing neurogenic inflammation and pain per-\nception. Finally, chronic pelvic pain is maintained by the \ncontinued sensitization of nerve endings and the hyper-\ninnervation of endometriotic lesions [72].\nBeyond its involvement in neurogenesis, Ninj1 has \nbeen implicated in promoting angiogenesis, modulating \np53-dependent cell survival and senescence, and mediat -\ning leukocyte migration, thus exacerbating inflammation. \nThese multifaceted properties of Ninj1 are pivotal in the \npathogenesis of endometriosis, suggesting its potential \nimpact not only on pain symptoms but also on the pro -\ngression of the disease itself [70].\nThe role of estrogen in pain and neuroinflammation \nin endometriosis\nEndometriosis lesions consist of specific cells, which \nexhibit different responses to estrogen and progester -\none [73]. The significant effect of estrogen on facilitating \ncommunication between immune cells, like mast cells, \nand macrophages and nerve fibers in endometriosis has \nbeen demonstrated [74]. Macrophages as a crucial con -\ntributor in the endometriosis pathophysiology affect \nlesion proliferation and vascularization. They are often \nlocated around nerve fibers within endometriosis lesions. \nIt has been elucidated a bidirectional interaction between \nnerves and macrophages in endometriosis, which is \nmediated by estradiol, a ligand produced in lesions due \nto the overexpression of steroidogenic enzymes like aro -\nmatase [75].\nEstradiol facilitates an elevation in chemokine ligand \n2 (Ccl-2) production via nerve fibers. This increase in \n\nPage 7 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nTable 1 The mechanisms, their descriptions, and the associated signaling pathways that are influenced by estradiol in endometriosis\nMechanism Description Signaling Pathways\nPromotes growth of endometriotic lesions  [87] Estradiol promoting lesion growth ERK/MAPK pathway: Activated by estrogen binding to estrogen recep-\ntors (ER-α, ER-β) to promote cell growth\nLocal production of estradiol [88] Endometriotic lesions produce estradiol locally via overexpression \nof aromatase, creating a positive feedback loop for growth\nAromatase signaling: Increased expression of aromatase converts \nandrogens to estradiol locally\nEnhances inflammation [89] Estradiol increases proinflammatory cytokine release, sustaining chronic \ninflammation\nNF-κB signaling: Activated by estradiol to increase the production \nof proinflammatory cytokines\nStimulates angiogenesis [90] Estradiol promotes the formation of new blood vessels by upregulating \nVEGF\nVEGF/ERK pathway: Estradiol stimulates VEGF production, which drives \nangiogenesis through the ERK pathway\nModulates immune function [91] Estradiol alters immune responses, reducing NK cell activity and pro-\nmoting macrophage-mediated inflammation\nER signaling in immune cells: Estrogen influences immune cell activity \nand cytokine release\nEnhances nerve growth and sensitization [92] Estradiol promotes nerve growth (via NGF) and sensitizes sensory \nnerves, increasing pain perception in endometriotic lesions\nNGF/TrkA pathway: Estradiol upregulates NGF, activating nerve growth \nthrough TrkA signaling\nContributes to progesterone resistance [93] Estradiol contributes to progesterone resistance, reducing the inhibi-\ntory effect of progesterone on lesion growth\nPI3K/Akt pathway: Estradiol-mediated signaling leads to reduced \nresponsiveness to progesterone\nTherapeutic target\n[94–96]\nTreatments such as aromatase inhibitors, GnRH agonists, and SERMs \ntarget estradiol to inhibit lesion growth and inflammation\nER signaling: Therapeutics aim to block estrogen receptor activation \nor inhibit estrogen production\n\nPage 8 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nCcl-2 attracts macrophages, which subsequently exhibit \nheightened expression of BDNF and neurotrophin-3 (Nt-\n3), thereby inducing neurotrophic effects on nerves [75]. \nThe estrogen-induced activation of mast cells can lead to \nthe NGF release and sensitization of dorsal root ganglion \ncells [76]. Activating mast cells can also result in the pro -\ngression of neuropathic pain by recruiting leukocytes, \nwhich secrete pain-inducing mediators [77]. Estrogen \nplays a central role in endometriosis progression by bind-\ning to different estrogen receptors (ER ) present in the \ndisease. The specific action of estrogen on endometriosis \ndepends on the type and distribution of these receptors \n[78]. For instance, elevated ERβ expression and increased \nERα expression in endometriotic lesions are key factors \nin estrogen action [79]. Cross-talk between ERα and \ninterleukin (IL6) pathways has also been implicated in \npromoting the early initiation of endometriosis [80].