Growth hormone: Difference between revisions

Growth hormone 2 (placental)
Growth hormone 2 (placental)
Identifiers
Symbol	GH2
NCBI gene	2689
HGNC	4262
OMIM	139240
RefSeq	NM_002059
UniProt	P01242
Other data
Locus	Chr. 17 q22-q24
Structures
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Structures	Swiss-model
Domains	InterPro

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Structures	Swiss-model
Domains	InterPro

Growth hormone 1 (pituitary)
Growth hormone 1 (pituitary)
	Growth hormone
Identifiers
Symbol	GH1
NCBI gene	2688
HGNC	4261
OMIM	139250
RefSeq	NM_022562
UniProt	P01241
Other data
Locus	Chr. 17 q22-q24
Structures
Search for
Structures	Swiss-model
Domains	InterPro

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Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of insulin-like growth factor 1 (IGF-1) and increases the concentration of glucose and free fatty acids.^[1]^[2] It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

A recombinant form of HGH called somatropin (INN) is used as a prescription drug 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 licensed health care provider. In recent years in the United States, some health care providers are prescribing growth hormone in the elderly to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. Many of the functions of HGH remain unknown.^[3]

In its role as an anabolic agent, HGH has been used by competitors in sports since at least 1982 and has been banned by the IOC and NCAA. Traditional urine analysis does not detect doping with HGH, so the ban was not enforced 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.^[3] Use of the drug for performance enhancement is not currently 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. Retailers are permitted to label containers of milk as produced with or without bovine somatotropin.

Nomenclature

The names somatotropin (STH) or somatotropic hormone refer to the growth hormone produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated hGH. The main growth hormone produced by recombinant DNA technology has the approved generic name (INN) somatropin and the brand name Humatrope^[4] and is properly abbreviated rhGH in the scientific literature. Since its introduction in 1992, Humatrope has been a banned sports doping agent^[5] and in this context is referred to as HGH.

The term growth hormone has been incorrectly applied to refer to anabolic sex hormones in the European beef hormone controversy, which initially restricts the use of estradiol, progesterone, testosterone, zeranol, melengestrol acetate and trenbolone acetate.^[6]

Biology

Gene

Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17^[7]^[8] 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.^[9]

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,^[10] while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions.^[11] This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosylated variant of 23 kDa identified in the pituitary gland.^[12] 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). ^{[citation needed]}

Regulation

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.^[13]

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL.^[14] Maximal secretion of GH may occur within minutes of the onset of slow-wave (SW) sleep (stage III or IV).^[15] Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages.^[16] Surges of secretion during the day occur at 3- to 5-hour intervals.^[3] The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL.^[17] Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night.^[14] 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.^[18]^[19]

A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones.^[3] Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day.^[20] Sleep deprivation generally suppresses GH release, particularly after early adulthood.^[21]

Stimulators^[quantify] of growth hormone (GH) secretion include:

Peptide hormones
- GHRH (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR)^[22]
- Ghrelin through binding to growth hormone secretagogue receptors (GHSR)^[23]
Sex hormones^[24]
- Increased androgen secretion during puberty (in males from testes and in females from adrenal cortex)
- Testosterone and DHEA
- Estrogen
Clonidine, moxonidine and L-DOPA by stimulating GHRH release^[25]
α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine or moxonidine.^[26]^[27]^[28]
Hypoglycemia, arginine,^[29] pramipexole,^[30] ornitine, lysine, tryptophan, γ-Aminobutyric acid and propranolol by inhibiting somatostatin release^[25]
Deep sleep^[31]
Glucagon
Sodium oxybate or γ-Hydroxybutyric acid
Niacin as nicotinic acid (vitamin B₃)^[32]
Fasting^[33]
Insulin^[34]
Vigorous exercise^[35]

Inhibitors^[quantify] of GH secretion include:

GHIH (somatostatin) from the periventricular nucleus ^[36]
circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)^[3]
Hyperglycemia^[25]
Glucocorticoids^[37]
Dihydrotestosterone
Phenothiazines

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.^[38]

Function

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other peptide hormones, GH acts by interacting with a specific receptor on the surface of cells.^{[citation needed]}

