The Hidden Burden: Connective Tissue, Mast Cell, and Autoimmune Comorbidities Cluster in POTS with Endometriosis

The Hidden Burden: Connective Tissue, Mast Cell, and Autoimmune Comorbidities Cluster in POTS with Endometriosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Hidden Burden: Connective Tissue, Mast Cell, and Autoimmune Comorbidities Cluster in POTS with Endometriosis Adeline Yilin Chin, Ryan G. Rilinger, Phoebe Leboit, Mackaleigh Levine, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9113464/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose To characterize and compare the prevalence of autoimmune, connective tissue, neurological, and psychiatric comorbidities between POTS patients with and without endometriosis, and to compare these rates to published general population estimates. Methods In a retrospective cohort analysis, we reviewed medical records for 458 patients with POTS who presented to our autonomic center from 2018 to 2024. POTS was defined by symptoms of orthostatic intolerance accompanied by a heart rate increase of ≥ 30 beats per minute within the first 10 minutes of head-up tilt table testing. A clinical or surgical diagnosis of endometriosis was defined by a gynecologic specialist. Results 458 female patients with POTS were included in the analysis. When compared to POTS patients without endometriosis, POTS patients with endometriosis had statistically significantly higher rates of Ehlers-Danlos syndrome (EDS) (33.6% vs. 12.7%, p < 0.001), Mast cell activation syndrome (MCAS) (19.2% vs. 3.5%, p < 0.001), chronic migraines (55.9% vs. 39.3%, p < 0.001), fibromyalgia (23.1% vs. 11.4%, p = 0.001) and Raynaud’s phenomenon (15.7% vs. 6.6%, p = 0.003). Compared to the general population, POTS patients demonstrated higher rates of EDS, chronic migraines, and fibromyalgia. POTS patients with endometriosis also demonstrated higher rates of MCAS and Raynaud’s phenomenon compared to the general population. Conclusions POTS patients with endometriosis exhibit significantly higher rates of connective tissue disorders, mast cell-mediated disease, autoimmune conditions, and chronic pain syndromes, with prevalence rates far exceeding general population estimates. These findings suggest shared pathophysiological mechanisms between POTS and endometriosis and support the need for comprehensive screening and multidisciplinary management in this population. Postural Orthostatic Tachycardia Syndrome Endometriosis Ehlers-Danlos syndrome Mast cell activation syndrome Connective tissue disorders Figures Figure 1 Figure 2 1. Introduction Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system characterized by an excessive heart rate increase upon standing (≥ 30 bpm within 10 minutes) in the absence of orthostatic hypotension [ 1 ]. POTS disproportionately affects women, with a female-to-male ratio of approximately 5:1; symptoms often appear during the 2nd or 3rd decade of life [ 2 ]. POTS is associated with substantial morbidity, including chronic fatigue, cognitive dysfunction, and significantly reduced quality of life [ 1 , 3 ]. Endometriosis, defined by the presence of endometrial-like tissue outside the uterine cavity, affects 10% of reproductive-aged women globally [ 4 ]. Beyond the gynecological manifestations including pelvic pain, dysmenorrhea, and infertility, endometriosis is increasingly recognized as a systemic inflammatory condition with far-reaching effects on multiple organ systems [ 5 , 6 ]. Emerging evidence suggests significant overlap between endometriosis and autonomic dysfunction, with studies demonstrating altered heart rate variability and dysautonomia symptoms in affected patients [ 7 , 8 ]. Both POTS and endometriosis have been independently associated with connective tissue disorders, particularly Ehlers-Danlos syndrome (EDS), as well as autoimmune conditions and chronic pain syndromes [ 9 , 10 ]. The overlap of mast cell disorder, POTS, and connective tissue abnormalities suggests shared pathophysiological mechanisms [ 11 ]. The concept of a "triad" comprising POTS, EDS, and mast cell activation syndrome (MCAS) has gained increasing recognition [ 12 , 13 ], though its intersection with endometriosis remains poorly characterized. Despite these reports of a potential clinical overlap, no studies have directly compared comorbidity profiles between POTS patients with and without endometriosis or contextualized these findings against general population prevalence data [ 14 ]. Understanding the distinct comorbidity burden in this population may inform clinical screening practices, further elucidate disease mechanisms, and guide therapeutic approaches. In this retrospective cohort study, we aimed to characterize and compare the prevalence of autoimmune, connective tissue, neurological, and psychiatric comorbidities between POTS patients with and without endometriosis, and to compare observed prevalence rates to published general population estimates to quantify the magnitude of comorbidity elevation. 2. Materials and Methods 2.1 Study Design and Population We performed a retrospective cohort analysis conducted at a single tertiary academic medical center (Cleveland Clinic, Cleveland, Ohio, USA). All patients who presented for an initial visit to a POTS specialist between January 1, 2018, and December 31, 2024, were analyzed. The study was approved by the Cleveland Clinic Institutional Review Board (FWA00005367, Protocol #25–157). Informed consent was not required because the study involved only secondary use of existing clinical data and posed minimal risk to participants. Using Epic SlicerDicer (Epic Systems Corporation, Verona, WI, USA), we identified 3,839 patient charts with International Classification of Disease (ICD) codes for POTS. Patients included in the study were ≥ 18 years old at time of head-up tilt table test (HUTT), had a confirmed diagnosis of POTS by a Cleveland Clinic specialist, defined as symptoms of orthostatic intolerance accompanied by a heart rate increase of ≥ 30 bpm within 10 minutes of HUTT without orthostatic hypotension. Patients were excluded from the study if tilt tests were negative, performed outside of the Cleveland Clinic hospital system, or were never completed. A clinical diagnosis of endometriosis was defined by a gynecologic specialist based on history (cyclic pelvic pain, dysmenorrhea) and physical exam findings, specialized pelvic ultrasound or magnetic resonance imaging (MRI), or response to suppression therapy, in the absence of surgical pathology.[ 15 ] A surgical diagnosis of endometriosis was confirmed by histopathology from laparoscopic or open procedures from gynecologic specialists. A random number generator was utilized to select a simple random sample of our patients with a diagnosis of POTS without endometriosis to be used as a 1:1 control group (Fig. 1 ). 2.2 Data Collection Demographic data including age at visit, body mass index (BMI), and race were extracted from electronic medical records. The following comorbidities were assessed as listed diagnoses in the medical history: Autoimmune conditions: Sjögren's syndrome, celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis Connective tissue disorders: EDS Neurological conditions: Chiari malformation type 1, chronic migraine Vascular/inflammatory conditions: Raynaud's phenomenon, MCAS Chronic pain syndromes: Fibromyalgia Endocrine conditions: Polycystic ovary syndrome (PCOS), hypertension Psychiatric conditions: Anxiety, depression 2.3 General Population Prevalence Data Published prevalence estimates for each comorbidity were obtained from peer-reviewed systematic reviews, meta-analyses, and epidemiological studies. When available, sex-specific prevalence data for women were used. Sources included the Global Burden of Disease Study, World Health Organization reports, and condition-specific systematic reviews. 2.4 Statistical Analysis All electronic study data were collected and managed via Research Electronic Data Capture (REDCap), a secure, web-based application designed to support data capture for research studies [ 16 ]. All statistical analyses were completed using R version 4.4.1 (R Core Team, 2025. