Altered CNS metabolism-In healthy men going through two 4.5 hour long sessions of induced hypoglycemia, TSH, fT3 and fT4 are significantly reduced  . Perinatal asphyxia, recognized by low Apgar scores, is associated with  a depression of TSH, T4 and T3, and the reductions are greatest in infants with hypoxic/ischemic encephalopaty. In this study 6 of 11 infants with FT4 < 2ng/dl died  . These data suggest that reduced substrate or O2 supply to the CNS could induce hypothalamic/pituitary dysfunction.(105,106)

Administration of glucagon to dogs caused a significant fall in serum T3, suggesting that the stress-induced hyperglucagonemia may be a contributor to the NTIS syndrome by altering intracellular metabolism of T4 (107).

Dopamine given in support of renal function and cardiac function must play a role in many patients who develop low hormone levels while in an intensive care unit setting. Dopamine inhibits TSH secretion directly, depresses further the already abnormal thyroid hormone production, and induces significant worsening of the low hormone levels. Withdrawal of dopamine infusion is followed by a prompt dramatic elevation of TSH, a rise in T4 and T3, and an increase of the T3/rT3 ratio ( 78). All of these changes suggested to Van den Berghe et al. ( 108) that dopamine makes some patients with NTIS hypothyroid, inducing a condition of iatrogenic hypothyroidism, and that treatment (presumably by administering thyroid hormone), "should be evaluated".

Leptin plays a key role in control of thyroid hormone levels during starvation in animals. During starvation, leptin levels drop. With this there is diminished stimulation of TRH, thus diminished secretion of TSH, and lowered thyroid hormone levels. Administration of leptin appears to work via the arcuate nucleus of the hypothalamus to induce production of POMC and thus aMSH, and reduce AGRP. aMSH normally stimulates the melanocortin 4 receptor (MC4R), whereas AGRP suppresses it. Presumably through these actions, a lack of leptin during starvation leads to diminished stimulation of the MC4R receptor on the TRH neurons in ventricular nuclear centers, and thus diminished TRH secretion. Administration of leptin partially reverses this sequence. These actions appear to be part of an energy conserving scheme related to thyroid changes during starvation and are associated with leptin-induced increase in appetite, decreased energy expenditure, and modified neuroendocrine function. Naturally the relevance of this to human physiology is as yet unclear, but the data strongly suggests that leptin is involved in the down-regulation of thyroid function during acute starvation.(109-111) In clinical trials, stimulation of growth hormone secretion, by GH secretogogues lead to increased insulin and leptin levels in severely ill ICU patients  . Studies of leptin levels in patients with NTIS have to date indicated they are normal or elevated, not low. (112,113) Atrial natriuretic peptides, including amino acids 1 – 30, amino acids 31 – 67, known as vessel dilator, and 79 – 98 (kaliuretic hormone), and 99 – 126 (atrial natriuretic hormone), derived from the ANH prohormone, significantly decreased circulating concentrations of total T4, free T4, and free T3, when given to healthy humans for 60 minutes. A reciprocal increase in TSH lasted for two or three hours after cessation of the administration of these hormones, suggesting that the effect was a direct inhibition of thyroid hormone release from the thyroid gland, rather than an action of the hormones upon the hypothalamus or pituitary. No data is available on these factors in NTIS (114).