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Prepro-thyrotrophin-releasing hormone (TRH) (178–199), a 22-amino acid cleavage product of the TRH prohormone, has been postulated to act as an adrenocorticotrophin hormone (ACTH)-release inhibitor. Indeed, although in vitro evidence indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent anterior pituitary primary cultures and cell lines, not all studies concur and no study has as yet evaluated the effect of this peptide in Cushing’s disease. The present study aimed to test the effect of preproTRH(178–199) in human tumoural corticotrophs. Twenty-four human ACTH-secreting pituitary tumours (13 macroadenomas, 11 microadenomas) were collected during surgery and incubated with 10 or 100 nm preproTRH(178–199). ACTH secretion was assessed after 4 and 24 h of incubation by immunometric assay and expressed relative to levels observed in control, unchallenged wells (= 100%). Parallel experiments were performed in rat anterior pituitary primary cultures. A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens (for 10 nm ppTRH: 70 ± 4% control at 4 h and 83 ± 5% control at 24 h; for 100 nm ppTRH: 70 ± 4% control at 4 h and 85 ± 5% control at 24 h), whereas a mild and short-lasting stimulatory effect was observed in three tumours and no changes in ACTH secretion in the remaining nine tumoural specimens. The inhibitory effect of preproTRH(178–199) was more evident in macroadenomas and significantly correlated with sensitivity to dexamethasone inhibition. Significant inhibition of ACTH secretion by preproTRH(178–199) in rat pituitary cultures was observed after 24 h of incubation. The present study conducted in a large series of human corticotroph tumours shows that preproTRH(178–199) inhibits tumoural ACTH secretion in a sizable proportion of specimens, in close relation to the size of the tumour and its sensitivity to glucocorticoid negative feedback. This appears a promising avenue of research and further studies are warranted to explore the full scope of preproTRH(178–199) as a regulator of ACTH secretion. [ABSTRACT FROM AUTHOR]

Abstract: Non-glucocorticoid inhibitors of the HPA-system are of utmost interest in the treatment of diseases with impaired regulation of this system, like the metabolic syndrome and depression. In rats, a fragment of the thyreotropin-releasing hormone (TRH) preprohormone, preproTRH(178–199), has been demonstrated to inhibit basal and stimulated secretion of cortisol. Our pilot study aimed to explore the first time similar effects of the homologue peptide preproTRH(158–183) in healthy humans. In a double-blind within-subject comparison, eight healthy young men were infused intravenously with placebo and preproTRH(158–183) at varying doses of 5, 10, 25 and 50mg/kg of body weight. After 15min of infusion a corticotropin-releasing hormone (CRH)/vasopressin-test was performed. Plasma concentrations of pituitary hormones and free thyroxine, blood pressure, heart rate and feelings of activation and mood were assessed repeatedly at close intervals. Individual hormone profiles and collapsed data across all doses did not reveal any effects of preproTRH(158–183) on HPA-activity, although it increased TSH and fT4, stimulated the release of GH and increased systolic blood pressure in the course of the experiment (p <0.05, for all effects). Self-reports indicated enhanced feelings of activation and general well-being following preproTRH (p <0.05). Our data exclude a substantial inhibitory effect of preproTRH(158–183) on HPA secretory activity and, thus, contrast with findings in rats. In humans, the peptide appears to even exert an albeit weak stimulatory effect on autonomic stress systems as indicated by increased cardiovascular activity in combination with enhanced subjective arousal. [Copyright &y& Elsevier]