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

Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway.^[39] Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
GH also stimulates, through the JAK-STAT signaling pathway,^[39] the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin.^[40] 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,^[41] ^{[citation needed]} and strengthens and increases the mineralization of bone
Increases muscle mass through sarcomere hypertrophy
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^[42]
Contributes to the maintenance and function of pancreatic islets
Stimulates the immune system
Increases deiodination of T4 to T3^[43]
Induces insulin resistance^[44]

Biochemistry

GH has a short biological half-life of about 10 to 20 minutes.^[45]^[46]

Clinical significance

Excess

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.^{[citation needed]}

Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting in heaviness of the jaw and increased size of digits, 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.^{[citation needed]}

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.^{[citation needed]}

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.^[47]

Deficiency

The effects of growth hormone (GH) deficiency vary depending on the age at which they occur. Alterations in somatomedin can result in growth hormone deficiency with two known mechanisms; failure of tissues to respond to somatomedin, or failure of the liver to produce somatomedin.^[48] Major manifestations of GH deficiency in children are growth failure, the development of a short stature, and delayed sexual maturity. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis.^[48] However, deficiency is rare in adults, with the most common cause being a pituitary adenoma.^[49] Other adult causes include a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.^[49]

Adults with GHD "tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life".^[49]

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.^{[citation needed]}

Psychological effects

Quality of life

Several studies, primarily involving patients with GH deficiency, have suggested a crucial role of GH in both mental and emotional well-being and maintaining a high energy level. Adults with GH deficiency often have higher rates of depression than those without.^[50] While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown.^[50]

Cognitive function

GH has also been studied in the context of cognitive function, including learning and memory.^[51] GH in humans appears to improve cognitive function and may be useful in the treatment of patients with cognitive impairment that is a result of GH deficiency.^[51]

Medical uses

Replacement therapy

GH is used as replacement therapy in adults with GH deficiency of either childhood-onset 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. Long acting growth hormone (LAGH) analogues are now available for treating growth hormone deficiency both in children and adults. These are once weekly injections as compared to conventional growth hormone which has to be taken as daily injections. LAGH injection 4 times a month has been found to be as safe and effective as daily growth hormone injections.^[52]

Other approved uses

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, Growth failure secondary to chronic kidney disease in children,^[53] Prader–Willi syndrome, intrauterine growth restriction, 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").^{[citation needed]}

One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS.^[54]

Off-label use

Off-label prescription of HGH is controversial and may be illegal.^[55]

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.^[56] 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.^[57]^[58]^[59] 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".^[60]

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.^[57] 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.^[57] 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.^{[citation needed]}

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.^{[citation needed]}

In 1990, the US Congress passed an omnibus crime bill, the Crime Control Act of 1990, that amended the Federal Food, Drug, and Cosmetic Act, that classified anabolic steroids as controlled substances and added a new section that stated that a person who "knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services" has committed a felony.^[61]^[62]

The Drug Enforcement Administration of the US Department of Justice considers off-label prescribing of HGH to be illegal, and to be a key path for illicit distribution of HGH.^[55] This section has also been interpreted by some doctors, most notably^[63] the authors of a commentary article published in the Journal of the American Medical Association in 2005, as meaning that prescribing HGH off-label may be considered illegal.^[64] And some articles in the popular press, such as those criticizing the pharmaceutical industry for marketing drugs for off-label use (with concern of ethics violations) have made strong statements about whether doctors can prescribe HGH off-label: "Unlike other prescription drugs, HGH may be prescribed only for specific uses. U.S. sales are limited by law to treat a rare growth defect in children and a handful of uncommon conditions like short bowel syndrome or Prader-Willi syndrome, a congenital disease that causes reduced muscle tone and a lack of hormones in sex glands."^[65]^[66] At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business.^[65]^[67] In a 2012 article in Vanity Fair, when asked how HGH prescriptions far exceed the number of adult patients estimated to have HGH-deficiency, Dragos Roman, who leads a team at the FDA that reviews drugs in endocrinology, said "The F.D.A. doesn't regulate off-label uses of H.G.H. Sometimes it's used appropriately. Sometimes it's not."^[67]

Side effects

Injection site reactions are common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes.^[57] In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma.^[68]

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.^[69]

Performance enhancement

The first description of the use of GH as a doping agent was Dan Duchaine's "Underground Steroid handbook" which emerged from California in 1982; it is not known where and when GH was first used this way.^[70]

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.^[71]^[72]^[73] Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. However, because GH is a potent endogenous protein, it is very difficult to detect GH doping. In the United States, GH is legally available only by prescription from a medical doctor.^{[citation needed]}

