Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Endometriosis is a gynecologic condition often described as the “chameleon of gynecology” because of its elusive symptoms. The World Health Organization acknowledges its severe impact on quality of life due to pain, fatigue, depression, and infertility. There is limited literature on the prevalence of endometriosis, knowledge of which is essential for effective prevention, treatment strategies, and funding. We aim to structure and present the published data on endometriosis prevalence, synthesizing the discrepancy between health insurance and clinical data. PubMed, Cochrane CENTRAL, and LIVIVO were researched for peer‐reviewed articles published between January 2000 and July 2023 on women of reproductive age. Health insurance companies argue that few women (~1%) are affected by endometriosis. Interestingly, the prevalence of clinical data studies (6.8%), population‐based surveys/self‐reported studies (6.6%), and symptomatic patient data (21%) revealed a different picture. Based on the data gathered, a multi‐layered prevalence model has been proposed to illustrate the large discrepancy in the prevalence numbers, leading to the disease being underestimated and underfunded. This variability may be influenced by the heterogeneity in designs and the analyzed data, and clinical complexity. In summary, this narrative review reveals that the prevalence of endometriosis is higher than health insurance and other stakeholders might have previously assumed.

Endometriosis is a chronic inflammatory disease where endometrial-like lesions settle outside the uterus, resulting in extensive inflammatory reactions. It is a complex disease that presents with a range of symptoms, with pain and infertility being the most common. Along with severe dysmenorrhea, cyclic and acyclic lower abdominal pain, cyclic dysuria and dyschezia, dyspareunia, and infertility, there are also nonspecific complaints that can cause confusion and make endometriosis the chameleon among gynecological diseases. These symptoms include unspecific intestinal complaints, cyclic diarrhea, but also constipation, nausea, vomiting, and stomach complaints. It appears that in addition to general bowel symptoms, there are also specific symptoms related to endometriosis such as cyclic bloating of the abdomen, known as endo belly. During the second half of the menstrual cycle leading up to menstruation, the abdomen becomes increasingly bloated causing discomfort and pain due to elevated sensitivity of the intestinal wall. Patients with endometriosis exhibit a reduced stretch pain threshold of the intestinal wall. Here, we review the endo belly, for the first time, pathophysiology and the influence of other diseases (such as irritable bowel syndrome—IBS), microbiome, hormonal levels, inflammation, and diet on the presentation of this condition.

Mucolipidosis II (MLII) and III alpha/beta are autosomal-recessive diseases of childhood caused by mutations in GNPTAB encoding the α/β-subunit precursor protein of the GlcNAc-1-phosphotransferase complex. This enzyme modifies lysosomal hydrolases with mannose 6-phosphate targeting signals. Upon arrival in the Golgi apparatus, the newly synthesized α/β-subunit precursor is catalytically activated by site-1 protease (S1P). Here we performed comprehensive expression studies of GNPTAB mutations, including two novel mutations T644M and T1223del, identified in Brazilian MLII/MLIII alpha/beta patients. We show that the frameshift E757KfsX1 and the non-sense R587X mutations result in the retention of enzymatically inactive truncated precursor proteins in the endoplasmic reticulum (ER) due to loss of cytosolic ER exit motifs consistent with a severe clinical phenotype in homozygosity. The luminal missense mutations, C505Y, G575R and T644M, partially impaired ER exit and proteolytic activation in accordance with less severe MLIII alpha/beta disease symptoms. Analogous to the previously characterized S399F mutant, we found that the missense mutation I403T led to retention in the ER and loss of catalytic activity. Substitution of further conserved residues in stealth domain 2 (I346 and W357) revealed similar biochemical properties and allowed us to define a putative binding site for accessory proteins required for ER exit of α/β-subunit precursors. Interestingly, the analysis of the Y937_M972del mutant revealed partial Golgi localization and formation of abnormal inactive β-subunits generated by S1P which correlate with a clinical MLII phenotype. Expression analyses of mutations identified in patients underline genotype–phenotype correlations in MLII/MLIII alpha/beta and provide novel insights into structural requirements of proper GlcNAc-1-phosphotransferase activity.

Purpose: Endometriosis (EM) is one of the most frequent differential diagnoses concerning chronic pelvic pain. Women under hormonal therapy (HT) often benefit from it but sometimes suffer a setback and develop acyclical pelvic pain. Due to the assumption that mechanisms of neurogenic inflammation are involved in the generation of chronic pelvic pain, we aimed to investigate the expression of sensory nerve markers in EM-associated nerve fibers of patients with/without HT. Methods: Laparoscopically excised peritoneal samples from 45 EM and 10 control women were immunohistochemically stained for: PGP9.5, Substance P (SP), NK1R, NGFp75, TRPV-1, and TrkA. Demographics and severity of pain were documented. Results: EM patients showed a higher nerve fiber density (PGP9.5 and SP) and increased expression of NGFp75, TRPV1, TrkA, and NK1R in blood vessels and immune cells compared with controls. Patients with HT have cycle-dependent pelvic pain but suffer from acyclical pelvic pain. Interestingly, reducing NK1R expression in blood vessels under HT was observed. A correlation between dyspareunia severity and nerve fibers density and between NGFRp75 expression in blood vessels and cycle-dependent pelvic pain severity was observed. Conclusion: Patients under HT have no ovulation and no (menstrual) bleeding, which correlate with inflammation and cyclical pain. However, acyclical pain seems to be due to peripheral sensitization once it is present under treatment. Neurotransmitters, like SP and their receptors, are involved in mechanisms of neurogenic inflammation, which are relevant for pain initiation. These findings indicate that in both groups (EM with/without HT), neurogenic inflammation is present and responsible for acyclical pain.

Pain in endometriosis involves not only nociceptive but also neuropathic and neurogenic components, reflecting its complex nature. Histamine, a biogenic amine, has emerged as a critical mediator connecting inflammation and nerve sensitization. This study aimed to characterize histamine receptor (HRH1–HRH4) expression, localization, and related inflammatory mediators in peritoneal, deep infiltrating, and ovarian endometriosis. Gene expression datasets were analyzed, and immunofluorescence staining of endometriotic lesions was performed using immune and neuronal markers. Histamine and its metabolite methylhistamine were quantified in serum, peritoneal fluid, and urine samples. HDC expression was significantly elevated in all endometriotic lesions compared with controls (all p < 0.01), paralleling increased IL-6, COX-2, NGF, and NGFR levels (p < 0.0001). In contrast, HRH1–HRH4 transcript levels showed no significant differences between groups. Immunofluorescence demonstrated robust HRH1–HRH4 protein expression in epithelial, immune, and nerve fibers, with subtype-specific colocalization patterns. Serum histamine concentrations were significantly higher in endometriosis patients than controls (0.484 vs. 0.153 ng/mg protein; p = 0.0014), whereas peritoneal histamine and urinary methylhistamine showed no group differences. Overall, these findings highlight histamine signaling as a potentially important component of endometriosis pathophysiology and point toward new directions for mechanistic studies and therapeutic exploration.