Why Your Chronic Illness Got Dramatically Worse in Perimenopause: The Hormonal Cascade Driving Gut, Mast Cell, Brain Fog, and Fatigue Symptoms in Your 40s — The Five Mechanisms by Which Perimenopause Drives Chronic Illness Flares

Each of the cascade elements above drives chronic illness biology through specific mechanisms. Five mechanisms in particular are responsible for most of the chronic illness worsening that perimenopausal women experience. Mechanism One: Estrogen Driven Mast Cell Activation Mast cells express estrogen receptors directly on their cell surface. Estrogen binding to these receptors lowers the threshold for mast cell activation, increases the granule content available for release, and amplifies the response to other activating stimuli. The mast cell that was stable at a given trigger threshold in a low estrogen environment becomes reactive at a substantially lower trigger threshold in a high estrogen environment. Erratic perimenopausal estrogen with high spikes produces a clinically devastating pattern. The mast cell threshold drops abruptly with each estrogen spike. Triggers that were inconsequential become symptomatic. The patient develops new sensitivities to foods, fragrances, temperature, exercise, alcohol, supplements, and medications she tolerated her whole life. The pattern often correlates with cycle phase initially, with worsening in the late follicular and ovulatory phase when estrogen peaks. As cycles become more irregular, the correlation becomes harder to read, and the patient experiences mast cell flares that seem random because the underlying estrogen pattern has becom