Corticotrophin-releasing activity of desmopressin in Cushing's disease: lack of correlation between in vivo and in vitro responsiveness

Desmopressin (DDAVP), an arginine vasopressin analogue, markedly stimulates ACTH secretion in patients with Cushing's disease, in contrast to its minimal effect in normal subjects. However, little is known about the mechanisms underlying this action and it appeared to be of interest to evaluate the effect of DDAVP on ACTH-secreting pituitary adenomas in vitro, in comparison with its effect in the same patients in vivo. Pituitary adenomas from 14 patients with Cushing's disease were incubated with DDAVP, corticotrophin-releasing hormone (CRH) and DDAVP together with vasopressin receptor antagonists or CRH. Incubation with DDAVP induced a modest dose-dependent increase in ACTH concentrations which appeared maximal at 10 nM. CRH stimulated ACTH to a greater extent compared with DDAVP and potentiated the effect of DDAVP alone. The DDAVP-induced ACTH increase appeared blunted by vasopressin V(2) and V(3) receptor antagonists. V(3) receptor gene expression was detected by RT-PCR in all adenoma samples except for two which were not responsive to DDAVP in vitro but responsive to the peptide in vivo. Surprisingly, no difference in the in vitro ACTH secretory response was observed between in vivo DDAVP-responsive (ACTH peak>150% baseline) and -unresponsive (ACTH peak<120% baseline) patients, suggesting that the pituitary adenoma is not the sole mediator of the ACTH-releasing effect of DDAVP. In conclusion, the marked stimulatory effect of DDAVP observed in patients with Cushing's disease appears to be mainly dependent on an extrapituitary action, possibly the inhibition of a corticotrophin release-inhibitory factor.