Growth hormone (GH), also referred to as somatotropin, plays an important role in animal growth and development. It regulates a variety of physiological effects. The molecular mechanism of these biological effects involves the binding of gowth hormone to a specific plasma membrane receptor, referred to as growth hormone receptor (GHR). Growth hormones from different species share a significant level of sequence homology. A human growth hormone (HGH) is a hormone which is continuously secreted from the pituitary gland not only during a growth period but also all through life in a normal human. Human growth hormone is a member of a family of homologous hormones that include placental lactogens, prolactins, and other genetic and species variants of growth hormone. The term "human growth hormone" generally refers to growth hormones in native-sequence or in variant form, and from any source, whether natural, synthetic, or recombinant. Examples include natural human growth hormone (hGH), which is natural or recombinant GH with the human native sequence (somatotropin or somatropin), and recombinant growth hormone (rGH), which is produced by means of recombinant DNA technology, including somatrem, somatotropin, and somatropin. Human growth hormone, hGH, is a protein consisting of a single chain of 191 amino acids. There are two known types of human growth hormone derived from the pituitary gland: one having a molecular weight of about 22,000 (22K or kDa hGH) and the other having a molecular weight of about 20,000 (20K hGH). 20K HGH is made in the pituitary and secreted into the blood. 20K HGH has an amino acid sequence which corresponds to that of 22K hGH consisting of 191 amino acids except that 15 amino acid residues from the 32nd to the 46th inclusive from the N-terminal of 22K hGH are lacked. It makes up about 5% of growth hormone output of adults, and about 20% of growth hormone output of children. It has the same growth promoting activity as 22 kD growth hormone, and has been reported to have equal to or greater the amount of lipolytic activity as the 22 kD form. It binds to growth hormone receptors with equal affinity as the 22 kD growth hormone, and has one tenth the lactogenic (prolactin-like) bioactivity as the 22 kD hormone. Unlike 22 kD, the 20k-HGH has weak anti-insulin activity. 20K hGH has been found to be a growth hormone which exhibits lower risks and higher activity than 22K hGH and has become a novel growth hormone expected to be useful as a pharmaceutical product. 22K hGH is used for manufacturing pharmaceutical products, by means of recombinant DNA technology, for the treatment of pituitary dwarfism, pediatric chronic renal failure, and etc. Recombinant DNA technology opens the way to the large-scale commercial production of human growth hormone, and the recombinant hGH appears to have equivalent biological efficacies and pharmacokinetic propertie. Recombinant hGH (22 kDa) has been available commercially for several years. It is preferred over the pituitary derived products because the product prepared from human tissue might be contaminated and transmit infections.
Human growth hormone participates in much of the regulation of normal human growth and development. Human growth hormone is coded for by two genes, hGH-N and hGH-V, which are clustered on chromosome 17 together with the highly homologous placental lactogen (hPL) gene. Human growth hormone is a key factor in the regulation of certain physiological processes, such as growth and differentiation of muscle and bone cells. The hGH signal is mediated by homodimerization of two identical human growth hormone receptors (hGHR). HGH interacts with each receptor using two distinct binding epitopes, that both bind at the domain interface of the extracellular part of the receptor. Growth hormone appears to affect the growth of virtually every organ and tissue in the body. In normal development, HGH and the somatomedins are responsible for many manifestations of normal growth. Growth hormone regulates the secretion of Insulin-like growth factor (IGF-1) which accounts for most of its biological activity. It is known that physiological roles are probably due both to direct actions of HGH and indirect actions mediated by the peptide hormones known as somatomedins. Somatomedins are stimulated predominantly by the action of HGH and include insulin-like growth factor-I and IGF-II. Human growth hormone is involved in the regulation of normal human somatic growth and also affects a variety of physiological and metabolic functions, including linear bone growth, lactation and cellular energy use, among others. The primary purpose of hGH is that of stimulating growth, cell repair and regeneration. Once the growth period is over, its primary function becomes that of cell regeneration and repair, helping to regenerate skin, bones, heart, lungs, liver and kidneys to their former youthful cell levels. Elevating hGH levels appears to benefit the immune system. Evidence that growth hormone stimulates the synthesis of messenger RNA, ribosomal RNA, and transfer RNA in liver has led to the hypothesis that growth hormone promotes protein synthesis via gene activation. It has also been reported the risk factors for heart attack and stroke may be potentially diminished. Human growth hormone is synthesized in the acidophilic somatotropes, which are specialized cells located in the anterior of the pituitary gland. Secretion of the growth hormone by the pituitary gland is episodic. The anterior pituitary operates in conjunction with the hypothalamus and adrenal glands as an integrated unit. The large array of physiological factors that effect growth hormone secretion act on the pituitary gland through the hypothalamus. The hypothalamus controls this secretion by causing the release of either growth hormone release stimulating or inhibiting factors. These factors result in the release or retention of human growth hormone by the pituitary gland.
