Endometriosis, POTS, MCAS, and Long COVID: Is There a Shared Genetic Link in Women?

By the surgeons of Endometriosis Surgical Specialists International (ESSI)

Featuring Dr. Andrea Vidali, Dr. Madhu Bagaria, and Dr. Osbert Fernandez

If you have endometriosis and also struggle with a racing heartbeat when you stand up, flushing, food and medication sensitivities, joint hypermobility, brain fog, or unexplained fatigue, you are not imagining the connection. A growing body of research suggests that endometriosis, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), hypermobile Ehlers–Danlos syndrome (hEDS), and long COVID share a deeper biology than medicine has historically appreciated — one shaped by sex, immunity, connective tissue, and very likely, your genes.

Key Takeaways

• Endometriosis, POTS, MCAS, hEDS, and long COVID disproportionately affect women and frequently cluster in the same patient.

• A 2025 UK Biobank study confirmed a shared genetic basis between endometriosis and several autoimmune diseases, including rheumatoid arthritis and multiple sclerosis.

• Long COVID has unmasked POTS and MCAS in many women who previously seemed healthy — suggesting a pre-existing susceptibility activated by infection.

• There is no single “endo gene,” but a polygenic, sex-biased background appears to predispose certain women to this whole-body phenotype.

• Recognizing this pattern matters: it changes how endometriosis should be evaluated, treated, and supported after surgery.

The Pattern Patients Recognize Before Doctors Do

Walk into any endometriosis support community and the same conversation surfaces again and again. Women describe the textbook pelvic pain and heavy periods — but also a lengthening list of symptoms that no single specialist seems to own: lightheadedness on standing, palpitations, hives that come and go, sudden food intolerances, dizzy spells in hot showers, joints that dislocate too easily, migraines, IBS-like flares around their cycle, and a fatigue that no amount of sleep resolves.

For decades these symptoms were dismissed as anxiety, deconditioning, or “just part of having a difficult period”. We now know better. Postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are real, measurable conditions — and they cluster, in striking patterns, with endometriosis.

Figure 1. The symptom clusters of endometriosis, POTS, MCAS, hEDS, and long COVID overlap heavily. Long COVID has acted as a population-wide trigger that brought this pattern into clinical view.

What Is the Connection Between Endometriosis and POTS?

POTS is a form of dysautonomia — a malfunction of the autonomic nervous system that controls heart rate, blood pressure, digestion, and temperature regulation. Diagnostically, POTS is defined by a sustained heart-rate increase of at least 30 beats per minute (40 in adolescents) within ten minutes of standing, without a drop in blood pressure, accompanied by symptoms such as lightheadedness, palpitations, fatigue, brain fog, and exercise intolerance.

POTS overwhelmingly affects young and middle-aged women. In the largest case series, roughly 80% of women with POTS report at least one comorbidity, with chronic migraine, hEDS/HSD, autoimmune disease, and small-fiber neuropathy at the top of the list — and a higher prevalence of endometriosis, fibroids, and PCOS than the general population. The reverse is also true: women with endometriosis report orthostatic intolerance, palpitations, and exercise intolerance at much higher rates than expected.

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The Mast Cell Connection: Why MCAS and Endometriosis Co-Travel

Mast cells are immune cells best known for releasing histamine during allergic reactions. In MCAS, mast cells are inappropriately activated and release a flood of mediators that cause flushing, hives, GI upset, palpitations, anxiety, brain fog, and sensitivities to foods, medications, scents, heat, and stress.

Mast cells are also densely concentrated within endometriotic lesions. Studies have reported elevated mast cells in up to 80% of endometriosis tissue samples examined, often in their degranulated (activated) form. These mast cells release nerve growth factor, histamine, tryptase, and pro-inflammatory cytokines that drive lesion progression, fibrosis, and most importantly — pain. Estrogen directly activates mast cells, which is one reason endometriosis pain often worsens around ovulation and menses.

Figure 2. The mast cell sits at the center of endometriosis biology. Estrogen and other triggers activate mast cells, which then release mediators that drive both local lesion pain and systemic MCAS-type symptoms.

