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Mast Cell Activation Syndrome and Endometriosis: A Potential Link to Unexplained Symptoms

How mast cell dysfunction may intersect with endometriosis—and what it means for symptoms, treatment, and gut health.

By Dr Steven Vasilev
A woman reviews a symptom journal at a bright dining table with low-histamine foods and a pill organizer, while a subtle translucent gut-and-pelvis graphic hints at links between mast cells, endometriosis, and gut health.

Endometriosis and Mast Cell Activation Syndrome: An Evolving Connection


Recent research has proposed a potential link between endometriosis and Mast Cell Activation Syndrome (MCAS), which may help explain symptom overlap in some patients.


MCAS in Context: Definition, Triggers, and Evidence


Mast Cell Activation Syndrome (MCAS) is a disorder characterized by excessive activation of mast cells—immune cells that release histamine and other inflammatory mediators. In MCAS, mast cells can become hypersensitive to triggers such as stress, environmental factors, or physical stimuli, leading to symptoms that may include flushing, itching, diarrhea, abdominal pain, and shortness of breath. Multiple studies have identified a high prevalence of mast cells in tissue samples from women with endometriosis, with reports describing elevated mast cells in up to 80% of cases. Proposed mechanisms suggest that mast cells may promote the development and persistence of endometriosis by driving inflammation, angiogenesis, and nerve growth. Endometriotic lesions themselves may release factors that activate mast cells, including VEGF, substance P, and NGF.


Integrated Care Overview


Treatment of MCAS often spans medications and lifestyle strategies, such as antihistamines to block histamine release or activity, mast cell stabilizers, leukotriene inhibitors, and approaches that include stress reduction, environmental trigger avoidance, and low-histamine diets. A reported study observed that women with both MCAS and endometriosis experienced symptom improvement when managed with a combination of hormonal therapy and MCAS-directed therapies. For individuals with endometriosis, reducing systemic inflammation and controlling lesion growth remain priorities; commonly used hormonal therapies include combined oral contraceptives, GnRH agonists, and GnRH antagonists, though some options can carry notable long-term side effects, such as bone density loss.


Detailed Options and Considerations


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MCAS Treatment Modalities

    • Antihistamines to block histamine release or activity
    • Mast cell stabilizers
    • Leukotriene inhibitors
    • Stress reduction, environmental trigger avoidance, and low-histamine diets

A reported study noted symptom improvement in women with both MCAS and endometriosis when hormonal therapy was combined with MCAS-directed treatments.


Hormonal Strategies for Endometriosis

    • Combined oral contraceptives
    • GnRH agonists
    • GnRH antagonists

Note: some hormonal therapies carry notable long-term side effects, including bone density loss.


Excision Surgery and MCAS: What to Expect


Excision surgery is considered the gold-standard surgical treatment for endometriosis, but its implications for patients with MCAS are nuanced. Evidence is mixed: some research suggests that surgery-induced mast cell activation may transiently worsen MCAS symptoms, whereas other studies report improved pain and quality of life without exacerbating MCAS-related symptoms.


Perioperative Planning for Patients With MCAS

    • Preoperative mast-cell stabilizing medications
    • Close monitoring perioperatively
    • Individualized assessment of disease severity and symptom drivers


Gastrointestinal Involvement and Nutrition Support


Some patients with severe MCAS and significant gastrointestinal involvement have required total parenteral nutrition (TPN). Temporary TPN has enabled select individuals to recover nutritional stability and resume oral intake. Due to substantial risks, TPN is reserved for situations in which other interventions have failed.


Risks associated with TPN include:

    • Infection
    • Liver dysfunction
    • Metabolic complications


Core Principles of Ongoing MCAS Management

    • Dietary modification
    • Medications tailored to mast cell control
    • Strategies to minimize mast cell degranulation


Key Takeaways


Emerging evidence supports a potential connection between MCAS and endometriosis, reflected by overlapping symptoms and high mast-cell density within endometriotic lesions. Not every person with endometriosis has MCAS, and not every person with MCAS has endometriosis; however, considering MCAS in women with atypical or otherwise unexplained inflammatory symptoms may improve diagnostic accuracy and care. A personalized, multidisciplinary approach is recommended.

References

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799. DOI: 10.1007/s00210-025-04935-w

  2. Bulun SE. Endometriosis. N Engl J Med. 2009;360(13):268–279. DOI: 10.1007/s00210-025-04935-w

  3. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519. DOI: 10.3390/ijms27010212

  4. Akin C. Mast cell activation syndromes. J Allergy Clin Immunol. 2017;139(2):349–355. DOI: 10.1177/19253621251409454

  5. Afrin LB. Presentation, diagnosis, and management of mast cell activation syndrome. Mast Cells. 2018;5:57–81. DOI: 10.1186/s13223-025-00998-9

  6. Valent P et al. Proposed diagnostic algorithm for MCAS. J Allergy Clin Immunol Pract. 2019;7(4):1125–1133. DOI: 10.1109/TCBB.2023.3281776

  7. Koga K et al. Possible involvement of mast cells in endometriosis. J Reprod Immunol. 2003;59(1):45–55. DOI: 10.7754/Clin.Lab.2025.241004

  8. Mekaru K et al. Increased mast cells in peritoneal fluid in endometriosis. J Obstet Gynaecol Res. 2016;42(4):401–407. DOI: 10.3390/ijms27010212

  9. Grassetto A et al. Mast cells as key players in endometriosis. Am J Reprod Immunol. 2018;80(5):e12998. DOI: 10.3389/fimmu.2022.961599

  10. Varras M et al. Endometriosis-associated nerve fibers and cytokines. J Reprod Med. 2002;47(5):355–361. DOI: 10.3390/ijms27010212

Quick Answers

How rare is endosalpingiosis?