A growth hormone is associated with various events in the body, such as lipolysis, protein anabolism and osteogenesis. Therefore, in growth hormone-deficient patients, a lipolytic activity, an insulin-like growth factor I secreting activity, a protein synthesis stimulating activity, a bone metabolizing activity or the like are being decreased. Among them, the decrease in lipolytic activity is one of the factors to cause accumulation of subcutaneous fat or visceral fat, which results in marked obesity. In growth hormone-deficient patients, a complication with hyperlipemia is known to occur in many cases and the morbidity in circulatory disorders such as arteriosclerosis and the mortality from cardiovascular diseases are reported to be high. Because of its anabolic properties, hGH is considered to be a candidate for use in the treatment of a variety of other medical conditions. Growth hormone therapy is used in children to promote growth and in adults to improve muscle strength, reduce fat mass and improve metabolic profiles, which could predispose to cardiovascular disease. Proper human growth from infancy is contingent upon adequate growth hormone secretion. Growth hormone deficiency during the childhood growing period is manifested by profound short stature. HGH is used to stimulate linear growth in patients with hypopituitary dwarfism or Turner's syndrome but other indications have also been suggested. Treatment of human obesity with hGH has been advocated because of its remarkable effects on body composition with lipid metabolism. As a replacement therapy for growth hormone-deficient patients, administrations of the 22-kilodalton human growth hormone produced by a recombinant DNA technique to the patients have been tried. The increase of growth hormone levels following the administration of compounds which induce GH release can lead to growth acceleration and muscular mass increase. Treatments with recombinant human growth hormone have been shown to stimulate growth in children with pituitary dwarfism, renal insufficiencies, Tumer's syndrome and short stature. Recombinant human GH is presently commercialized in Europe and in the United States for children's growth retardation caused by a GH deficiency and for children's renal insufficiencies. A decrease in GH secretion causes changes in body composition during aging. Treatment with recombinant human GH has been reported an increase in the muscle mass and in the thickness of skin, a decrease in fat mass with a slight increase in bone density in a population of aged patients. Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of growth hormone. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. The increase of growth hormone levels in mammals can be achieved by administering known growth hormone release agents or HGH releasers such as growth hormone release hormones (GHRH). Stimulated growth hormone (GH) secretion by a variety of provocative agents including L-dopa, clonidine, arginine and insulin has been used to assess GH secretory capability in children with short stature and in adults with a variety of disorders associated with GH deficiency, such as osteoporosis, muscle atrophy, reduced LDL cholesterol metabolism, poor immune function, etc.
The production of injectable HGH is licensed by the Food and Drug Administration (FDA) and manufactured by large pharnaceutical companies using recombinant DNA technology. The reason that oral drug forms of HGH are not effective is because the hormone is a large protein molecule that is too large to penetrate intact membranes to any significant degree. If swallowed, it is broken down during the process of digestion. However, when administered to humans, human growth homone was also shown to have some drawbacks and side effects. HGH injections are painful and inconvenient, and the cost usually exceeds $10,000 per year. There can be side effects if the injected dosage is too high for the individual. Injections require careful monitoring of blood laboratory tests and careful physician follow-up. There is concern that the administration of human growth hormones to adults tends to induce glucose intolerance. Growth hormone replacement therapy, if taken in excess or if not carefully monitored, can cause diabetes mellitus in otherwise healthy individuals. Growth hormone can also stimulate the growth of connective tissue, which can cause forms of arthritis or other joint disorders. Excessive GH production during skeletal growth produces gigantism, an endocrine and metabolic disorder chracterized by abnormal size or overgrowth of the entire body or any of its parts. Excessive growth hormone production following growth cessation produces the irreversible disorder acromegaly that presents as enlarged hands, feet, and facial features. Recombinant GH therapy may also cause edema (fluid retention), hypertension, carpal tunnel syndrome, hyperinsulinemia and impaired glucose tolerance. HGH supplementation can lead to enlargement of organs (the effect on the spleen can impair insulin production, which can lead to diabetes mellitus), an incrase of blood size can lead to hypertension, which also places stress on the heart due to increased blood viscosity or thickening, carpal tunel compression. Fow women, fluid retention and joint pain have posed significant problems. Thus, there remains a need for alternatives to GH replacement that provide an effective therapeutic means for increasing levels of GH secretion in subjects exhibiting reduced GH levels.
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