The neuroendocrine response (NER) is an essential component of the adaptive 
process to trauma, brain injury, and major surgery. While receiving additive 
humoral and neural afferent inputs, the brain nuclei responsible for the NER act 
mainly by efferent pathways to the hypothalamic-pituitary-adrenal (HPA) axis and 
the sympathoadrenal system, the activations of which induce subsequent 
circulatory and metabolic responses. The NER to brain injury is similar to the 
response observed in patients with extracerebral injury, even if the response 
after brain injury is extremely variable. Generally, there is a biphasic 
pattern, with a sympathoadrenal storm associated with variable and altered 
stimulation of the HPA during the ebb phase. The first phase is followed by a 
decrease in both responses while other endocrine changes develop, involving 
mainly the counter-regulatory, gonadal, and thyroid hormones. The outcome after 
brain injury is closely correlated with the intensity of these changes, 
particularly with catecholamine plasma levels and the severity of the low 
triiodothyronine syndrome. Alterations of the thyroid hormones are largely 
related to a reduction in peripheral deiodination of thyroxin. Recent research 
shows that increased free-radical production and decreased selenium (an 
antioxidant) serum levels play an important role in thyroid metabolism. Two 
major issues remain unsolved: a) the precise definition of cerebral death, since 
endocrine brain function is not abolished in the state currently defined as 
brain death; and b) the question of whether substitutive hormone therapy should 
be applied in severe brain injury.