Dietary supplements

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.^[74]

Agricultural use

In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, and is legal to use GH in raising cows for beef; see article on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.^{[citation needed]}

The use of GH in poultry farming is illegal in the United States.^[75]^[76] Similarly, no chicken meat for sale in Australia is administered hormones.^[77]

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.^[78]

Drug development history

Genentech pioneered the use of recombinant human growth hormone for human therapy, which was approved by the FDA in 1985.^{[citation needed]}

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.^[79] 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.^[80] 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."^[80] 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.^[81]

In 1985, unusual cases of Creutzfeldt–Jakob 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.^[20]

In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere.^{[citation needed]}

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).^[82] 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^[83]).

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^ Alba-Roth J, Müller OA, Schopohl J, von Werder K (December 1988). "Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion". The Journal of Clinical Endocrinology and Metabolism. 67 (6): 1186–9. doi:10.1210/jcem-67-6-1186. PMID 2903866. S2CID 7488757.
^ Samuels, Ebony R; Hou, Ruihua H; Langley, Robert W; Szabadi, Elemer; Bradshaw, Christopher M (June 19, 2007). "Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers". British Journal of Clinical Pharmacology. 64 (5): 591–602. doi:10.1111/j.1365-2125.2007.02938.x. ISSN 0306-5251. PMC 2203276. PMID 17578485.
^ Van Cauter E, Latta F, Nedeltcheva A, Spiegel K, Leproult R, Vandenbril C, Weiss R, Mockel J, Legros JJ, Copinschi G (June 2004). "Reciprocal interactions between the GH axis and sleep". Growth Hormone & IGF Research. 14 Suppl A: S10–7. doi:10.1016/j.ghir.2004.03.006. PMID 15135771.
^ Quabbe HJ, Luyckx AS, L'age M, Schwarz C (August 1983). "Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189)". The Journal of Clinical Endocrinology and Metabolism. 57 (2): 410–4. doi:10.1210/jcem-57-2-410. PMID 6345570.
^ Nørrelund H (April 2005). "The metabolic role of growth hormone in humans with particular reference to fasting". Growth Hormone & IGF Research. 15 (2): 95–122. doi:10.1016/j.ghir.2005.02.005. PMID 15809014.
^ "Greenspan's Basic & Clinical Endocrinology 10th Edition"
^ Kanaley JA, Weltman JY, Veldhuis JD, Rogol AD, Hartman ML, Weltman A (November 1997). "Human growth hormone response to repeated bouts of aerobic exercise". Journal of Applied Physiology. 83 (5): 1756–61. doi:10.1152/jappl.1997.83.5.1756. PMID 9375348.
^ Guillemin R, Gerich JE (1976). "Somatostatin: physiological and clinical significance". Annual Review of Medicine. 27: 379–88. doi:10.1146/annurev.me.27.020176.002115. PMID 779605.
^ Allen DB (September 1996). "Growth suppression by glucocorticoid therapy". Endocrinology and Metabolism Clinics of North America. 25 (3): 699–717. doi:10.1016/S0889-8529(05)70348-0. PMID 8879994.
^ Scarth JP (2006). "Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 36 (2–3): 119–218. doi:10.1080/00498250600621627. PMID 16702112. S2CID 40503492.
^ ^a ^b Binder G, Wittekindt N, Ranke MB (February 2007). Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy. Vol. 67. pp. 45–49. doi:10.1159/000097552 (inactive 1 November 2024). ISBN 978-3-8055-8255-1. S2CID 84531041. {{cite book}}: |journal= ignored (help)CS1 maint: DOI inactive as of November 2024 (link)
^ "Actions of Anterior Pituitary Hormones: Physiologic Actions of GH". Medical College of Georgia. 2007. Archived from the original on 2008-01-11. Retrieved 2008-01-16.
^ Ahmad A, Thomas J, Clewes A, Hokins MT, Guzder R, Ibrahim H, Durham B, Vora JP, Fraser WD (2003-06-01). "Effects of Growth Hormone Replacement on Parathyroid Hormone Sensitivity and Bone Mineral Metabolism". The Journal of Clinical Endocrinology & Metabolism. 88 (6): 2860–2868. doi:10.1210/jc.2002-021787. PMID 12788900.
^ King MW (2006). "Structure and Function of Hormones: Growth Hormone". Indiana State University. Archived from the original on 2007-12-06. Retrieved 2008-01-16.
^ T.F. Davies (ed.), A Case-Based Guide to Clinical Endocrinology, 2008, pag.16
^ Sharma, Rita; Kopchick, John J.; Puri, Vishwajeet; Sharma, Vishva M. (2020-12-01). "Effect of Growth Hormone on Insulin Signaling". Molecular and Cellular Endocrinology. 518: 111038. doi:10.1016/j.mce.2020.111038. ISSN 0303-7207. PMC 7606590. PMID 32966863.
^ Artwelle G, Wislon FG (2008). New Human Growth Hormone Research. Nova Publishers. pp. 12–. ISBN 978-1-60456-438-9.
