Growth Hormone Notes 2024 PDF

Physiology- Growth Hormone Page 1 of 9 Dr. Todd Leff Growth Hormone Session Learning Objectives: 1. Describe the hormonal signals from the hypothalamus that regulate GH secre- tion, and the cellular signal...

Physiology- Growth Hormone Page 1 of 9 Dr. Todd Leff Growth Hormone Session Learning Objectives: 1. Describe the hormonal signals from the hypothalamus that regulate GH secre- tion, and the cellular signaling pathways they activate in pituitary somatotrophs. 2. Describe the regulatory feedback loops that govern GH secretion. 3. List the physiological conditions that modulate (stimulate or suppress) GH pro- duction. 4. Describe the specific differences between the acute metabolic effects of GH and its more long-term growth-promoting effects. 5. Describe the receptor and signaling pathways that are activated by GH in its tar- get tissues. 6. Describe the IGF1 receptor and cellular signaling pathway, and their relationship to insulin signaling. 7. Describe the causes and outcomes of abnormal elevation or suppression of GH production or GH action. Session Outline: 1. Growth hormone synthesis 2. Growth hormone action 3. Regulation of the growth hormone – IGF1 axis 4. Pathologies associated with GH action Physiology- Growth Hormone Page 2 of 9 Dr. Todd Leff The primary hormones that affect linear body growth during childhood and orches- trate the coordinated growth of all the organ systems are growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Growth Hormone (GH) synthesis Pre-mRNA 5´ 3´ Somatotroph cells of the pituitary synthesize and secrete GH. The growth Intron Exon hormone gene is transcribed in to two splice variant mRNAs that produce ei- ther a 22.5-kDa protein (191 amino ac- ids) or a 20-kDa protein (176 amino ac- ids). The somatotroph stores mature pre–22.5-kDa pre–20-kDa growth hormone growth hormone GH in granules until the hypothalamic mRNA mRNA hormone GHRH (growth hormone re- Nucleus leasing hormone) stimulates the somato- troph to secrete GH. The 22-kDa version is the dominant form of GH. pre-pro- pre-pro- Rough ER hormone hormone The growth hormone gene family GH is a member of a family of biolog- ically related proteins; the somatotro- Golgi pin/prolactin family of hormones. These pro- pro- hormone hormone include GH itself, the placental lacto- gens, also known as placental chorionic somatomammotropins (yellow shaded 20-kDa growth 22-kDa growth Secretory rows in table), and prolactin. With the hormone (191 granules hormone (176 amino acids). amino acids). exception of prolactin, these genes are expressed from the same locus on Secreted chromosome 17. hormones Figure 48-1 Synthesis of GH. Somatotrophic cells in the anterior pituitary are responsible for the synthesis of GH. The cell transcribes five exons to form Hormone Number ofGH messenger Amino Acids RNA Homology (mRNA) for eitherChromosome the 22-kDa protein (191 amino acids) or the 20-kDa protein (176 amino acids). Alternative splicing in the third exon, Human GH (hGH1, hGH, hGH-N) which removes the RNA-encoding amino acids 32 to 46, is responsible for 191 100% 17 the two isoforms found in the pituitary. Both mRNAs have a signal sequence pvGH (hGH2, hCS-L) that causes them to be translated 191 93% in the rough17 endoplasmic reticulum (ER) and enter the secretory pathway. Subsequent processing converts the two Human CS1 (hCS1, or hCS-A) pre–pro-GHs first to the pro-GHs 191 84% and then to 17 the mature GHs. The cleavage of the pro-sequence and disulfide bond formation occur during transit through Human CS2 (hCS2, or hCS-B) the Golgi bodies. The somatotroph 191 84% stores mature 17 GH in granules until GHRH stimulates the somatotroph to secrete the hormones. The 22-kDa version is Human PRL (hPRL) 199 the dominant form of GH.16% 6 Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved.  Physiology- Growth Hormone Page 3 of 9 Dr. Todd Leff Hypothalamic regulation of GH secretion The secretion of growth hormone is primarily under the control of two hypothalamic hormones: GHRH, which stimulates GH release from the pituitary, and somatostatin, which suppresses its release. GHRH, produced in the arcuate nucleus of the hypothal- amus, is a potent agonist of GH secretion. Somatostatin is a 14-amino acid peptide produced in the periventricular 1 Neurosecretory cells in the region of the hypothalamus. arcuate nucleus secrete growth GHRH stimulates GH re- hormone–releasing hormone (GHRH), a 43–amino acid lease and synthesis via a spe- peptide that reaches the somato- cific GPCR and the cAMP/PKA 2 trophs via the hypophyseal signaling pathway. Somatosta- Cells in the periventricular portal blood supply. 1 tin activates a different GPCR region release somatostatin, Neurosecretory cells in the a hormone that is a potent arcuatePeriventricular nucleus secrete growth Arcuate on somatotrophs that is linked region inhibitor of growth hormonehormone–releasing hormone nucleus to an inhibitory G-protein that (GH) secretion, into the (GHRH), a 43–amino acid peptide that reaches the somato- reduces the activity of adenyl- portal blood supply. 