The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P,0·05), normal intra-pituitary TSH content, and no significant changes in and TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P,0·01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P,0·05), while TRH receptor mRNA levels were importantly increased (78%, P,0·05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7·1-and 4·0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P,0·05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.

We investigated the influence of hypo-and hyperthyroidism on the ability of leptin to modulate TSH secretion. Two hours after receiving leptin (8 µg leptin/100 g BW; s.c.), hyperthyroid rats (10 µg thyroxine (T4)/100 g body weight (BW) for 5 days) showed a 1·7-fold increase in serum TSH (P<0·05); in hypothyroid rats, leptin had no effect. Hemi-pituitaries of hyperthyroid rats incubated with 10 9 and 10 7 M leptin showed reductions in TSH release of 40 and 50% respectively (P<0·05); incubation with 1:2000 and 1:500 dilutions of antiserum against leptin resulted in 3-and 4-fold higher TSH release (P<0·05 and P<0·001 respectively). However, in hypothyroid pituitaries leptin or the antiserum had no effect. The results suggest that the in vivo and in vitro responsiveness of TSH to leptin is abolished in hypothyroidism and is preserved in short-term hyperthyroidism, in comparison to previous reports in euthyroidism. In addition, the inhibitory action of pituitary leptin is enhanced in hyperthyroid glands, which may suggest a role for locally produced leptin in the suppression of TSH release associated with hyperthyroidism.

No abstract

We examined the acute effects of endocannabinoid, anandamide, and of synthetic cannabinoid receptor antagonist, AM251[N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], on TSH, thyroxine (T 4 ), and triiodothyronine (T 3 ) secretions. Euthyroid male rats showed a 42% decrease in serum TSH, 2 h after a single i.p. injection of 0 . 02, but not 0 . 2 mg/kg body weight (BW), anandamide, accompanied by a 39% reduction in serum T 4 , without alteration in serum T 3 . At 0 . 5 and 1 h, these serum hormones showed no significant change. Hypothyroid rats showed a 35% reduction in serum TSH (P!0 . 01), 2 h after anandamide injection, which had no effect on hyperthyroid rats. In both thyroid states, no modification of serum thyroid hormones was observed.Intraperitoneal injection of 0 . 17 or 1 . 7 mg/kg BW AM251 in euthyroid rats caused, 1 . 5 h later, 1 . 7-fold or 4 . 3-fold increase in serum TSH respectively, without changing thyroid hormones. Stimulatory effect of 0 . 17 mg/kg BW AM251 and inhibitory effect of anandamide was abolished in the group injected with AM251 followed by an anandamide injection, 30 min later. Intracerebroventricular injection of 20 ng (but not 200 ng) anandamide induced a decrease in serum TSH at 60 min after injection, which tended to disappear at 120 min. Anterior pituitary explants presented significant reduction in TSH release in the presence of 10 K7 M anandamide in incubation medium, which was blocked by 10 K7 M AM251. In conclusion, anandamide has the ability to acutely inhibit TSH release in eu-and hypothyroid rats, acting at the hypothalamus-pituitary axis. Since, in addition, the cannabinoid receptor antagonist AM251 increased TSH release, we suggest that endocannabinoid system has a role as negative regulator of TSH secretion.