\nIn the context of neuroinflammation and pain associ -\nated with endometriosis, it is recognized that the dis -\nease is dependent on estrogen. Estrogen stimulates the \nchemokine secretion from peripheral nerves, which \nleads to the macrophage recruitment and polarization \nin endometriotic tissue. These macrophages, then are \ninvolved in the expression of NGF, contributing to an \nimbalance in neurogenesis in an estrogen-dependent pat-\ntern [81]. The coexistence of macrophages and nerves \nunder estrogen influence creates a novel neuro-immune \ncommunication [74]. Inflammatory cytokines released \nby macrophages continuously activate peripheral nerve \nnociceptors, resulting in neuroinflammation by releas -\ning inflammatory neurotransmitters. This estrogen-regu-\nlated neuro-immune interaction can sensitize peripheral \nnerves and cause neuropathic pain due to endometriosis \n[36]. Macrophages are the main producers of chemokines \npro-inflammatory and cytokines in this condition. Fur -\nthermore, both ERβ and ERα are significantly overex -\npressed in macrophages linked to endometriosis[82].\nThere is evidence suggesting that estrogen also influ -\nences alterations in nerve fiber patterns. Specifically, \nestrogen has been observed to inhibit the outgrowth of \nsympathetic nerve fibers by regulating the synthesis of \nBDNF [83]. Furthermore, in environments with elevated \nconcentrations of estrogen, heightened levels of NGF \ntend to facilitate the growth of sensory nerve fibers while \nconcurrently inhibiting the outgrowth of mature sym -\npathetic ganglia. Consequently, estrogen plays a crucial \nrole in regulating aberrant innervation within the female \nreproductive system [84, 85]. Notably, progesterone has \nbeen shown to reverse estrogen effects on sympathetic \nnerve fibers, suggesting its efficacy as a pain-relieving \ntherapeutic agent for endometriotic patients [86].\nWe summarized the role of estrogen in endometriosis \nin Table 1.\nThe contribution of neuropeptides to endometriosis\nIn endometriosis, intense pain episodes frequently occur \nduring menstruation. The dysregulation of inflammatory \nsignaling pathways and the release of neurotransmitters, \nparticularly CGRP, are associated with the onset of acute \npain episodes[97].\nThe increased expression of neuropeptides and neuro -\ntrophins is a significant contributor to the development \nof hypersensitivity in endometriosis. Some studies have \nshown elevated levels of the neurotransmitter TAC1  \nwhich encodes the neuropeptide substance P in endo -\nmetriosis lesions. Pro-inflammatory cytokines (TNF-α \nand IL-1β) are able to stimulate the expression of TAC1 \nin surrounding neurons and immune cells, leading to \nincreased Substance P levels. Substance P , in turn, can \nfurther promote inflammation by recruiting immune \ncells like macrophages and mast cells, creating a vicious \ncycle [98]. Also, the presence of more nerves in the \nlesions can increase the local production and release of \nTAC1-encoded neuropeptides. Elevated levels of TAC1 \nand SP can promote the formation of new blood vessels, \nsupporting lesion growth and persistence [99]. SP has \nbeen immunolocalized to these lesions suggesting hyper -\nsensitization of nerves within the peritoneal lining of \nwomen with pain and shedding light on the mechanisms \nunderlying chronic hypersensitivity [100]. Additionally, \nneuropeptide hormones such as neurotrophin-3 (NT-3) \nand nerve growth factor (NGF), released from peritoneal \nlesions, promote the growth of nerve fibers in and around \nendometriotic lesions, which contributes to adhesions \nand pain [101]. Neurotrophic factors, including NGF, are \ncrucial for neural sprouting and hypertrophy, which may \nlead to an increased density of nerves in endometriosis. \nNGF can lower the activation threshold of certain noci -\nceptors and trigger the release of pain-related neuropep -\ntides, resulting in hyperalgesia [102].