{"paper_id":"ed456a37-cee1-45aa-925a-09a8cf8215c0","body_text":"The Hidden Burden: Connective Tissue, Mast Cell,\nand Autoimmune Comorbidities Cluster in POTS\nwith Endometriosis\nAdeline Yilin Chin \nCleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of\nCase Western Reserve University https://orcid.org/0000-0002-8394-479X\nRyan G. Rilinger \nCleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of\nCase Western Reserve University\nPhoebe Leboit \nCleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of\nCase Western Reserve University\nMackaleigh Levine \nCleveland Clinic Department of Neuromuscular Medicine\nAmy S. Nowacki \nCleveland Clinic Department of Quantitative Health Sciences\nAshley R. Brant \nCleveland Clinic OB GYN and Women's Health Institute\nCheryl Cameron \nCase Western Reserve University, Department of Nutrition\nAshley Gubbels \nCleveland Clinic, Section of Minimally Invasive Gynecologic Surgery and Chronic Pelvic Pain, Obstetrics\nand Gynecology Institute\nRobert Wilson \nCleveland Clinic Department of Neuromuscular Medicine\nResearch Article\nKeywords: Postural Orthostatic Tachycardia Syndrome, Endometriosis, Ehlers-Danlos syndrome, Mast\ncell activation syndrome, Connective tissue disorders\nPosted Date: March 24th, 2026\nPage 1/16\n\nDOI: https://doi.org/10.21203/rs.3.rs-9113464/v1\nLicense:   This work is licensed under a Creative Commons Attribution 4.0 International License.  \nRead Full License\nVersion of Record: A version of this preprint was published at Clinical Autonomic Research on\nSeptember 21st, 2026. See the published version at https://doi.org/10.1007/s10286-026-01244-x.\nPage 2/16\n\nAbstract\nPurpose\nTo characterize and compare the prevalence of autoimmune, connective tissue, neurological, and\npsychiatric comorbidities between POTS patients with and without endometriosis, and to compare these\nrates to published general population estimates.\nMethods\nIn a retrospective cohort analysis, we reviewed medical records for 458 patients with POTS who\npresented to our autonomic center from 2018 to 2024. POTS was defined by symptoms of orthostatic\nintolerance accompanied by a heart rate increase of ≥ 30 beats per minute within the first 10 minutes of\nhead-up tilt table testing. A clinical or surgical diagnosis of endometriosis was defined by a gynecologic\nspecialist.\nResults\n458 female patients with POTS were included in the analysis. When compared to POTS patients without\nendometriosis, POTS patients with endometriosis had statistically significantly higher rates of Ehlers-\nDanlos syndrome (EDS) (33.6% vs. 12.7%, p < 0.001), Mast cell activation syndrome (MCAS) (19.2% vs.\n3.5%, p < 0.001), chronic migraines (55.9% vs. 39.3%, p < 0.001), fibromyalgia (23.1% vs. 11.4%, p = 0.001)\nand Raynaud’s phenomenon (15.7% vs. 6.6%, p = 0.003). Compared to the general population, POTS\npatients demonstrated higher rates of EDS, chronic migraines, and fibromyalgia. POTS patients with\nendometriosis also demonstrated higher rates of MCAS and Raynaud’s phenomenon compared to the\ngeneral population.\nConclusions\nPOTS patients with endometriosis exhibit significantly higher rates of connective tissue disorders, mast\ncell-mediated disease, autoimmune conditions, and chronic pain syndromes, with prevalence rates far\nexceeding general population estimates. These findings suggest shared pathophysiological\nmechanisms between POTS and endometriosis and support the need for comprehensive screening and\nmultidisciplinary management in this population.\n1. Introduction\nPostural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic\nnervous system characterized by an excessive heart rate increase upon standing (≥ 30 bpm within 10\nminutes) in the absence of orthostatic hypotension [1]. POTS disproportionately affects women, with a\nPage 3/16\n\nfemale-to-male ratio of approximately 5:1; symptoms often appear during the 2nd or 3rd decade of life\n[2]. POTS is associated with substantial morbidity, including chronic fatigue, cognitive dysfunction, and\nsignificantly reduced quality of life [1, 3].\nEndometriosis, defined by the presence of endometrial-like tissue outside the uterine cavity, affects 10%\nof reproductive-aged women globally [4]. Beyond the gynecological manifestations including pelvic pain,\ndysmenorrhea, and infertility, endometriosis is increasingly recognized as a systemic inflammatory\ncondition with far-reaching effects on multiple organ systems [5, 6]. Emerging evidence suggests\nsignificant overlap between endometriosis and autonomic dysfunction, with studies demonstrating\naltered heart rate variability and dysautonomia symptoms in affected patients [7, 8].