GROWTH HORMONE, HUMAN

Basic Information

Growth hormone (GH), also called human growth hormone (HGH or hGH) or somatotropic hormone, somatotropin is a single polypeptide chain of 191 amino acids^[1](qv) having two disulfide bonds, one between Cys-53 and Cys-165, forming a large loop in the molecule, and the other between Cys-182 and Cys-189, forming a small loop near the C-terminus. The structure of GH is shown in Figure 1; molecular mass is 22,125; the empirical formula is C990H1529N262O300S7.

Purified GH is a white amorphous powder in its lyophilized form. It is readily soluble (concentrations>10 mg/mL) in dilute aqueous buffers at pH values above 7.2. The isoelectric point is 5.2 and the generally accepted value for the extinction coefficient at 280 nm is 17, 700 (M•cm)−1, although other values have been reported. The equilibrium denaturation of GH has been studied. A two-state mechanism is indicated with a Gibbs free energy of unfolding of 60.7 ± 4 kJ/mol (14.5 ± 1 kcal/mol).
In solution, GH exists predominantly as a monomer, with a small fraction as a dimer and higher molecular weight oligomers. Under certain conditions, GH can be induced to form larger amounts of dimers, trimers, and higher oligomers although the conditions leading to self-association are not well understood. GH is a globular protein having approximately 55% α-helical character, a value determined independently in studies using circular dichroism and Raman spectroscopy. A protein of a high degree of homology and structural similarity is porcine growth hormone, the crystal structure of which has been solved. This structure shows four antiparallel helices connected by strands of polypeptide having little structure. A crystal structure of GH complexed with the extracellular domain of its receptor has been reported. In this complex, the structure of GH is readily obvious and shows the four-helical bundle connected in an up–up–down–down fashion rather than the more common up–down–up–down. This work has convincingly shown that GH possesses two binding sites for its receptor and that the hormone functions by dimerizing its receptor on the cell membrane^[2].
The product should be stored at –20 °C. The lyophilized product remains active for one year at –20 °C. Upon reconstitution, the cytokine can be stored at 2–8 °C for short term only or at –20 °C to –80 °C in aliquots for long term. Avoid repeated freeze-thaw cycles^[3].

Physiological Effects

GH is produced by the pituitary gland in the brain-the pea-sized pituitary gland located at the base of the brain, released into the bloodstream and is an important part of the body’s endocrine system^[4][5].
The human GH cDNA encodes a 217 amino acid (aa) residue precursor protein with a 26 aa putative signal peptide. By alternative splicing, at least four isoforms of GH have been identified^[9].
In serum, GH exists as a complex combination of different molecular forms (isoforms), including the major 22-kDa form and minor isoforms such as the 20-kDa form. Furthermore, GH also exists as aggregates of these isoforms (dimers and oligomers, forming both homoand heterodimers). Following secretion into the blood circulation, the 22-kDa GH has a short half-life of 10-20 minutes^[10].
Human GH is a pleiotropic cytokine that exerts its biological actions by binding to the transmembrane GH receptor, which is present in many cell types. GH may act directly on tissues, but much of its effect is mediated by stimulation of the liver and other tissues to produce and release insulin-like growth factors, primarily insulin-like growth factor 1 (IGF-1; formerly called somatomedin)^[11][12], which regulates growth and metabolism. GH, directly or indirectly via IGF-1, can act on B cells, T cells, NK cells, macrophages and neutrophils to exert immunomodulatory activities. In addition, GH can act directly on various cell types to induce lipolysis, lactation, amino acid uptake and protein synthesis^[9]. It also antagonizes (opposes) the action of insulin^[6].
The two distinct types of effects of growth hormone activity: direct effects, indirect effects can be diagramed as follows^[7]:

Control of growth hormone release

Growth hormone release is not continuous; it is released in a number of ‘bursts’ or pulses every three to five hours^[13]. The pulsatile release of GH into circulation is regulated by the concerted actions of the hypothalamic hormones GH-releasing hormone (GHRH), which stimulates the pituitary to release growth hormone, and somatostatin (SST), which inhibits that release as well as by signals from the periphery ghrelin and leptin^[9]. In addition, one hormone called Ghrelin from the stomach binds to receptors on somatotrophs and potently stimulates secretion of growth hormone. The control process can be shown as follows^[7]:

