Endocrine Adaptations to Prolonged Fasting: From Physiology, Clinical Uncertainties, Translational Challenges to Healthspan Implications

Objectives: Intermittent fasting regimens that include periods of prolonged fasting may mimic certain well-documented benefits of calorie restriction. In this narrative review, we synthesize preclinical and human data on endocrine adaptations during prolonged fasting protocols. Methods: We conducted a structured search of relevant databases, followed by data extraction and synthesis, with a focus on endocrine adaptations during prolonged fasting and their potential implications for healthspan. Results: Across various endocrine axes, prolonged fasting appears to induce a reproducible pattern marked by diminished anabolic signaling and transient activation of potential stress resilience pathways. However, the evidence is limited by small sample sizes, short follow-up durations, methodological heterogeneity, and dependence on surrogate endpoints. Endocrine outcomes are frequently secondary and reported inconsistently. Potential risks include transient hypogonadism, relative hypothyroidism, hypercortisolemia, orthostatic intolerance, electrolyte imbalances, catabolic loss of lean mass, and refeeding challenges. Conclusions: Overall, prolonged fasting activates conserved endocrine mechanisms that may confer plausible cardiometabolic benefits; however, their translation to clinical practice remains speculative. We highlight key knowledge gaps and propose directions for future research in this emerging field.