The hidden burden: connective tissue, mast cell, and autoimmune comorbidities cluster in POTS with endometriosis

Postural Orthostatic Tachycardia Syndrome, Endometriosis, Ehlers-Danlos syndrome, Mast cell activation syndrome, Connective tissue disorders Posted Date: March 24th, 2026 Page 1/16 DOI: https://doi.org/10.21203/rs.3.rs-9113464/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License.   Read Full License Version of Record: A version of this preprint was published at Clinical Autonomic Research on September 21st, 2026. See the published version at https://doi.org/10.1007/s10286-026-01244-x. Page 2/16

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.

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.

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.

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. 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 Page 3/16 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 ≥  Page 4/16 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 Page 5/16 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/m2) 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 (Q1-Q3) 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). Page 6/16 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 activationsyndrome 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. Page 7/16 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 Page 8/16 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 Page 9/16 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 Page 10/16 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.

We thank Dawn Caraballo, Dr. Kerry Levin, and Dr. John Morren for technical support.

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