Disease caused by growth hormone deficiency and excess

GH is vital for normal physical growth in children; its levels rise progressively during childhood and peak during the growth spurt that occurs in puberty, and declines from middle age onward. However, some individuals are affected by abnormalities in GH secretion, which involve either deficiency or overabundance of the hormone^[5][6].
Growth Hormone Deficiency
Too little growth hormone (deficiency) results in poor growth in children which is one of the many causes of short stature and dwarfism. GH deficiency often persists into adulthood, although some people affected in childhood have normal GH secretion in adulthood. GH deficiency in adults causes fatigue, a reduced sense of wellbeing, decreased energy, depressed mood, increased fat, increased risk of heart disease and weak heart, muscles and bones. The condition may be present from birth where the cause can be unknown, genetic or due to injury to the pituitary gland (during development or at birth)^[6][13].
Growth Hormone Excess
Too much growth hormone causes too much growth[13]. Very rarely, increased growth hormone levels can occur in children before they reach their final height, which can lead to excessive growth of long bones, resulting in the child being abnormally tall. This is commonly known as gigantism (a very large increase in height) which happens in young children or adolescents.
In adults, excessive growth hormone for a long period of time produces a condition known as acromegaly, in which patients have swelling of the hands and feet and altered facial features. The onset of this disorder is typically inside, occurring over several years. These patients also have organ enlargement and serious functional disorders such as high blood pressure, diabetes and heart disease. Over 99% of cases are due to benign tumours of the pituitary gland, which produce growth hormone. This condition is more common after middle-age when growth is complete so affected individuals do not get any taller. The excessive growth hormone and IGF-I also lead to a number of metabolic derangements, including hyperglycemia^[7].

Methods to boost growth hormone

GH production decreases with age. In middle age, the brain starts producing lower quantities of growth hormone. People may also suppress normal GH production due to sleep deprivation or disruption. Both normal age-related reduction in GH levels, as well as that caused by lack of sleep, cause side effects such as weight gain, lowered cognitive and physical performance, reduced muscle mass, and other effects associated with aging such as thinning hair and higher risk of diabetes and heart disease^[8].
GH has been shown to slow the progression of age-related degenerative diseases, as well as increase sex drive, help maintain mental acuity, and engender a general sense of well-being^[14].
GH’s association with anti-aging properties has spurred interest in the use of supplemental hormones to keep the body young. Market grew to quickly meet the demand with an abundance of GH over-the-counter products, supplements, creams and pills. However, the effectiveness of many of these is not widely accepted by credible medical authorities, and is not approved by the FDA^[8]. GH can be obtained only through a doctor’s prescription in the United States. For those who lack GH sensitivity, a doctor may prescribe pure IGF-1. Although not uncommon, obtaining GH through illegal means can be dangerous—you can’t be certain of what you’re actually getting—and very expensive^[4]. Because GH is a peptide, it must be injected to have any effect. Any GH packaged in pills or creams are 100% scams^[15].
Without a GH prescription, two major factors can contribute to increase GH levels: weight training and proper sleep. The more you exercise, the more GH you release naturally. GH is also secreted while you sleep, and studies have shown a spike in GH levels at the onset of deep sleep, so getting the recommended seven to nine hours per night is essential to maintaining GH.
Diet is the third major factor in keeping GH levels topped off. It’s necessary to eat a balanced diet. Eating to stay lean is also key; fat gain leads to low levels of GH.
While a multivitamin may give you some of the nutrients needed to provide a small boost in GH levels, a new study reveals that arginine and glutamine can dramatically raise GH levels, but only if taken in proper ratios. You could try to mix these aminos yourself, but if you want something proven to work, you need a specialty supplement. One of our favorites is Growth Factor-9, the only supplement proven to provide a mean GH increase of 682% in a wide range of study subjects^[14].
Besides, fasting can also increase growth hormone^[16]. Fasting is a great stimulus to GH secretion. During fasting, there is the spike in the early morning, but there is regular secretion throughout the day as well. Hartman et al also showed a 5 fold increase in GH in response to a 2 day fast.
GH starts at 0.73 and peaks at 9.86. That is a 1,250% increase in growth hormone. A shorter 5 day fast gives a 300% increase. All this GH increases without drugs^[17].

On healthy people

A healthy supply of GH keeps you healthy psychologically—it maintains your sense of well-being, keeping you happy, engaged, and able to handle stress—and physically, keeping your heart healthy, your cholesterol levels down, inflammation down, bones solid. It even boosts your body’s ability to heal faster. But that doesn’t mean GH is right for every guy^[15].
Studies of healthy adults taking human growth hormone are limited. Although it appears that human growth hormone can increase muscle mass and reduce the amount of body fat in healthy older adults, the increase in muscle doesn't translate into increased strength. It isn't clear if human growth hormone might provide other benefits to healthy adults.
Human growth hormone might cause a number of side effects for healthy adults, including:

• Carpal tunnel syndrome
• Increased insulin resistance
• Swelling in the arms and legs (edema)
• Joint and muscle pain
• For men, enlargement of breast tissue (gynecomastia)

