Strenuous exercise activates the hypothalamic-pituitary-adrenal (HPA) axis. Exercise-induced stress has emotional components, but may also convey excitation by peripheral mechanisms. PURPOSE To determine the effects of the muscle contraction and metabolism on the HPA axis response to exercise. METHODS Muscular and endocrine responses to eighty isokinetic contractions of the knee flexor and extensor muscle groups for each leg (180°/s angular velocity) were evaluated in twenty athletes (13 endurance-trained, EA, 7 power-trained, PA). Before, immediately after the exercise and at different time points in the subsequent 120 minutes, plasma ACTH, serum GH, salivary cortisol, and serum lactate levels were determined and EMG signals were recorded from the vastus lateralis during isometric maximal voluntary contractions of the dominant leg. Mean frequency (MNF) of the EMG signal spectrum, average rectified value (ARV), and muscle fiber conduction velocity (CV) were estimated. RESULTS The peak extension torque value recorded by the dominant leg and its rate of change during the isokinetic exercise were found significantly higher in PA than EA. No differences were found for ARV both before and after the exercise, while the prepost exercise variations of CV and MNF were found higher in PA than EA. PA showed higher hormonal and lactate responses than EA, as indicated comparing the areas under the response curve, AURC, calculated as areas under the absolute concentration curves corrected for baseline values (ACTH: PA, 126.1±106.4 vs EA, 28.3±18.4, p=0.02; GH: PA, 4023.2±3755.5 vs EA, 1369.8±2871.3, p=0.02; cortisol: PA, 768.4±591.8 vs EA, 499.0±387.6, p=0.05; lactate: PA, 824.0±230.2 vs EA, 476.2±207.0, p=0.006, mean±SD, Mann-Whitney test). The Spearman correlation analysis showed significant relationships between lactate peak values and the following variables: ACTH peak (r=0.66, p=0.001), cortisol peak (r=0.52, p=0.02), GH peak (r=0.45, p=0.04), GH AURC (r=0.46, p=0.04). CONCLUSIONS The differences between EA and PA in muscle and endocrine responses, together with the positive correlations between lactate and hormones, suggest that muscle and HPA axis activities can be related. The mechanism underlying a peripheral modulation of the HPA axis response to exercise may consist in the following cascade of events: lactate production and variations of the composition of muscular microenvironment, activation of type III and IV muscle afferents (so-called metaboreceptors), activation of the spinohypothalamic tract neurons of the dorsal longitudinal fasciculus, and eventually the stimulation of pituitary. Supported by MIUR Project “ENERME”. Posters Displayed: One and one-half hour author presentation times are staggered among authors from 2:00–3:30 p.m. and 3:30–5:00 p.m.