^ "Norditropin® (somatropin) injection, for subcutaneous use" (PDF). Novo Nordisk A/S. U.S. Food and Drug Administration.
^ Varlamov EV, McCartney S, Fleseriu M (April 2019). "Functioning Pituitary Adenomas - Current Treatment Options and Emerging Medical Therapies". European Endocrinology. 15 (1): 30–40. doi:10.17925/EE.2019.15.1.30. PMC 6587904. PMID 31244908.
^ ^a ^b Ignatavicius D, Workman L (2015). Medical-Surgical Nursing: Patient-Centered Collaborative Care (8 ed.). Saunders. p. 1267. ISBN 978-1455772551.
^ ^a ^b ^c Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML, Stephens PA (May 2006). "Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 91 (5): 1621–34. doi:10.1210/jc.2005-2227. PMID 16636129.
^ ^a ^b Prodam F, Caputo M, Belcastro S, Garbaccio V, Zavattaro M, Samà MT, Bellone S, Pagano L, Bona G, Aimaretti G (December 2012). "Quality of life, mood disturbances and psychological parameters in adult patients with GH deficiency". Panminerva Medica. 54 (4): 323–31. PMID 23123585.
^ ^a ^b Nyberg F, Hallberg M (June 2013). "Growth hormone and cognitive function". Nature Reviews. Endocrinology. 9 (6): 357–65. doi:10.1038/nrendo.2013.78. PMID 23629538. S2CID 33876345.
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^ ^a ^b DEA, US Department of Justice. DEA: Genotropin Archived 2015-04-04 at the Wayback Machine Quote: "The illicit distribution of hGH occurs as the result of physicians illegally prescribing it for off-label uses, and for the treatment of FDA-approved medical conditions without examination and supervision"
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^ "No proof that growth hormone therapy makes you live longer, study finds". PhysOrg.com. 2007-01-16. Retrieved 2009-03-16.
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^ ^a ^b Caruso D, Donn J (December 21, 2012). "Big Pharma Cashes in on HGH Abuse". AP Impact. Associated Press. Archived from the original on August 12, 2014. Retrieved August 10, 2014.
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^ Swerdlow AJ, Higgins CD, Adlard P, Preece MA (July 2002). "Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study". Lancet. 360 (9329): 273–7. doi:10.1016/S0140-6736(02)09519-3. PMID 12147369. S2CID 16216532.
^ Holt RI, Erotokritou-Mulligan I, Sönksen PH (August 2009). "The history of doping and growth hormone abuse in sport". Growth Hormone & IGF Research. 19 (4): 320–6. doi:10.1016/j.ghir.2009.04.009. PMID 19467612.
^ Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR (May 2008). "Systematic review: the effects of growth hormone on athletic performance". Annals of Internal Medicine. 148 (10): 747–58. doi:10.7326/0003-4819-148-10-200805200-00215. PMID 18347346.
^ Randall T (2008-03-17). "Athletes Don't Benefit From Human Growth Hormone, Study Finds". Bloomberg. Retrieved 2011-08-28.
^ Gaffney G (2008-03-17). "Steroid Nation: Review from Stanford says HGH no benefit as PED". Steroid Nation. Retrieved 2011-08-28.
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^ "Chicken from Farm to Table | USDA Food Safety and Inspection Service". Fsis.usda.gov. 2011-04-06. Archived from the original on 2011-09-03. Retrieved 2011-08-26.
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^ "Hormones". Australian Chicken Meat Federation. Archived from the original on 1 July 2016. Retrieved 20 June 2016.
^ "Center for Veterinary Medicine Master" (PDF). www.fda.gov. 2011-04-06. Retrieved 2011-08-28.
^ Maybe NG (1984). "Direct expression of human growth in Escherichia coli with the lipoprotein promoter". In Bollon AP (ed.). Recombinant DNA products: insulin, interferon, and growth hormone. Boca Raton: CRC Press. ISBN 978-0-8493-5542-4.
^ ^a ^b Beck JC, Mcgarry EE, Dyrenfurth I, Venning EH (May 1957). "Metabolic effects of human and monkey growth hormone in man". Science. 125 (3253): 884–5. Bibcode:1957Sci...125..884B. doi:10.1126/science.125.3253.884. PMID 13421688.
^ Beck JC, McGARRY EE, Dyrenfurth I, Venning EH (November 1958). "The metabolic effects of human and monkey growth hormone in man". Annals of Internal Medicine. 49 (5): 1090–105. doi:10.7326/0003-4819-49-5-1090. PMID 13595475.
^ "FDA Response to three Citizen Petitions against biosimilars" (PDF), FDA, 30 May 2006, retrieved 23 November 2015
^ In 2023, the FDA approved a different sustained-release form of growth hormone, Sogroya® (somapacitan-beco) (Novo) for both pediatric patients (2.5 years and older) and adult patients, whom have growth failure due to inadequate secretion of endogenous growth hormone (rHGH). Previously, the human growth hormone analog had only been approved for adult patients with growth hormone deficiency (AGHD). "Genentech and Alkermes Announce Decision to Discontinue Commercialization of Nutropin Depot". Press Release. Business Wire. 2004-06-01. Retrieved 2011-08-28.

