growth hormone

Growth hormone 1

Growth hormone
Identifiers
Symbol	GH1
Entrez	2688
HUGO	4261
OMIM	139250
RefSeq	NM_022562
UniProt	P01241
Other data
Locus	Chr. 17 q22-q24

Growth hormone (GH) is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. Somatotropin (STH) refers to the growth hormone 1 produced naturally in animals, whereas the term somatropin refers to growth hormone produced by recombinant DNA technology,^[1] and is abbreviated "HGH" in humans.

Growth hormone is used as a prescription drug in medicine to treat children's growth disorders and adult growth hormone deficiency. In the United States, it is only available legally from pharmacies, by prescription from a doctor. In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, HGH is still considered a very complex hormone, and many of its functions are still unknown.^[2]

In its role as an anabolic agent, HGH has been abused by competitors in sports since the 1970s, and it has been banned by the IOC and NCAA. Traditional urine analysis could not detect doping with HGH, so the ban was unenforceable until the early 2000s when blood tests that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA at the 2004 Olympic Games in Athens, Greece targeted primarily HGH.^[2] This use for the drug is not approved by the FDA.

GH has been studied for use in raising livestock more efficiently in industrial agriculture and several efforts have been made to obtain governmental approval to use GH in livestock production. These uses have been controversial. In the United States, the only FDA-approved use of GH for livestock is the use of a cow-specific form of GH called bovine somatotropin for increasing milk production in dairy cows. Now retailers are permitted to label containers of milk as produced with or without bovine somatotropin.

Biology

Gene locus

Genes for human growth hormone, known as growth hormone 1 (somatotropin) and growth hormone 2, are localized in the q22-24 region of chromosome 17^[3][4] and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.

Structure

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. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor.^[5]

Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio,^[6] while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions.^[7] This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosilated variant of 23 kDa identified in the pituitary gland.^[8] Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS).

Biological regulation

Peptides released by neurosecretory nuclei of the hypothalamus (Growth hormone-releasing hormone/somatocrinin and Growth hormone-inhibiting hormone/somatostatin) into the hypophyseal 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)^[9] Stimulators of HGH secretion include:

• peptide hormones
  • Growth hormone-releasing hormone (GHRH) through binding to the growth hormone-releasing hormone receptor (GHRHR)^[10]
  • ghrelin through binding to growth hormone secretagogue receptors (GHSR)^[11]
• sex hormones^[12]
  • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
  • estrogen
• clonidine and L-DOPA by stimulating GHRH release^[13]
• hypoglycemia, arginine^[14] and propranolol by inhibiting somatostatin release^[13]

• deep sleep^[15]
• niacin as nicotinic acid ^[16]
• fasting^[17]
• vigorous exercise ^[18]

Inhibitors of GH secretion include:

• somatostatin from the periventricular nucleus ^[19]
• circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)^[2]
• hyperglycemia^[13]
• glucocorticoids^[20]
• dihydrotestosterone

In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function.^[21]

HGH is synthesized and secreted from the anterior pituitary gland in a pulsatile manner throughout the day; surges of secretion occur at 3- to 5-hour intervals.^[2] The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL.^[22] The largest and most predictable of these GH peaks occurs about an hour after onset of sleep.^[23] Otherwise there is wide variation between days and individuals. Nearly fifty percent of HGH secretion occurs during the third and fourth NREM sleep stages.^[24] Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night.^[23] Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL.^[25][26]

A number of factors are known to affect HGH secretion, such as age, gender, diet, exercise, stress, and other hormones.^[2] Young adolescents secrete HGH at the rate of about 700 μg/day, while healthy adults secrete HGH at the rate of about 400 μg/day.^[27]

Normal functions of GH produced by the body

Main pathways in endocrine regulation of growth.

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.

Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

1. Because polypeptide hormones are not fat-soluble, they cannot penetrate sarcolemma. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway.^[28] Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
2. GH also stimulates, through the JAK-STAT signaling pathway,^[28] the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin.^[29] 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 what appears to be 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 sarcomere hyperplasia
• Promotes lipolysis
• Increases protein synthesis
• Stimulates the growth of all internal organs excluding the brain
• Plays a role in homeostasis
• Reduces liver uptake of glucose
• Promotes gluconeogenesis in the liver^[30]
• Contributes to the maintenance and function of pancreatic islets
• Stimulates the immune system

Problems caused when the body produces too much GH

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 size of digits is referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), 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 pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary.

Problems caused when the body produces too little GH

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,^[31] 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.^[31]

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

GH in human medicine

See sections above for problems caused when the body produces too much GH or too little GH.

FDA-approved treatments with GH related to deficiency of GH

Treatment with exogenous GH is indicated only in limited circumstances,^[31] 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.

FDA-approved treatments with GH unrelated to deficiency of GH

GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable 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 normal ("physiologic"). Despite the higher doses, side-effects during treatment are rare, and vary little according to the condition being treated.

One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS.^[32]

Experimental uses

The following discussion describes experimental uses of GH, that are legal when the GH is prescribed by a doctor. However, the efficacy and safety of use of GH as anti-aging agent are unknown as this use has not been tested in a double-blinded clinical trial.

In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, hGH is still considered a very complex hormone, and many of its functions are still unknown.^[2]

Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60.^[33] At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, 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 that GH is an effective anti-aging agent.^[34][35][36] This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an "anti-aging agent".^[37]

A Stanford University School of Medicine meta-analysis 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.^[34] 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.^[34] Researchers also did not 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.

GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn's disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

Side-effects

Use of GH as a drug has been approved by the FDA for several indications. This means that the drug has acceptable safety in light of its benefits when used in the approved way. Like every drug, there are several side effects caused by GH, some common, some rare. Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes.^[34] In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma.^[38]

One survey of adults that 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 and prostate cancer, but linkage with the GH treatment was not established.^[39]

Non-medical use in athletic enhancement

Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes.^[40][41][42] Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. In the United States, GH is legally available only by prescription from a medical doctor.

Use of GH in production of meat and milk

In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, but it is not legal to use GH in raising cows for beef; see articles on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.

Use in poultry farming is illegal in the United States as per the poultry farming article.

Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn.^[43][44]

History of use and manufacture of GH as a drug

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. Attempts to create a wholly synthetic HGH failed. Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature.^[45] Very limited clinical studies of growth hormone derived from an old world monkey, the Rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s.^[46] The study published in 1957, which was conducted on "a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma," found that: "Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage...(and) there was a retention of potassium, phosphorus, calcium, and sodium. ...There was a gain in body weight during both periods.... There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone.... Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone."^[46] The other study, published in 1958, was conducted on six people: the same subject as the Science paper; an 18 year old male with statural and sexual retardation and a skeletal age of between 13 and 14 years; a 15 year old female with well documented hypopituitarism secondary to a craniopharyngioma; a 53 year old female with carcinoma of the breast and widespread skeletal metastases; a 68 year old female with advanced postmenopausal osteoporosis; and a healthy 24 year old medical student without any clinical or laboratory evidence of systemic disease.^[47]

In 1985, unusual cases of Creutzfeldt-Jacob disease were found in individuals that had received cadaver-derived HGH ten to fifteen years previously. Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market.^[27]

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere.

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 Administration (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 by Genentech/Alkermes in 2004 for financial reasons (Nutropin Depot required significantly more resources to produce than the rest of the Nutropin line^[48]).

Dietary supplements claiming relation to GH

To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements have websites selling products linked to GH in the advertising text, with medical-sounding names described as "HGH Releasers". Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations.^[49]

References