The direct endocrine actions of growth hormone (GH) include the stimulation of IGF-I, IGFBP-3, and ALS production in the liver, as well as the exertion of paracrine effects in bone through the local production of IGF-I. The relationship between GH and IGF-I involves GH acting through the GH receptor (GHR), which triggers the activation of the JAK/STAT signaling pathway. This leads to the phosphorylation of STAT5b, which then stimulates the transcription of GH-responsive genes. GH also activates other signaling pathways such as MAPK and PI3K. In the fed state, GH functions as a protein anabolic hormone, promoting cellular amino acid uptake and incorporation into protein, resulting in nitrogen retention and decreased urea production. The decline in GH secretion during aging has been proposed as a potential cause of muscle wasting. In children, GH is crucial for skeletal, muscular, and visceral growth, and its deficiency can lead to growth stunting or dwarfism. GH also plays a role in promoting cartilage growth and the linear and appositional growth of long bones. The production of IGF-I in response to GH stimulation requires insulin, which supports GH receptor expression and signaling in hepatocytes. When a balanced supply of nutrients is available, high serum glucose levels stimulate insulin secretion, while high serum amino acid levels promote GH secretion. These conditions are optimal for growth, and GH, in turn, stimulates liver production of IGF-I. IGFs have mitogenic and anabolic effects on various organs and tissues, including muscle, cartilage, and bone. GH and IGF-I work together to promote chondrocyte proliferation, differentiation, and hypertrophy during endochondral ossification. After the closure of the epiphyses, longitudinal growth ceases, but appositional growth of long bones continues. IGF-I stimulates osteoblast replication and the synthesis of collagen and bone matrix. Serum levels of IGF correlate well with growth in children. The role of GH changes with alterations in nutritional status. If the diet is high in calories but low in amino acids, for example, high carbohydrate availability promotes insulin secretion, but low serum amino acid levels inhibit GH and IGF production, creating conditions unfavorable for growth. Conversely, in the fasted state, when nutrient availability decreases, serum GH levels rise, and serum insulin levels fall in response to hypoglycemia.
•Fig. 41.19 RelationshipofGHandIGF-I.GHhasdirectendocrineactionsongrowthandstimulatestheproductionofIGF-I,IGFBP-3andALSintheliver.CirculatingIGF-Iexertsendocrineactionsontargetorgans.IGF-1isalsoproducedlocallyinbone,whereitexertsparacrineeffects.Part,butnotallofthislocalIGF-IproductionisGH-dependent.
GH acts through a specific GH receptor (GHR) that is a member of the cytokine receptor family. A GHR dimer binds to GH, which triggers activation of the JAK/STAT signaling pathway (see
Fig. 41.17 ). This results in phosphorylation of STAT5b, which translocates to the nucleus to stimulate transcription of GH-responsive genes. Additional signaling pathways activated by GH include MAPK and PI3K among others.
In the fed state, GH is a protein anabolic hormone that increases cellular amino acid uptake and incorporation into protein. Consequently it produces nitrogen retention (positive nitrogen balance) and decreases urea production. The muscle wasting that occurs concomitant with aging has been proposed to be caused at least in part by the decrease in GH secretion that occurs during senescence. In children, GH increases skeletal, muscular, and visceral growth; children without GH show growth stunting or dwarfism. GH promotes cartilage growth and both linear and appositional growth of long bones (
Fig. 41.20 , green arrowheads).
Although GH is an effective stimulator of IGF production, this response requires insulin, which supports GH receptor expression and signaling in hepatocytes. When a balanced supply of nutrients is available, high serum glucose levels stimulate insulin secretion and high serum amino acid levels promote GH secretion (
Fig. 41.21, top ). These conditions are appropriate for growth, and GH in turn stimulates IGF-I production by the liver. IGFs are mitogenic and have profound anabolic effects on many organs and tissues, including muscle, cartilage, and bone. Together, GH and IGF-I promote chondrocyte proliferation, differentiation, and hypertrophy during the process of endochondral ossification (see
Fig. 41.20, green arrowheads). After closure of the epiphyses, longitudinal growth ceases but appositional growth of long bones continues. IGF-I stimulates osteoblast replication and synthesis of collagen and bone matrix. Not surprisingly, serum IGF levels correlate well with growth in children. The role of GH changes with alteration of nutritional status. If the diet is high in calories but low in amino acids, for example, high carbohydrate availability promotes insulin secretion but low serum amino acid levels inhibit GH and IGF production (see
Fig. 41.21, middle). These responses allow dietary carbohydrates and fats to be stored, but conditions are unfavorable for growth.
In the fasted state, on the other hand, when nutrient availability wanes, serum GH levels rise and serum insulin levels fall in response to hypoglycemia (see