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria)[ 17 ] within RStudio version 2025.05.1 + 513 (RStudio Team, 2025). Age and BMI at initial visit for POTS were compared among POTS patients with versus without endometriosis using Wilcoxon-rank sum tests. Comorbidity prevalences were compared using Fisher's exact tests in anticipation of low prevalence for some conditions. Fold-increase ratios were calculated by dividing the observed prevalence in each POTS group by the midpoint of published general population prevalence ranges. P-values < 0.05 were considered statistically significant. 3. Results A total of 458 female patients with confirmed POTS by tilt-table test were included in the analysis. 229 patients had a co-occurring diagnosis of endometriosis. There were no significant demographic differences between the group with diagnosis of POTS without endometriosis and with diagnoses of both POTS and endometriosis (Table 1 ). Table 1 Patient Characteristics Age (years) POTS only (n = 229) POTS and Endometriosis (n = 229) P-value 30 (23–39) 31 (23–39) 0.97 BMI (kg/m 2 ) 23.8 (20.7–27.3) 24.6 (21.5–29.7) 0.25 Race (white) 203 (88%) 207 (90%) 0.16 Descriptive statistics are reported as either median (Q 1 -Q 3 ) or count (%). Comorbidity prevalence was significantly higher in POTS patients with endometriosis compared to those without in EDS, MCAS, chronic migraine, fibromyalgia, and Raynaud’s phenomenon (Table 2 ). Table 2 Comorbidity Prevalence in POTS Patients With and Without Endometriosis Comorbidity POTS only (n = 229) POTS and Endometriosis (n = 229) P-value Ehlers-Danlos syndrome 29 (12.7%) 77 (33.6%) < 0.001* Sjögren's syndrome 8 (3.5%) 14 (6.1%) 0.27 Celiac disease 6 (2.6%) 5 (2.2%) 0.99 Hashimoto's thyroiditis 8 (3.5%) 16 (7.0%) 0.14 Rheumatoid arthritis 2 (0.9%) 5 (2.2%) 0.45 Mast cell activation syndrome 8 (3.5%) 44 (19.2%) < 0.001* Chronic migraine 90 (39.3%) 128 (55.9%) < 0.001* Chiari malformation 1 (0.4%) 4 (1.7%) 0.372 Fibromyalgia 26 (11.4%) 53 (23.1%) 0.001* Raynaud's phenomenon 15 (6.6%) 36 (15.7%) 0.003* PCOS 18 (7.9%) 31 (13.5%) 0.07 Hypertension 27 (11.8%) 32 (14.0%) 0.58 Anxiety 112 (48.9%) 128 (55.9%) 0.16 Depression 90 (39.3%) 109 (47.6%) 0.09 *p < 0.05; Fisher's exact test used for all comparisons. We also compared the observed comorbidity prevalence rates in our POTS patient sample to published general population estimates (Fig. 2 ). 3.1 Comorbidity Domains 3.1.1 Connective Tissue Disorders The prevalence of EDS in our POTS without endometriosis group (12.7%) represents a 64-fold increase compared to the upper estimate of general population prevalence (0.2%)[ 18 ]. In the POTS with endometriosis group (33.6%), this represents a 168-fold increase[ 18 ]. EDS was also significantly more prevalent in POTS patients with endometriosis compared to those without endometriosis (33.6% vs 12.7%, p < 0.001), representing a nearly three-fold between-group difference and the largest absolute difference observed among all comorbidities assessed. 3.1.2 Autoimmune Conditions Patients with POTS and endometriosis demonstrated significantly elevated rates of Raynaud’s phenomenon (15.7% vs. 6.6%, p = 0.003) compared to POTS patients without endometriosis. Prevalence of Sjögren's syndrome (6.1% vs. 3.5%, p = 0.27), Rheumatoid arthritis (2.2% vs. 0.9%, p = 0.45), Hashimoto's thyroiditis (7.0% vs. 3.5%, p = 0.14), and Celiac disease (2.6% vs. 2.2%, p = 0.99) did not differ in our POTS cohorts. Compared to the general population, Sjögren's syndrome and celiac disease showed a fold-increase compared to general population estimates [ 19 , 20 ]. 3.1.3 Mast Cell Activation Syndrome MCAS was significantly more prevalent in POTS patients with endometriosis compared to those without (19.2% vs 3.5%, p < 0.001). POTS patients with endometriosis also demonstrated a four-fold increase compared to general population estimates of 4.4%[ 21 ]. 3.1.4 Neurological and Pain Conditions Chronic migraine was significantly more common in POTS patients with endometriosis compared to POTS patients without endometriosis (55.9% vs 39.3%, p < 0.001), a two to three-fold increase over general population rates [ 22 ]. Fibromyalgia rates were approximately doubled in POTS patients with endometriosis compared to those without (23.1% vs 11.4%, p = 0.001). There was no significant difference in Chiari malformation rates in POTS patients with endometriosis compared to POTS patients without endometriosis (1.7% vs 0.4%, p = 0.37). 3.1.5 Psychiatric Conditions While POTS patients with and without endometriosis demonstrated high rates of anxiety (48.9–55.9%) and depression (39.3–47.6%), these did not differ significantly between groups. Notably, the prevalence of anxiety and depression were markedly higher compared to general population estimates of 21.7% for anxiety disorders and 8.2% for major depression [ 23 ]. 4. Discussion This study provides a novel comparison of comorbidity profiles between POTS patients with and without concomitant endometriosis, contextualized against general population prevalence data. Our findings reveal that POTS patients with endometriosis exhibit a distinct phenotype characterized by dramatically elevated rates of connective tissue disorders, mast cell-mediated disease, Raynaud’s phenomenon, and chronic pain syndromes. 4.1 Connective Tissue Abnormalities and Autonomic Dysfunction We identified a striking elevation of EDS prevalence in our cohorts, 12.7% in POTS without endometriosis and 33.6% in POTS with endometriosis, compared to 0.2% in the general population. This 64- to 168-fold increase supports a possible connection between connective tissue integrity and autonomic function. EDS, particularly the hypermobile subtype (hEDS), has been increasingly recognized as a component of a multisystem disorder spectrum that includes POTS, MCAS, and various chronic pain conditions [ 12 ]. Mechanistic links may involve defective collagen synthesis affecting vascular compliance, leading to venous pooling and the compensatory tachycardia characteristic of POTS [ 24 ]. Recent evidence suggests that connective tissue abnormalities may also affect the extracellular matrix surrounding autonomic nerve fibers, potentially contributing to dysautonomia [ 25 ]. Endometriosis has similarly been associated with connective tissue abnormalities, including altered extracellular matrix composition and enhanced tissue invasiveness [ 26 ]. Our results suggest that the combination of POTS and endometriosis may identify a subset of patients with particularly severe connective tissue dysfunction, warranting consideration of a rheumatological evaluation. 4.2 Mast Cell Activation Syndrome One of our most substantial findings was the nearly six-fold elevation of MCAS in POTS patients with endometriosis compared to those without (19.2% vs 3.5%), with the rate in POTS patients with endometriosis far exceeding published general population estimates. Importantly, MCAS prevalence in POTS without endometriosis patients (3.5%) is similar to general population estimates (4.4%), suggesting that concomitant endometriosis specifically potentiates mast cell dysfunction. Mast cells have been increasingly recognized as central players in the pathophysiology of both POTS and endometriosis. In POTS, mast cell activation may contribute to vasodilation, tachycardia, flushing, and systemic symptoms through histamine and other mediator release [ 27 ]. In endometriosis, mast cells densely infiltrate ectopic lesions and contribute to pain, inflammation, and disease progression [ 28 ]. Peritoneal fluid in patients with endometriosis has been found to contain elevated levels of mast cell mediators, including histamine, tryptase, and prostaglandins [ 29 ]. The significant elevation of MCAS in our cohort of patients with POTS and endometriosis suggests that combined autonomic and gynecological dysfunction may create a permissive environment for mast cell dysregulation—or, conversely, that underlying mast cell disease may predispose to both conditions. This has important therapeutic implications, as mast cell-targeted therapies (H1/H2 antihistamines, mast cell stabilizers such as cromolyn and ketotifen) may benefit patients with this phenotype and deserve prospective evaluation. 