Cadegiani FA, et al. - In this cross-sectional study, 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18–50 years old, males, with BMI 20–30 kg/m², with comparable baseline features, who underwent gold-standard exercise-independent tests were involved in order to define the theory of the novel hormonal conditioning mechanism using the findings from the Endocrine and Metabolic Responses on Overtraining Syndrome study. For cortisol, growth hormone (GH), and prolactin, in ATL vs NPAC, responses to insulin tolerance test (ITT) were significantly earlier and higher. Between ATL and NPAC, cortisol response to CST was comparable. In NPAC, prolactin response was absent, while being present in ATL. Therefore, enough evidence to suggest the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not bound to any axis, revealing an intrinsic and independent process of “hormonal conditioning” in athletes, comparable to those seen in the cardiovascular and neuromuscular systems were discovered. Moreover, this novel conditioning process could be the lacking connection for understanding the enhanced responses seen in athletes to adverse situations, traumas, infections, inflammations, and psychiatric conditions.