Acromegaly pathogenesis and treatment
Shlomo Melmed
Shlomo Melmed
Published November 2, 2009
Citation Information: J Clin Invest. 2009;119(11):3189-3202. https://doi.org/10.1172/JCI39375.
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Science in Medicine

Acromegaly pathogenesis and treatment

Abstract

Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly — a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.

Authors

Shlomo Melmed

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Figure 4

Depiction of intracellular pathways associated with somatotroph transformation and proliferation.

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Depiction of intracellular pathways associated with somatotroph transfor...
GH transcription and somatotroph proliferation are induced by cAMP acting through CREB (26). SRIF inhibits cAMP and CREB activity (S43) to suppress GH secretion. Pituitary CDKs likely exhibit overlapping functions in G1 cell-cycle progression. Somatotroph mitogenic factors include POU1F1, GHRH, and GNAS as well as endocrine hormones. Mitogenic constraints include SRIF and tumor suppressor genes, including MEN1. Cell-cycle progression through G/S is mediated by CDKs that phosphorylate Rb to release E2F proteins that drive DNA synthesis. In somatotroph tumors, the cAMP pathway may be constitutively activated. Furthermore, HMGA2 and PTTG, overexpression, and CDK inhibitor loss have been shown to result in experimental pituitary tumorigenesis. Chromosomal instability, DNA damage, and senescence, hallmarks of GH-secreting adenomas, may act to constrain malignant transformation of somatotroph tumors. Modified with permission from the Journal of molecular endocrinology (ref. S44, S45; copyrighted by the Society for Endocrinology).