Our study suggests that PC2 expression and Akt phosphorylation are related at the molecular level, resulting in a change in cell cycle and an increase in pituitary adenoma size. An elevation of plasma alphaMSH could conjecture the activation of the phosphatidylinositol 3/Akt cascade in PC2-positive APPAs and may become a valuable clinical marker of tumor growth in Cushing's disease.

Proopiomelanocortin processing in corticotroph cells is known to be operated by prohormone convertase (PC) 1/3 which is activating several pro-proteins and prohormones by intracellular limited proteolysis processing. In this study, we hypothesized that PC1/3 expression differs between Cushing's disease (CD) and silent corticotroph adenoma (SCA), and investigated whether PC1/3 expression is involved in the adrenocorticotropin (ACTH) silence of SCA. We performed immunohistochemical analysis of pituitary adenoma specimens for six adenohypophysial hormones, PC1/3 and chromogranin A (CgA). Subjects for this study consisted of 12 anterior pituitary adenomas of CD (1 male, 11 female; 14-70 years old) and 31 non-functioning adenomas (23 male, 8 female; 32-71 years old).ACTH immunoreactivity was observed in all of CD and three of 31 non-functioning adenomas. The three cases diagnosed as SCA were also positive for growth hormone and follicle-stimulating hormone. Cushing's adenomas and SCAs were all positive for PC1/3. PC1/3-positive cells did not always colocalize with ACTH but some of them colocalized with CgA in SCAs. Even if PC1/3 is not present in corticotroph cells, PC1/3 immunoreactivity in SCA may originate from CgA-positive cells. We conclude that immunohistochemistry for PC1/3 is not helpful for differential diagnosis between CD and SCA in clinical practice, though the regulation of PC1/3 expression is likely to be an important etiological factor in ACTH silence of SCA. The diversity of immunohistochemical properties of SCA leads us to speculate that it is not a single entity and may be a general diagnostic term for adenomas of varying etiology.

No abstract

The present study investigated the role of K(+) channels in the inhibitory effect of glucocorticoid on adrenocorticotropin (ACTH) release induced by corticotropin-releasing hormone (CRH) using cultured rat anterior pituitary cells. Apamin and charybdotoxin (CTX) did not have a significant effect on ACTH release induced by CRH (1 nM). Tetraethylammonium (TEA), a broad spectrum K(+) channel blocker, increased the ACTH response to CRH only at the highest concentration (10 mM). The exposure to 100 nM corticosterone for 60 min inhibited the CRH-induced ACTH release. Neither TEA, apamin, nor CTX affected the inhibitory effect of corticosterone. In contrast, astemizole (Ast) and E-4031, ether-a-go-go-related gene (erg) K(+) channel blockers, abolished the inhibitory effect of corticosterone on CRH-induced ACTH release (1.25+/-0.10 vs. 1.45+/-0.11 ng/well at 10 microM Ast, p>0.05, 1.71+/-0.16 vs. 1.91+/-0.32 ng/well at 10 microM E-4031, p>0.05, vehicle vs. corticosterone). RT-PCR demonstrated all three subtypes of rat-erg mRNAs in the pituitary and corticosterone increased only erg1 mRNA up to 2.47+/-0.54 fold. In conclusion, erg K(+) channels were up-regulated by glucocorticoid, and have indispensable roles in delayed glucocorticoid inhibition of CRH-induced ACTH release by rat pituitary cells.

Correspondence to: yutaka oKI, M.d., Ph.d., second division, department