ACTH-secreting
pituitary tumors are by definition partially autonomous, i.e., secrete
ACTH independent of physiological control. However, only few, small-sized studies on
proopiomelanocortin (
POMC) and its regulation by
corticotropin-releasing hormone (CRH) or
glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and
dexamethasone-regulated
POMC, CRH (CRH-R1), and
glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope
adenomas. Fifty-three
ACTH-secreting
adenomas were incubated with 10 nM CRH or 10 nM
dexamethasone for 24 h.
POMC, CRH-R1, NR3C1, and its alpha and beta
isoforms were quantified and medium
ACTH measured. Constitutive
POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas.
POMC increased during CRH in most specimens; conversely, changes induced by
dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between
POMC and
ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during
dexamethasone;
glucocorticoid receptor α was the more abundant
isoform and subject to down-regulation by
dexamethasone. Our results demonstrate a considerable variability in
POMC expression among
tumors and no correlation between
POMC and
ACTH, suggesting that
POMC peptide processing/transport plays a major role in modulating
ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected
ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into
Cushing's disease pathophysiology.