External links

Media related to Growth hormones at Wikimedia Commons

[pmid21584161-1] Ranabir S, Reetu K (January 2011). "Stress and hormones". Indian Journal of Endocrinology and Metabolism. 15 (1): 18–22. doi:10.4103/2230-8210.77573. PMC 3079864. PMID 21584161.

[pmid5960526-2] Greenwood FC, Landon J (April 1966). "Growth hormone secretion in response to stress in man". Nature. 210 (5035): 540–1. Bibcode:1966Natur.210..540G. doi:10.1038/210540a0. PMID 5960526. S2CID 1829264.

[ped-3] Powers M (2005). "Performance-Enhancing Drugs". In Leaver-Dunn D, Houglum J, Harrelson GL (eds.). Principles of Pharmacology for Athletic Trainers. Slack Incorporated. pp. 331–332. ISBN 978-1-55642-594-3.

[4] Daniels ME (1992). "Lilly's Humatrope Experience". Nature Biotechnology. 10 (7): 812. doi:10.1038/nbt0792-812a. S2CID 46453790.

[pmid16799101-5] Saugy M, Robinson N, Saudan C, Baume N, Avois L, Mangin P (July 2006). "Human growth hormone doping in sport". British Journal of Sports Medicine. 40 (Suppl 1): i35–9. doi:10.1136/bjsm.2006.027573. PMC 2657499. PMID 16799101.

[6] William A Kerr & Jill E Hobbs (February 2002). "The North American-European Union Dispute Over Beef Produced Using Growth Hormones: A Major Test for the New International Trade Regime". The World Economy. 25 (2): 283–296. doi:10.1111/1467-9701.00431. S2CID 154707486.

[7] "GH1 growth hormone 1 (Homo sapiens) - Gene". National Center for Biotechnology Information, U.S. National Library of Medicine.

[8] "GH2 growth hormone 2 (Homo sapiens) - Gene". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid12082127-9] Yi S, Bernat B, Pál G, Kossiakoff A, Li WH (July 2002). "Functional promiscuity of squirrel monkey growth hormone receptor toward both primate and nonprimate growth hormones". Molecular Biology and Evolution. 19 (7): 1083–92. doi:10.1093/oxfordjournals.molbev.a004166. PMID 12082127.

[pmid12217902-10] Leung KC, Howe C, Gui LY, Trout G, Veldhuis JD, Ho KK (October 2002). "Physiological and pharmacological regulation of 20-kDa growth hormone". American Journal of Physiology. Endocrinology and Metabolism. 283 (4): E836–43. doi:10.1152/ajpendo.00122.2002. PMID 12217902.