4.3 Central Sensitization The findings that chronic migraines and fibromyalgia are significantly more prevalent in POTS patients with and without endometriosis compared to the general population suggests the role of central sensitization in disease mechanisms. Central sensitization, characterized by amplified neural signaling and reduced pain thresholds, has been implicated in both fibromyalgia and chronic migraines [ 30 ]. Both POTS and endometriosis have been associated with altered pain processing and evidence of central sensitization [ 31 , 32 ]. The clustering of chronic migraine and fibromyalgia in our cohorts may reflect shared neurobiological vulnerabilities involving trigeminal-autonomic pathways. 4.4 The POTS-Endometriosis Phenotype: Clinical Implications Our findings support the existence of a distinct phenotype of patients with both POTS and endometriosis characterized by high rates of EDS, marked elevation of MCAS, chronic migraine in more than half of patients, autoimmune conditions, and elevated fibromyalgia. This phenotype may represent a specific subtype of POTS with distinct pathophysiology and therapeutic implications. These results support the need for screening this patient population for hypermobility / EDS, MCAS, and chronic pain syndromes. The multisystem involvement in this patient population also necessitates coordinated care involving autonomic specialists, gynecologists, rheumatologists, allergists/immunologists, neurologists, and pain specialists. Further studies are warranted to investigate shared genetic susceptibility, particularly comparing genes affecting connective tissue, immune function, and inflammation in POTS patients with and without endometriosis. These findings may inform targeted therapeutic approaches for POTS patients with endometriosis. 4.5 Limitations This study has several limitations. First, the retrospective design relies on documented diagnoses, potentially underestimating true comorbidity prevalence due to underdiagnosis—a particular concern for conditions like EDS and MCAS that often go unrecognized. Second, the study was conducted at a single tertiary referral center, which may limit generalizability and introduce referral bias toward more complex cases. Third, we did not assess disease severity, treatment responses, or temporal relationships between conditions as these data items are not routinely collected. Finally, general population prevalence estimates vary across studies and populations, introducing uncertainty in fold-increase calculations. 5. Conclusions POTS patients with concomitant endometriosis represent a distinct phenotype characterized by dramatically elevated rates of Ehlers-Danlos syndrome (33.6%, representing up to 168-fold increase vs. general population), Mast cell activation syndrome (19.2%), chronic migraine (55.9%), Raynaud’s phenomenon and fibromyalgia. These prevalence rates far exceed what would be expected by chance and support the concept of shared pathophysiological mechanisms involving connective tissue dysfunction, mast cell dysregulation, and immune dysregulation. Clinicians caring for patients with both POTS and endometriosis should maintain a high index of suspicion for these comorbidities, pursue additional screening, and consider a multidisciplinary approach to evaluation and management. Future research should investigate the genetic and molecular underpinnings of this phenotype and evaluate targeted therapeutic approaches. Declarations Funding sources This study was funded by the Autonomic Research Fund. Declaration of Competing Interests None declared for all authors. Ethics Statement This study was approved by the Cleveland Clinic Institutional Review Board (IRB #25-157). Author contributions Conception of the research topic: Adeline Y. Chin, Robert Wilson Data collection and creation of database: Adeline Y. Chin, Ryan G. Rilinger, Phoebe Leboit, Mackaleigh Levine Analysis of study data: Adeline Y. Chin, Amy S. Nowacki Interpretation of study results: Adeline Y. Chin, Robert Wilson Composition of the manuscript: Adeline Y. Chin, Ryan G. Rilinger All authors read and approved the final manuscript. Acknowledgements We thank Dawn Caraballo, Dr. Kerry Levin, and Dr. John Morren for technical support. References Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope. Heart Rhythm 2015;12:e41–63. https://doi.org/10.1016/j.hrthm.2015.03.029. Thieben MJ, Sandroni P, Sletten DM, et al. Postural Orthostatic Tachycardia Syndrome: The Mayo Clinic Experience. Mayo Clin Proc 2007;82:308–13. https://doi.org/10.4065/82.3.308. Benarroch EE. Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder. Mayo Clin Proc 2012;87:1214–25. https://doi.org/10.1016/j.mayocp.2012.08.013. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382:1244–56. https://doi.org/10.1056/NEJMra1810764. Kvaskoff M, Mu F, Terry KL, et al. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update 2015;21:500–16. https://doi.org/10.1093/humupd/dmv013. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382:1244–56. https://doi.org/10.1056/NEJMra1810764. Wei Y, Liang Y, Lin H, et al. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation 2020;17:80. https://doi.org/10.1186/s12974-020-01752-1. Hao M, Liu X, Rong P, et al. Reduced vagal tone in women with endometriosis and auricular vagus nerve stimulation as a potential therapeutic approach. Sci Rep 2021;11:1345. https://doi.org/10.1038/s41598-020-79750-9. Hakim A, O’Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type. Am J Med Genet C Semin Med Genet 2017;175:168–74. https://doi.org/10.1002/ajmg.c.31543. Shigesi N, Kvaskoff M, Kirtley S, et al. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update 2019;25:486–503. https://doi.org/10.1093/humupd/dmz014. Cheung I, Vadas P. A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. J Allergy Clin Immunol 2015;135:AB65. https://doi.org/10.1016/j.jaci.2014.12.1146. Kucharik AH, Chang C. The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clin Rev Allergy Immunol 2020;58:273–97. https://doi.org/10.1007/s12016-019-08755-8. Halverson CME, Cao S, Perkins SM, et al. Comorbidity, misdiagnoses, and the diagnostic odyssey in patients with hypermobile Ehlers-Danlos syndrome. Genet Med Open 2023;1:100812. https://doi.org/10.1016/j.gimo.2023.100812. Farley M, Estrada-Mendizabal RJ, Gansert EA, et al. Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: A systematic review. Ann Allergy Asthma Immunol 2025;135:97–102. https://doi.org/10.1016/j.anai.2025.03.022. As-Sanie S, Mackenzie SC, Morrison L, et al. Endometriosis: A Review. JAMA 2025;334:64. https://doi.org/10.1001/jama.2025.2975. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. https://doi.org/10.1016/j.jbi.2008.08.010. R Core Team (2025). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. . n.d. Demmler JC, Atkinson MD, Reinhold EJ, et al. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case–control comparison. BMJ Open 2019;9:e031365. https://doi.org/10.1136/bmjopen-2019-031365. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16:823-836.e2. https://doi.org/10.1016/j.cgh.2017.06.037. Thurtle E, Grosjean A, Steenackers M, et al. Epidemiology of Sjögren’s: A Systematic Literature Review. Rheumatol Ther 2024;11:1–17. https://doi.org/10.1007/s40744-023-00611-8. Zaghmout T, Maclachlan L, Bedi N, et al. Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders. J Allergy Clin Immunol Pract 2024;12:753–61. https://doi.org/10.1016/j.jaip.2023.11.041. Burch RC, Loder S, Loder E, et al. The Prevalence and Burden of Migraine and Severe Headache in the U nited S tates: Updated Statistics From Government Health Surveillance Studies. Headache J Head Face Pain 2015;55:21–34. https://doi.org/10.1111/head.12482. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2024 National Survey on Drug Use and Health (HHS Publication No. PEP25-07-007, NSDUH Series H-60). 2025. Raj SR. Postural Tachycardia Syndrome (POTS). Circulation 2013;127:2336–42. https://doi.org/10.1161/CIRCULATIONAHA.112.144501. Rowe PC, Barron DF, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr 1999;135:494–9. https://doi.org/10.1016/S0022-3476(99)70173-3. Young VJ, Brown JK, Saunders PTK, et al. The role of the peritoneum in the pathogenesis of endometriosis. Hum Reprod Update 2013;19:558–69. https://doi.org/10.1093/humupd/dmt024. Shibao C, Arzubiaga C, Roberts LJ, et al. Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders. Hypertension 2005;45:385–90. https://doi.org/10.1161/01.HYP.0000158259.68614.40. Anaf V, Chapron C, El Nakadi I, et al. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86:1336–43. https://doi.org/10.1016/j.fertnstert.2006.03.057. Osuga Y, Koga K, Hirota Y, et al. Lymphocytes in Endometriosis: LYMPHOCYTES IN ENDOMETRIOSIS. Am J Reprod Immunol 2011;65:1–10. https://doi.org/10.1111/j.1600-0897.2010.00887.x. Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011;152:S2–15. https://doi.org/10.1016/j.pain.2010.09.030. Orr NL, Huang AJ, Liu YD, et al. Association of Central Sensitization Inventory Scores With Pain Outcomes After Endometriosis Surgery. JAMA Netw Open 2023;6:e230780. https://doi.org/10.1001/jamanetworkopen.2023.0780. Staud R. Autonomic dysfunction in fibromyalgia syndrome: Postural orthostatic tachycardia. Curr Rheumatol Rep 2008;10:463–6. https://doi.org/10.1007/s11926-008-0076-8. Sadler B, Kuensting T, Strahle J, et al. Prevalence and Impact of Underlying Diagnosis and Comorbidities on Chiari 1 Malformation. Pediatr Neurol 2020;106:32–7. https://doi.org/10.1016/j.pediatrneurol.2019.12.005. Arout CA, Sofuoglu M, Bastian LA, et al. Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study. J Womens Health 2018;27:1035–44. https://doi.org/10.1089/jwh.2017.6622. Haque A, Hughes M. Raynaud’s phenomenon. Clin Med 2020;20:580–7. https://doi.org/10.7861/clinmed.2020-0754. Venetsanopoulou AI, Alamanos Y, Voulgari PV, et al. Epidemiology and Risk Factors for Rheumatoid Arthritis Development. Mediterr J Rheumatol 2023;34:404. https://doi.org/10.31138/mjr.301223.eaf. Wang J, Wang B, Li C, et al. Evolving global trends in PCOS burden: a three-decade analysis (1990–2021) with projections to 2036 among adolescents and young adults. Front Endocrinol 2025;16:1569694. https://doi.org/10.3389/fendo.2025.1569694. Hu X, Chen Y, Shen Y, et al. Global prevalence and epidemiological trends of Hashimoto’s thyroiditis in adults: A systematic review and meta-analysis. Front Public Health 2022;10:1020709. https://doi.org/10.3389/fpubh.2022.1020709. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 20 Mar, 2026 Reviewers invited by journal 18 Mar, 2026 Editor assigned by journal 16 Mar, 2026 First submitted to journal 13 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9113464","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":608512764,"identity":"6f2023b8-a717-4897-b557-94fb526c6738","order_by":0,"name":"Adeline Yilin Chin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYDACCcYGBsY/NgwMzAdI0tKQxsDAlkC0FiBmbDhMghb+2c1tD37uOC/P38bA+LjiFzGW3DnYbth75rbhjGMMzIZn+4jQYiCR2CbBw3Y7wUC+gU2ysYdILZJ/2M4lGLAxkKBFmrftAERLww8itEjcAGqROZMM9Atjs2FjAxFa+GekP5N8U2EHDDHmgw8b/hChBQmA4rSNNC0gQKIto2AUjIJRMDIAALHDNFeWPLuZAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8394-479X","institution":"Cleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University","correspondingAuthor":true,"prefix":"","firstName":"Adeline","middleName":"Yilin","lastName":"Chin","suffix":""},{"id":608512765,"identity":"9b8a9647-b6b2-4bf9-8519-8b8b3b3f361f","order_by":1,"name":"Ryan G. Rilinger","email":"","orcid":"","institution":"Cleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"G.","lastName":"Rilinger","suffix":""},{"id":608512766,"identity":"328e664f-94e6-40eb-a282-5abfadb404bd","order_by":2,"name":"Phoebe Leboit","email":"","orcid":"","institution":"Cleveland Clinic Lerner College of Medicine of CWRU: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Phoebe","middleName":"","lastName":"Leboit","suffix":""},{"id":608512767,"identity":"94262e4e-dd42-49e0-a504-57f6496d02c0","order_by":3,"name":"Mackaleigh Levine","email":"","orcid":"","institution":"Cleveland Clinic Department of Neuromuscular Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mackaleigh","middleName":"","lastName":"Levine","suffix":""},{"id":608512768,"identity":"c8ff0630-25b8-48a3-9962-b7acc306c2cd","order_by":4,"name":"Amy S. Nowacki","email":"","orcid":"","institution":"Cleveland Clinic Department of Quantitative Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Amy","middleName":"S.","lastName":"Nowacki","suffix":""},{"id":608512769,"identity":"9a9341a0-5155-493e-9aa5-a15a0535ad54","order_by":5,"name":"Ashley R. Brant","email":"","orcid":"","institution":"Cleveland Clinic OB GYN and Women's Health Institute","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"R.","lastName":"Brant","suffix":""},{"id":608512770,"identity":"a6ed9e85-5e26-46d9-9db8-57247d13df15","order_by":6,"name":"Cheryl Cameron","email":"","orcid":"","institution":"Case Western Reserve University, Department of Nutrition","correspondingAuthor":false,"prefix":"","firstName":"Cheryl","middleName":"","lastName":"Cameron","suffix":""},{"id":608512771,"identity":"ac7bb89a-d6b0-44bf-9276-0c9e29748d6b","order_by":7,"name":"Ashley Gubbels","email":"","orcid":"","institution":"Cleveland Clinic, Section of Minimally Invasive Gynecologic Surgery and Chronic Pelvic Pain, Obstetrics and Gynecology Institute","correspondingAuthor":false,"prefix":"","firstName":"Ashley","middleName":"","lastName":"Gubbels","suffix":""},{"id":608512772,"identity":"975eaa54-47fd-4fbc-a93f-875875ee9333","order_by":8,"name":"Robert Wilson","email":"","orcid":"","institution":"Cleveland Clinic Department of Neuromuscular Medicine","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Wilson","suffix":""}],"badges":[],"createdAt":"2026-03-13 10:12:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9113464/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9113464/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105292202,"identity":"1a3730a2-b24b-428a-ab43-65492e613da6","added_by":"auto","created_at":"2026-03-24 12:28:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":188885,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT Flowchart Diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9113464/v1/e172bd9dea42eb7b6eaa7241.png"},{"id":105292226,"identity":"a47f3e2c-abe0-4bde-8ae9-e5e5175afdca","added_by":"auto","created_at":"2026-03-24 12:28:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101643,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKey comorbidity prevalence in POTS cohorts compared to general population estimates\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"22.png","url":"https://assets-eu.researchsquare.com/files/rs-9113464/v1/30817f0afb02278c9e966fb1.png"},{"id":105564838,"identity":"982c52b4-7f7c-4b8a-ade3-bd12e074bc70","added_by":"auto","created_at":"2026-03-27 12:51:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1048091,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9113464/v1/59d61509-446d-4d25-adcf-2df59451ddf2.pdf"},{"id":105292230,"identity":"6f5fc8dd-4061-4a08-ac0e-ff229721dfdb","added_by":"auto","created_at":"2026-03-24 12:28:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24046,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9113464/v1/4d586df298c33df1445275ad.docx"}],"financialInterests":"","formattedTitle":"The Hidden Burden: Connective Tissue, Mast Cell, and Autoimmune Comorbidities Cluster in POTS with Endometriosis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePostural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system characterized by an excessive heart rate increase upon standing (\u0026ge;\u0026thinsp;30 bpm within 10 minutes) in the absence of orthostatic hypotension [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. POTS disproportionately affects women, with a female-to-male ratio of approximately 5:1; symptoms often appear during the 2nd or 3rd decade of life [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. POTS is associated with substantial morbidity, including chronic fatigue, cognitive dysfunction, and significantly reduced quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEndometriosis, defined by the presence of endometrial-like tissue outside the uterine cavity, affects 10% of reproductive-aged women globally [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Beyond the gynecological manifestations including pelvic pain, dysmenorrhea, and infertility, endometriosis is increasingly recognized as a systemic inflammatory condition with far-reaching effects on multiple organ systems [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Emerging evidence suggests significant overlap between endometriosis and autonomic dysfunction, with studies demonstrating altered heart rate variability and dysautonomia symptoms in affected patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBoth POTS and endometriosis have been independently associated with connective tissue disorders, particularly Ehlers-Danlos syndrome (EDS), as well as autoimmune conditions and chronic pain syndromes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The overlap of mast cell disorder, POTS, and connective tissue abnormalities suggests shared pathophysiological mechanisms [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The concept of a \"triad\" comprising POTS, EDS, and mast cell activation syndrome (MCAS) has gained increasing recognition [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], though its intersection with endometriosis remains poorly characterized.