The Estrogen-Mast Cell Axis: A Testable Immuno-Endocrine Framework for Female-Predominant Depression and Endometriosis

Julian Vester
2026 · doi:10.5281/zenodo.20582308 · W7163809498
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-07-18 ⓘ

This paper proposes that estrogen activates mast cells through ERα and GPR30, creating an immuno-endocrine loop driving female-predominant depression and endometriosis across the lifespan.

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⚙ AI-generated deep summary by qwen3.7-flash, 2026-09-02 · read from full text ⓘ

This paper proposes an immuno-endocrine framework linking female-predominant depression and endometriosis through a shared estrogen-mast cell axis. It details three mechanistic pathways within endometriotic lesions involving ERα, GPR30, and aromatase, suggesting that SSRIs alleviate endometriosis pain by stabilizing mast cells via P2X receptors rather than through serotonin modulation. The authors present seven falsifiable predictions to test this model across various stages of female reproductive life. Relevance to endometriosis: Centrally about the condition — specifically proposing that estrogen-driven mast cell activation in endometriotic lesions contributes to both pain and comorbid depression.

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Abstract

This paper proposes a testable immuno-endocrine framework in which female-predominant depression and endometriosis arise as parallel tissue-specific outputs of a shared biological loop: estrogen directly activates mast cells via ERα and GPR30. The framework's central strength is its lifespan timeline — a single variable, estrogen, makes correct directional predictions at every stage of female reproductive life, from the prepubertal absence of the female depression excess through menarche, PMDD, postpartum depression, perimenopause, and post-menopause. Three mechanistically distinct estrogen-mast cell pathways are documented in endometriotic lesions (ERα/NLRP3 genomic pathway; GPR30/FGF2 non-genomic pathway; aromatase feedforward loop). The cross-syndrome efficacy of SSRIs in endometriosis pain is explained by P2X mast cell stabilization, independent of serotonin. ALAN exposure is proposed as an amplifying trigger that converges with estrogen on the same mast cell target. Seven falsifiable predictions are proposed, two testable by reanalysis of existing trial data.
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The Estrogen-Mast Cell Axis: A Testable Immuno-Endocrine Framework for Female-Predominant Depression and Endometriosis Authors/Creators Description This paper proposes a testable immuno-endocrine framework in which female-predominant depression and endometriosis arise as parallel tissue-specific outputs of a shared biological loop: estrogen directly activates mast cells via ERα and GPR30. The framework's central strength is its lifespan timeline — a single variable, estrogen, makes correct directional predictions at every stage of female reproductive life, from the prepubertal absence of the female depression excess through menarche, PMDD, postpartum depression, perimenopause, and post-menopause. Three mechanistically distinct estrogen-mast cell pathways are documented in endometriotic lesions (ERα/NLRP3 genomic pathway; GPR30/FGF2 non-genomic pathway; aromatase feedforward loop). The cross-syndrome efficacy of SSRIs in endometriosis pain is explained by P2X mast cell stabilization, independent of serotonin. ALAN exposure is proposed as an amplifying trigger that converges with estrogen on the same mast cell target. Seven falsifiable predictions are proposed, two testable by reanalysis of existing trial data. Files Vester_2026_Estrogen_Mast_Cell_Depression_Endometriosis.pdf Files (48.7 kB) | Name | Size | Download all | |---|---|---| | md5:7c35f7f79e1856ce37a5287d9df8b622 | 48.7 kB | Preview Download | Additional details Dates - Issued - 2026-06-07

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