\nNeuropeptides and neurotransmitters seem to have \nimportant roles in the development and symptoms of \nconditions like endometriosis and adenomyosis. Phoe -\nnixin, referred to as PNX-14, is a newly identified neu -\nropeptide [103]. In both in  vitro and in  vivo preclinical \nstudies, Phoenixin has demonstrated beneficial effects by \nreducing inflammation and oxidative stress. This posi -\ntions Phoenixin as a promising candidate for the develop-\nment of new anti-inflammatory medications, especially \nfor treating endometriosis [104].\nPhoenixin, known as PNX-14, functions as a neuropep -\ntide that regulates the hypothalamic-pituitary–gonadal \n(HPG) axis and reproductive functions. Research has \nshown that the Phoenixin precursor protein and its \nreceptor are present in the human endometrium, with \nreduced levels of PNX-14 noted in cases of endome -\ntriosis. Decreased PNX-14 levels are associated with an \n\nPage 9 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nincreased LH/FSH ratio and higher 17β-estradiol levels \nin endometriosis with ovarian involvement. This suggests \na potential role for PNX-14 in addressing endometrial \nepithelial dysfunction and implies its potential effective -\nness in treating endometriosis [105, 106].\nKisspeptin, another neuropeptide, is associated with \nregulating the hypothalamic-pituitary–gonadal (HPG) \naxis and reproductive functions [107]. Studies have \nexplored the connection between dysregulations of the \nKISS1/KISS1R system and issues such as infertility, pre -\nmature ovarian failure, and abnormal puberty onset, but \nclear results are yet to be established [108]. Research has \nalso shown differential expression of Kisspeptin and its \nreceptor in endometriosis patients which may contrib -\nute to the invasiveness of this condition. This suggests a \npotential role of Kisspeptin in addressing endometriosis \ninvasiveness [109]. In endometriosis, the altered expres -\nsion of Kisspeptin and KISS1R can affect several key path-\nways, such as PI3K/AKT, ERK/MAPK, NF-κB, mTOR, \nand others [110, 111]. These pathways are involved in \nprocesses such as cell proliferation, inflammation, apop -\ntosis resistance, angiogenesis, and tissue remodeling. The \nprecise effects of Kisspeptin signaling in endometriosis \nlikely depend on the local hormonal and inflammatory \nenvironment, which may lead to either promotion or \nsuppression of lesion growth and survival [112]. Akad \net  al. in their study compared serum kisspeptin levels \nin female patients with endometriosis and infertility to \nthose of healthy patients with regular menstruation and \nat least one child. They found significant differences in \nkisspeptin levels between the two groups. The research -\ners concluded that elevated serum kisspeptin values in \nendometriosis patients may represent compensatory-\nadaptive mechanisms that help restrain the spread of \nendometriomas in the early stages of the disease. Thus, \nthe KISS1/KISS1R system plays a crucial role in repro -\nductive functions [3]. In contrast, Abdelkareem et  al. \nreported the opposite results in their study. They found \nsignificantly lower kisspeptin levels in patients with ovar -\nian endometriomas compared to healthy patients. They \nproposed that the downregulation of KISS1 levels might \ncontribute to the invasiveness of endometrial implanta -\ntion [112].\nGalectin-3 contributes to the development of endo -\nmetriosis through its involvement in multiple signaling \npathways, including PI3K/AKT/mTOR, Wnt/β-catenin, \nTGF-β/SMAD, NF-κB, FAK, and ERK/MAPK [113, \n114]. Galectin-3 can stabilize β-catenin via the Wnt/β-\ncatenin signaling pathway in the cytoplasm and facili -\ntate its translocation to the nucleus, where it promotes \nthe transcription of target genes associated with prolif -\neration and invasion, thereby contributing to the persis -\ntence and dissemination of endometriotic lesions [115]. \nAlso, Galectin-3 can activate FAK signaling, promoting \nthe adhesion and invasive behavior of endometrial cells \nin ectopic sites [116]. Yamashita et al. found that galec -\ntin-3 in the endometrium plays a role in the develop -\nment of endometriosis by enhancing the survival and \nengraftment of eutopic endometrial cells within the \nperitoneal cavity. They noted that galectin-3 was over -\nexpressed and secreted by eutopic endometrial stromal \ncells in patients with endometriosis compared to those \nwithout the condition. Galectin-3 promoted the adhe -\nsion and migration of endometrial stromal cells, while \ninhibitors of galectin-3 hindered these processes. Addi -\ntionally, galectin-3 diminished the cytotoxicity of natu -\nral killer cells against endometrial stromal cells without \ninfluencing cell proliferation [117].