\u003c/p\u003e \u003cp\u003eDespite these reports of a potential clinical overlap, no studies have directly compared comorbidity profiles between POTS patients with and without endometriosis or contextualized these findings against general population prevalence data [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Understanding the distinct comorbidity burden in this population may inform clinical screening practices, further elucidate disease mechanisms, and guide therapeutic approaches.\u003c/p\u003e \u003cp\u003eIn this retrospective cohort study, we aimed to characterize and compare the prevalence of autoimmune, connective tissue, neurological, and psychiatric comorbidities between POTS patients with and without endometriosis, and to compare observed prevalence rates to published general population estimates to quantify the magnitude of comorbidity elevation.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Design and Population\u003c/h2\u003e \u003cp\u003eWe performed a retrospective cohort analysis conducted at a single tertiary academic medical center (Cleveland Clinic, Cleveland, Ohio, USA). All patients who presented for an initial visit to a POTS specialist between January 1, 2018, and December 31, 2024, were analyzed. The study was approved by the Cleveland Clinic Institutional Review Board (FWA00005367, Protocol #25\u0026ndash;157). Informed consent was not required because the study involved only secondary use of existing clinical data and posed minimal risk to participants.\u003c/p\u003e \u003cp\u003eUsing Epic SlicerDicer (Epic Systems Corporation, Verona, WI, USA), we identified 3,839 patient charts with International Classification of Disease (ICD) codes for POTS. Patients included in the study were \u0026ge;\u0026thinsp;18 years old at time of head-up tilt table test (HUTT), had a confirmed diagnosis of POTS by a Cleveland Clinic specialist, defined as symptoms of orthostatic intolerance accompanied by a heart rate increase of \u0026ge;\u0026thinsp;30 bpm within 10 minutes of HUTT without orthostatic hypotension. Patients were excluded from the study if tilt tests were negative, performed outside of the Cleveland Clinic hospital system, or were never completed. A clinical diagnosis of endometriosis was defined by a gynecologic specialist based on history (cyclic pelvic pain, dysmenorrhea) and physical exam findings, specialized pelvic ultrasound or magnetic resonance imaging (MRI), or response to suppression therapy, in the absence of surgical pathology.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] A surgical diagnosis of endometriosis was confirmed by histopathology from laparoscopic or open procedures from gynecologic specialists. A random number generator was utilized to select a simple random sample of our patients with a diagnosis of POTS without endometriosis to be used as a 1:1 control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Collection\u003c/h2\u003e \u003cp\u003eDemographic data including age at visit, body mass index (BMI), and race were extracted from electronic medical records.\u003c/p\u003e \u003cp\u003eThe following comorbidities were assessed as listed diagnoses in the medical history:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAutoimmune conditions: Sj\u0026ouml;gren's syndrome, celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eConnective tissue disorders: EDS\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNeurological conditions: Chiari malformation type 1, chronic migraine\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVascular/inflammatory conditions: Raynaud's phenomenon, MCAS\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eChronic pain syndromes: Fibromyalgia\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEndocrine conditions: Polycystic ovary syndrome (PCOS), hypertension\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePsychiatric conditions: Anxiety, depression\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 General Population Prevalence Data\u003c/h2\u003e \u003cp\u003ePublished prevalence estimates for each comorbidity were obtained from peer-reviewed systematic reviews, meta-analyses, and epidemiological studies. When available, sex-specific prevalence data for women were used. Sources included the Global Burden of Disease Study, World Health Organization reports, and condition-specific systematic reviews.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eAll electronic study data were collected and managed via Research Electronic Data Capture (REDCap), a secure, web-based application designed to support data capture for research studies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. All statistical analyses were completed using R version 4.4.1 (R Core Team, 2025. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] within RStudio version 2025.05.1\u0026thinsp;+\u0026thinsp;513 (RStudio Team, 2025).\u003c/p\u003e \u003cp\u003eAge and BMI at initial visit for POTS were compared among POTS patients with versus without endometriosis using Wilcoxon-rank sum tests. Comorbidity prevalences were compared using Fisher's exact tests in anticipation of low prevalence for some conditions. Fold-increase ratios were calculated by dividing the observed prevalence in each POTS group by the midpoint of published general population prevalence ranges. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 458 female patients with confirmed POTS by tilt-table test were included in the analysis. 229 patients had a co-occurring diagnosis of endometriosis. There were no significant demographic differences between the group with diagnosis of POTS without endometriosis and with diagnoses of both POTS and endometriosis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePOTS only (n\u0026thinsp;=\u0026thinsp;229)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePOTS and Endometriosis (n\u0026thinsp;=\u0026thinsp;229)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (23\u0026ndash;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (23\u0026ndash;39)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.8 (20.7\u0026ndash;27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.6 (21.5\u0026ndash;29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace (white)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e203 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e207 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDescriptive statistics are reported as either median (Q\u003csub\u003e1\u003c/sub\u003e-Q\u003csub\u003e3\u003c/sub\u003e) or count (%).\u003c/p\u003e \u003cp\u003eComorbidity prevalence was significantly higher in POTS patients with endometriosis compared to those without in EDS, MCAS, chronic migraine, fibromyalgia, and Raynaud\u0026rsquo;s phenomenon (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComorbidity Prevalence in POTS Patients With and Without Endometriosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePOTS only (n\u0026thinsp;=\u0026thinsp;229)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePOTS and Endometriosis (n\u0026thinsp;=\u0026thinsp;229)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEhlers-Danlos syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29 (12.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77 (33.