This explains a puzzle that frustrates many patients: pain that persists after a technically successful surgery, or pain that flares when nothing visible has returned. If mast cells in the surrounding peritoneum and pelvic nerves remain primed, they can continue to drive pain even when lesions are gone. It also explains why some endometriosis patients respond unexpectedly well to antihistamines, mast-cell stabilizers, or low-dose naltrexone — treatments that target the mast cell, not the lesion.

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Hypermobility, Connective Tissue, and the Endometriosis Body

A third piece of the puzzle is connective tissue. Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are characterized by joint laxity, soft skin, easy bruising, and tissue fragility. Patients with hEDS/HSD also report extraordinarily high rates of gynecologic symptoms: heavy periods (up to 76%), painful periods (72%), painful intercourse (63%), and chronic pelvic pain (over 90%).

The relationship between hypermobility and endometriosis itself is debated — some studies show comparable rates to the general population, while a recent cross-sectional analysis found joint hypermobility in up to 60% of women with stage IV (severe) endometriosis, suggesting that the most advanced disease may be enriched in connective-tissue laxity. The full picture is still emerging, but the overlap is too consistent to be coincidence.

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Long COVID Made the Pattern Impossible to Ignore

Before 2020, this clustering was a quiet conversation among specialists. The pandemic changed that. Roughly 30% of patients with post-acute COVID-19 syndrome meet criteria for POTS, and many also develop new MCAS-like symptoms. Critically, long COVID disproportionately affects women, especially those of reproductive age — the same demographic most affected by endometriosis.

In a 2024 deep-phenotyping study of long-COVID POTS, 88% of participants were female, and the majority had been healthy before infection. A 2023 review in Frontiers in Rehabilitation Sciences documented that 33–62% of premenopausal long-COVID patients experience perimenstrual symptom worsening, and that connective-tissue disorders are significantly enriched in long-COVID cohorts.

In other words: a viral trigger, acting on a sex-biased and likely genetically predisposed host, produced exactly the dysautonomia + mast-cell + connective-tissue phenotype that endometriosis specialists had been seeing in their clinics for years.

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Is There a Genetic Link Between Endometriosis and These Conditions?

This is the question patients ask most often, and the honest answer requires nuance. There is no single “endometriosis–POTS–MCAS gene”. But the genetic story is far more substantial than skeptics once allowed.

Endometriosis is heritable and genetically correlated with autoimmune disease

Endometriosis is approximately 50% heritable, with about 26% of risk attributable to common genetic variants. The most recent multi-ancestry genome-wide association study (GWAS) identified 42 genome-wide significant loci associated with endometriosis — a major leap in our understanding of the disease’s genetic architecture.

In April 2025, a landmark study published in Human Reproduction, drawing on UK Biobank data from over 8,000 endometriosis cases and 64,000 immune-disease cases, demonstrated that women with endometriosis have a 30–80% increased risk of developing rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis. More importantly, the analysis showed direct genetic correlation between endometriosis and rheumatoid arthritis (rg = 0.27), osteoarthritis (rg = 0.28), and multiple sclerosis — with Mendelian randomization suggesting a causal link to rheumatoid arthritis.

The shared loci point to biological pathways involving extracellular matrix remodeling (MMP9, ITGB3) and arachidonic-acid/prostaglandin metabolism — pathways that govern tissue repair, immune cell trafficking, and pain signaling. These are precisely the pathways implicated in MCAS, dysautonomia, and connective-tissue disorders.

POTS, hEDS, and MCAS each have genetic signatures — but not single causes

Candidate-gene studies in POTS implicate HLA loci, SLC6A2 (the norepinephrine transporter), GNB3, and NOS3 (endothelial nitric oxide synthase), with epigenetic changes affecting how these genes are expressed. The “autoimmune POTS” hypothesis — supported by some studies finding autoantibodies against adrenergic and muscarinic receptors — remains an active area of research, with both confirmatory and conflicting data.

Hypermobile EDS is the only EDS subtype with no identified causal gene to date, despite clear familial inheritance. MCAS likewise lacks a single gene, but family clustering and the discovery of hereditary alpha-tryptasemia (caused by extra copies of the TPSAB1 gene) suggest at least some heritable forms exist.

Figure 3. The most defensible model is not “one gene, one disease” but a polygenic, sex-biased susceptible host that, when met with the right trigger, expresses any combination of these overlapping conditions.

