Why Your Chronic Illness Got Dramatically Worse in Perimenopause: The Hormonal Cascade Driving Gut, Mast Cell, Brain Fog, and Fatigue Symptoms in Your 40s — Why HRT Helps Some Women and Worsens Others

The variable response to hormone replacement therapy is one of the most clinically confusing features of perimenopausal chronic illness. Some women experience dramatic improvement on HRT. Some women experience modest improvement. Some women experience worsening, particularly of histamine and mast cell symptoms. The variability is not random. It is mechanistic. The HRT helpful pattern. Women whose perimenopausal symptoms are dominated by the consequences of estrogen and progesterone deficit (vasomotor symptoms, sleep disruption from progesterone loss, mood changes from neurosteroid loss, mitochondrial decline from estrogen loss, GABA tone loss from allopregnanolone decline) often respond well to HRT because the intervention addresses the specific deficits driving their symptoms. The mast cell load in these women is not the dominant driver. Their gut is reasonably regulated. Their HPA axis is responsive. HRT supplies the missing inputs and the system stabilizes. The HRT harmful or partially harmful pattern. Women whose perimenopausal symptoms are dominated by the consequences of high estrogen spikes against low progesterone (mast cell flares, histamine symptoms, estrobolome driven gut dysregulation) often experience worsening or partial improvement on HRT because the estrogen component of the HRT adds to the already high estrogen mediated mast cell activation. The women in this p