[pmid19003817-11] Kohler M, Püschel K, Sakharov D, Tonevitskiy A, Schänzer W, Thevis M (November 2008). "Detection of recombinant growth hormone in human plasma by a 2-D PAGE method". Electrophoresis. 29 (22): 4495–502. doi:10.1002/elps.200800221. PMID 19003817. S2CID 22525768.

[pmid19579232-12] Bustamante JJ, Gonzalez L, Carroll CA, Weintraub ST, Aguilar RM, Muñoz J, Martinez AO, Haro LS (July 2009). "O-Glycosylated 24 kDa human growth hormone has a mucin-like biantennary disialylated tetrasaccharide attached at Thr-60". Proteomics. 9 (13): 3474–88. doi:10.1002/pmic.200800989. PMC 2904392. PMID 19579232.

[isbn0-321-53910-9-13] Bartholomew EF, Martini F, Nath JL (2009). Fundamentals of anatomy & physiology. Upper Saddle River, NJ: Pearson Education Inc. pp. 616–617. ISBN 978-0-321-53910-6.

[Takahashi-14] Takahashi Y, Kipnis DM, Daughaday WH (September 1968). "Growth hormone secretion during sleep". The Journal of Clinical Investigation. 47 (9): 2079–90. doi:10.1172/JCI105893. PMC 297368. PMID 5675428.

[pmid10984255-15] Van Cauter E, Copinschi G (April 2000). "Interrelationships between growth hormone and sleep". Growth Hormone & IGF Research. 10 (Suppl B): S57–62. doi:10.1016/s1096-6374(00)80011-8. PMID 10984255.

[pmid11817985-16] Mehta A, Hindmarsh PC (2002). "The use of somatropin (recombinant growth hormone) in children of short stature". Paediatric Drugs. 4 (1): 37–47. doi:10.2165/00128072-200204010-00005. PMID 11817985. S2CID 23663131.

[pmid808970-17] Natelson BH, Holaday J, Meyerhoff J, Stokes PE (August 1975). "Temporal changes in growth hormone, cortisol, and glucose: relation to light onset and behavior". The American Journal of Physiology. 229 (2): 409–15. doi:10.1152/ajplegacy.1975.229.2.409. PMID 808970.

[pmid11408427-18] Nindl BC, Hymer WC, Deaver DR, Kraemer WJ (July 2001). "Growth hormone pulsatility profile characteristics following acute heavy resistance exercise". Journal of Applied Physiology. 91 (1): 163–72. doi:10.1152/jappl.2001.91.1.163. PMID 11408427. S2CID 16101442.

[pmid8719443-19] Juul A, Jørgensen JO, Christiansen JS, Müller J, Skakkeboek NE (1995). "Metabolic effects of GH: a rationale for continued GH treatment of GH-deficient adults after cessation of linear growth". Hormone Research. 44 Suppl 3 (3): 64–72. doi:10.1159/000184676 (inactive 1 November 2024). PMID 8719443.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)

[isbn0-07-144011-9-20] Gardner DG, Shoback D (2007). Greenspan's Basic and Clinical Endocrinology (8th ed.). New York: McGraw-Hill Medical. pp. 193–201. ISBN 978-0-07-144011-0.

[pmid8875441-21] Mullington J, Hermann D, Holsboer F, Pollmächer T (September 1996). "Age-dependent suppression of nocturnal growth hormone levels during sleep deprivation". Neuroendocrinology. 64 (3): 233–41. doi:10.1159/000127122. PMID 8875441. S2CID 3328167.

[pmid12424433-22] Lin-Su K, Wajnrajch MP (December 2002). "Growth Hormone Releasing Hormone (GHRH) and the GHRH Receptor". Reviews in Endocrine & Metabolic Disorders. 3 (4): 313–23. doi:10.1023/A:1020949507265. PMID 12424433. S2CID 6263928.

[pmid11089570-23] Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (November 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology. 141 (11): 4325–8. doi:10.1210/endo.141.11.7873. PMID 11089570.

[pmid16984231-24] Meinhardt UJ, Ho KK (October 2006). "Modulation of growth hormone action by sex steroids". Clinical Endocrinology. 65 (4): 413–22. doi:10.1111/j.1365-2265.2006.02676.x. PMID 16984231. S2CID 20688016.

[pmid1901390-25] Low LC (1991). "Growth hormone-releasing hormone: clinical studies and therapeutic aspects". Neuroendocrinology. 53 (Suppl 1): 37–40. doi:10.1159/000125793. PMID 1901390.