2 trophs via the hypophyseal ate cyclase and inhibits the Cells in the periventricular portal blood supply. region release somatostatin, same PKA signaling pathway, a hormone that is a potent Periventricular Arcuate counteracting the effects of inhibitor of growth hormone region nucleus (GH) secretion, into the GHRH on GH secretion (inset portal blood supply. Hypothalamus in figure). Released Released GHRH somatostatin Hypothalamus GHRH GHRH Anterior lobe receptor Released of pituitary Released GHRH Somatotroph SS somatostatin receptor γ α β AC SS GH GHRH GHRH Anterior lobe receptor (Stimulating) of pituitary Somatotroph SS G-protein receptor α γ α AC cAMPSS β Somatotrophs β γ GH (Stimulating) G-protein (Inhibitory) α G-protein Ca2+ Somatotrophs cAMP β γ (Inhibitory) PKA 2+ G-protein Ca Ca2+ 3 PKA GHRH causes somatotrophs to 2+ Ca synthesize and release GH. 3 GHRH causes somatotrophs 4 to synthesize Somatostatin inhibits the and release release GH. by somatotrophs. of GH 4 Figure 48-3 inhibits Somatostatin Synthesis and of the release release of GHRH and SS and the control of GH release. Small-bodied GH by somatotrophs. neurons in the arcuate nucleus of the hypothalamus secrete GHRH, a 43–amino acid peptide that Figure reaches48-3 theSynthesis and release somatotrophs of anterior in the GHRH and SS andthrough pituitary the control theoflong GH release. Small-bodied portal veins. GHRH stimulates neurons in the arcuate nucleus of the hypothalamus secrete GHRH, a 43–amino acid peptide that 2+ the somatotrophs to release GH stored in secretory granules by raising [cAMP]i and [Ca ]i. reaches the somatotrophs in the anterior pituitary through the long portal veins. GHRH stimulates Neurons in the periventricular the somatotrophs region to release GH stored of the hypothalamus in secretory synthesize granules by raising [cAMP]iSS, and a[Ca 14–amino 2+ ]i. acid neuropeptide. SS, which also travels to the anterior pituitary through the long portal vessels, is a Physiology- Growth Hormone Page 4 of 9 Dr. Todd Leff Factors that affect growth hormone secretion Growth hormone is released from the pituitary in a highly pulsatile fashion, with spikes of secretion throughout the day. However, the overall pattern of secretion follows a diurnal pattern with elevated secretion at night, particularly about 1 hour after the on- set of sleep, which is typically the period of slow wave deep sleep, or stage 3 Non-REM sleep. Multiple additional physiological factors and conditions affect GH secretion (Ta- ble). The resting plasma concentration of GH is ~ 1 ng/ml but can rise to rapidly to 50- 100 ng/ml. GH has a half-life of 20-25 minutes. The amplitude of the GH releases pulses is reduced by aging. Factors that suppress GH secretion Growth hormone IGF1, by direct action on somatotrophs & by feedback via the hypothalamus Hyperglycemia Cortisol Xenobiotics, e.g. certain endocrine disruptors Factors that stimulate GH secretion Energy deficiency: hypoglycemia, vigorous exercise, fasting Certain Amino Acids: ingestion of a protein rich meal, infusion of arginine Hormones: sex steroids, glucagon Deep Sleep (later stages of non-REM sleep) Physiology- Growth Hormone Page 5 of 9 Dr. Todd Leff GH Action GH itself does not have growth-promoting activity Curiously, GH itself does not possess independent growth-promoting activity. This is most clearly seen in an in vitro bioassay for growth-promotion (using cultured cells). In this assay, purified GH does not promote cell division or growth when added directly to cells. This finding suggests that GH must stimulate the activity or amount of another hormone that carries out its growth-promoting effects. We now know that this second- ary downstream hormone is insulin-like growth factor 1 or IGF1. Direct cellular actions of GH GH acts directly on its target cells by binding to and activating a Gp130 receptor, the GH receptor, or GHR. Binding of GH to GHR initiates a JAK/STAT based intracellular signaling cascade, that leads to the activation the STAT family of transcription factors. Once activated, these proteins induce transcription of a specific set of genes (GH target genes), including IGF1. In the liver, one of the primary GH target organs, GH action leads to the production of release into circulation of IGF1. Physiology- Growth Hormone Page 6 of 9 Dr. Todd Leff Growth Promoting vs. Metabolic Effects of GH In addition to stimulating the production of IGF1, GH has a wide variety of acute ef- fects in many tissues that affect aspects of energy metabolism and the distribution and use of nutrient stores. These acute effects of GH shift metabolic balance toward a more diabetic state, and in pathological circumstances of chronic GH excess can actually promote diabetes. The IGFs IGF1 and IGF2 are very similar peptide hormones. IGF-2 has a less well understood physiological role but may be important for fetal and neonatal growth. Both IGFl and IGF2 have insulin-like activities, and thier primary sequences reveal significant structur- al similarities to insulin. In response to growth hormone, IGF-l is produced by the liver, and carries out essentially all the growth