Growth hormone

Overview
Growth hormone (GH) or somatotropin (STH) refers to a protein hormone produced by the acidophil cells, that promotes the inhibition of glucose utilization, body growth, and fat mobilization. Growth hormone is secreted by the anterior pituitary under stimulation from Growth hormone-releasing hormone (GHRH) and with feedback by Somatostatin, Ghrelin and IGF-I (insulin-like growth factor-I) it acts on adipose cell receptors directly to affect lipid metabolism but mainly acts by stimulating IGF-I secretion from tissues such as the liver. Growth hormone receptor is expressed most in the liver and cartilage. It is likely this mitigates growth hormone deficiency, either because of disease in the hypothalamus-pituitary axis or due to mutants of the hormone or GHRH that render it dysfunctional.

Terminology

 * See articles on GH treatment for more complete discussions of GH therapy and the HGH issue.

Growth hormone (GH) is also called "somatotropin" (British): "somatotrophin").

"hGH" refers to human growth hormone and is an abbreviation for human GH secreted by, or measured in extracts from, human pituitary glands.

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. Biosynthetic human growth hormone, also referred to as recombinant human growth hormone, is also called "somatropin" and abbreviated as "rhGH".

Since the mid-1980s the abbreviation HGH has begun to carry paradoxical connotations, and now rarely refers to real GH used for indicated purposes.

History
The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. The history of GH use, from extraction of GH from human pituitary glands to the limited catastrophe of Creutzfeldt-Jakob Disease to the expanded use and enormous costs of synthetic GH is outlined in the article on GH treatment.

As of 2005, synthetic growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices. In 2005 an Israeli company, Teva, offered Tev-Tropin in the U.S. at a lower price. In 2006, the U.S. Food and Drug Association (FDA) approved a follow-on version of rhGH called Onmitrope (Sandoz). A sustained-release form of growth hormone, Nutropin Depot (Genentech and Alkermes) was approved by the FDA in 1999, allowing for fewer injections (every 2 or 4 weeks instead of daily); the product was discontinued in 2004.

Structure and gene of the human GH molecule
The genes for human growth hormone are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (hCS, also known as placental lactogen) genes. GH, human chorionic somatomammotropin (hCS), and prolactin (PRL) are a group of homologous hormones with growth-promoting and lactogenic activity.

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of about 22,000 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. GH is structurally and apparently evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and primate growth hormones have significant effects in humans.

Secretion of GH
Several molecular forms of GH circulate. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.

GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency.

Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.

Stimulators of GH secretion include:
 * growth hormone releasing hormone (GHRH) from the arcuate nucleus
 * ghrelin
 * sleep
 * exercise
 * low levels of blood sugar (hypoglycemia)
 * dietary protein
 * estradiol
 * arginine

Inhibitors of GH secretion include:


 * somatostatin from the periventricular nucleus
 * circulating concentrations of GH and IGF-1 (negative feedback)
 * dietary carbohydrate
 * glucocorticoids

In addition to control by endogenous processes, a number of foreign compounds (xenobiotics) are now known to influence GH secretion and function, highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals ( see endocrine disruptor).

Secretion patterns
Most of the physiologically important secretion occurs as several large pulses or peaks of GH release each day. The plasma concentration of GH during these peaks may range from 5 to 35 ng/mL or more. Peaks typically last from 10 to 30 minutes before returning to basal levels. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Between the peaks, basal GH levels are low, usually less than 3 ng/mL for most of the day and night.

The amount and pattern of GH secretion change throughout life. Basal levels are highest in early childhood. The amplitude and frequency of peaks is greatest during the pubertal growth spurt. Healthy children and adolescents average about 8 peaks per 24 hours. Adults average about 5 peaks. Basal levels and the frequency and amplitude of peaks decline throughout adult life.

Decreased

 * Central nervous system (CNS) radiation
 * CNS surgery
 * Craniopharyngioma
 * Empty Sella Syndrome
 * Genetic
 * Idiopathic
 * Septo-optic dysplasia

Increased

 * Benign pituitary tumor
 * Dysregulation of hypothalamic-pituitary-GH axis
 * Ectopic source
 * Intracranial source

Functions of GH
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones GH acts by interacting with a specific receptor on the surface of cells.

Increasing height
Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms.


 * 1) GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children's long bones (arms, legs, digits).
 * 2) GH also stimulates production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process, and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

Other functions
Although height growth is the best known effect of GH, it serves many other metabolic functions as well.


 * It increases calcium retention, and strengthens and increases the mineralization of bone.
 * It increases muscle mass through the creation of new muscle cells (i.e. hyperplasia, which differs from hypertrophy)
 * It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
 * It increases protein synthesis and stimulates the growth of all internal organs excluding the brain.
 * It plays a role in fuel homeostasis.
 * It reduces liver uptake of glucose, an effect that opposes that of insulin.
 * It promotes liver gluconeogenesis.
 * It contributes to the maintenance and function of pancreatic islets.
 * It stimulates the immune system.