\nUrocortin ( UCN) is a neuropeptide that is part of the \ncorticotrophin-releasing hormone ( CRH) family, and its \nexpression in both eutopic and ectopic human endo -\nmetria has been extensively investigated concerning \nendometriosis [118]. Neuropeptides associated with \nendometrial stress, such as CRH  and UCN , appear to \nexert their biological effects locally within the uterus, \nas both the human endometrium and myometrium \nexpress the relevant receptors, particularly endometrial \nCRH [119].\nCRH plays a role in enhancing inflammation and \npain through the CRF-R1 receptor, leading to recruit -\ning immune cells and the release of inflammatory \nmediators [120]. UCN mainly acts through the CRF-\nR2 receptor, where it can promote anti-inflammatory \nresponses, tissue protection, and cell survival [121]. \nBoth neuropeptides influence several pathways, includ -\ning the cAMP/PKA and MAPK/ERK pathways, which \nare involved in inflammation, immune modulation, \npain, and cell survival. CRH  contributes to the pro-\ninflammatory environment in endometriosis and pro -\nmotes chronic pain, while UCN  has a more protective \nrole, balancing inflammation and promoting lesion sur -\nvival [8 , 122].\nVergetaki et  al. revealed that both CRH  and UCN  \nreceptor subtypes, CRHR1b and CRHR2a, were pre -\nsent at endometriotic sites. Moreover, their expression \nwas significantly higher in the eutopic endometrium of \nwomen with endometriosis compared to healthy women, \nobserved at both the mRNA and protein levels. These \nresults indicate that CRH  and UCN  may play an immu -\nnoregulatory role in endometriotic sites, potentially \ninfluencing reproductive processes such as decidualiza -\ntion and implantation in women with endometriosis [8].\nVergetaki et al. propose that Galectin-1 may play a sig -\nnificant role in the pathology of endometriosis and the \ninfertility issues experienced by affected women. Galec -\ntin-1 is regulated by UCN  and CRH and could contribute \n\nPage 10 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nto the immune imbalance that characterizes endometrio-\nsis [123].\nAdditionally, a decrease in CRH-R1 mRNA expression \nhas been noted in endometriosis, indicating a disruption \nin the local CRH/Ucn/CRH-R1 pathway, which may be \nlinked to the reduced fertility associated with this condi -\ntion [122].\nKey regulatory factors, such as CRH  and UCN , have \nbeen investigated for their involvement in endometri -\nosis-related inflammation. Modulating these factors, \nlike using CRH-R2 antagonists, could potentially be a \nnew treatment approach for endometriosis-related pain. \nPlasma Urocortin-1 level evaluation has also shown \npromise as a noninvasive diagnostic test for endometrio -\nsis. [2, 124].\nStudies suggest that neuropeptide receptors including \nSP, CGRP, and noradrenaline receptors, along with the \nneurotransmitter acetylcholine, may influence the devel -\nopment and progression of adenomyosis. In contrast, \nvagus nerve-derived neurotransmitter acetylcholine may \nstall the progression of adenomyosis [125].\nNPSR1 (Neuropeptide S receptor 1) plays a role in \nregulating inflammation, pain, and immune responses \nin endometriosis [126]. Inflammation modulation is \nachieved through the cAMP/PKA and calcium sign -\naling pathways, affecting immune cells and reducing \nor enhancing inflammatory cytokine production. The \nMAPK/ERK and NF-κB pathways activated by NPSR1  \ncause the survival and proliferation of ectopic endome -\ntrial cells, as well as the chronic inflammation seen in \nendometriotic lesions [99, 127]. In a study by Tapmeier \net al., NPSR1 has been explored as a therapeutic option \nfor endometriosis. Increased NPSR1  gene expression has \nbeen observed in leukocytes and monocytes of the PF in \nendometriosis patients, along with enhanced expression \nof inflammatory cytokines. Inhibition of the NPSR1 gene \nmay help reduce chronic inflammation and alleviate pain \nin endometriosis patients [128].