Human Growth Hormone (HGH) is a 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 human growth hormone produced natively in animals, the term somatropin refers to human growth hormone produced by recombinant DNA technology, and is abbreviated "rhHGH".

Human Growth Hormone has a variety of functions in the body, the most noticeable of which is the increase of height throughout childhood, and there are several diseases which can be treated through the therapeutic use of HGH.

Gene locus

The genes for human human growth hormone, known as Human Growth Hormone 1, are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. HGH, 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 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 HGH receptor. HGH is structurally and apparently evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between human growth hormone from different species, only human and primate growth hormones have significant effects in humans.

Secretion

Several molecular isoforms of HGH circulate in the plasma. Much of the human growth hormone in the circulation is bound to a protein (human growth hormone binding protein, HGHBP) which is derived from the human growth hormone receptor, and an acid label sub unit (ALS).

Regulation

Peptides released by neurosecretory nuclei of the hypothalamus (Human Growth Hormone releasing hormone and somatostatin) into the portal venous blood surrounding the pituitary are the major controllers of HGH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines HGH release, this balance is affected by many physiological stimulators (e.g exercise, nutrition, sleep) and inhibitors of HGH secretion (e.g. Free fatty acids).

Stimulators of HGH secretion include:

• human growth hormone releasing hormone (HGHRH) from the arcuate nucleus
• ghrelin
• sleep
• exercise
• low levels of blood sugar (hypoglycemia)
• dietary protein
• estradiol
• arginine

Inhibitors of HGH secretion include:

• somatostatin from the periventricular nucleus
• circulating concentrations of HGH and IGF-1 (negative feedback)
• hyperglycemia
• glucocorticoids

In addition to control by endogenous processes, a number of foreign compounds (xenobiotics) are now known to influence HGH secretion and function, highlighting the fact that the HGH-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 HGH release each day. The plasma concentration of HGH 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 HGH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Between the peaks, basal HGH levels are low, usually less than 3 ng/mL for most of the day and night.

The amount and pattern of HGH 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. Also may have impact/help growth of colon, lung, and breast cancer.

Functions of HGH

Effects of human growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones HGH 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 HGH, and appears to be stimulated by at least two mechanisms.

1. HGH 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. HGH 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 HGH 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, human 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 HGH 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 HGH. For years, the principal clinical problems are those of HGH 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 HGH 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.

HGH-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 HGH can cause excessive growth, traditionally referred to as pituitary gigantism.

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

Deficiencies

The effects of human growth hormone deficiency vary depending on the age at which they occur. In children, growth failure and short stature are the major manifestations of HGH deficiency. It can also cause sexual immaturity. 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 HGH 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 HGH deficiency involves a multiple step diagnostic process, usually culminating in HGH stimulation test(s) to see if the patient's pituitary gland will release a pulse of HGH when provoked by various stimuli.

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

HGH is used as replacement therapy in adults with HGH 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

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

HGH treatment improves muscle strength and slightly reduces body fat in Prader-Willi syndrome, which are significant concerns beyond the need to increase height. HGH is also useful in maintaining muscle mass in wasting due to AIDS. HGH can also be used in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

Uses that are controversial include:

• HGH treatment for remission of Multiple sclerosis
• HGH treatment to reverse effects of aging in older adults (see below)
• HGH treatment to enhance weight loss in obesity
• HGH treatment for fibromyalgia
• HGH treatment for Crohn's disease and ulcerative colitis
• HGH treatment for idiopathic short stature
• HGH treatment for bodybuilding or athletic enhancement
• The use of bovine somatotropin to increase milk production in cattle

Anti-aging agent

Claims for HGH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study where HGH 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 HGH had reversed the aging process itself, their results were mis-interpreted as indicating HGH 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 HGH 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 HGH. 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 HGH merely let the body to store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass. Regular application of HGH 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 HGH treatment may increase the risks of diabetes, especially in those with other predispositions treated with higher doses. One survey of adults who had been treated with replacement cadaver HGH (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 HGH treatment was not established.

History

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

Prior to its production by recombinant DNA technology, human growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. In 1985, biosynthetic human human growth hormone replaced pituitary-derived human human growth hormone for therapeutic use in the U.S. and elsewhere. HGH 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 rhHGH called Omnitrope (Sandoz). A sustained-release form of human 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.

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