PreproTRH (178199), a 22-aminoacid cleavage product of the TRH prohormone, has been postulated to act as an ACTH-releasing inhibitor. Indeed, in vitro evidence indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent anterior pituitary primary cultures and cell lines (Redei 1995, Revskoy 2001), although not all studies concur (Nicholson 1996). Aim of the present study was to test the effect of preproTRH(178199) in human tumoral corticotropes.
Methods: Twenty-four human ACTH-secreting pituitary tumors were collected during surgery, dispersed and established in culture. After a 35 day attachment period, cells were incubated with 10100 nM rat preproTRH(178199), with 10 nM human CRH or with 10 nM dexamethasone (all from Sigma Co., St. Louis, USA) and medium samples collected after 4 and 24 h for measurement of ACTH concentrations by IRMA. ACTH secretion was standardized to % unchallenged wells (=control).
Results: A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens (for 10 nM ppTRH: 70.3±4.52% control at 4 h and 83.4±5.33% control at 24 h; for 100 nM ppTRH: 70.1±3.93% control at 4 h and 84.8±4.88% control at 24 h), whereas a mild and short-lasting stimulatory effect was observed in the other tumors (for 10 nM ppTRH: 128.6±9.45% control at 4 h and 104.7±4.26% control at 24 h; for 100 nM ppTRH: 108.4±3.42% control at 4 h and 103.3±3.63% control at 24 h). Interestingly, the effect of preproTRH(178199) was significantly correlated with the potency of dexamethasone inhibition while no association with CRH stimulation was observed.
Conclusions: Our study in a large series of human corticotrope tumors shows that preproTRH (178199) exerts variable effects on tumoral ACTH secretion, closely linked to sensitivity to glucocorticoid negative feedback. Further studies might shed light on its usefulness as an inhibitor of ACTH secretion by human corticotrope adenomas.