\nBoth POTS and endometriosis have been independently associated with connective tissue disorders,\nparticularly Ehlers-Danlos syndrome (EDS), as well as autoimmune conditions and chronic pain\nsyndromes [9, 10]. The overlap of mast cell disorder, POTS, and connective tissue abnormalities\nsuggests shared pathophysiological mechanisms [11]. The concept of a \"triad\" comprising POTS, EDS,\nand mast cell activation syndrome (MCAS) has gained increasing recognition [12, 13], though its\nintersection with endometriosis remains poorly characterized.\nDespite these reports of a potential clinical overlap, no studies have directly compared comorbidity\nprofiles between POTS patients with and without endometriosis or contextualized these findings against\ngeneral population prevalence data [14]. Understanding the distinct comorbidity burden in this\npopulation may inform clinical screening practices, further elucidate disease mechanisms, and guide\ntherapeutic approaches.\nIn this retrospective cohort study, we aimed to characterize and compare the prevalence of autoimmune,\nconnective tissue, neurological, and psychiatric comorbidities between POTS patients with and without\nendometriosis, and to compare observed prevalence rates to published general population estimates to\nquantify the magnitude of comorbidity elevation.\n2. Materials and Methods\n2.1 Study Design and Population\nWe performed a retrospective cohort analysis conducted at a single tertiary academic medical center\n(Cleveland Clinic, Cleveland, Ohio, USA). All patients who presented for an initial visit to a POTS specialist\nbetween January 1, 2018, and December 31, 2024, were analyzed. The study was approved by the\nCleveland Clinic Institutional Review Board (FWA00005367, Protocol #25–157). Informed consent was\nnot required because the study involved only secondary use of existing clinical data and posed minimal\nrisk to participants.\nUsing Epic SlicerDicer (Epic Systems Corporation, Verona, WI, USA), we identified 3,839 patient charts\nwith International Classification of Disease (ICD) codes for POTS. Patients included in the study were ≥ \nPage 4/16\n\n18 years old at time of head-up tilt table test (HUTT), had a confirmed diagnosis of POTS by a Cleveland\nClinic specialist, defined as symptoms of orthostatic intolerance accompanied by a heart rate increase\nof ≥ 30 bpm within 10 minutes of HUTT without orthostatic hypotension. Patients were excluded from\nthe study if tilt tests were negative, performed outside of the Cleveland Clinic hospital system, or were\nnever completed. A clinical diagnosis of endometriosis was defined by a gynecologic specialist based\non history (cyclic pelvic pain, dysmenorrhea) and physical exam findings, specialized pelvic ultrasound or\nmagnetic resonance imaging (MRI), or response to suppression therapy, in the absence of surgical\npathology.[15] A surgical diagnosis of endometriosis was confirmed by histopathology from\nlaparoscopic or open procedures from gynecologic specialists. A random number generator was utilized\nto select a simple random sample of our patients with a diagnosis of POTS without endometriosis to be\nused as a 1:1 control group (Fig. 1).\n2.2 Data Collection\nDemographic data including age at visit, body mass index (BMI), and race were extracted from electronic\nmedical records.\nThe following comorbidities were assessed as listed diagnoses in the medical history:\nAutoimmune conditions: Sjögren's syndrome, celiac disease, Hashimoto's thyroiditis, rheumatoid\narthritis\nConnective tissue disorders: EDS\nNeurological conditions: Chiari malformation type 1, chronic migraine\nVascular/inflammatory conditions: Raynaud's phenomenon, MCAS\nChronic pain syndromes: Fibromyalgia\nEndocrine conditions: Polycystic ovary syndrome (PCOS), hypertension\nPsychiatric conditions: Anxiety, depression\n2.3 General Population Prevalence Data\nPublished prevalence estimates for each comorbidity were obtained from peer-reviewed systematic\nreviews, meta-analyses, and epidemiological studies. When available, sex-specific prevalence data for\nwomen were used. Sources included the Global Burden of Disease Study, World Health Organization\nreports, and condition-specific systematic reviews.\n2.4 Statistical Analysis\nAll electronic study data were collected and managed via Research Electronic Data Capture (REDCap), a\nsecure, web-based application designed to support data capture for research studies [16]. All statistical\nanalyses were completed using R version 4.4.1 (R Core Team, 2025. R: A Language and Environment for\nPage 5/16\n\nStatistical Computing. R Foundation for Statistical Computing, Vienna, Austria)[17] within RStudio\nversion 2025.05.1 + 513 (RStudio Team, 2025).