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Roundtable: ESSI Surgeons on What This Means for Endometriosis Patients

Three of our surgeons — Dr. Andrea Vidali, Dr. Madhu Bagaria, and Dr. Osbert Fernandez — share how this evolving science reshapes their thinking in the clinic and the operating room.

Dr. Andrea Vidali — Founder & CMO, ESSI; Reproductive Endocrinologist, Reproductive Immunologist, and Master Robotic Endometriosis Surgeon (NY/NJ)

“For twenty-five years I have argued that endometriosis is not a gynecologic disease that happens to spread — it is a systemic, immune-driven disease that happens to involve the pelvis. The genetic correlations published in 2025 between endometriosis and rheumatoid arthritis, multiple sclerosis, and osteoarthritis are not a curiosity. They are the molecular fingerprint of what we have been treating for decades. When a patient walks in with endometriosis plus POTS, plus MCAS, plus hypermobility, I am not seeing five diseases. I am seeing one susceptible biology expressed in five organ systems. That is why excision alone, as essential as it is, is rarely enough — we have to address the immune and neuroinflammatory background as well.”

Dr. Madhu Bagaria — Endometriosis Surgeon (NY/NJ); Mayo Clinic–trained in Minimally Invasive Gynecologic Surgery and Advanced Pelvic Surgery (Emory)

“What patients tell me, over and over, is that they were healthy until they weren’t — and then everything happened at once. Often there is a trigger: a viral infection, a surgery, a pregnancy, sometimes COVID. From a surgical standpoint this matters because these patients heal differently. They flare with anesthesia, they react to standard pain medications, they need antihistamine pre-treatment, and they often have a hypertonic pelvic floor that no surgery alone will fix. Recognizing the pattern up front lets us protect them perioperatively, choose the right adjuncts, and set realistic expectations. Excision is still the gold standard for the lesions — but the patient around the lesions deserves the same precision.”

Dr. Osbert Fernandez — Endometriosis Surgeon, ESSI Miami; dual board-certified in Family Medicine and Obstetrics & Gynecology

“My dual training in family medicine and OB/GYN is exactly why I find this conversation so important. Family doctors see these women first — the dizzy spells, the rashes, the fatigue, the bowel issues — and they see them years before anyone says the word endometriosis. If primary care, gynecology, and immunology talked to each other, the average diagnostic delay of seven to ten years would collapse. The shared-genetics data finally gives us a reason to insist on that conversation. When I see a patient with endometriosis, I now actively screen for orthostatic intolerance, mast-cell symptoms, and hypermobility — and I encourage every primary-care colleague to do the reverse.”

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A Shared Conclusion from the ESSI Team

None of these conditions cancels the others, and none of them is treated by ignoring the rest. The most successful outcomes we see are in patients whose care plan acknowledges all of it: meticulous excision of endometriotic disease, hormonal modulation when appropriate, mast-cell stabilization, autonomic rehabilitation, pelvic-floor therapy, and attention to the connective-tissue substrate.

Endometriosis is not a local problem in a small organ. It is, increasingly, a marker of a particular kind of immune and connective-tissue biology — and treating it well means treating the whole patient.

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Frequently Asked Questions

• Can endometriosis cause POTS? Endometriosis itself does not directly cause POTS, but the two conditions cluster in the same patients far more often than chance would predict. Both are believed to share underlying drivers — chronic inflammation, mast-cell activation, autonomic dysregulation, and a likely shared genetic susceptibility — and one can flare or unmask the other, particularly after a viral illness, surgery, or pregnancy.

• Is MCAS the cause of my endometriosis pain? MCAS is unlikely to be the sole cause of endometriosis pain, but it can be a major contributor. Mast cells are densely concentrated within endometriotic lesions and release mediators that amplify pain signaling. Patients whose pain persists after technically successful excision — or who have flares triggered by foods, stress, heat, or hormones — may be benefiting from a mast-cell–directed evaluation in addition to surgical care.

• Should I be tested for hypermobility if I have endometriosis? It is reasonable, especially if you also have chronic joint pain, easy bruising, recurrent injuries, or a history of dislocations. Hypermobility can be screened in a few minutes using the Beighton score. Identifying it changes physical-therapy strategy, perioperative planning, and recovery expectations — and it can explain symptoms that would otherwise seem unrelated.

