Effects of Pyridostigmine and Naloxone on the Abnormal TSH Response to TRH during Starvation in Humans

Abstract

Background

Starvation is associated with a blunted TSH response to thyrotropin-releasing hormone (TRH) (peak minus baseline <5 mIU/L), despite basal TSH and thyroid hormone levels within the normal range. In light of the inhibitory effect of somatostatin on TSH secretion, we examined whether this condition is caused by an increased hypothalamic somatostatinergic tone in starving subjects. The possible involvement of endogenous opioids in the mechanism underlying the abnormal TSH response to TRH was also evaluated.

Methods

The TSH response to TRH (25 µg in an intravenous bolus), serum total and free T4 and T3 levels, and 24-hour urinary-free cortisol levels were measured in 28 normal men (age 27-35 years) within 10% of their ideal body weight. They were randomly divided into 4 groups of 7. In 21 subjects (groups 1, 2, and 3), TRH tests were performed after an overnight (8 hours) fast, placebo administrations (control test), and after prolonged (56 hours) starvation. TRH tests after prolonged starvation were performed either after placebos (in all subjects) or the administration of pyridostigmine (180 mg orally) (in 7 subjects, group 1); naloxone (0.8 mg in an IV bolus injection) (in 7 subjects, group 2); or the combination of pyridostigmine and naloxone (in 7 subjects, group 3). The remaining 7 subjects (group 4) were tested at weekly intervals with TRH plus placebo, TRH plus naloxone, TRH plus pyridostigmine, and TRH plus naloxone plus pyridostigmine after a fasting period of 8 hours.

Results

In all subjects of groups 1, 2, and 3, TRH-induced TSH rise was significantly lower after prolonged starvation than after overnight fast. Neither pyridostigmine nor naloxone, given alone, changed the basal levels of TSH and the TSH response to TRH after prologed starvation. In contrast, the concomitant administration of naloxone and pyridostigmine significantly enhanced the TRH-induced TSH rise. After overnight fasting, naloxone administration in group 4 subjects did not change the TSH response to TRH, whereas pyridostigmine significantly enhanced the TSH response to TRH. When naloxone was given together with pyridostigmine and TRH the TSH response was similar to that observed in the TRH plus pyridostigmine test.

Conclusions

These data indicate that naloxone-sensitive endogenous opioids exert an inhibitory effect on the cholinergic stimulatory control of TSH secretion during prolonged starvation. This suggests that an enhanced hypothalamic somatostatinergic activity is involved in the mechanism underlying the reduced TSH response to TRH.