\nAge and BMI at initial visit for POTS were compared among POTS patients with versus without\nendometriosis using Wilcoxon-rank sum tests. Comorbidity prevalences were compared using Fisher's\nexact tests in anticipation of low prevalence for some conditions. Fold-increase ratios were calculated by\ndividing the observed prevalence in each POTS group by the midpoint of published general population\nprevalence ranges. P-values < 0.05 were considered statistically significant.\n3. Results\nA total of 458 female patients with confirmed POTS by tilt-table test were included in the analysis. 229\npatients had a co-occurring diagnosis of endometriosis. There were no significant demographic\ndifferences between the group with diagnosis of POTS without endometriosis and with diagnoses of\nboth POTS and endometriosis (Table 1).\nTable 1\nPatient Characteristics\nAge (years) POTS only (n = 229)POTS and Endometriosis (n = 229)P-value\n30 (23–39) 31 (23–39) 0.97\nBMI (kg/m2) 23.8 (20.7–27.3) 24.6 (21.5–29.7) 0.25\nRace (white)203 (88%) 207 (90%) 0.16\nDescriptive statistics are reported as either median (Q1-Q3) or count (%).\nComorbidity prevalence was significantly higher in POTS patients with endometriosis compared to those\nwithout in EDS, MCAS, chronic migraine, fibromyalgia, and Raynaud’s phenomenon (Table 2).\nPage 6/16\n\nTable 2\nComorbidity Prevalence in POTS Patients With and Without Endometriosis\nComorbidity POTS only (n = 229) POTS and Endometriosis (n = 229) P-value\nEhlers-Danlos syndrome 29 (12.7%) 77 (33.6%) < 0.001*\nSjögren's syndrome 8 (3.5%) 14 (6.1%) 0.27\nCeliac disease 6 (2.6%) 5 (2.2%) 0.99\nHashimoto's thyroiditis 8 (3.5%) 16 (7.0%) 0.14\nRheumatoid arthritis 2 (0.9%) 5 (2.2%) 0.45\nMast cell activationsyndrome 8 (3.5%) 44 (19.2%) < 0.001*\nChronic migraine 90 (39.3%) 128 (55.9%) < 0.001*\nChiari malformation 1 (0.4%) 4 (1.7%) 0.372\nFibromyalgia 26 (11.4%) 53 (23.1%) 0.001*\nRaynaud's phenomenon 15 (6.6%) 36 (15.7%) 0.003*\nPCOS 18 (7.9%) 31 (13.5%) 0.07\nHypertension 27 (11.8%) 32 (14.0%) 0.58\nAnxiety 112 (48.9%) 128 (55.9%) 0.16\nDepression 90 (39.3%) 109 (47.6%) 0.09\n*p < 0.05; Fisher's exact test used for all comparisons.\nWe also compared the observed comorbidity prevalence rates in our POTS patient sample to published\ngeneral population estimates (Fig. 2).\n3.1 Comorbidity Domains\n3.1.1 Connective Tissue Disorders\nThe prevalence of EDS in our POTS without endometriosis group (12.7%) represents a 64-fold increase\ncompared to the upper estimate of general population prevalence (0.2%)[18]. In the POTS with\nendometriosis group (33.6%), this represents a 168-fold increase[18]. EDS was also significantly more\nprevalent in POTS patients with endometriosis compared to those without endometriosis (33.6% vs\n12.7%, p < 0.001), representing a nearly three-fold between-group difference and the largest absolute\ndifference observed among all comorbidities assessed.\nPage 7/16\n\n3.1.2 Autoimmune Conditions\nPatients with POTS and endometriosis demonstrated significantly elevated rates of Raynaud’s\nphenomenon (15.7% vs. 6.6%, p = 0.003) compared to POTS patients without endometriosis. Prevalence\nof Sjögren's syndrome (6.1% vs. 3.5%, p = 0.27), Rheumatoid arthritis (2.2% vs. 0.9%, p = 0.45),\nHashimoto's thyroiditis (7.0% vs. 3.5%, p = 0.14), and Celiac disease (2.6% vs. 2.2%, p = 0.99) did not\ndiffer in our POTS cohorts. Compared to the general population, Sjögren's syndrome and celiac disease\nshowed a fold-increase compared to general population estimates [19, 20].\n3.1.3 Mast Cell Activation Syndrome\nMCAS was significantly more prevalent in POTS patients with endometriosis compared to those without\n(19.2% vs 3.5%, p < 0.001). POTS patients with endometriosis also demonstrated a four-fold increase\ncompared to general population estimates of 4.4%[21].\n3.1.4 Neurological and Pain Conditions\nChronic migraine was significantly more common in POTS patients with endometriosis compared to\nPOTS patients without endometriosis (55.9% vs 39.3%, p < 0.001), a two to three-fold increase over\ngeneral population rates [22]. Fibromyalgia rates were approximately doubled in POTS patients with\nendometriosis compared to those without (23.1% vs 11.4%, p = 0.001). There was no significant\ndifference in Chiari malformation rates in POTS patients with endometriosis compared to POTS patients\nwithout endometriosis (1.7% vs 0.4%, p = 0.37).