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSj\u0026ouml;gren's syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCeliac disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHashimoto's thyroiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMast cell activation syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic migraine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90 (39.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128 (55.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChiari malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (1.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.372\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibromyalgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53 (23.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRaynaud's phenomenon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36 (15.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e112 (48.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e128 (55.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90 (39.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e109 (47.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Fisher's exact test used for all comparisons.\u003c/p\u003e \u003cp\u003eWe also compared the observed comorbidity prevalence rates in our POTS patient sample to published general population estimates (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Comorbidity Domains\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1 Connective Tissue Disorders\u003c/h2\u003e \u003cp\u003eThe prevalence of EDS in our POTS without endometriosis group (12.7%) represents a 64-fold increase compared to the upper estimate of general population prevalence (0.2%)[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the POTS with endometriosis group (33.6%), this represents a 168-fold increase[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. EDS was also significantly more prevalent in POTS patients with endometriosis compared to those without endometriosis (33.6% vs 12.7%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), representing a nearly three-fold between-group difference and the largest absolute difference observed among all comorbidities assessed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.1.2 Autoimmune Conditions\u003c/h2\u003e \u003cp\u003ePatients with POTS and endometriosis demonstrated significantly elevated rates of Raynaud\u0026rsquo;s phenomenon (15.7% vs. 6.6%, p\u0026thinsp;=\u0026thinsp;0.003) compared to POTS patients without endometriosis. Prevalence of Sj\u0026ouml;gren's syndrome (6.1% vs. 3.5%, p\u0026thinsp;=\u0026thinsp;0.27), Rheumatoid arthritis (2.2% vs. 0.9%, p\u0026thinsp;=\u0026thinsp;0.45), Hashimoto's thyroiditis (7.0% vs. 3.5%, p\u0026thinsp;=\u0026thinsp;0.14), and Celiac disease (2.6% vs. 2.2%, p\u0026thinsp;=\u0026thinsp;0.99) did not differ in our POTS cohorts. Compared to the general population, Sj\u0026ouml;gren's syndrome and celiac disease showed a fold-increase compared to general population estimates [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.1.3 Mast Cell Activation Syndrome\u003c/h2\u003e \u003cp\u003eMCAS was significantly more prevalent in POTS patients with endometriosis compared to those without (19.2% vs 3.5%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). POTS patients with endometriosis also demonstrated a four-fold increase compared to general population estimates of 4.4%[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.1.4 Neurological and Pain Conditions\u003c/h2\u003e \u003cp\u003eChronic migraine was significantly more common in POTS patients with endometriosis compared to POTS patients without endometriosis (55.9% vs 39.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), a two to three-fold increase over general population rates [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Fibromyalgia rates were approximately doubled in POTS patients with endometriosis compared to those without (23.1% vs 11.4%, p\u0026thinsp;=\u0026thinsp;0.001). There was no significant difference in Chiari malformation rates in POTS patients with endometriosis compared to POTS patients without endometriosis (1.7% vs 0.4%, p\u0026thinsp;=\u0026thinsp;0.37).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.1.5 Psychiatric Conditions\u003c/h2\u003e \u003cp\u003eWhile POTS patients with and without endometriosis demonstrated high rates of anxiety (48.9\u0026ndash;55.9%) and depression (39.3\u0026ndash;47.6%), these did not differ significantly between groups. Notably, the prevalence of anxiety and depression were markedly higher compared to general population estimates of 21.7% for anxiety disorders and 8.2% for major depression [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study provides a novel comparison of comorbidity profiles between POTS patients with and without concomitant endometriosis, contextualized against general population prevalence data. Our findings reveal that POTS patients with endometriosis exhibit a distinct phenotype characterized by dramatically elevated rates of connective tissue disorders, mast cell-mediated disease, Raynaud\u0026rsquo;s phenomenon, and chronic pain syndromes.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Connective Tissue Abnormalities and Autonomic Dysfunction\u003c/h2\u003e \u003cp\u003eWe identified a striking elevation of EDS prevalence in our cohorts, 12.7% in POTS without endometriosis and 33.6% in POTS with endometriosis, compared to 0.2% in the general population. This 64- to 168-fold increase supports a possible connection between connective tissue integrity and autonomic function.\u003c/p\u003e \u003cp\u003eEDS, particularly the hypermobile subtype (hEDS), has been increasingly recognized as a component of a multisystem disorder spectrum that includes POTS, MCAS, and various chronic pain conditions [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Mechanistic links may involve defective collagen synthesis affecting vascular compliance, leading to venous pooling and the compensatory tachycardia characteristic of POTS [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recent evidence suggests that connective tissue abnormalities may also affect the extracellular matrix surrounding autonomic nerve fibers, potentially contributing to dysautonomia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEndometriosis has similarly been associated with connective tissue abnormalities, including altered extracellular matrix composition and enhanced tissue invasiveness [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our results suggest that the combination of POTS and endometriosis may identify a subset of patients with particularly severe connective tissue dysfunction, warranting consideration of a rheumatological evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Mast Cell Activation Syndrome\u003c/h2\u003e \u003cp\u003eOne of our most substantial findings was the nearly six-fold elevation of MCAS in POTS patients with endometriosis compared to those without (19.2% vs 3.5%), with the rate in POTS patients with endometriosis far exceeding published general population estimates. Importantly, MCAS prevalence in POTS without endometriosis patients (3.5%) is similar to general population estimates (4.4%), suggesting that concomitant endometriosis specifically potentiates mast cell dysfunction.