\nNovel strategies for the treatment of endometriosis\nSurgical Intervention is the first available treatment \napproach, which involves excising or ablating endometri-\notic lesions, with hysterectomy considered in some cases. \nIt is important to note that surgery aims to remove all \nlesions, but response rates vary, and recurrence is com -\nmon [62]. Non-hormonal therapeutics constitute the \nsecond treatment strategy. Non-hormonal options, such \nas NSAIDs and opioids target inflammation and allevi -\nate pain [62]. Newer agents of this group precisely tar -\nget inflammatory factors that promote angiogenesis and \nneuroangiogenesis. These agents have shown promising \neffects for the treatment of pain in the context of endo -\nmetriosis [57]. Resveratrol, a natural phenolic compound, \nis emerging as a potential therapeutic option for prevent -\ning and treating endometriosis. Its primary mechanism \nof action is attributed to its anti-inflammatory effects. \nResveratrol works by inhibiting the synthesis of prosta -\nglandins (PGs) through the suppression of cyclooxyge -\nnase (COX) enzyme synthesis and inhibits activating \nimmune cells and pro-inflammatory cytokines [129]. \nMoreover, reactive oxygen species (ROS) lead to the \noxidative modification of proteins, and elevated levels \nof protein oxidative stress markers are observed in the \nperitoneal fluid of women with endometriosis [130]. \nThe use of oral antioxidants, such as vitamin E and vita -\nmin C, targeting oxidized proteins, has shown a signifi -\ncant reduction in reported chronic pain in women with \nendometriosis compared to a placebo [62]. Another anti-\ninflammatory drug, which has been shown to contribute \nto pain alleviation in endometriosis, is sulforaphane. It \neffectively relieved pain in sciatic endometriosis by inhib-\niting ectopic endometrial tissue growth, reducing VEGF \nlevels, and decreasing pro-inflammatory cytokines (IL6, \nIL-1β, TNF-α) in preclinical studies. Sulforaphane also \ninfluenced key regulatory proteins (DOX2, INOS, Keap1, \nNrf2) associated with inflammation [131].\nThe third type of endometriosis treatment is based on \nthe application of hormonal therapeutic agents. GnRH \nagonists, aromatase inhibitors, and oral contraceptives \nare hormonal treatments that suppress pain symptoms \nby inhibiting estrogen and regulating menstrual cycles \n[62]. These medical treatments mimic some conditions \nin which women experience relief from endometriosis \nsymptoms such as pregnancy, breastfeeding, or meno -\npause [ 31]. Selective estrogen receptor modulators such \nas raloxifene have shown potential for treating chronic \npelvic pain in endometriosis patients. They decreased \nthe production of nitric oxide (NO), IL-1β, and IL-6 \nand exhibited anti-inflammatory effects by reducing M1 \nmonocytes, macrophage density, and NF-κB response \n[81]. Notably, because of the variability of lesions in \nendometriosis, hormonal therapy for endometriosis may \nnot be effective in some cases, with some not requiring \nestrogens for growth and others being progesterone-\nresistant [73].\nThe diverse nature of endometriosis, with 40% of \nwomen experiencing noncyclical pelvic pain, implies \nthat focusing solely on surgery, anti-inflammatory, \nor hormonal treatments may miss specific patients. \nExploring alternatives, such as modulating ion chan -\nnels and targeting pain receptors could offer a new, \nnon-hormonal treatment for those with chronic pelvic \npain [132]. For instance, targeting the EP4 receptor rep -\nresents a promising strategy for inhibiting endometrial \ncell proliferation, regulating anti-inflammatory activity, \nand alleviating inflammatory pain. The presence of the \n\nPage 11 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nTable 2 Treatment strategies for endometriosis\nTreatment type Description Examples/agents Mechanism of action\nNon-hormonal therapeutics Target inflammation, alleviate pain. promoting \nangiogenesis and neuroangiogenesis\nNSAIDs, opioids, Resveratrol, oral