\n3.1.5 Psychiatric Conditions\nWhile POTS patients with and without endometriosis demonstrated high rates of anxiety (48.9–55.9%)\nand depression (39.3–47.6%), these did not differ significantly between groups. Notably, the prevalence\nof anxiety and depression were markedly higher compared to general population estimates of 21.7% for\nanxiety disorders and 8.2% for major depression [23].\n4. Discussion\nThis study provides a novel comparison of comorbidity profiles between POTS patients with and without\nconcomitant endometriosis, contextualized against general population prevalence data. Our findings\nreveal that POTS patients with endometriosis exhibit a distinct phenotype characterized by dramatically\nelevated rates of connective tissue disorders, mast cell-mediated disease, Raynaud’s phenomenon, and\nchronic pain syndromes.\n4.1 Connective Tissue Abnormalities and Autonomic\nDysfunction\nPage 8/16\n\nWe identified a striking elevation of EDS prevalence in our cohorts, 12.7% in POTS without endometriosis\nand 33.6% in POTS with endometriosis, compared to 0.2% in the general population. This 64- to 168-fold\nincrease supports a possible connection between connective tissue integrity and autonomic function.\nEDS, particularly the hypermobile subtype (hEDS), has been increasingly recognized as a component of a\nmultisystem disorder spectrum that includes POTS, MCAS, and various chronic pain conditions [12].\nMechanistic links may involve defective collagen synthesis affecting vascular compliance, leading to\nvenous pooling and the compensatory tachycardia characteristic of POTS [24]. Recent evidence\nsuggests that connective tissue abnormalities may also affect the extracellular matrix surrounding\nautonomic nerve fibers, potentially contributing to dysautonomia [25].\nEndometriosis has similarly been associated with connective tissue abnormalities, including altered\nextracellular matrix composition and enhanced tissue invasiveness [26]. Our results suggest that the\ncombination of POTS and endometriosis may identify a subset of patients with particularly severe\nconnective tissue dysfunction, warranting consideration of a rheumatological evaluation.\n4.2 Mast Cell Activation Syndrome\nOne of our most substantial findings was the nearly six-fold elevation of MCAS in POTS patients with\nendometriosis compared to those without (19.2% vs 3.5%), with the rate in POTS patients with\nendometriosis far exceeding published general population estimates. Importantly, MCAS prevalence in\nPOTS without endometriosis patients (3.5%) is similar to general population estimates (4.4%),\nsuggesting that concomitant endometriosis specifically potentiates mast cell dysfunction.\nMast cells have been increasingly recognized as central players in the pathophysiology of both POTS\nand endometriosis. In POTS, mast cell activation may contribute to vasodilation, tachycardia, flushing,\nand systemic symptoms through histamine and other mediator release [27]. In endometriosis, mast cells\ndensely infiltrate ectopic lesions and contribute to pain, inflammation, and disease progression [28].\nPeritoneal fluid in patients with endometriosis has been found to contain elevated levels of mast cell\nmediators, including histamine, tryptase, and prostaglandins [29]. The significant elevation of MCAS in\nour cohort of patients with POTS and endometriosis suggests that combined autonomic and\ngynecological dysfunction may create a permissive environment for mast cell dysregulation—or,\nconversely, that underlying mast cell disease may predispose to both conditions. This has important\ntherapeutic implications, as mast cell-targeted therapies (H1/H2 antihistamines, mast cell stabilizers\nsuch as cromolyn and ketotifen) may benefit patients with this phenotype and deserve prospective\nevaluation.\n4.3 Central Sensitization\nThe findings that chronic migraines and fibromyalgia are significantly more prevalent in POTS patients\nwith and without endometriosis compared to the general population suggests the role of central\nsensitization in disease mechanisms. Central sensitization, characterized by amplified neural signaling\nand reduced pain thresholds, has been implicated in both fibromyalgia and chronic migraines [30]. Both\nPage 9/16\n\nPOTS and endometriosis have been associated with altered pain processing and evidence of central\nsensitization [31, 32]. The clustering of chronic migraine and fibromyalgia in our cohorts may reflect\nshared neurobiological vulnerabilities involving trigeminal-autonomic pathways.