\u003c/p\u003e \u003cp\u003eMast cells have been increasingly recognized as central players in the pathophysiology of both POTS and endometriosis. In POTS, mast cell activation may contribute to vasodilation, tachycardia, flushing, and systemic symptoms through histamine and other mediator release [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In endometriosis, mast cells densely infiltrate ectopic lesions and contribute to pain, inflammation, and disease progression [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Peritoneal fluid in patients with endometriosis has been found to contain elevated levels of mast cell mediators, including histamine, tryptase, and prostaglandins [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The significant elevation of MCAS in our cohort of patients with POTS and endometriosis suggests that combined autonomic and gynecological dysfunction may create a permissive environment for mast cell dysregulation\u0026mdash;or, conversely, that underlying mast cell disease may predispose to both conditions. This has important therapeutic implications, as mast cell-targeted therapies (H1/H2 antihistamines, mast cell stabilizers such as cromolyn and ketotifen) may benefit patients with this phenotype and deserve prospective evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Central Sensitization\u003c/h2\u003e \u003cp\u003eThe findings that chronic migraines and fibromyalgia are significantly more prevalent in POTS patients with and without endometriosis compared to the general population suggests the role of central sensitization in disease mechanisms. Central sensitization, characterized by amplified neural signaling and reduced pain thresholds, has been implicated in both fibromyalgia and chronic migraines [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Both POTS and endometriosis have been associated with altered pain processing and evidence of central sensitization [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The clustering of chronic migraine and fibromyalgia in our cohorts may reflect shared neurobiological vulnerabilities involving trigeminal-autonomic pathways.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.4 The POTS-Endometriosis Phenotype: Clinical Implications\u003c/h2\u003e \u003cp\u003eOur findings support the existence of a distinct phenotype of patients with both POTS and endometriosis characterized by high rates of EDS, marked elevation of MCAS, chronic migraine in more than half of patients, autoimmune conditions, and elevated fibromyalgia. This phenotype may represent a specific subtype of POTS with distinct pathophysiology and therapeutic implications. These results support the need for screening this patient population for hypermobility / EDS, MCAS, and chronic pain syndromes. The multisystem involvement in this patient population also necessitates coordinated care involving autonomic specialists, gynecologists, rheumatologists, allergists/immunologists, neurologists, and pain specialists.\u003c/p\u003e \u003cp\u003eFurther studies are warranted to investigate shared genetic susceptibility, particularly comparing genes affecting connective tissue, immune function, and inflammation in POTS patients with and without endometriosis. These findings may inform targeted therapeutic approaches for POTS patients with endometriosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Limitations\u003c/h2\u003e \u003cp\u003eThis study has several limitations. First, the retrospective design relies on documented diagnoses, potentially underestimating true comorbidity prevalence due to underdiagnosis\u0026mdash;a particular concern for conditions like EDS and MCAS that often go unrecognized. Second, the study was conducted at a single tertiary referral center, which may limit generalizability and introduce referral bias toward more complex cases. Third, we did not assess disease severity, treatment responses, or temporal relationships between conditions as these data items are not routinely collected. Finally, general population prevalence estimates vary across studies and populations, introducing uncertainty in fold-increase calculations.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003ePOTS patients with concomitant endometriosis represent a distinct phenotype characterized by dramatically elevated rates of Ehlers-Danlos syndrome (33.6%, representing up to 168-fold increase vs. general population), Mast cell activation syndrome (19.2%), chronic migraine (55.9%), Raynaud\u0026rsquo;s phenomenon and fibromyalgia. These prevalence rates far exceed what would be expected by chance and support the concept of shared pathophysiological mechanisms involving connective tissue dysfunction, mast cell dysregulation, and immune dysregulation.\u003c/p\u003e\n\u003cp\u003eClinicians caring for patients with both POTS and endometriosis should maintain a high index of suspicion for these comorbidities, pursue additional screening, and consider a multidisciplinary approach to evaluation and management. Future research should investigate the genetic and molecular underpinnings of this phenotype and evaluate targeted therapeutic approaches.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Autonomic Research Fund.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared for all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Cleveland Clinic Institutional Review Board (IRB #25-157).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception of the research topic: Adeline Y. Chin, Robert Wilson\u003c/p\u003e\n\u003cp\u003eData collection and creation of database: Adeline Y. Chin, Ryan G. Rilinger, Phoebe Leboit, Mackaleigh Levine\u003c/p\u003e\n\u003cp\u003eAnalysis of study data: Adeline Y. Chin, Amy S. Nowacki\u003c/p\u003e\n\u003cp\u003eInterpretation of study results: Adeline Y. Chin, Robert Wilson\u003c/p\u003e\n\u003cp\u003eComposition of the manuscript: Adeline Y. Chin, Ryan G. Rilinger\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dawn Caraballo, Dr. Kerry Levin, and Dr. John Morren for technical support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope. Heart Rhythm 2015;12:e41\u0026ndash;63. https://doi.org/10.1016/j.hrthm.2015.03.029.\u003c/li\u003e\n\u003cli\u003eThieben MJ, Sandroni P, Sletten DM, et al. Postural Orthostatic Tachycardia Syndrome: The Mayo Clinic Experience. Mayo Clin Proc 2007;82:308\u0026ndash;13. https://doi.org/10.4065/82.3.308.\u003c/li\u003e\n\u003cli\u003eBenarroch EE. Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder. Mayo Clin Proc 2012;87:1214\u0026ndash;25. https://doi.org/10.1016/j.mayocp.2012.08.013.\u003c/li\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382:1244\u0026ndash;56. https://doi.org/10.1056/NEJMra1810764.\u003c/li\u003e\n\u003cli\u003eKvaskoff M, Mu F, Terry KL, et al. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update 2015;21:500\u0026ndash;16. https://doi.org/10.1093/humupd/dmv013.\u003c/li\u003e\n\u003cli\u003eZondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382:1244\u0026ndash;56. https://doi.org/10.1056/NEJMra1810764.\u003c/li\u003e\n\u003cli\u003eWei Y, Liang Y, Lin H, et al. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation 2020;17:80. https://doi.org/10.1186/s12974-020-01752-1.\u003c/li\u003e\n\u003cli\u003eHao M, Liu X, Rong P, et al. Reduced vagal tone in women with endometriosis and auricular vagus nerve stimulation as a potential therapeutic approach. Sci Rep 2021;11:1345. https://doi.org/10.1038/s41598-020-79750-9.\u003c/li\u003e\n\u003cli\u003eHakim A, O\u0026rsquo;Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in Ehlers\u0026ndash;Danlos syndrome\u0026mdash;Hypermobile type. Am J Med Genet C Semin Med Genet 2017;175:168\u0026ndash;74. https://doi.org/10.1002/ajmg.c.31543.\u003c/li\u003e\n\u003cli\u003eShigesi N, Kvaskoff M, Kirtley S, et al. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update 2019;25:486\u0026ndash;503. https://doi.org/10.1093/humupd/dmz014.\u003c/li\u003e\n\u003cli\u003eCheung I, Vadas P. A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. J Allergy Clin Immunol 2015;135:AB65. https://doi.org/10.1016/j.jaci.2014.12.1146.\u003c/li\u003e\n\u003cli\u003eKucharik AH, Chang C. The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clin Rev Allergy Immunol 2020;58:273\u0026ndash;97. https://doi.org/10.1007/s12016-019-08755-8.\u003c/li\u003e\n\u003cli\u003eHalverson CME, Cao S, Perkins SM, et al. Comorbidity, misdiagnoses, and the diagnostic odyssey in patients with hypermobile Ehlers-Danlos syndrome. Genet Med Open 2023;1:100812. https://doi.org/10.1016/j.gimo.2023.100812.\u003c/li\u003e\n\u003cli\u003eFarley M, Estrada-Mendizabal RJ, Gansert EA, et al. Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: A systematic review. Ann Allergy Asthma Immunol 2025;135:97\u0026ndash;102. https://doi.org/10.1016/j.anai.2025.03.022.\u003c/li\u003e\n\u003cli\u003eAs-Sanie S, Mackenzie SC, Morrison L, et al. Endometriosis: A Review. JAMA 2025;334:64. https://doi.org/10.1001/jama.2025.2975.\u003c/li\u003e\n\u003cli\u003eHarris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)\u0026mdash;A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377\u0026ndash;81. https://doi.org/10.1016/j.jbi.2008.08.010.