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

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.