antioxidants (e.g., \nvitamin E, vitamin C), sulforaphane\nInhibition of prostaglandin synthesis, suppression \nof cyclooxygenase (COX) production, reduction \nof VEGF and pro-inflammatory cytokines, antioxidant \neffects, modulation of regulatory proteins associated \nwith inflammation\nHormonal therapeutic agents Suppress pain symptoms by inhibiting estrogen \nand regulating menstrual cycles\nGnRH agonists, aromatase inhibitors, oral contra-\nceptives, selective estrogen receptor modulators \n(e.g., raloxifene)\nInhibition of estrogen, reduction of NO, IL-1β, IL-6, \nanti-inflammatory effects, modulation of monocytes \nand macrophages, regulation of endometrial cell \nproliferation\nNeuromodulation and receptor targeting Target neuropeptides, nerve pathways, and spe-\ncific receptors for pain reduction\nDrugs blocking SP and CGRP receptors, cannabi-\nnoid receptor type 1 (CB1R) activation, selective \nestrogen receptor modulators (SERMs), NPSR1 \nantagonists (e.g., SHA 68)\nReduction of pain via neuropeptide receptor \nblocking, modulation of nerve pathways, inhibition \nof neuroinflammatory pathways\n\nPage 12 of 16Mosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \nEP4 receptor in sensory nociceptive nerve fibers sug -\ngests that human PGE2 receptor subtype 4 antagonists \ncould offer a new treatment option for endometrio -\nsis [19, 133]. Additionally, treatments such as activat -\ning cannabinoid receptor type 1 (CB1R), expressed by \nnerves in endometrial lesions, show promise in reduc -\ning endometriosis-associated hyperalgesia [134]. \nResearchers indicate that Δ9-tetrahydrocannabinol \n(THC) can alleviate mechanical hypersensitivity and \npain, inhibiting the proliferation of the cyst and restor -\ning function [135]. Furthermore, Coexisting nerve \npathways linking the female reproductive tract, bladder, \nand colon contribute to co-morbidities through cross-\norgan sensitization. Animal models of chronic pain \nconditions, such as irritable bowel syndrome (IBS), \ndemonstrate successful pain modulation by targeting \nperipheral pathways. This approach holds potential \nfor future chronic pelvic pain management in endo -\nmetriosis [136, 137]. Also, Selective estrogen receptor \nmodulators (SERMs ), which have both agonistic and \nantagonistic effects on ER, offer potential treatment \nstrategies for endometriosis [138].\nMedications that can suppress neurogenic inflamma -\ntion, and thus the release of neuropeptides, may have a \nrole in managing endometriosis [31]. Drugs that block \nthe receptors for neuropeptides, such as SP and CGRP , \nmay help reduce pain associated with endometrio -\nsis. Antagonism of SP and CGRP receptors, stalls the \ndevelopment and fibrogenesis of endometriotic lesions \nthrough EMT, FMT, and transdifferentiation to SMC \n[54]. Compounds that block the activity of NPSR1, \nsuch as specific antagonists (SHA 68), could potentially \nreducing pain and inflammation. Inhibition of NPSR1 \nsignaling may also impact neuroinflammatory path -\nways [ 128]. It’s important to note that while research \ninto neuropeptides and endometriosis is ongoing, these \ntreatment options are still under investigation and may \nnot be widely available or approved for use in clinical \npractice [139]. We summarized the key points of this \nsection in Table 2 .\nConclusions and future perspective\nIn conclusion, the data presented in this article highlight \nthe significant involvement of the nervous system, neu -\nropeptides, and estrogen in the pathogenesis of endome -\ntriosis. Understanding these molecular mechanisms can \naid in the development of targeted therapies for manag -\ning inflammation, pain, and disease progression in endo -\nmetriosis patients. Further studies are essential to fully \nexplain the complex interplay across the neuropeptide, \nand endometriosis, and to explore potential therapeutic \nintervention.