Hormonal Modulation in Chronic Coronary Syndrome: From Neurohormonal Activation to Endocrine Targets

Background: Chronic coronary syndrome (CCS) has evolved from a stenosis-centered concept to a dynamic clinical entity in which obstructive and non-obstructive coronary disease, microvascular dysfunction, and vasomotor abnormalities coexist with complex neurohormonal and endocrine activation. However, CCS has rarely been examined through an integrated endocrine lens, and no unified hormonal-phenotype framework currently links neurohormonal, sex-hormone, thyroid, and cardiometabolic pathways across CCS presentations. Objective: To synthesize contemporary evidence on how neurohormonal and endocrine pathways shape CCS phenotypes and to outline potential endocrine targets for phenotype-guided therapy. Methods for Synthesis of Data: We performed a structured literature appraisal in PubMed, Embase, the Cochrane Library, and ScienceDirect from inception to May 2026, using CCS/stable coronary artery disease and hormone-related search terms, and included comparative clinical studies in adults that evaluated neurohormonal or endocrine interventions with clinically relevant cardiovascular outcomes. Results: From 851 records, 34 studies were retained for qualitative synthesis, encompassing randomized trials, observational cohort studies, systematic reviews, and consensus documents. These data support a central role for renin-angiotensin-aldosterone and sympathetic activation, counterregulatory natriuretic peptides, endothelin-1, sex and thyroid hormones, and adipose-derived mediators in modulating CCS phenotypes, symptoms, and residual risk. Hormone-targeting therapies-including RAAS blockade, beta-blockers, mineralocorticoid receptor antagonists, sex- and thyroid-hormone modulation, and cardiometabolic agents such as GLP-1 receptor agonists and SGLT2 inhibitors-show variable yet often significant impact on outcomes across specific CCS subsets. Conclusions: CCS is best conceptualized as a state of coordinated neurohormonal and endocrine disturbance rather than a purely anatomical disease. A hormonal phenotype framework may support more biologically rational, individualized management and define a research agenda for phenotype-stratified trials in CCS. This review proposes a hormonal-phenotype framework that is conceptually novel compared with anatomy- or comorbidity-based CCS classifications and is intended to be hypothesis-generating rather than prescriptive, by highlighting specific knowledge gaps and potential endocrine targets for future phenotype-guided trials.