Somatotropin



Growth hormone is a polypeptide hormone synthesised and secreted by the anterior pituitary gland which stimulates growth and cell reproduction in humans and other vertebrate animals.

This article describes human growth hormone physiology, with brief mentions of the diseases of GH deficiency, GH excess (acromegaly and pituitary gigantism), as well as GH treatment, and HGH quackery. Each of these topics is treated more fully in separate articles.

Terminology
Growth hormone (GH) is also called somatropin and somatotropin (British: somatotrophin). hGH refers to human growth hormone and is an abbreviation for human GH measured in the blood or extracted 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 (British: somatrophin) and abbreviated as rhGH. Since the mid-1990s the abbreviation HGH has begun to carry paradoxical connotations, and now rarely refers to real GH used for indicated purposes. See articles on GH treatment and HGH quackery for fuller discussions of GH therapy and the HGH issue.

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.

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
GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. 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.

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. Growth hormone releasing hormone (GHRH) from the arcuate nucleus and ghrelin promote GH secretion, and somatostatin from the periventricular nucleus inhibits it. GH secretion is also affected by negative feedback from circulating concentrations of GH and IGF-1.

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 (among others) sleep, exercise, hypoglycemia, dietary protein, and estradiol. Inhibitors of GH secretion include dietary carbohydrate and glucocorticoids.

Most of the physiologically important GH 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 30 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.

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.

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.

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 (IGF1, 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.

Although height growth is the best known effect of GH, it serves many other metabolic functions as well. GH increases calcium retention, and strengthens and increases the mineralization of bone. It increases muscle mass. It induces protein synthesis and growth of many different organ systems of the body, resulting in a "positive nitrogen balance".

GH stimulates the immune system.

GH plays a role in fuel homeostasis. GH reduces liver uptake of glucose, an effect that opposes that of insulin. GH also contributes to the maintenance and function of pancreatic islets. It tends to promote lipolysis, which results in some reduction of adipose tissue (body fat) and rising amounts of free fatty acids and glycerol in the blood.

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 (or muscle) to get it into the blood. 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 other benefits than height. GH treatment improves muscle strength and slightly reduce 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 parenteral nutrition.

Uses that are controversial include
 * GH treatment to reverse effects of aging in older adults
 * 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

Risks of GH treatment
Risks of treatment are quite rare when GH is given in replacement doses to deficient children and adults. Risks are uncommon even when used in "pharmacologic doses" for other reasons, but there are more unanswered questions about risk:benefit ratios for other uses.

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 (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.

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 HGH quackery.