• Did COVID cause my POTS or MCAS? COVID-19 is a well-documented trigger for both POTS and MCAS, but in most cases the infection unmasks a pre-existing susceptibility rather than creating it from nothing. Many women who developed long-COVID symptoms had subtle hints of dysautonomia, mast-cell activation, or hypermobility for years beforehand. The infection acted as the immune amplifier.

• Is there a genetic test for these conditions? Not yet — not in a clinically actionable way. Endometriosis has 42 known GWAS loci but no single-gene test. POTS, MCAS, and hEDS lack a unifying genetic test as well, although hereditary alpha-tryptasemia (TPSAB1) and certain rare EDS subtypes can be confirmed genetically. The most useful clinical tool today remains a thorough history, a careful physical exam, and a physician who recognizes the pattern.

• Can excision surgery still help if I have all of these conditions? Yes — and arguably it is even more important. Removing the endometriotic disease eliminates one of the most powerful inflammatory drivers in your body, which can quiet downstream mast-cell and autonomic activity. The key is choosing a surgical team that understands the whole picture, can plan around your sensitivities, and integrates with the rest of your care.

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Care That Treats the Whole Picture

Endometriosis Surgical Specialists International (ESSI) was built around the conviction that endometriosis is a whole-body disease and deserves whole-body care. Our team — led by Dr. Andrea Vidali — brings together advanced robotic excision, reproductive immunology, multidisciplinary surgical expertise, and an explicit recognition that conditions like POTS, MCAS, and hypermobility belong in the conversation, not on the sidelines.

If you suspect that your endometriosis is part of a larger pattern — or you have been told that your “other symptoms” are unrelated — we would like to hear your story. Request a consultation at internationalendo.com.

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References

• Vernino S, Bourne KM, Stiles LE, et al. Postural orthostatic tachycardia syndrome (POTS): state of the science and clinical care from a 2019 NIH expert consensus meeting. Auton Neurosci. 2021;235:102828.

• Blitshteyn S. Postural orthostatic tachycardia syndrome, menopause and hormone replacement therapy: clinical decisions in times of uncertainty. J Pers Med. 2024;14(11):1101.

• 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(5):1336–1343.

• Theoharides TC. The role of mast cells in endometriosis. EMJ Reviews. 2022.

• Hugon-Rodin J, Lebegue G, Becourt S, et al. Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility-type Ehlers–Danlos syndrome: a cohort study. Orphanet J Rare Dis. 2016;11:124.

• Cross-sectional analysis of joint hypermobility in women with endometriosis: stage IV disease is associated with hypermobility rates of up to 60%. J Chronic Heredit Res. 2024.

• Fedorowski A, Sutton R. Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome. Nat Rev Cardiol. 2023;20:281–282.

• Long-COVID postural tachycardia syndrome: a deep phenotyping study (Stanford). MedRxiv. 2025.

• Pollack B, von Saltza E, McCorkell L, et al. Female reproductive health impacts of long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review. Front Rehabil Sci. 2023;4:1122673.

• Saha R, Pettersson HJ, Svedberg P, et al. Heritability of endometriosis. Fertil Steril. 2015;104(4):947–952.

• Rahmioglu N, Mortlock S, Ghiasi M, et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet. 2023;55(3):423–436.

• Sapkota Y, Rahmioglu N, et al. The phenotypic and genetic association between endometriosis and immunological diseases. Hum Reprod. 2025;40(6):1195–1210.

• Genetic variants associated with POTS: HLA, SLC6A2, GNB3, NOS3 — candidate-gene reviews. Auton Neurosci. 2021.

• Gunning WT 3rd, Kvale H, Kramer PM, et al. Postural orthostatic tachycardia syndrome is associated with elevated G-protein coupled receptor autoantibodies. J Am Heart Assoc. 2019;8(18):e013602. (See also Hall et al., Circulation 2022, for negative findings using standardized methodology.)

This article is for educational purposes and does not replace personalized medical advice. The science discussed here is evolving, and several of the proposed mechanisms remain active areas of research. Patients with overlapping symptoms of endometriosis, POTS, MCAS, hypermobility, or long COVID should be evaluated by clinicians familiar with all of these conditions.