Maintenance of fluid homeostasis during periods of heightened physical stress can be best evaluated in humans using exercise as a model. Although it is well established that arginine vasopressin (AVP), aldosterone and atrial natriuretic peptide (ANP) are the principle hormones regulating fluid balance at rest, the potential contributions of other related endocrine factors, such as oxytocin (OT) and brain natriuretic peptide (BNP), have not been well described during exercise. Seven endurance-trained runners completed three separate running trials: a maximal test to exhaustion (high intensity), a 60-min treadmill run (steady state), and a 56 km ultramarathon (prolonged endurance exercise). Statistically significant pre- to post-run increases were found only following the ultramarathon in [AVP](p) (1.9 vs 6.7 pg/ml; P<0.05), [OT](p) (1.5 vs 3.5 pg/ml; P<0.05), [NT-proBNP](p) (23.6 vs 117.9 pg/ml; P<0.01), [interleukin 6](p) (4.0 vs 59.6 pg/ml; P<0.05), [cortisol](p) (14.6 vs 32.6 microg/ml; P<0.01), [corticosterone](p) (652.8 vs 3491.4 ng/ml; P<0.05) and [11-deoxycortisol](p) (0.1 vs 0.5 microg/ml; P<0.05) while a significant post-run increase in [aldosterone](p) was documented after high-intensity (4.9 vs 12.5 ng/ml; P<0.05), steady-state (6.1 vs 16.9 ng/ml; P<0.05) and prolonged endurance running (2.6 vs 19.7 ng/ml; P<0.05). Similarly, changes in fluid balance parameters were significantly different between the ultramarathon versus high-intensity and steady-state running with regard to plasma volume contraction (less % contraction), body weight loss (increased % weight loss), plasma [Na(+)] Delta (decreased from baseline), and urine osmolality Delta (increase from baseline). Hypothetically driven relationships between [OT](p) and [AVP](p) (r=0.69; P<0.01) and between [NT-proBNP](p) Delta and plasma [Na(+)] Delta (r=-0.79; P<0.001)--combined with the significant and unexpected pre- to post-race increases after prolonged endurance exercise--allows for possible speculation that OT and BNP may assist their better known companion hormones (AVP and ANP) in the regulation of fluid balance during conditions of extreme physical stress.