Deficiency
Lifetime deficiency states are manifest by:
 * Short stature
 * Growth retardation

Phenotype can be variable and more complex than just this. Investigation of some GH mutations has revealed that abnormal GH can affect the production of other pituitary hormones and hence pituitary function. .

Although deficiency can be associated with the pathologies of early aging life span in man appears to be enhanced typically to ages of 80-90 years. .
 * wrinkled skin
 * obesity
 * insulin resistance
 * osteopenia

Growth hormone excess: (acromegaly and pituitary gigantism)
The most common disease of GH excess is a pituitary tumor comprised of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.

Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased thickness of digits is referred to as acromegaly. Accompanying problems can include pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.

GH-secreting tumors are typically recognized in the 5th decade of life. It is extremely rare for such a tumor to occur in childhood, but when it does the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.

Surgical removal is the usual treatment for GH-producing tumors. In some circumstances focused radiation or a GH antagonist such as bromocriptine or octreotide may be employed to shrink the tumor or block function.

Growth hormone deficiency (GHD)
Deficiency of GH produces significantly different problems at various ages. In children, growth failure and short stature are the major manifestations of GH deficiency. In adults the effects of deficiency are more subtle, and may include deficiencies of strength, energy, and bone mass, as well as increased cardiovascular risk.

There are many causes of GH deficiency, including mutations of specific genes, congenital malformations involving the hypothalamus and/or pituitary gland, and damage to the pituitary from injury, surgery or disease.

Diagnosis of GH deficiency involves a multiple step diagnostic process, usually culminating in GH stimulation test(s) to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli.

GH deficiency is treated by replacing GH. All GH in current use is a biosynthetic version of human GH, manufactured by recombinant DNA technology. As GH is a large protein molecule, it must be injected into subcutaneous tissue to get it into the blood (injections no longer have to enter muscle mass since 1985 with the production of synthetic GH). When the patient has had a long-standing deficiency of GH, benefits of treatment are often dramatic and gratifying and side effects of treatment are rare. Increased growth in childhood can result in dramatically improved adult height.

GH is used as replacement therapy in adults with GH deficiency of either childhood-onset (after completing growth phase) or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.

This topic is treated more fully in the articles growth hormone deficiency and growth hormone treatment.

Other GH uses and treatment indications
Many other conditions besides GH deficiency cause poor growth, but growth benefits (height gains) are often poorer than when GH deficiency is treated. Examples of other causes of shortness often treated with growth hormone are Turner syndrome, chronic renal failure, Prader-Willi syndrome, intrauterine growth retardation, and severe idiopathic short stature. Higher ("pharmacologic") doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above physiologic. Despite the higher doses, side effects during treatment are rare, and vary little according to the condition being treated.

Sometimes GH is used for benefits other than increasing height. GH treatment improves muscle strength and slightly reduces body fat in Prader-Willi syndrome, benefits more important to these children than increased height. It has also been shown to help maintain muscle mass in AIDS wasting. GH can also be used in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

Uses that are controversial include
 * GH treatment for remission of Multiple sclerosis
 * GH treatment to reverse effects of ageing in older adults (see below)
 * GH treatment to enhance weight loss in obesity
 * GH treatment for fibromyalgia
 * GH treatment for Crohn's disease and ulcerative colitis
 * GH treatment for idiopathic short stature
 * GH treatment for bodybuilding or athletic enhancement

Anti-aging agent
Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study where GH was used to treat 12 men over 60. At the conclusion of the study all the men showed statistically significant increases in lean body mass and bone mineral, while the control group did not. The authors of the study noted that these were the kind of changes that would occur naturally over a 10 to 20 year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were mis-interpreted as indicating GH was an effective anti-aging agent.

A Stanford University School of Medicine survey of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. Researchers also didn't discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass. Regular application of GH did show several negative side effects such as joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes.

Risks and side effects of GH treatment
Side effects in adults may include fluid retention, joint pain, and nerve compression symptoms. There is theoretical concern that GH treatment may increase the risks of diabetes or cancer, especially in those with other predispositions treated with higher doses. It is pointed out, however, that diabetes is a disease that develops over perhaps 30 or 40 years of poor eating habits, and the most likely cause of diabetes is the poor nutrition which the patient had prior to the use of growth hormone. One survey of adults who had been treated with replacement cadaver GH (which has not been used anywhere in the world, since 1985) during childhood showed a mildly increased incidence of colon cancer, but linkage with the GH treatment was not established.

HGH quackery
Consumers should understand that use of the term "HGH" by marketers since 1990 is a nearly infallible sign that a product so labeled contains no effective amount of growth hormone. Endocrinologists tend to use other terms, and the specific term HGH is often an indicator of questionable claims or information. For fuller discussion, see growth hormone treatment.