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

Julian Vester
2026 · doi:10.5281/zenodo.20582309 · W7163820786
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⚙ AI-generated summary by claude@2026-07, 2026-07-09 ⓘ

This paper proposes that estrogen activates mast cells via ERα and GPR30, forming a shared immuno-endocrine loop underlying female-predominant depression and endometriosis across the lifespan.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

The paper proposes an immuno-endocrine framework in which female-predominant depression and endometriosis are parallel outputs of a shared estrogen–mast cell loop, with estrogen activating mast cells through ERα and GPR30. It argues that lifespan timing makes the model predictive, claiming directional fit across stages of female reproductive life, and reports three distinct estrogen–mast cell pathways documented in endometriotic lesions (ERα/NLRP3 genomic, GPR30/FGF2 non-genomic, and an aromatase feedforward loop). It further explains cross-syndrome SSRI effects in endometriosis pain via P2X mast cell stabilization independent of serotonin and proposes ALAN exposure as an amplifying trigger converging on the same mast cell target, while noting that the framework is testable through seven falsifiable predictions including two via reanalysis of existing trial data. This paper is centrally about endometriosis — it develops and supports an estrogen–mast cell axis with multiple mechanistic pathways in endometriotic lesions.

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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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