Role of somatostatin receptors in normal and tumoral pituitary corticotropic cells

Normal and tumoral pituitary corticotropic cells express sst(2) and sst(5), of which sst(5) is the predominantly expressed receptor subtype. Somatostatin (SS) inhibits pituitary adrenocorticotropin hormone (ACTH) secretion in vitro, but the sensitivity to SS is strongly regulated by glucocorticoids. In pathological conditions of a low endogenous cortisol level, i.e. in patients with adrenal insufficiency and in patients with Nelson's syndrome, SS and sst(2)-preferring SS analogs (SSA), such as octreotide, are able to lower circulating ACTH and cortisol levels. On the other hand, sst(2)-preferring SSA seem not effective in lowering ACTH and cortisol levels in patients with untreated Cushing's disease (CD), in which circulating cortisol levels are high. This is likely due to the downregulation of sst(2) receptors by glucocorticoids. sst(5) receptor expression is more resistant to the inhibitory effect of glucocorticoids. In recent years, novel sst subtype-selective and universal SSA have been developed. In particular, SSA with a high sst(5)-binding affinity are potent inhibitors of ACTH secretion by pituitary corticotropic adenoma cells. This knowledge has initiated clinical trials evaluating the efficacy of these novel SSA in patients with CD, with the aim to lower circulating ACTH and cortisol levels by targeting multiple ssts on the corticotropic adenoma cells. In this minireview, the effects of SS in the regulation of normal and tumoral ACTH secretion, the role of sst subtypes involved herein, as well as the potentials of novel SSA in the treatment of patients with recurrent or persisting CD are discussed.