[pmid18042647-26] Fedi M, Bach LA, Berkovic SF, Willoughby JO, Scheffer IE, Reutens DC (February 2008). "Association of a nicotinic receptor mutation with reduced height and blunted physostigmine-stimulated growth hormone release". The Journal of Clinical Endocrinology and Metabolism. 93 (2): 634–7. doi:10.1210/jc.2007-1611. PMID 18042647.

[pmid6818588-27] Wilkins JN, Carlson HE, Van Vunakis H, Hill MA, Gritz E, Jarvik ME (1982). "Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers". Psychopharmacology. 78 (4): 305–8. doi:10.1007/BF00433730. PMID 6818588. S2CID 37559511.

[pmid6508989-28] Coiro V, d'Amato L, Borciani E, Rossi G, Camellini L, Maffei ML, Pignatti D, Chiodera P (November 1984). "Nicotine from cigarette smoking enhances clonidine-induced increase of serum growth hormone concentrations in men". British Journal of Clinical Pharmacology. 18 (5): 802–5. doi:10.1111/j.1365-2125.1984.tb02547.x. PMC 1463553. PMID 6508989.

[pmid2903866-29] Alba-Roth J, Müller OA, Schopohl J, von Werder K (December 1988). "Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion". The Journal of Clinical Endocrinology and Metabolism. 67 (6): 1186–9. doi:10.1210/jcem-67-6-1186. PMID 2903866. S2CID 7488757.

[30] Samuels, Ebony R; Hou, Ruihua H; Langley, Robert W; Szabadi, Elemer; Bradshaw, Christopher M (June 19, 2007). "Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers". British Journal of Clinical Pharmacology. 64 (5): 591–602. doi:10.1111/j.1365-2125.2007.02938.x. ISSN 0306-5251. PMC 2203276. PMID 17578485.

[pmid15135771-31] Van Cauter E, Latta F, Nedeltcheva A, Spiegel K, Leproult R, Vandenbril C, Weiss R, Mockel J, Legros JJ, Copinschi G (June 2004). "Reciprocal interactions between the GH axis and sleep". Growth Hormone & IGF Research. 14 Suppl A: S10–7. doi:10.1016/j.ghir.2004.03.006. PMID 15135771.

[pmid6345570-32] Quabbe HJ, Luyckx AS, L'age M, Schwarz C (August 1983). "Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189)". The Journal of Clinical Endocrinology and Metabolism. 57 (2): 410–4. doi:10.1210/jcem-57-2-410. PMID 6345570.

[pmid15809014-33] Nørrelund H (April 2005). "The metabolic role of growth hormone in humans with particular reference to fasting". Growth Hormone & IGF Research. 15 (2): 95–122. doi:10.1016/j.ghir.2005.02.005. PMID 15809014.

[34] "Greenspan's Basic & Clinical Endocrinology 10th Edition"

[pmid9375348-35] Kanaley JA, Weltman JY, Veldhuis JD, Rogol AD, Hartman ML, Weltman A (November 1997). "Human growth hormone response to repeated bouts of aerobic exercise". Journal of Applied Physiology. 83 (5): 1756–61. doi:10.1152/jappl.1997.83.5.1756. PMID 9375348.

[pmid779605-36] Guillemin R, Gerich JE (1976). "Somatostatin: physiological and clinical significance". Annual Review of Medicine. 27: 379–88. doi:10.1146/annurev.me.27.020176.002115. PMID 779605.

[pmid8879994-37] Allen DB (September 1996). "Growth suppression by glucocorticoid therapy". Endocrinology and Metabolism Clinics of North America. 25 (3): 699–717. doi:10.1016/S0889-8529(05)70348-0. PMID 8879994.

[pmid16702112-38] Scarth JP (2006). "Modulation of the growth hormone-insulin-like growth factor (GH-IGF) axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 36 (2–3): 119–218. doi:10.1080/00498250600621627. PMID 16702112. S2CID 40503492.

[Binder_2007-39] Binder G, Wittekindt N, Ranke MB (February 2007). Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy. Vol. 67. pp. 45–49. doi:10.1159/000097552 (inactive 1 November 2024). ISBN 978-3-8055-8255-1. S2CID 84531041. {{cite book}}: |journal= ignored (help)CS1 maint: DOI inactive as of November 2024 (link)

[40] "Actions of Anterior Pituitary Hormones: Physiologic Actions of GH". Medical College of Georgia. 2007. Archived from the original on 2008-01-11. Retrieved 2008-01-16.

