Preoperative Normalization of Cortisol Levels in Cushing's Disease After Medical Treatment: Consequences for Somatostatin and Dopamine Receptor Subtype Expression and In Vitro Response to Somatostatin Analogs and Dopamine Agonists

Abstract

Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D₂R) and somatostatin receptor subtype 5 (sst₅). The sst₂ expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst₂-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. Our objective was to compare sst and D₂R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. The sst₂ mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst₅ and D₂R mRNA expression or in sst₂, sst₅, and D₂R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. After achieving normocortisolism induced by medical therapy, cortisol-mediated sst₂ downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst₂ protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.