Stress and Neuroendocrine Dysregulation in Colorectal Cancer: Clinical Assessment, HPA–HPT Axis Interactions, and Translational Implications

Colorectal cancer (CRC) is accompanied by substantial psychological, metabolic, inflammatory, and endocrine disturbances that may evolve throughout diagnosis, treatment, and disease progression. Psychological distress and circadian disruption can influence hypothalamic–pituitary–adrenal (HPA) axis activity, while systemic illness, inflammation, nutritional deterioration, and anticancer therapies may concurrently modify hypothalamic–pituitary–thyroid (HPT) axis function. This narrative review critically examines how these interconnected processes can be assessed and interpreted in patients with CRC, with particular attention to psychological stress, cortisol dynamics, allostatic load, systemic thyroid parameters, treatment-related endocrine dysfunction, and tumor-specific thyroid signaling. Structured PubMed/MEDLINE search prioritized evidence published between January 2020 and July 2026, supplemented by selected earlier landmark studies. Current evidence indicates that psychological distress is clinically relevant across the CRC trajectory, whereas altered cortisol rhythms and increased allostatic burden may provide complementary information on neuroendocrine and multisystem adaptation. Reduced FT3 concentrations and FT3/FT4 ratios have been associated with adverse clinical outcomes, but their interpretation is complicated by non-thyroidal illness syndrome, systemic inflammation, nutritional status, disease burden, and treatment exposure. Importantly, circulating thyroid parameters should not be considered direct surrogates of thyroid hormone activity within the tumor microenvironment, where deiodinases, thyroid hormone receptors, integrin αvβ3, WNT/β-catenin signaling, stromal metabolism, and local TSH–TSHR interactions may independently modify tumor behavior and antitumor immunity. Emerging evidence involving SP/NK-1R and CGRP/CRLR signaling further suggests that neuropeptide pathways may contribute to systemic–tumor communication in CRC. Overall, these findings support a multidimensional clinical framework rather than interpretation of isolated stress or endocrine biomarkers. Prospective longitudinal studies integrating validated psychometric assessment, circadian and endocrine profiling, inflammatory and nutritional status, treatment exposure, and matched tumor analyses are required to determine whether neuroendocrine phenotypes provide prognostic or predictive information beyond established clinicopathological factors.