Abstract
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.
Highlights
ACTH-secreting pituitary tumors are characterized by autonomous yet still responsive ACTH secretion
Subgroup analysis showed that macroadenomas exhibit higher levels of POMC compared to microadenomas (180.6 ± 61.05 vs. 49.5 ± 14.62 normalized expression, p \ 0.05) but none of the other variables, e.g., sex, age, and surgical outcome, proved a significant contributor to POMC variability
The corticotropin-releasing hormone (CRH)-R1 receptor gene was expressed at variable levels in corticotrope tumors (Fig. 1b); no difference according to tumor size was observed (0.09 ± 0.01 vs. 0.08 ± 0.02 normalized expression for macro- and microadenomas, respectively, N.S.)
Summary
ACTH-secreting pituitary tumors are characterized by autonomous yet still responsive ACTH secretion. ACTH secretion is autonomous in as much as the tumoral corticotrope continues to secrete ACTH notwithstanding high cortisol levels, appears insensitive to physiological negative feedback. ACTH secretion by tumoral corticotropes is sensitive to stimulation by corticotropin-releasing hormone (CRH) and inhibition by high doses of synthetic steroids. Alterations in factors which modulate corticosteroid action on the proopiomelanocortin (POMC) promoter, e.g., Brg1 [3], or its intrapituitary availability, e.g., 11ßHSD [4] have been reported but appear variably linked to tumoral sensitivity to steroidinduced suppression. POMC expression itself has been evaluated in studies reporting on 20 tumoral specimens at most [7, 8]
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