Work

Pathogenesis of nonfamilial somatotroph adenomas

Year: 2026

Type: article

Abstract: CONTEXT: Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes. EVIDENCE ACQUISITION: We searched PubMed for relevant English-language original research and review articles on signaling pathways and molecular drivers implicated in the pathogenesis of nonfamilial somatotroph adenomas in patients with acromegaly. EVIDENCE SYNTHESIS: Somatotroph cells express cognate G protein-coupled receptors for both hypothalamic stimulatory GH-releasing hormone (GHRH) and inhibitory somatostatin. Somatotroph GH transcription and secretion, as well as somatotroph cell lineage development, proliferation, and differentiation, are mediated by GHRH signaling through its cognate receptor (growth hormone-releasing hormone receptor [GHRHR]), driving increased intracellular cyclic adenosine monophosphate (cAMP) levels. Point mutations in GNAS and other genomic and nongenomic aberrations in the tightly regulated GHRH-GHRHR signaling pathway result in persistent cAMP signaling, inducing GH production and somatotroph proliferation, and potentially favoring the development of sporadic somatotroph adenomas. Enhanced cAMP signaling also increases DNA damage markers and activates DNA damage response pathways, leading to a senescent adenomatous phenotype tightly linked to GH overproduction. CONCLUSION: The cAMP pathway appears to be a dominant molecular driver of somatotroph adenoma pathogenesis. Elevated cAMP drives GH hypersecretion and somatotroph proliferation and also induces DNA damage, as evidenced by increased genomic instability and a senescent signature. Collectively, these findings elucidate a molecular framework for the biological behavior of these adenomas and their responsiveness to therapies targeting cAMP-dependent pathways, including somatostatin receptor ligands.

Source: The Journal of Clinical Endocrinology & Metabolism

DOI: 10.1210/clinem/dgag116

Authors: Anat Ben-Shlomo, Shlomo Melmed

Institution: Cedars-Sinai Medical Center

Language: English

Topic: Pituitary Gland Disorders and Treatments

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,750