Preparation and Uses

Growth hormone was identified in the 1920s as a growth promoting factor. Scientists began to harvest GH from the pituitary glands of cadavers in the 1950s, but didn’t synthesize the first GH in laboratories until 1981, with its use as a performance-enhancing drug becoming popular shortly thereafter^[14]. By mid to late 1980s scientists were able to produce this 191-residue protein hormone in bacteria using recombinant DNA technology.
With the availability of large quantities of this recombinant hormone, therapeutic uses of growth hormone became possible. Children and adults with growth hormone deficiency can now be treated with growth hormone supplements. Also, patients suffering from diseases that lead to muscle wasting and weakness (like AIDS) also benefit from such supplements. However, in some cases these supplements are exploited to reverse symptoms of aging, to increase muscle mass in athletes and to increase the height of growing children. Used by athletes and weightlifters is banned^[18]. In the food industry, the cow and pig versions of this recombinant hormone protein are used to accelerate growth in farm animals. Although some concerns have been expressed regarding possible effects of consuming meat and milk from these animals, studies show that the growth hormone from these animals does not act on humans^[19].
Other uses of GH, eg, for burns, wound healing, cachexia, osteoporosis, malnutrition, and obesity, are being investigated^[2].
Using GH can cause some side-effects, which could include headache, muscle pain, joint pain, salt and water retention and rare instances of carpal tunnel syndrome (pain or tingling in the first three or four fingers of the hand). Children treated with the drug over the long term develop antibodies to it, but these do not seem to have any harmful effects^[20].

Reference

[1]https://www.novusbio.com/products/growth-hormone-biologically-active-protein_nbc1-18450
[2]Becker, G. W., MacKellar, W. C., Riggin, R. M., & Wroblewski, V. J.. Hormones, Human Growth Hormone. Kirk-Othmer Encyclopedia of Chemical Technology. 2000: 1-11
[3]https://www.sigmaaldrich.com/catalog/product/sigma/h5916?lang=zh®ion=CN
[4]https://www.mayoclinic.org/healthy-lifestyle/healthy-aging/in-depth/growth-hormone/art-20045735
[5]https://www.health.harvard.edu/diseases-and-conditions/growth-hormone-athletic-performance-and-aging;
[6]https://www.britannica.com/science/growth-hormone;
[7]http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/gh.html;
[8]https://www.tuck.com/sleep-hgh/
[9]https://www.rndsystems.com/cn/products/recombinant-human-growth-hormone-gh-protein_1067-gh
[10]https://www.wada-ama.org/en/questions-answers/human-growth-hormone-hgh-testing
[11] https://www.menshealth.com/health/a19523398/truth-about-hgh/;
[12]https://www.peprotech.com/recombinant-human-growth-hormone
[13]http://www.yourhormones.info/hormones/growth-hormone/
[14]https://www.muscleandfitness.com/supplements/build-muscle/everything-you-need-know-about-human-growth-hormone
[15]https://www.mensjournal.com/food-drink/fit-guys-guide-human-growth-hormone/
[16]https://www.healthline.com/nutrition/11-ways-to-increase-hgh
[17]https://www.dietdoctor.com/fasting-and-growth-hormone
[18]https://www.thefreedictionary.com/human+growth+hormone
[19] https://pdb101.rcsb.org/motm/52
[20]http://www.aidsmap.com/Human-growth-hormone/page/1731628/

Chemical Properties

Human Growth Hormone (hGH) is very stable, with no change when left at room temperature for 48h, and its activity can be maintained for several years under freezing conditions. The isoelectric point is 5.2, and the sedimentation coefficient is S20,w2.179. GH from different animals is race-specific, and only primate GH is active in human.

Originator

Somatotrope,Choay,France,1951

Uses

Somatotropin (STH) has been used to study its effects on repressing hepatic H2S production post-transcriptionally. It has also been used as one of the components of a medium to culture primordial follicles.

Definition

Hormone secreted by the anterior lobe of the pituitary. It causes an increase in general body growth and also affects carbohydrate and lipid metabolism.

Manufacturing Process

It has been found that the growth hormone can be obtained in crystalline form from human pituitary glands by procedures comprising (1) extraction of the fresh glands with acetone, (2) extraction of the acetone residue with aqueous salt solutions, (3) precipitation from aqueous salt solutions by the addition of suitable miscible organic solvents of alkaline and acid pH, and finally crystallization from aqueous salt solutions by the addition of suitable miscible organic solvents.

Therapeutic Function

Growth stimulant

General Description

Somatotropin or growth hormone is a peptide hormone that is secreted by the anterior pituitary gland. It is essential for growth. The hormone increases muscle mass, reduces fat mass, helps in maintaining normal blood glucose levels and also promotes a balanced lipid profile.

Biochem/physiol Actions

Increases mass of most tissues by increasing cell number rather than cell size, mobilizes fat stores

Side effects

• Carpal tunnel syndrome
• Increased insulin resistance
• Type 2 diabetes
• Swelling in the arms and legs (edema)
• Joint and muscle pain
• For men, enlargement of breast tissue (gynecomastia)
• Increased risk of certain cancers

Description

GH Human Recombinant produced in E.Coli is a single, non-glycosylated, polypeptide chain containing 191 amino acids and having a molecular mass of 22kDa. Growth Hormone is purified by proprietary chromatographic techniques.

Source

Escherichia Coli

Background

GH is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature.