MCAS and Endometriosis: A Mechanistic View

Yoon Hang Kim MD

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MCAS and Endometriosis: A Mechanistic View
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Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

About Dr. Kim

Dr. Yoon Hang Kim is board-certified in Preventive Medicine with more than 20 years of clinical experience. He completed a fellowship at the University of Arizona Andrew Weil Center for Integrative Medicine and holds certifications in preventive medicine and medical acupuncture. His clinical focus includes low-dose naltrexone (LDN), autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue syndrome, mast cell activation syndrome (MCAS), and mold toxicity. He is the author of 8 books and more than 25 peer-reviewed articles. Professional: www.yoonhangkim.com | Clinical: www.directintegrativecare.com

Mast cells show up repeatedly in endometriosis tissue — more of them, more activated, clustered around nerve fibers. That observation has generated real excitement and real confusion at the same time. Patients with endometriosis who also carry symptoms of mast cell activation syndrome (MCAS) understandably ask whether the two conditions share a root cause. Clinicians encounter overlapping symptom profiles — pelvic pain, gastrointestinal distress, fatigue, histamine-driven flushing — that blur the line between gynecologic pathology and systemic immune dysregulation.

This article walks through the mechanistic evidence connecting mast cells to endometriosis pathobiology, distinguishes what has been demonstrated from what remains speculative, and clarifies the critical difference between local mast-cell activation within an endometriotic lesion and a systemic mast-cell activation syndrome. Conflating them leads to diagnostic errors and therapeutic dead ends.

Readers of the companion piece on MCAS and uterine fibroids will recall that the fibroid story is a modest one — variable tissue histology and theoretical matrix-remodeling pathways. The endometriosis–mast cell connection is different. Multiple convergent signaling axes (estrogen-driven recruitment, nerve-immune crosstalk, peritoneal inflammatory amplification) give it genuine mechanistic plausibility. But plausibility is not proof that treating MCAS will treat endometriosis, or that endometriosis causes MCAS.

The Estrogen–Mast Cell Axis

Endometriosis is an estrogen-dependent disease. What elevates the mast-cell connection beyond coincidence is that estrogen directly modulates mast cell behavior through several well-characterized pathways — not just correlating with mast cell presence, but actively driving their recruitment, maturation, and degranulation.

SCF/KIT signaling. Endometriotic lesions contain significantly elevated levels of stem cell factor (SCF, also called KIT ligand) compared to matched eutopic endometrium from the same patients. SCF is the principal growth factor for mast cell expansion, differentiation, and tissue survival. A 2022 study using both human lesion tissue and a C57BL/6 mouse model of endometriosis confirmed that the ectopic lesion microenvironment upregulates genes critical to mast cell recruitment and maturation — including CPA3, VCAM1, CCL2, CMA1, CCR1, and KITLG — creating conditions that actively pull in mast cell progenitors and drive their differentiation into mature, tissue-resident mast cells. (McCallion et al., Front Immunol, 2022)

CCL8/CCR1 crosstalk. A separate group (Li et al., 2020) described reciprocal signaling between endometrial cells and mast cells through the CCL8/CCR1 axis. Endometrial-cell interaction drove mast cells to secrete more of the chemokine CCL8, which in turn promoted endometrial-cell migration and angiogenesis — processes central to lesion establishment and growth. This is direct endometrial-cell–mast-cell crosstalk rather than a bystander effect, and it marks CCL8/CCR1 as a potential treatment target. (Li et al., Biomed Pharmacother, 2020)

Estrogen receptor–mediated degranulation. Mast cells express both classical estrogen receptors (ERα) and the membrane G protein-coupled estrogen receptor GPR30. Ectopic endometriotic tissue synthesizes estrogen locally via aromatase, creating high local estrogen concentrations. Estrogen binding to these receptors directly triggers mast cell degranulation and mediator release — an IgE-independent activation mechanism. This creates a feedforward loop: the lesion produces estrogen, which activates local mast cells, whose mediators promote further inflammation and lesion growth, which drives more estrogen production. (Int J Biol Sci, 2025)

NLRP3 inflammasome activation. A 2021 study demonstrated that estrogen activates the NLRP3 inflammasome in mast cells via the nuclear-initiated signaling pathway, leading to production of mature IL-1β. In their mouse model, targeted inhibition of NLRP3 restrained lesion progression and fibrogenesis. This connects the estrogen-mast cell axis directly to the innate immune inflammasome machinery. (Guo et al., Front Immunol, 2021)

Taken together, the endometriotic lesion actively recruits mast cells, the local estrogen environment activates them through multiple receptor pathways, and those activated mast cells release mediators that sustain and amplify the disease. This is a self-reinforcing inflammatory cycle. One caution, though: most of the human data here is cross-sectional and cannot separate cause from consequence — whether mast cells help initiate lesions or are simply recruited by them is a question McCallion’s group explicitly left open. “Active participant” is as far as the evidence reaches; “driver” is not yet earned.

The Mast Cell–Nerve Feedforward Loop

The most clinically relevant mechanistic finding in the endometriosis-mast cell literature is the bidirectional signaling between mast cells and sensory nerve fibers within endometriotic lesions — demonstrated histologically, biochemically, and in animal models.

Proximity and co-localization. Endometriotic lesions are densely innervated by sensory nerve fibers, including nociceptive afferents positive for TRPV1 and CGRP. Mast cells in these lesions cluster in close physical proximity to nerve structures. In patients with pain, tryptase-positive mast cells are found in significantly higher numbers within nerve fiber bundles compared to pain-free patients, and the mast cell count correlates with pain severity. (Xu et al., Front Immunol, 2023)

The feedforward cycle works like this:

  1. Estrogen drives local mast cell accumulation and activation (as described above).
  2. Activated mast cells degranulate, releasing histamine, tryptase, NGF (nerve growth factor), FGF2 (fibroblast growth factor 2), TNF-α, and prostaglandins into the surrounding tissue.
  3. NGF and FGF2 promote the sprouting and growth of new sensory nerve fibers into the lesion (neuroangiogenesis), while simultaneously lowering the activation threshold of existing nociceptors.
  4. Histamine and tryptase directly sensitize these nerve fibers, amplifying pain signaling.
  5. The sensitized nerve fibers release substance P and CGRP (calcitonin gene-related peptide), which act back on mast cells to trigger further degranulation.
  6. This creates a self-sustaining loop of neurogenic inflammation that can persist independently of the original stimulus.

The FGF2–FGFR1 axis. A study specifically examining mast cell-derived FGF2 found elevated concentrations in peritoneal fluid of patients with stage III–IV endometriosis. FGF2-positive mast cells were increased in ovarian endometriosis lesions, and FGF2 interaction with FGFR1 on nerve fibers was identified as a key mediator of endometriosis-related pain. (Xu et al., Front Immunol, 2023)

MRGPRX2: a non-IgE mast cell activation pathway. Mao et al. (2025) demonstrated that MRGPRX2 (mas-related G protein-coupled receptor member X2), a receptor restricted to connective-tissue mast cells that mediates IgE-independent activation, is upregulated in endometriotic lesions. Mast cell knockout alleviated endometriosis-induced hyperalgesia in their model, and the mechanism traced through MRGPRX2-mediated histamine release activating HRH1 receptors on sensory neurons, which then sensitized TRPV1 channels. This is significant because it demonstrates a non-IgE, non-allergic pathway for mast cell activation in endometriosis that is mechanistically distinct from classical allergy.

Central sensitization. The peripheral mast cell–nerve signaling doesn’t stay peripheral. Mast cell-derived mediators contribute to elevated responsiveness of dorsal horn neurons and increased neurotransmitter release in the spinal dorsal horn, driving central sensitization — the structural and biochemical changes in the central nervous system that make chronic pain self-sustaining even after the peripheral trigger is managed. Increased spinal mast cell degranulation has been associated with elevated NGF and c-FOS expression in animal models. (Trends in Immunol, 2026)

This nerve-mast cell axis is the strongest mechanistic argument for why endometriosis pain is so difficult to treat with standard hormonal or anti-inflammatory approaches. The loop, once established, has its own momentum. One distinction to carry forward: this is the evidence for pain. That mast cells initiate or enlarge lesions is a thinner, mostly preclinical claim — so mast-cell-directed therapy is a plausible way to treat the pain, not a demonstrated way to shrink the disease.

The Peritoneal Environment

The mast cell story extends beyond the lesion itself into the surrounding peritoneal cavity.

Peritoneal fluid in endometriosis patients contains elevated concentrations of mast cell mediators — histamine, tryptase, TNF-α, PGE2, NGF — along with chemokines including RANTES/CCL5. These mediators actively shape the peritoneal immune microenvironment through at least three mechanisms.

Angiogenesis. Mast cell-derived VEGF, along with tryptase and chymase (which have direct pro-angiogenic effects), supports neovascularization within and around endometriotic implants. Lesion survival depends on establishing a blood supply, and mast cell products contribute to this process. The finding of increased blood vessel density in endometriotic cysts that correlates with mast cell number supports this mechanistically.

Fibrogenesis and ECM remodeling. Mast cell proteases (tryptase, chymase, carboxypeptidase A3) degrade and remodel extracellular matrix, facilitating tissue invasion and fibrotic change. This mirrors the matrix remodeling role observed — though less convincingly — in uterine fibroids. In endometriosis, however, the evidence is more direct: the NLRP3 inflammasome pathway described above connects mast cell activation to fibrogenesis in mouse models, and inhibiting that pathway reduced fibrotic change.

Immune dysregulation. The peritoneal environment in endometriosis shows dysregulated immune surveillance. Peritoneal macrophages fail to adequately clear ectopic endometrial tissue. Mast cell mediators contribute to this dysfunction by modulating macrophage polarization, promoting Th17 cell dysregulation (IL-17 and Th17 cells are implicated in endometriosis severity), and impairing natural killer cell cytotoxicity. The immune environment created by mast cell activation may help explain why ectopic endometrial implants survive rather than being cleared.

The peritoneal findings reinforce a central theme: mast cells in endometriosis are not simply responding to inflammation. They are active participants in creating the permissive immune environment that allows ectopic endometrial tissue to establish, vascularize, and persist.

Clinical Overlap: The MCAS–POTS–hEDS–Endometriosis Cluster

Clinicians working with MCAS patients have long observed that endometriosis, POTS (postural orthostatic tachycardia syndrome), and hypermobile Ehlers-Danlos syndrome (hEDS) cluster in the same individuals — a pattern now supported by emerging cohort data, though the evidence base remains observational.

Comorbidity prevalence data. A 2026 cohort study (Chin et al.) of 1,322 POTS patients found that, among women with POTS, those with endometriosis had significantly higher rates of MCAS (18.8% vs 3.1%) and Ehlers-Danlos syndrome (33.2% vs 13.1%) than those without — a striking signal, though drawn from a single autonomic referral center. Clinical education materials from centers such as the Bateman Horne Center likewise list endometriosis among the comorbidities associated with mast cell activation, alongside POTS and ME/CFS.

Shared genetic susceptibility. A 2025 UK Biobank study (Shigesi et al.) of over 8,000 endometriosis cases and 64,000 immune-disease cases found that women with endometriosis have a 30–80% increased risk of developing autoimmune conditions including rheumatoid arthritis. This does not directly implicate MCAS, which is not an autoimmune disease — so it belongs here as adjacent context, evidence of shared immune-regulatory architecture rather than of the mast-cell link specifically.

The ME/CFS–MCA–endometriosis link. A comprehensive vascular pathomechanism hypothesis connects ME/CFS, mast cell activation (notably using “MCA” rather than “MCAS” to avoid the narrow consensus diagnostic criteria), endometriosis, POTS, and small fiber neuropathy through shared vasoactive mediator pathways. The authors argue that inappropriate mast cell activation — whether or not it meets formal MCAS criteria — and endometriosis may represent parallel expressions of shared underlying vascular and immune dysregulation. (Wirth & Löhn, Medicina, 2023)

EHR-based comorbidity analysis. A 2025 analysis (Khan et al.) of over 43,000 endometriosis patients across University of California medical centers identified 661 significantly enriched comorbidities (in the UCSF cohort) spanning nearly all ICD chapters. Allergic disorders, migraines, GERD, and sinusitis appeared at significantly elevated rates, many of which overlap with common MCAS presentations. The clustering analyses identified distinct patient subpopulations with different comorbidity patterns, suggesting that endometriosis may not be a single disease entity. (Cell Reports Medicine, 2025)

What the clustering means — and doesn’t mean. The co-occurrence of these conditions is real and clinically important. But co-occurrence is not causation. Whether endometriosis causes or unmasks MCAS, whether MCAS creates a permissive immune environment for endometriosis establishment, or whether both reflect a shared upstream vulnerability (connective tissue fragility, immune dysregulation, autonomic dysfunction) remains unresolved. Some of the clustering is also likely ascertainment artifact rather than shared biology: MCAS, POTS, hEDS, and endometriosis are overlapping, loosely-defined diagnoses often made by the same subspecialists, so a patient in one clinic’s orbit can pick up all four labels at rates that partly reflect who is looking. The most honest current position: these conditions co-travel, patients deserve screening for the full cluster, and treatment of each condition should proceed on its own merits.

Therapeutic Implications

If mast cells are this deeply embedded in endometriosis pathobiology, the natural therapeutic question follows: can mast cell-targeted interventions help?

Mast cell stabilizers — preclinical signal, no clinical validation. The most direct evidence comes from ketotifen, a mast cell stabilizer and H1 antihistamine. In a rat model of surgically induced endometriosis, oral ketotifen significantly reduced hyperalgesia, cyst diameter, histopathologic scores, mast cell number and degranulation, blood vessel density, and expression of NGF, COX-2, ICAM-1, and VEGF in cysts. It also reduced NGF and TRPV1 expression in dorsal root ganglia, and lowered serum histamine and TNF-α. (Zhu et al., J Pain Res, 2019)

These are striking preclinical results — ketotifen hit nearly every node in the mechanistic chain described above. However, no published human clinical trial has established its efficacy for endometriosis pain or lesion reduction.

JAK/STAT pathway inhibitors — an emerging hypothesis. A 2025 review in Frontiers in Immunology proposed repurposing JAK inhibitors for endometriosis, based on the convergence of mast cell activation, neuroinflammation, and immune dysregulation on the JAK/STAT signaling pathway. IL-6 from ectopic endometrial tissue activates JAK/STAT signaling, which upregulates PGE2 and CGRP production, exacerbating inflammation and pain. The authors argue that JAK inhibitors could simultaneously target lesion development, immune activation, and pain generation. (Golinska et al., Front Immunol, 2025)

Conceptually attractive, but entirely preclinical. JAK inhibitors carry significant immunosuppressive risks, and no clinical data yet support their use in endometriosis.

MRGPRX2 as a therapeutic target. The identification of MRGPRX2-mediated, non-IgE mast cell activation in endometriosis has attracted pharmaceutical interest. Patent filings describe MRGPRX2 modulators for endometriosis among other inflammatory conditions. The histamine/HRH1/TRPV1 pathway downstream of MRGPRX2 activation provides a druggable cascade. But again — this is early-stage work.

Antihistamines — symptom management, not disease modification. For patients with both MCAS and endometriosis, antihistamines (H1 and H2 blockers) may provide symptomatic relief of the mast cell mediator-driven component — flushing, GI distress, urticaria, possibly some component of pain. But antihistamine therapy has not been shown to reduce endometriotic lesion burden, modify disease progression, or substitute for established endometriosis treatments (hormonal suppression, surgical excision).

What’s missing. The field needs prospective human studies that stratify endometriosis patients by mast cell mediator levels (peritoneal fluid tryptase, serum markers) and systematically evaluate mast cell-targeted therapies. Without this, the mechanistic evidence — however compelling — remains preclinical.

One note on the evidence base. A striking share of the mechanistic work above — the NLRP3, GPR30/FGF2, MRGPRX2, and CCL8/CCR1 findings, plus the ketotifen proof-of-concept — comes from a single research group (Zhang and colleagues, Zhejiang University). The pathways are biologically distinct, which is real support, but they represent substantially one program’s model rather than independent replication across the field. Convergence within one lab is weaker than convergence across many, and the therapeutic optimism here should be read with that in mind.

The Critical Distinction: Local Activation vs. MCAS

This is the clinical line that matters most — the same distinction drawn in the companion fibroid discussion, but carrying more weight here because the local mast cell involvement in endometriosis is so much more robust.

The evidence reviewed above demonstrates that mast cells are locally activated within endometriotic lesions and the surrounding peritoneal environment — recruited, degranulated, releasing mediators that drive pain, angiogenesis, fibrogenesis, and neuroinflammation. This is local tissue-level mast cell pathology.

It helps to be precise about the word, because “MCAS” is not a single target. Consensus criteria define it narrowly; much of the comorbidity literature uses “mast cell activation” loosely; and some authors avoid “MCAS” altogether to sidestep those criteria. Where this article says mast cells are “activated” in endometriosis, it means a local tissue phenomenon — not that a patient meets systemic MCAS criteria.

MCAS, by consensus criteria, is a systemic diagnosis. It requires:

  1. Recurrent episodes involving at least two organ systems (e.g., skin flushing/urticaria together with GI symptoms, respiratory symptoms, or hemodynamic instability).
  2. Objective evidence of mediator release during an episode — preferably a serum tryptase rise exceeding the formula: 1.2 × baseline + 2 ng/mL.
  3. Clinical improvement with mast cell mediator-directed therapy (antihistamine response alone is insufficient).

The presence of activated mast cells in an endometriotic lesion, or elevated peritoneal fluid tryptase, does not establish that the patient has MCAS. Similarly, a patient can have both endometriosis and MCAS as independent diagnoses — and some patients do. The mechanistic evidence reviewed here provides biological plausibility for their co-occurrence but does not demonstrate that one causes the other.

Where the distinction matters clinically:

  • A patient with endometriosis alone and locally activated mast cells in her lesions does not need systemic MCAS workup unless she has symptoms involving other organ systems.
  • A patient with both endometriosis and systemic mast cell activation symptoms (multisystem episodes, mediator-driven flushing/GI/cardiovascular symptoms) deserves formal MCAS evaluation as a separate diagnostic question.
  • Treating endometriosis with mast cell stabilizers remains experimental — it should not replace evidence-based endometriosis management (hormonal therapy, surgical excision) pending clinical trial data.
  • Treating MCAS with standard mast cell mediator-directed therapy may improve a patient’s systemic mast cell symptoms but should not be expected to treat the endometriosis itself.

The local-versus-systemic distinction is not a reason to dismiss the mast cell connection. It is a reason to take it seriously as biology while remaining honest about what it does — and does not — justify therapeutically.

Summary and Clinical Takeaways

The mast cell–endometriosis connection is substantially more developed than the mast cell–fibroid connection, resting on multiple convergent mechanistic pathways:

  • The estrogen–mast cell axis recruits and activates mast cells (via SCF/KIT and estrogen-receptor signaling), while CCL8/CCR1 crosstalk drives endometrial-cell migration and angiogenesis — together a feedforward inflammatory cycle.
  • The nerve–mast cell feedforward loop — mediated by NGF, FGF2, substance P, CGRP, histamine, and tryptase — drives both peripheral pain sensitization and neuroangiogenesis, and contributes to central sensitization.
  • Non-IgE activation pathways including MRGPRX2 and NLRP3 inflammasome activation provide mechanistic routes for mast cell degranulation that don’t require classical allergic sensitization.
  • Clinical clustering of MCAS, POTS, hEDS, and endometriosis is real and supported by emerging cohort data, though the direction of causality remains uncertain.
  • Therapeutic exploration — mast cell stabilizers, JAK inhibitors, MRGPRX2 modulators — shows preclinical promise but no human clinical validation for endometriosis.

For the clinician evaluating a patient with endometriosis and suspected MCAS:

  • Evaluate each diagnosis on its own criteria. Endometriosis is diagnosed by laparoscopy/imaging plus clinical presentation. MCAS requires systemic multiorgan episodes, objective mediator evidence, and treatment response.
  • Do not assume that activated mast cells in lesion tissue equal a systemic MCAS diagnosis.
  • Do screen for the full comorbidity cluster (POTS, hEDS, MCAS) when the clinical picture suggests it — the co-occurrence is frequent enough that missing one delays appropriate management.
  • Use mast cell mediator-directed therapy for systemic mast cell symptoms, but do not rely on it as a substitute for evidence-based endometriosis treatment.
  • Watch this space. The mechanistic foundation is strong enough that targeted clinical trials — particularly with mast cell stabilizers stratified by lesional mast cell density or peritoneal tryptase levels — could meaningfully change how we treat the pain component of endometriosis.

The biology is compelling. The clinical translation remains ahead of us — and that gap is exactly where the next generation of research needs to aim. The cleanest test of the framework will be a simple one: a well-powered trial of a mast-cell stabilizer that moves endometriosis pain — or fails to.

Important: This article is for educational purposes and summarizes the current research literature. It is not medical advice and does not create a physician–client relationship. Clinical decisions should be individualized in consultation with a qualified clinician.

Sources

Yoon Hang Kim, MD, MPH is the author of MCAS: Epidemic in Plain Sight and LDN Primer, both available on Amazon, and the founder of the LDN Support Group.

Professional: www.yoonhangkim.com  |  Clinical: www.directintegrativecare.com

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