Endocrine Signaling and Tissue Remodeling in Gynecomastia: Implications for Treatment Response

To critically synthesize evidence on treatment response in gynecomastia using a framework that distinguishes biological response, structural response, and patient-important benefit. We searched PubMed, PubMed Central, and targeted journals through 11 September 2026. Priority was given to gynecomastia-specific human studies; evidence from other breast systems, animal models, and general biomarker methodology was treated as indirect. The randomized anastrozole trial showed an endocrine effect but did not demonstrate superiority over placebo on the prespecified structural endpoint. Receptor expression in surgical specimens provides biological plausibility but does not establish receptor functionality, endocrine dependence, or predictive value. Stromal composition may influence lesion regression, but this remains a hypothesis requiring direct testing. Ultrasonography and elastography may support pretreatment characterization, but current studies do not validate imaging features as surrogates for fibrosis or endocrine responsiveness. Gynecomastia-derived organoids offer a disease-relevant model for functional studies, although donor numbers are small and endocrine responsiveness, cellular representativeness, and reproducibility across patients require further evaluation remain uncertain. Biological response, structural response, and patient-important benefit need not occur together or in a fixed sequence. Further research should link tissue and model findings to pretreatment markers, compare treatment benefits, and establish clinical utility before marker-guided care.