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 2

Normal and disrupted GHRH–GH–IGF1 axis and molecular targets for therapy.

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Normal and disrupted GHRH–GH–IGF1 axis and molecular targets for therapy...
Pituitary somatotroph cell development and gene expression are determined by the POU1F1 transcription factor. Net GH secretion is determined by integration of hypothalamic, nutritional, hormonal, and intrapituitary signals. GH synthesis and secretion are induced by hypothalamic GHRH and gut-derived ghrelin. GHRH may also act as a coagonist for the ghrelin receptor (28). Hypothalamic SRIF suppresses GH secretion mainly by high-affinity binding to SSTR2 and SSTR5 receptor subtypes expressed on somatotrophs (90). SSTR ligands (SRLs) signal through SSTR2 and SSTR5 to control GH hypersecretion and shrink tumor mass. GH secretion patterns in a normal subject and in acromegaly are depicted in the insets showing secretory bursts (mainly at night) and daytime troughs. Insets modified with permission from Expert opinion on biological therapy (S41).