The Insulin–Cortisol–Vitamin C Axis: A Missing Regulatory Framework in Metabolic and Hormonal Homeostasis A Narrative Review

Bioidentical hormone replacement therapy (BHRT) traditionally operates within a triad consisting of sex hormones, thyroid hormones, and adrenal glucocorticoids. Despite widespread adoption, a substantial proportion of patients experience persistent dysglycemia, adrenal instability, fluctuations in symptom control, and inconsistent responses to therapy even when laboratory values appear biochemically normalized. These clinical patterns suggest that an essential regulatory element is missing from the current BHRT conceptual model.This narrative review proposes the Insulin–Cortisol–Vitamin C (ICV) Axis as a previously unrecognized hormonal network central to metabolic and endocrine homeostasis. Insulin profoundly influences sex-hormone binding globulin (SHBG), estradiol and testosterone bioavailability, progesterone responsiveness, thyroid hormone conversion, mitochondrial ATP production, and cortisol reactivity—yet insulin is rarely evaluated in BHRT. Cortisol, in turn, directly modulates insulin sensitivity and metabolic function, while vitamin C is required for cortisol synthesis, adrenal recovery, endothelial nitric oxide signaling, mitochondrial redox regulation, and antioxidant defense. Together, disturbances in these three components can generate characteristic clinical presentations frequently encountered in BHRT practice.In parallel, emerging evidence—including metabolic insights from GLP-1 receptor agonist therapy—indicates that vitamin C status and oxidative stress modulation play broader roles in insulin sensitivity and hormonal signaling than previously recognized. Integrating these findings, the ICV Axis provides a systems-level framework capable of explaining BHRT treatment failures, variable patient responses, and persistent symptomatology despite standard hormone optimization.The purpose of this review is to synthesize biochemical, endocrine, and nutritional evidence supporting this new axis, and to outline a clinically actionable update to BHRT incorporating insulin dynamics and vitamin C sufficiency. Recognition of the ICV Axis represents a conceptual advancement that can improve therapeutic outcomes across metabolic, endocrine, and integrative medical practice.