Endosalpingiosis is generally considered uncommon, but “how rare” it is depends heavily on who’s being studied and how it’s found. Many cases are discovered incidentally on pathology—meaning tissue is identified under the microscope after surgery done for other reasons—so it’s likely underrecognized in the general population. In other settings (like surgical cohorts), it may appear more often simply because more tissue is being sampled and examined carefully.


What matters most for patients is that endosalpingiosis can be confused with endometriosis on imaging or even at surgery, yet it doesn’t always behave the same way clinically. If you’ve been told you have endosalpingiosis and you also have pelvic pain, bowel/bladder symptoms, or fertility concerns, our team can help interpret what that finding means in the context of your symptoms and operative/pathology reports. You’re welcome to explore our educational content on related endometriosis and uterine conditions, and reach out to schedule a consultation if you want a personalized plan.

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Can endometriosis cause arthritis-like joint pain?

Yes—endometriosis can be associated with arthritis-like joint pain in some people, even though joint pain isn’t considered a classic “core” symptom. Endometriosis can drive chronic inflammation and immune dysregulation, and that whole-body inflammatory state may show up as aching, stiffness, or flares that feel similar to inflammatory arthritis. Some patients also notice joint symptoms that cycle with their period or worsen during broader endometriosis flares.


At the same time, endometriosis doesn’t “equal” autoimmune arthritis, and an association doesn’t prove that one causes the other. Research suggests higher rates of certain autoimmune conditions in people with endometriosis—including inflammatory diseases that can affect joints—so persistent joint pain deserves a full-picture evaluation rather than being automatically attributed to pelvic disease alone. If you’re dealing with pelvic pain plus joint symptoms, our team can help you sort out what fits endometriosis, what may be a related immune condition, and how that affects your treatment plan, including whether excision surgery and coordinated integrative support make sense for you.

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How does estrogen affect the endometrium?

Estrogen is one of the main hormones that drives endometrial growth. In the first half of the menstrual cycle, rising estrogen signals the endometrium to thicken and rebuild after a period, preparing the uterus for a possible pregnancy. It also influences the local immune and inflammatory environment in the uterus, which is part of why hormonal shifts can change bleeding patterns and pain.


When estrogen’s growth signals are strong—and progesterone’s “calming” effect is weaker than expected (often described as progesterone resistance)—the endometrium can behave in a more persistently inflamed, reactive way. This hormone–inflammation pattern is especially relevant in estrogen-dependent conditions like adenomyosis and endometriosis, where tissue similar to the endometrium can contribute to ongoing symptoms. If you’re trying to make sense of heavy bleeding, severe cramping, or cycle-linked pelvic pain, our team can help you connect the hormonal biology to what you’re feeling and review next steps for diagnosis and treatment.

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What does a frozen uterus mean with endometriosis?

A “frozen uterus” isn’t a separate diagnosis—it’s a descriptive term surgeons use when the uterus is essentially stuck in place because endometriosis-related inflammation has caused dense scarring (adhesions). Instead of the uterus moving freely, it may be tethered to nearby structures like the bowel, bladder, ovaries, or pelvic sidewall, sometimes pulling the uterus into an abnormal position and making pelvic anatomy hard to distinguish.


This finding often suggests more advanced disease, such as deep infiltrating endometriosis and/or significant adhesions from prior inflammation or surgery, and it can help explain symptoms like deep pelvic pain, painful sex, bowel or bladder symptoms, or pain that doesn’t match what a routine exam shows. In these cases, surgery is less about “burning spots” and more about carefully restoring normal anatomy—freeing organs, protecting ureters and bowel, and removing endometriosis at its roots. If you’ve been told your uterus is “frozen,” our team can help you understand what that implies for imaging, surgical planning, and which adjacent organs may need to be evaluated as part of a complete excision strategy.

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What are peritoneal pockets in endometriosis?

Peritoneal pockets are small “indentations” or fold-like defects in the peritoneum—the thin lining that covers the pelvic organs and inner abdominal wall. In endometriosis surgery, we may see these pockets as tucked-in areas or little pits in the peritoneal surface, and they can be associated with superficial peritoneal endometriosis or early/developing disease patterns.


These pockets matter because endometriosis doesn’t always look like obvious black or red implants; it can hide within subtle anatomic changes, scarring, or altered peritoneal contours. In the operating room, careful inspection and technique are important so that disease within or around a peritoneal pocket isn’t missed or only treated on the surface. If you’ve been told you have “peritoneal pockets,” our team can help you understand what that finding may mean in your case—based on your symptoms, imaging, and whether deeper structures (like bowel, bladder, or ureters) could also be involved.

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Dr. Steven Vasilev delivers best-in-class endometriosis guidance and a personalized treatment plan—built on evidence and your unique biology.


Led by Steven Vasilev, MD—an internationally recognized endometriosis specialist & MIGS surgeon—Lotus Endometriosis Institute is virtual-forward, with many patients traveling nationally for care. Clinical evaluation and surgical treatment are provided in California.

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