[41] Ahmad A, Thomas J, Clewes A, Hokins MT, Guzder R, Ibrahim H, Durham B, Vora JP, Fraser WD (2003-06-01). "Effects of Growth Hormone Replacement on Parathyroid Hormone Sensitivity and Bone Mineral Metabolism". The Journal of Clinical Endocrinology & Metabolism. 88 (6): 2860–2868. doi:10.1210/jc.2002-021787. PMID 12788900.

[42] King MW (2006). "Structure and Function of Hormones: Growth Hormone". Indiana State University. Archived from the original on 2007-12-06. Retrieved 2008-01-16.

[43] T.F. Davies (ed.), A Case-Based Guide to Clinical Endocrinology, 2008, pag.16

[44] Sharma, Rita; Kopchick, John J.; Puri, Vishwajeet; Sharma, Vishva M. (2020-12-01). "Effect of Growth Hormone on Insulin Signaling". Molecular and Cellular Endocrinology. 518: 111038. doi:10.1016/j.mce.2020.111038. ISSN 0303-7207. PMC 7606590. PMID 32966863.

[ArtwelleWislon2008-45] Artwelle G, Wislon FG (2008). New Human Growth Hormone Research. Nova Publishers. pp. 12–. ISBN 978-1-60456-438-9.

[Norditropin-Label-46] "Norditropin® (somatropin) injection, for subcutaneous use" (PDF). Novo Nordisk A/S. U.S. Food and Drug Administration.

[47] Varlamov EV, McCartney S, Fleseriu M (April 2019). "Functioning Pituitary Adenomas - Current Treatment Options and Emerging Medical Therapies". European Endocrinology. 15 (1): 30–40. doi:10.17925/EE.2019.15.1.30. PMC 6587904. PMID 31244908.

[Ignatavicius-2015-48] Ignatavicius D, Workman L (2015). Medical-Surgical Nursing: Patient-Centered Collaborative Care (8 ed.). Saunders. p. 1267. ISBN 978-1455772551.

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v t e GH/IGF-1 axis signaling modulators
GH (somatotropin)	Agonists: Albusomatropin Bovine somatotropin Efpegsomatropin Eftansomatropin alfa Growth hormone Human placental lactogen Lonapegsomatropin Placental growth hormone (growth hormone variant) Somagrebove Somapacitan Somatosalm Somatotropin Somatropin pegol Somatrem Sometribove Somatrogon (MOD-4023; hGH-CTP) Somavaratan Somavubove Somidobove Antagonists: G120K-hGH Pegvisomant Antisense oligonucleotides: Atesidorsen Binding proteins: GHBPTooltip Growth hormone-binding protein
GHIH (somatostatin)	Agonists: BIM-23052 CH-275 Cortistatin-14 Depreotide Edotreotide Ilatreotide L-803,087 L-817,818 Lanreotide NNC 26-9100 Octreotate Octreotide Pasireotide Pentetreotide RC-160 Seglitide Somatostatin (GHIH) Somatostatin (1-28) SRIF-14 SRIF-28 TT-232 Vapreotide Veldoreotide Antagonists: BIM-23056 Cyclosomatostatin CYN-154806 Satoreotide
GHRH (somatocrinin)	Agonists: Peptide: ALRN-5281 CJC-1295 Dumorelin GHRH Modified GRF (1-29) Rismorelin Sermorelin Somatorelin Tesamorelin Antagonists: MZ-5-156
GHS (ghrelin)	Agonists: Peptide: Alexamorelin Cortistatin-14 EP-51216 Examorelin (hexarelin) Ghrelin GHRP-1 GHRP-3 GHRP-4 GHRP-5 GHRP-6 Ipamorelin Lenomorelin Livoletide LY-444711 Pralmorelin (GHRP-2) Relamorelin Tabimorelin Ulimorelin; Non-peptide: Adenosine Anamorelin Capromorelin CP-464709 Ibutamoren (MK-677) L-692,585 Macimorelin SM-130686; Unsorted: LY-426410 LY-444711 Antagonists: A-778193 Cortistatin-8 (D-Lys³)-GHRP-6 JMV2959 YIL-781
IGF-1 (somatomedin)	See here instead.