Selective activation of ER-β and GPER1—via co-administration of low-dose estradiol and a buffering SERM like raloxifene—constitutes a receptor-specific therapeutic model that delivers neurotrophic gene upregulation, inflammatory attenuation, monoaminergic modulation, and HPA axis recalibration (14, 18, 21, 23, 26), targeting key pathophysiological domains in TR-BD. This evidence concerns the gene ESR2 and Behcet disease.