Growth Hormone Resistance—Special Focus on Inflammatory Bowel Disease

Abstract

Growth hormone (GH) plays major anabolic and catabolic roles in the body and is important for regulating several aspects of growth. During an inflammatory process, cells may develop a state of GH resistance during which their response to GH stimulation is limited. In this review, we will emphasize specific mechanisms governing the formation of GH resistance in the active phase of inflammatory bowel disease. The specific molecular effects mediated through individual inflammatory mediators and processes will be highlighted to provide an overview of the transcriptional, translational and post-translational inflammation-mediated impacts on the GH receptor (GHR) along with the impacts on GH-induced intracellular signaling. We also will review GH’s effects on mucosal healing and immune cells in the context of experimental colitis, human inflammatory bowel disease and in patients with short bowel syndrome.

Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis

“…We evaluated the direct effects of inflammation on both GHR expression and its function by assaying downstream STAT5 phosphorylation. Based on prior publications, we decided to evaluate the effects of TNF-α and IL-1β collectively and IL-6 separately, as these mediators impact GHR expression and signalling through separate mechanisms [ 15 ].…”

“…Mechanistically, GH responsiveness and the GH–IGF-1-axis are subject to regulation, both in terms of negative feedback on GH and IGF-1 secretion, but also in terms of GH receptor (GHR) and IGF-1 receptor (IGF1R) signalling. During inflammation, mediators may impact the GHR in two distinct ways to induce GH resistance [ 15 ]. First, in vitro studies have shown that the mediators tumor necrosis factor (TNF)-α and interleukin (IL)-1β both impair liver GHR expression, causing blunting of the GH response, an effect which is potentiated when the mediators are used in combination [ 16 , 17 , 18 , 19 ].…”

The pre-treatment characteristics and evaluation of the effects of recombinant human growth hormone therapy in children with growth hormone deficiency and celiac disease or inflammatory bowel disease

“…Pathogenesis of growth retardation in children with CD and IBD is multifactorial [ 2 - 4 , 6 , 8 - 11 , 19 , 22 , 34 - 36 ]. Generalised or selective malnutrition, resulting from reduced food intake, protein malabsorption, increased intestinal protein loss, increased energy expenditure, and chronic inflammation, is considered to be the main cause of short stature [ 2 - 4 , 6 , 8 , 9 , 22 ]. Chronic inflammation itself could also lead to growth retardation independently of malnutrition [ 2 - 4 , 34 - 36 ].…”

“…The pathogenesis of growth retardation associated with CD and IBD is mainly related to generalised or selective malnutrition resulting from systemic inflammation and a local impact of the affected epithelium on absorption, and to the inflammatory process itself [ 2 , 3 , 6 , 9 , 11 , 19 , 20 ]. Increased levels of proinflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) lead to changes in secretion and sensitivity of the GH/IGF-1 system, causing partial GH resistance, inhibition of growth hormone receptor (GHR) expression and action, and a decrease in IGF-1 irrespective of GH levels [ 2 - 5 , 7 - 9 , 11 , 20 - 23 ].…”

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks

“…The extracellular domain attaches to the circulating GH and corresponds to the circulating GH binding protein [ 89 ]. Activation of the receptor is induced through the interaction of GH to a preformed GHR dimer, leading to a conformational change in the intracellular domain that results in the phosphorylation and activation of STAT5 through Janus Kinase 2 [ 90 , 91 , 92 ].…”