\n4.4 The POTS-Endometriosis Phenotype: Clinical\nImplications\nOur findings support the existence of a distinct phenotype of patients with both POTS and endometriosis\ncharacterized by high rates of EDS, marked elevation of MCAS, chronic migraine in more than half of\npatients, autoimmune conditions, and elevated fibromyalgia. This phenotype may represent a specific\nsubtype of POTS with distinct pathophysiology and therapeutic implications. These results support the\nneed for screening this patient population for hypermobility / EDS, MCAS, and chronic pain syndromes.\nThe multisystem involvement in this patient population also necessitates coordinated care involving\nautonomic specialists, gynecologists, rheumatologists, allergists/immunologists, neurologists, and pain\nspecialists.\nFurther studies are warranted to investigate shared genetic susceptibility, particularly comparing genes\naffecting connective tissue, immune function, and inflammation in POTS patients with and without\nendometriosis. These findings may inform targeted therapeutic approaches for POTS patients with\nendometriosis.\n4.5 Limitations\nThis study has several limitations. First, the retrospective design relies on documented diagnoses,\npotentially underestimating true comorbidity prevalence due to underdiagnosis—a particular concern for\nconditions like EDS and MCAS that often go unrecognized. Second, the study was conducted at a single\ntertiary referral center, which may limit generalizability and introduce referral bias toward more complex\ncases. Third, we did not assess disease severity, treatment responses, or temporal relationships\nbetween conditions as these data items are not routinely collected. Finally, general population\nprevalence estimates vary across studies and populations, introducing uncertainty in fold-increase\ncalculations.\n5. Conclusions\nPOTS patients with concomitant endometriosis represent a distinct phenotype characterized by\ndramatically elevated rates of Ehlers-Danlos syndrome (33.6%, representing up to 168-fold increase vs.\ngeneral population), Mast cell activation syndrome (19.2%), chronic migraine (55.9%), Raynaud’s\nphenomenon and fibromyalgia. These prevalence rates far exceed what would be expected by chance\nand support the concept of shared pathophysiological mechanisms involving connective tissue\ndysfunction, mast cell dysregulation, and immune dysregulation.\nClinicians caring for patients with both POTS and endometriosis should maintain a high index of\nsuspicion for these comorbidities, pursue additional screening, and consider a multidisciplinary\nPage 10/16\n\napproach to evaluation and management. Future research should investigate the genetic and molecular\nunderpinnings of this phenotype and evaluate targeted therapeutic approaches.\nDeclarations\nFunding sources\nThis study was funded by the Autonomic Research Fund.\nDeclaration of Competing Interests\nNone declared for all authors.\nEthics Statement\nThis study was approved by the Cleveland Clinic Institutional Review Board (IRB #25-157).\nAuthor contributions\nConception of the research topic: Adeline Y. Chin, Robert Wilson\nData collection and creation of database: Adeline Y. Chin, Ryan G. Rilinger, Phoebe Leboit, Mackaleigh\nLevine\nAnalysis of study data: Adeline Y. Chin, Amy S. Nowacki\nInterpretation of study results: Adeline Y. Chin, Robert Wilson\nComposition of the manuscript: Adeline Y. Chin, Ryan G. Rilinger\nAll authors read and approved the final manuscript. \nAcknowledgements\nWe thank Dawn Caraballo, Dr. Kerry Levin, and Dr. John Morren for technical support.\nReferences\n1. Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society Expert Consensus Statement\non the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus\nTachycardia, and Vasovagal Syncope. Heart Rhythm 2015;12:e41–63.\nhttps://doi.org/10.1016/j.hrthm.2015.03.029.\n2. Thieben MJ, Sandroni P, Sletten DM, et al. Postural Orthostatic Tachycardia Syndrome: The Mayo\nClinic Experience. Mayo Clin Proc 2007;82:308–13. https://doi.org/10.4065/82.3.308.\nPage 11/16\n\n3. 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Front Public Health 2022;10:1020709.\nhttps://doi.org/10.3389/fpubh.2022.1020709.\nFigures\nPage 14/16\n\nFigure 1\nCONSORT Flowchart Diagram\nFigure 2\nPage 15/16\n\nKey comorbidity prevalence in POTS cohorts compared to general population estimates\nSupplementary Files\nThis is a list of supplementary files associated with this preprint. Click to download.\nSupplementaryTable1.docx\nPage 16/16","source_license":"public-domain-us","license_restricted":false}