Octreotide exerts different effects in vivo and in vitro in Cushing's disease

Abstract

The effect of the long-acting somatostatin analog octreotide (SMS 201-995) on adrenocorticotropin (ACTH) secretion was studied in five patients with untreated Cushing's disease in vivo and in six human corticotropic adenoma cell cultures in vitro. For the in vivo study, 100 micrograms of octreotide sc was given 30 and 180 min after cannulation of the cubital vein and 100 micrograms of corticotropin-releasing hormone (CRH) was injected iv at 210 min. Serum ACTH and cortisol levels were measured for 390 min. In vivo, octreotide had no significant effect either on basal or CRH-stimulated ACTH levels and did not influence cortisol levels. The in vitro studies were conducted with corticotropic adenoma cell cultures derived from adenoma tissue obtained from six patients with Cushing's disease. In four of six cell cultures, octreotide (1 nmol/l-1 mumol/l) inhibited basal ACTH secretion in a dose-dependent manner. The inhibition ranged from 70 to 92% for 1 nmol/l octreotide to 14-46% for 1 mumol/l octreotide as compared to controls (100%). In three of three octreotide-responsive adenoma cell cultures investigated. CRH-stimulated ACTH secretion was suppressed by octreotide. Hydrocortisone pretreatment in vitro abolished the inhibitory effect of octreotide on ACTH secretion in one octreotide-responsive corticotropic adenoma cell culture. In conclusion, we showed that octreotide in most cases could inhibit the ACTH release from human corticotropic adenoma cells in vitro but had no suppressive effect on ACTH levels of patients with Cushing's disease in vivo. This discrepancy could be due to a somatostatin receptor down-regulation by cortisol at the hypercortisolemic state in vivo.

New developments in the medical treatment of Cushing's syndrome

“…In contrast to GH-producing pituitary adenomas, which have a high degree of sst 2 expression, sst 2 expression by corticotroph adenomas is low (de Bruin et al 2009b). This explains why the sst 2 -targeting somatostatin analogs octreotide and lanreotide are generally ineffective in the treatment of CD (Lamberts et al 1989, Stalla et al 1994. The low sst 2 expression is thought to result from downregulating effects of high circulating cortisol levels.…”

“…The low sst 2 expression is thought to result from downregulating effects of high circulating cortisol levels. Indeed, several in vitro studies suggested that exposure to glucocorticoids diminishes sst 2 expression both in GH-and ACTH-secreting cell lines (Schonbrunn 1982, Stalla et al 1994, Xu et al 1995, Park et al 2003, de Bruin et al 2009a.…”

Pharmacological management of Cushing's syndrome: an update

“…However, subsequent studies in Nelson's syndrome have been less impressive and most patients with Cushing's disease have failed to respond (78)(79)(80)(81)(82). The chronic treatment of rat pituitary tumour cells and mouse corticotroph cells with glucocorticoid results in decreased binding of somatostatin (83).…”

“…The chronic treatment of rat pituitary tumour cells and mouse corticotroph cells with glucocorticoid results in decreased binding of somatostatin (83). In cultured human corticotroph, adenoma cells pre-treated with hydrocortisone resulted in abolition of octreotide-induced inhibition of basal and CRH induced ACTH release (82). The lack of clinical efficacy of octreotide may be due to the down regulation of somatostatin receptors by glucocorticoids.…”

Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas

“…O hipercortisolismo reduz a expressão do SSTR2 (134) , fato que justifica a predominância de expressão de SSTR5. Dessa forma, o LRS de nova geração, com maior afinidade ao SSTR5, podem apresentar maior eficácia (135) .…”