\nLimitations\nVariability across studies: The research included in this \nreview shows significant variability in terms of study \ndesign, participant characteristics, and methodologies. \nThis inconsistency makes it difficult to draw firm con -\nclusions and may reduce the applicability of the results \nto broader populations. Limited scope of research: \nAlthough the role of neuropeptides in endometriosis is \nincreasingly recognized, the current body of research \nis relatively limited. Many of the studies are prelimi -\nnary or involve small sample sizes, which could affect \nthe strength of their conclusions. Animal models: A sig -\nnificant proportion of the studies on neuropeptides and \nendometriosis are based on animal models. While these \nmodels provide valuable insights, they may not fully rep -\nlicate the complex pathophysiology of endometriosis in \nhumans. Therefore, caution is warranted when extrapo -\nlating these findings to clinical practice. Absence of longi-\ntudinal research: Most of the studies examined are either \ncross-sectional or short-term, offering only a brief view \nof neuropeptide involvement at a particular moment. \nLongitudinal research is needed to explore the ongoing \nchanges in neuropeptide levels and how these affect the \nprogression and treatment of endometriosis. Publication \nbias: The potential for publication bias cannot be over -\nlooked. Studies reporting positive outcomes are more \nlikely to be published, which may create a biased under -\nstanding of the role neuropeptides play in endometriosis.\nFuture directions\n Clinical trials: Future research should prioritize well-\nmade clinical trials to explore the therapeutic potential \nof targeting neuropeptides in endometriosis. Such stud -\nies should focus on assessing the efficacy and safety of \nneuropeptide-based treatments in diverse patient popu -\nlations. Longitudinal and large-scale studies: There is a \nneed for large-scale research and longitudinal studies \nto better understand the temporal relationship between \nneuropeptide expression and the clinical manifestations \nof endometriosis. These studies would help clarify what \nis the neuropeptides’ role in the development of the dis -\nease and their potential as biomarkers for diagnosis and \nprognosis. Molecular mechanisms: Further studies are \nessential to elucidate the precise molecular mechanisms \nby which neuropeptides contribute to the pathogenesis \nof endometriosis. Understanding these mechanisms may \nreveal novel therapeutic targets and improve the man -\nagement of the disease. Integration with other pathways: \nInvestigating how neuropeptides interact with other \nsignaling pathways involved in endometriosis, such as \nimmune responses and hormonal regulation, could iden -\ntify synergistic therapeutic approaches. Personalized \n\nPage 13 of 16\nMosleh et al. Middle East Fertility Society Journal           (2024) 29:49 \n \nmedicine: Future studies should explore the potential for \npersonalized medicine approaches that take into account \nindividual variations in neuropeptide expression and \nresponse to treatment. This could pave the way for more \npersonalized and effective treatment options for individ -\nuals with endometriosis.\nAcknowledgements\nWe are most grateful to Shahid Beheshti and Iran University of Medical Sci-\nences for conducting this research.\nAuthors’ contributions\n All authors reviewed and approved the final manuscript. MA and ZS were \nresponsible for study design, drafting the protocol, resolving conflicts, and \napproving the final manuscript version. HM conducted database searches, \nscreened and selected studies, performed data analysis, and approved the \nfinal manuscript. SH contributed by writing the manuscript, extracting data, \nand approving the final manuscript. NH and LM took part in study design, \nprotocol writing, conflict resolution, and approving the final version of the \nmanuscript.\nFunding\nNA.\nData availability\nNA.\nEthics approval and consent to participate.\nNA.\nConsent for publication\nAll authors consent to the publication of this study.\nCompeting interests\nThe authors declare that they have no competing interests.\nReceived: 18 June 2024   Accepted: 18 October 2024\nReferences\n 1. Yilmaz M (2022) Endometriosis: A Review of Systematic Reviews and \nMeta-Analysis. MAS J Appl Sci 7(1):73–80\n 2. Carrarelli P , Luddi A, Funghi L, Arcuri F, Batteux F, Dela Cruz C et al (2016) \nUrocortin and corticotrophin-releasing hormone receptor type 2 mRNA \nare highly expressed in deep infiltrating endometriotic lesions. Reprod \nBiomed Online. 33(4):476–83\n 3. 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