A highly complex mechanism as the proposed “Hormonal multi-resistance”, is unlikely to represent a simple evolutionary accident. We have suggested that elevated PGE2 signaling antagonizes multiple hormonal pathways, potentially functioning as an energy-conserving response to physiological stress. From an evolutionary perspective, a heightened form of multiple hormonal resistance may have been advantageous in contexts such as hibernation, where resistance to leptin, AVP ¹ and insulin supports hyperphagia, elevated glucose levels, and fat accumulation. Consistent with this view, hibernation is associated with transient leptin and insulin resistance ² as well as a shift toward fatty acid metabolism ², which liberates arachidonic acid (AA), providing substrate for COX-2-mediated PGE2 synthesis. Sustained PGE2 signaling – potentially driven by altered EP receptor balance – may reduce hormonal responsiveness, suppress sympathetic activity, and promote sleep-like states. While adaptive and reversible in hibernating species, prolonged activation in humans may be maladaptive, contributing to persistent homeostatic dysregulation. Although this framework remains speculative, it is supported by the comprehensive review of molecular adaptations in mammalian hibernators by van Breukelen and Martin (2002) ². 

1              Aoyagi, T. et al. Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice. Endocrinology 148, 2075-2084 (2007). https://doi.org/10.1210/en.2006-1315

2              Van Breukelen, F. & Martin, S. L. Invited review: molecular adaptations in mammalian hibernators: unique adaptations or generalized responses? J Appl Physiol (1985) 92, 2640-2647 (2002). https://doi.org/10.1152/japplphysiol.01007.2001