CRH responsiveness identifies larger, corticotroph-like somatotroph adenomas in acromegaly patients

Acromegaly, a chronic disorder caused by excessive growth hormone (GH) secretion, primarily stems from benign pituitary adenomas. While the corticotropin-releasing hormone (CRH) test is sometimes used in diagnosis, its utility in characterizing specific tumor subtypes and predicting clinical behavior has been poorly understood. A subset of patients exhibits a paradoxical increase in GH secretion following CRH administration, suggesting a unique underlying tumor biology. Understanding the characteristics of these CRH responders is crucial for refining diagnostic approaches and potentially guiding more targeted therapeutic strategies beyond standard somatostatin receptor ligands.

This retrospective study compared 22 CRH responders with 43 nonresponders among patients with acromegaly. Researchers analyzed clinical features, tumor characteristics (size, visual field impairment), and baseline hormone levels (GH, IGF-1). Tumor volume and diameter were correlated with the GH increase ratio during the CRH test. Immunohistochemical analyses were performed on adenoma samples to assess expression of corticotropin-releasing hormone receptor 1 (CRHR1), CRHR2, T-box transcription factor (TPIT), and adrenocorticotropic hormone (ACTH). Additionally, GH responses to CRH were correlated with responses to luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, oral glucose tolerance testing, and somatostatin receptor subtype 2 expression.

CRH responders exhibited significantly larger tumors and more frequent visual field impairment compared to nonresponders, despite comparable baseline GH and IGF-1 levels and disease duration. Tumor volume and diameter were positively correlated with the GH increase ratio in the CRH test. Conversely, GH and IGF-1 levels per tumor volume or diameter were significantly lower in CRH responders, indicating a reduced GH secretory capacity relative to tumor size. Immunohistochemical analyses revealed higher CRHR1 and lower CRHR2 expression in adenomas from CRH responders. Furthermore, TPIT and ACTH expression were significantly more frequent in adenomas from CRH responders, suggesting a distinct corticotroph-like phenotype. GH responses to CRH were significantly correlated with those to luteinizing hormone-releasing hormone, but not with thyrotropin-releasing hormone or oral glucose tolerance testing.

GH responsiveness to CRH identifies a biologically distinct subset of somatotroph adenomas characterized by corticotroph-like features, larger tumor size, and reduced GH secretory capacity. GH responses to CRH tended to be inversely correlated with somatostatin receptor subtype 2 expression, which is a predictor of first-generation somatostatin receptor ligand efficacy, but showed no correlation with octreotide response or MRI signal intensity.