growth hormone

growth hormone or somatotropin, glycoprotein hormone released by the anterior pituitary gland that is necessary for normal skeletal growth in humans (see protein). Evidence suggests that the secretion of human growth hormone (HGH) is regulated by the release of certain peptides by the hypothalamus of the brain. One such substance, called somatostatin, has been shown to inhibit the secretion of HGH. HGH is known to act upon many aspects of cellular metabolism, but its most obvious effect is the stimulation of the growth of cartilage and bone in children.

See also auxins (plant growth hormones).

Role in Dwarfism and Gigantism

A deficiency of growth hormone secretion before puberty (by the end of which the synthesis of new bone tissue is complete) results in pituitary dwarfism. Pituitary dwarfs, who can be as little as 3 to 4 ft (91-122 cm) tall, are generally well proportioned except for the head, which may be relatively large when compared to the body (this relationship of head to body is similar to that of normal children). Unlike cretins, whose dwarfism is caused by a deficiency of thyroxine, pituitary dwarfs are not mentally retarded; they are often sexually immature. They can be treated by injections of synthetic growth hormone, either somatrem or somatropin, which are produced by genetically engineered bacteria.

An excess of growth hormone in children results in gigantism; these children grow to be over 7 ft (213 cm) in height and have disproportionately long limbs. Excess growth hormone produced after puberty has little effect on the growth of the skeleton, but it results in a disease affecting terminal skeletal structures known as acromegaly.

Other Medical Uses

HGH has been used with some success to combat the weight loss and general wasting characteristic of AIDS and cancer. It is used illegally by bodybuilders and athletes to increase muscle mass. Controversy surrounds its use in normal children who simply want to be taller. In addition, a 1990 medical study that reported the reversal of many of the physiological effects of aging with regular injections of HGH has created a lucrative black market for it and has prompted funding of further trials. There has been no conclusive evidence, however, to support the use of HGH as an anti-aging treatment, and it can cause serious side effects, including diabetes, in older adults.

or somatotropin

Peptide hormone secreted by the anterior lobe of the pituitary gland. It promotes growth of bone and other body tissues by stimulating protein synthesis and fat breakdown (for energy). Excessive production causes gigantism, acromegaly, or other malformations; deficient production results in dwarfism, dramatically relieved if GH is given before puberty. Genetic engineering techniques now permit large-scale production of adequate amounts of GH for that purpose.

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Growth hormone (GH) is a peptide hormone that stimulates growth and cell reproduction in humans and other animals. It is a 191-amino acid, single chain polypeptide hormone which is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. Somatotrophin refers to the growth hormone produced natively in animals, the term somatropin refers to growth hormone produced by recombinant DNA technology, and is abbreviated "rhGH" in human.

Gene locus

The genes for human growth hormone, known as Growth hormone 1 and Growth hormone 2, are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin (PRL) are a group of homologous hormones with growth-promoting and lactogenic activity.

Molecular structures

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22 124 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

Several molecular isoforms of GH circulate in the plasma. 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, and an acid label sub unit (ALS).

Regulation

Peptides released by neurosecretory nuclei of the hypothalamus (Growth hormone releasing hormone and somatostatin) 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 (e.g exercise, nutrition, sleep) and inhibitors of GH secretion (e.g. Free fatty acids).

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
• increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
• arginine

Inhibitors of GH secretion include:

• somatostatin from the periventricular nucleus
• circulating concentrations of GH and IGF-1 (negative feedback)
• hyperglycemia
• glucocorticoids
• estradiol or any estrogen

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 even 45 ng/mL. Peaks typically last from 10 to 30 minutes before returning to basal levels (see a complete review, Laursen, 2003) 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 5 ng/mL for most of the day and night. Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks where situated around 10-20 ng/mL.

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.

Functions of GH

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

Stimulating the increase in height in childhood is the most widely known effect of GH, 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.

In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:

• Increases calcium retention, and strengthens and increases the mineralization of bone
• Increases muscle mass through the sarcomere hyperplasia
• Promotes lipolysis
• Increases protein synthesis
• Stimulating the growth of all internal organs excluding the brain
• Plays a role in fuel homeostasis
• Reduces liver uptake of glucose
• Promotes gluconeogenesis in the liver
• It contributes to the maintenance and function of pancreatic islets
• It stimulates the immune system

Excesses

The most common disease of GH excess is a pituitary tumor composed 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 fifth 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.

Deficiencies

The effects of growth hormone deficiency vary depending on the age at which they occur. In children, growth failure and short stature are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. It can also cause delayed sexual maturity. In adults, deficiency is rare, with the most common cause a pituitary adenoma, and others including a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.

Adults with GHD present with non-specific problems including truncal obesity with a relative decrease in muscle mass and, in many instances, decreased energy and quality of life.

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.

Treatment with external GH is only indicated in limited circumstances, and needs regular monitoring due to the frequency and severity of side-effects. 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.

Therapeutic use

Treatments unrelated to deficiency

GH can be used to treat conditions which produce short stature but are not related to deficiencies in GH, though results are not as dramatic when compared to short stature solely due to deficiency of GH. Examples of other causes of shortness often treated with GH 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.

GH treatment improves muscle strength and slightly reduces body fat in Prader-Willi syndrome, which are significant concerns beyond the need to increase height. GH is also useful in maintaining muscle mass in wasting due to AIDS. 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 aging 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
• The use of bovine somatotropin to increase milk production in cattle

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 improvements were the opposite of the changes that would normally occur 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 misinterpreted 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.

Side effects

There is theoretical concern that GH treatment may increase the risks of diabetes, especially in those with other predispositions treated with higher doses. If used for use of training, growth at a young age (25 or less) can cause severe symptoms. 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.

History

The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. Genentech pioneered the first use of recombinant human growth hormone for human therapy in 1981.

Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. GH is also known to increase chances of breast cancer and lung cancer.

As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Association (FDA) approved a version of rhGH called Omnitrope (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); however, the product was discontinued in 2004.

References