promoting effects assigned to GH. While the liver is the major site of IGF1 production, many peripheral tissues as well as the central nervous system can locally synthesize the hormone, which acts in an autocrine or para- crine fashion to alter local physiology and metabolism. Physiology- Growth Hormone Page 7 of 9 Dr. Todd Leff The majority of IGFs in circulation Extracellular are bound to carrier proteins, space IGF-1 RECEPTOR IGFBPs. IGFBPs prolong the biolog- IGF-2 ical half-life of the hormones and N N MANNOSE- blunt their biological effects by slowly INSULIN PHOSPHAT RECEPTOR RECEPTOR releasing small amounts of free hor- α mone. N N N S S S S IGF1 signaling S S Most the cellular actions of IGFs α are mediated by the IGF1 receptor S S S S (there is also an IGF2 (mannose-6- S S phosphate) receptor, but its biological function in not well understood). The IGF1 receptor has a similar structure to the insulin receptor, and given this it is not surprising that IGFs are ca- pable of binding to the insulin recep- β β C tor, although with a significantly lower affinity that insulin. The IGF1 recep- tor binds IGF1 with high affinity and C C C C lGF-2 and insulin with somewhat Tyrosine Tyrosine kinase kinase lower affinity. The IGF1 signaling domains domains cascade that is similar to that in- Cytosol duced by binding of insulin to its re- Figure 48-6 Comparison of insulin, IGF-1, and IGF-2 receptors. Both the insulin a ceptor. IGF-1 receptors are heterotetramers joined by disulfide bonds. For both, the cytop portions of the β subunits have tyrosine kinase domains as well as autophosphory IGF1 levels and growth sites. 1000 The IGF-2 receptor (also called M6P receptor) is a20single polypeptide chain IGF1 levels are low at birth, kinase domain. Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserv rise during childhood, peaking at 800 The pubertal peak rate of 16 growth corresponds to the peak puberty, and then falling gradu- serum concentrations of IGF-1. ally during adulthood. The [IGF-1] 600 Plasma 12 Rate of graph shows serum IGF-1 levels (µg/liter) height increase and height velocity (growth rate) 400 IGF-1 in serum 8 (cm/yr) as a function of age. The red curve is the mean plasma con- 200 4 centrations of IGF-1 in girls, Rate of height increase while the brown curve shows the 0 0 10 12 20 30 40 0 rate at which height increases Age Figure 48-7 Serum IGF-1 levels and height velocity as a function of age. The red curve (cm/yr). The biological function shows the mean plasma concentrations of IGF-1 as a function of age in female humans. of IGF2 is less clear than for IGF1,The butcurve appears to play for male humans a major is similar, roleis shifted but the peak in growth promotion to an older age by 3 to 4 years. The brown curve indicates mean female height velocity—the rate at which height during gestation. increases (cm/yr). The pubertal peak rate of growth corresponds to the peak serum concentrations of IGF-1. (Data from Reiter EO, Rosenfeld RG: Normal and aberrant growth. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR [eds]: Williams Textbook of Endocrinology, 9th ed, pp 1427-1507. Philadelphia: WB Saunders, 1998.) Physiology- Growth Hormone Page 8 of 9 Dr. Todd Leff Regulation of the GH-IGF1 axis The GH, IGF1 pathway is regulated by multiple negative feedback loops. Both GH and IGF1 feed-back on the somatotrophs in the anterior pituitary to decrease GH secre- tion (2 & 5 in the figure). In addition, IGF1 inhibits GH release by two additional indirect routes. The first indirect pathway is for IGF1 to suppress GHRH release in the hypo- thalamus (3). The second is for IGF-1 to increase secretion of somatostatin, which in turn inhibits GH production from the somatotroph (4). Physiology- Growth Hormone Page 9 of 9 Dr. Todd Leff Pathologies associated with GH action GH excess Hyper-secretion of GH during childhood leads to excessive linear body growth – gi- gantism (Left panes). The most common cause of elevated growth hormone release is a benign pituitary adenoma. If this occurs after the post-puberty closure of the epiphys- eal plates (when linear growth of long bones is no longer possible) the outcome is ac- romegaly, in which the bones become deformed rather than elongated (Right panels). Acromegaly is characterized by a coarsening of facial features including an increased size of the mandible, which can cause the jaw to protrude (prognathism). Cartilage in the larynx may thicken, making the voice deep and husky. Both conditions can be accompanied by insulin resistance and type 2 diabetes Deficiency of GH or GH action Inappropriately low growth hormone production or defects in any of the downstream signaling components of the GH-IGF1 pathway cause dwarfism. Dwarfism caused by growth hormone deficiency accounts for roughly 1/4 to 1/3 of all cases of dwarfism and is characterized by short stature with proportional body parts. An example of dwarfism caused by a genetic defect in GH signaling is Laron syndrome. This syndrome is cate- gorized as a Growth Hormone Insensitivity Syndrome (GHIS) and is caused by inacti- vating mutations in the GH receptor.