Physiology, Growth Hormone

Cellular Level

Human growth hormone is produced via the anterior pituitary of the brain in the acidophilic, somatotrophic cells. Its production is tightly regulated through several complex feedback mechanisms in response to stress, exercise, nutrition, sleep, and growth hormone itself. The primary regulation factors are growth hormone-releasing hormone (GHRH) produced in the hypothalamus, somatostatin, produced in various tissues throughout the body, and ghrelin, which is produced in the gastrointestinal tract. GHRH functions to promote HGH production and release. Somatostatin inhibits the release of GHRH as well as the HGH release response to GHRH stimulus and increases in hypoglycemia. Ghrelin is a hormone produced by the stomach as part of the hunger response. Functionally, the ghrelin response is protective against hypoglycemia. When elevated, ghrelin binds to somatotrophs to stimulate HGH secretion. Insulin-like growth factor-1 also acts to inhibit HGH by both directly inhibiting somatotrophic HGH release and indirectly through synergistically increasing the release of somatostatin. Additionally, HGH will negatively feedback into the hypothalamus, thus decreasing GHRH production. The net effect of this regulatory mechanism produces a pulsatile release of HGH into circulation that varies hourly. In general, HGH levels will be increased in childhood, spike to their highest levels during puberty, and subsequently decrease with increased age.[3][4][5]

Function

HGH has two mechanisms of effect: direct action and indirect action. The direct effects of HGH on the body are through its action on binding to target cells to stimulate a response. The indirect effects occur primarily by the action of insulin-like growth factor-1, which hepatocytes primarily secrete in response to elevated HGH binding to surface receptors. Once activated, the Janus activating tyrosine kinases (JAKs) 1 and 2 will bind to the latent cytoplasmic transcriptions factors STAT1, STAT3, and STAT5, and be transported into the nucleus inducing increased gene transcription and metabolism to produce insulin-like growth factor-1 for release into the circulation. Insulin-like growth factor-1 then has an impact on the growth and metabolism of peripheral tissues. One can think of the effects of HGH as a combined effect of both HGH and insulin-like growth factor-1.

Growth

HGH induces growth in nearly every tissue and organ in the body. However, it is most notorious for its growth-promoting effect on cartilage and bone, especially in the adolescent years. Chondrocytes and osteoblasts receive signals to increase replication and thus allow for growth in size via HGH’s activation of the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal-regulated kinases) 1 and 2 cellular signaling pathways. Activation of this phosphorylation intracellular signaling cascade results in a cascade of protein activation, which leads to increased gene transcription of the affected cells and ultimately causes increased gene replication and cellular growth.

Insulin-like growth factor-1 binds to its receptor, IGF-1R, on the cellular surface and activates a tyrosine kinase-mediated intracellular signaling pathway that phosphorylates various proteins intracellularly leading to increased metabolism, anabolism, and cellular replication and division. Furthermore, it acts to inhibit apoptosis of the cell, thus prolonging the lifespan of existing cells. The net result is to encourage the growth of tissue and to create a hyperglycemic environment in the body.

Metabolic Effects

HGH impacts metabolism primarily by up-regulating the production of insulin-like growth factor-1 and its subsequent effect on peripheral cells. The intracellular signaling activation that occurs, as stated above, also has a significant impact on the basal metabolic functions of organ tissues. In general, cells enter an anabolic protein state with increased amino acid uptake, protein synthesis, and decreased catabolism of proteins. Fats are processed and consumed by stimulating triglyceride breakdown and oxidation in adipocytes. Additionally, HGH suppresses the ability of insulin to stimulate the uptake of glucose in peripheral tissues and causes an increased rate of gluconeogenesis in the liver, leading to an overall hyperglycemic state.[6][7][8]

Related Testing

Due to the pulsatile nature of HGH levels found in the blood, conventional measurements of serum HGH are almost useless because the values may vary from undetectable to extremely high depending on environmental stressors and conditions. If a clinician suspects HGH deficiency, it is best to evaluate insulin-like growth factor I and insulin-like growth factor binding protein-3 levels and to perform HGH stimulation tests.

In an HGH stimulation test, the patient fasts overnight, and a pharmacological challenge is added in the morning with either L-dopa, clonidine, propranolol, glucagon, arginine, or insulin-induced hypoglycemia. HGH serum levels are then evaluated hourly for a response to increased hormone levels. Failure of this test to increase HGH levels, therefore, indicates HGH deficiency.[9][10]

Clinical Significance

HGH is extremely important for modulating growth during adolescence. Therefore, the major aberrations in the regulation of HGH may result in growth defects. HGH hypersecretion results in gigantism or acromegaly, whereas HGH deficiency will result in a growth deficit in children and the GH deficiency syndrome in adults.

Acromegaly

Acromegaly typically results from an HGH secreting pituitary adenoma with an onset after the closure of the epiphyseal growth plates, typically in adulthood. Therefore, bone growth primarily affects flat bones such as the skull, mandible, sternum, hands, and feet. Often the presenting complaint is of hats or gloves not fitting anymore due to swelling of the hands and head. Because the illness is due to a pituitary mass, hypopituitarism may also develop with secondary reproductive disorders and visual symptoms. In addition to bony growth, there is the growth of myocardium resulting in biventricular concentric hypertrophy and subsequent heart failure in later disease. Because HGH counteracts the effects of insulin on glucose and lipid metabolism, diabetes mellitus type 2 and hyperlipidemia are strongly associated with this disease. Treatment consists of surgery and radiation therapy targeting the underlying adenoma as well as symptomatic relief of the secondary effects of HGH as above.

Gigantism

This illness is very similar to acromegaly in all aspects, except the underlying pituitary adenoma develops before the closure of long bone epiphysis. Therefore, bone growth occurs in long bones such as the tibia, fibula, femur, humerus, radius, and ulna. Since epiphyseal closure occurs before adulthood, this is typically an illness with an onset seen in children. The organ and metabolic impacts are similar to acromegaly.

HGH Deficiency

In children, idiopathic HGH deficiency is the most common. In adult-onset, HGH deficiency typically presents as a constellation of hypopituitary deficiencies. The triggering incident is typically a pituitary adenoma, most likely a prolactinoma. However, other treatments, such as radiation therapy or surgery, might be the cause. Childhood-onset is associated with decreased growth of all skeletal structures, leading to dwarfism. Adult-onset HGH deficiency is less easily diagnosed as it has no single identifying feature that is pathognomonic. Typically adults have decreased skeletal muscle and increased fat mass in visceral tissue as well as decreased bone density and remodeling, which leads to osteoporosis. Dyslipidemia and insulin resistance are prevalent, which lead to secondary cardiovascular dysfunction, depressed mood, increased anxiety, and a lack of energy.[11][12][13]