\u003c/li\u003e\n\u003cli\u003eR Core Team (2025). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. \u0026lt;https://www.R-project.org/\u0026gt;. n.d.\u003c/li\u003e\n\u003cli\u003eDemmler JC, Atkinson MD, Reinhold EJ, et al. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case\u0026ndash;control comparison. BMJ Open 2019;9:e031365. https://doi.org/10.1136/bmjopen-2019-031365.\u003c/li\u003e\n\u003cli\u003eSingh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018;16:823-836.e2. https://doi.org/10.1016/j.cgh.2017.06.037.\u003c/li\u003e\n\u003cli\u003eThurtle E, Grosjean A, Steenackers M, et al. Epidemiology of Sj\u0026ouml;gren\u0026rsquo;s: A Systematic Literature Review. Rheumatol Ther 2024;11:1\u0026ndash;17. https://doi.org/10.1007/s40744-023-00611-8.\u003c/li\u003e\n\u003cli\u003eZaghmout T, Maclachlan L, Bedi N, et al. Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders. J Allergy Clin Immunol Pract 2024;12:753\u0026ndash;61. https://doi.org/10.1016/j.jaip.2023.11.041.\u003c/li\u003e\n\u003cli\u003eBurch RC, Loder S, Loder E, et al. The Prevalence and Burden of Migraine and Severe Headache in the U nited S tates: Updated Statistics From Government Health Surveillance Studies. Headache J Head Face Pain 2015;55:21\u0026ndash;34. https://doi.org/10.1111/head.12482.\u003c/li\u003e\n\u003cli\u003eSubstance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2024 National Survey on Drug Use and Health (HHS Publication No. PEP25-07-007, NSDUH Series H-60). 2025.\u003c/li\u003e\n\u003cli\u003eRaj SR. Postural Tachycardia Syndrome (POTS). Circulation 2013;127:2336\u0026ndash;42. https://doi.org/10.1161/CIRCULATIONAHA.112.144501.\u003c/li\u003e\n\u003cli\u003eRowe PC, Barron DF, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr 1999;135:494\u0026ndash;9. https://doi.org/10.1016/S0022-3476(99)70173-3.\u003c/li\u003e\n\u003cli\u003eYoung VJ, Brown JK, Saunders PTK, et al. The role of the peritoneum in the pathogenesis of endometriosis. Hum Reprod Update 2013;19:558\u0026ndash;69. https://doi.org/10.1093/humupd/dmt024.\u003c/li\u003e\n\u003cli\u003eShibao C, Arzubiaga C, Roberts LJ, et al. Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders. Hypertension 2005;45:385\u0026ndash;90. https://doi.org/10.1161/01.HYP.0000158259.68614.40.\u003c/li\u003e\n\u003cli\u003eAnaf V, Chapron C, El Nakadi I, et al. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86:1336\u0026ndash;43. https://doi.org/10.1016/j.fertnstert.2006.03.057.\u003c/li\u003e\n\u003cli\u003eOsuga Y, Koga K, Hirota Y, et al. Lymphocytes in Endometriosis: LYMPHOCYTES IN ENDOMETRIOSIS. Am J Reprod Immunol 2011;65:1\u0026ndash;10. https://doi.org/10.1111/j.1600-0897.2010.00887.x.\u003c/li\u003e\n\u003cli\u003eWoolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 2011;152:S2\u0026ndash;15. https://doi.org/10.1016/j.pain.2010.09.030.\u003c/li\u003e\n\u003cli\u003eOrr NL, Huang AJ, Liu YD, et al. Association of Central Sensitization Inventory Scores With Pain Outcomes After Endometriosis Surgery. JAMA Netw Open 2023;6:e230780. https://doi.org/10.1001/jamanetworkopen.2023.0780.\u003c/li\u003e\n\u003cli\u003eStaud R. Autonomic dysfunction in fibromyalgia syndrome: Postural orthostatic tachycardia. Curr Rheumatol Rep 2008;10:463\u0026ndash;6. https://doi.org/10.1007/s11926-008-0076-8.\u003c/li\u003e\n\u003cli\u003eSadler B, Kuensting T, Strahle J, et al. Prevalence and Impact of Underlying Diagnosis and Comorbidities on Chiari 1 Malformation. Pediatr Neurol 2020;106:32\u0026ndash;7. https://doi.org/10.1016/j.pediatrneurol.2019.12.005.\u003c/li\u003e\n\u003cli\u003eArout CA, Sofuoglu M, Bastian LA, et al. Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study. J Womens Health 2018;27:1035\u0026ndash;44. https://doi.org/10.1089/jwh.2017.6622.\u003c/li\u003e\n\u003cli\u003eHaque A, Hughes M. Raynaud\u0026rsquo;s phenomenon. Clin Med 2020;20:580\u0026ndash;7. https://doi.org/10.7861/clinmed.2020-0754.\u003c/li\u003e\n\u003cli\u003eVenetsanopoulou AI, Alamanos Y, Voulgari PV, et al. Epidemiology and Risk Factors for Rheumatoid Arthritis Development. Mediterr J Rheumatol 2023;34:404. https://doi.org/10.31138/mjr.301223.eaf.\u003c/li\u003e\n\u003cli\u003eWang J, Wang B, Li C, et al. Evolving global trends in PCOS burden: a three-decade analysis (1990\u0026ndash;2021) with projections to 2036 among adolescents and young adults. Front Endocrinol 2025;16:1569694. https://doi.org/10.3389/fendo.2025.1569694.\u003c/li\u003e\n\u003cli\u003eHu X, Chen Y, Shen Y, et al. Global prevalence and epidemiological trends of Hashimoto\u0026rsquo;s thyroiditis in adults: A systematic review and meta-analysis. Front Public Health 2022;10:1020709. https://doi.org/10.3389/fpubh.2022.1020709. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Postural Orthostatic Tachycardia Syndrome, Endometriosis, Ehlers-Danlos syndrome, Mast cell activation syndrome, Connective tissue disorders","lastPublishedDoi":"10.21203/rs.3.rs-9113464/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9113464/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo characterize and compare the prevalence of autoimmune, connective tissue, neurological, and psychiatric comorbidities between POTS patients with and without endometriosis, and to compare these rates to published general population estimates.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a retrospective cohort analysis, we reviewed medical records for 458 patients with POTS who presented to our autonomic center from 2018 to 2024. POTS was defined by symptoms of orthostatic intolerance accompanied by a heart rate increase of \u0026ge;\u0026thinsp;30 beats per minute within the first 10 minutes of head-up tilt table testing. A clinical or surgical diagnosis of endometriosis was defined by a gynecologic specialist.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e458 female patients with POTS were included in the analysis. When compared to POTS patients without endometriosis, POTS patients with endometriosis had statistically significantly higher rates of Ehlers-Danlos syndrome (EDS) (33.6% vs. 12.7%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Mast cell activation syndrome (MCAS) (19.2% vs. 3.5%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), chronic migraines (55.9% vs. 39.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fibromyalgia (23.1% vs. 11.4%, p\u0026thinsp;=\u0026thinsp;0.001) and Raynaud\u0026rsquo;s phenomenon (15.7% vs. 6.6%, p\u0026thinsp;=\u0026thinsp;0.003). Compared to the general population, POTS patients demonstrated higher rates of EDS, chronic migraines, and fibromyalgia. POTS patients with endometriosis also demonstrated higher rates of MCAS and Raynaud\u0026rsquo;s phenomenon compared to the general population.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePOTS patients with endometriosis exhibit significantly higher rates of connective tissue disorders, mast cell-mediated disease, autoimmune conditions, and chronic pain syndromes, with prevalence rates far exceeding general population estimates. These findings suggest shared pathophysiological mechanisms between POTS and endometriosis and support the need for comprehensive screening and multidisciplinary management in this population.\u003c/p\u003e","manuscriptTitle":"The Hidden Burden: Connective Tissue, Mast Cell, and Autoimmune Comorbidities Cluster in POTS with Endometriosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 12:28:11","doi":"10.21203/rs.3.rs-9113464/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-03-21T02:31:56+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-18T22:30:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T14:35:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2026-03-13T09:11:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"521ab8a4-bb4f-47e0-85f1-77ce0f54aa3c","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-06-26T16:59:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 12:28:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9113464","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9113464","identity":"rs-9113464","version":["v1"]},"buildId":"0SHbDDIpRTBOrFPTvp6pu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}