Somatotropin

Discovery

GH (Somatotropin) is secreted by the anterior pituitary in all classes of vertebrates. Somatotropin exhibits a wide range of biological activities, including somatic growth, energy metabolism, sexual maturation, and immune functions. In euryhaline teleosts, GH is involved in seawater adaptability. Pituitary gland-derived growth promoting activity was discovered in 1921, and the first GH was isolated in 1944. The primary structure of human GH was first proposed in 1969. Subsequently, several corrections have been added to this sequence, and its primary structure was determined in 1971. During that same period, the structure of bovine and ovine GH was also determined. In 2002, the structure of GH was determined in the sea lamprey, an extant representative of the Agnatha, a group of the most ancient vertebrates. However, it has not yet been determined in the hagfish.

Structure

GH (Somatotropin) is a single-chain polypeptide. Human Growth Hormone(Somatotropin) contains two highly conserved intramolecular disulfide bonds that are important for biological activity. Somatotropin consists of 178–191 aa residues with two disulfide bonds. In ostariophysan fish, GH contains an additional unpaired cysteine residue. Mr 20,000–22,000, pI 4.9–6.8. GH is soluble in weak acidic or alkaline buffers; insoluble in water, alcohol, acetone, benzene, and chloroform. Human GH is stable in 10M urea for 24 h at room temperature, and stable at 100°C for 10min.

Gene, mRNA, and precursor

In humans, the q22–24 region of chromosome 17 contains two GH genes (GH1, GH2) interspersed with three placental lactogen (PL) genes. GH1 has a Pit-1/GHF-1 regulatory element in the promoter region. In fish, there are two types of exon-intron structures: a five-exon type in the Cypriniformes, Siluriformes, Chondrichthyes, and Agnatha, and a six-exon type in the Salmoniformes, Perciformes, and Tetradontiformes. The six-exon type has an additional intron inserted in exon 5 of the six-exon type.The human GH mRNA has 804 b that encode a signal peptide of 26 aa residues and a mature protein of 191 aa residues. The GH gene is expressed in the acidophilic somatotropes in the pituitary. In the sea lamprey, GH cells are localized in the dorsal half of the proximal pars distalis of the pituitary.

Synthesis and release

The synthesis and release of GH are stimulated by growth hormone-releasing hormone and ghrelin, and are inhibited by somatostatin. Gonadotropin-releasing hormone, thyroid hormone, cortisol, insulin-like growth factor (IGF)-I, and activin are also involved in the regulation of GH synthesis and release.

Agonists and Antagonists

Purified and recombinant human GH are agonists. Antibodies to GHR and pegvisomant (GHR antagonist) are antagonists.

Receptors

The GH receptor (GHR) belongs to the type I cytokine receptor family.6 Human GHR (Somatotropin) consists of 638 aa residues that contain single extracellular, transmembrane, and intracellular domains. The extracellular domain of GHR has conserved cysteine residues and two antiparallel β-sheets holding the GH binding site in between while the intracellular domain has two conserved Pro-rich sequences, Box 1 and Box 2. The initial step in GH signaling is the dimerization of two GHRs,6 which leads to the activation of JAK2 by tyrosine phosphorylation. The activated JAK2 then interacts with and directly activates other signaling molecules such as STAT, SHC, FAK, and PLC. GH also activates the MAPK pathway.

Biological functions

In various vertebrate species, GH (Somatotropin) binds to GHR located in the liver, muscle, adipose tissue, mammary gland, bone, kidney, and embryonic stem cells. GHR is also localized in the immune system. Many of the actions of GH on somatic growth are mediated by IGF. GH stimulates the absorption of amino acids and protein synthesis, and is an important regulator of blood glucose and amino acid utilization. GH also contributes to sexual maturation, gametogenesis, and gonadal steroidogenesis. In euryhaline fish, GH is essential for seawater adaptation.

Clinical implications

GH deficiency (GHD) is a medical condition caused by problems arising in the pituitary that prevent the production of GH, commonly manifested in children as growth failure and short stature. Whereas excess production is rare in childhood but causes gigantism, it is common after epiphyseal plate closure and results in acromegaly with increased size of digits.

Description

Somatropin is a growth hormone useful in the treatment of hypopituitaxy dwarfism and other disorders resulting from growth hormone deficiencies. Lilly has used recombinant technology to produce human somatropin identical to the natural hormone. Somamm, the N-methionyl derivative of somatropin, was launched in 1985 by Genentech for the same indications.

Description

Somatotropin, a second-generation (methionine-free) human growth hormone produced by recombinant technology, was launched in the U.S.A. for the treatment of growth failure in children due to chronic renal insufficiency before transplantation and for the long term treatment of short stature in children with growth failure due to a lack of endogenous growth hormone secretion. The efficacy of somatotropin is reportedly comparable to the first biosynthetic growth hormone somatrem, which contains a methionyl residue, but with less frequent antibody formation and rarely causes allergic effects or impairs growth response. Somatotropin is also in clinical trials for the treatment of growth hormone deficiency in adults and is currently under approval review for Turner's syndrome.

Chemical Properties

White or almost white powder.

Originator

Lilly (USA)

Originator

Genentech (U.S.A.)

brand name

(Genentech); Genotropin (Pharmacia); Humatrope (Lilly);Nutropin (Genentech); Saizen (Serono); Serostim (Serono);22krl;Antuitrin growth;Antuitrin-t;Asellacrin;Cb 311;Corpormon;Crescormon;Grorm;Human groth hormone;Human growth hormon;Leutrophin;Nanormin;Nanormon;Phynatol;Phyol;Phyoneon;Protopin;Protropin;Rx 099916;Somacton;Somatonorm;Somatormone;Somatotrope choay;Somatrofin;Somatropin;Nutropln.

World Health Organization (WHO)

Somatropin, a pituitary-derived human growth hormone, has been used in the treatment of hypopituitary dwarfism for over twenty years. In 1985 it became known that Creutzfeldt-Jakob disease, a potentially fatal form of brain degeneration resulting from a slow neurotropic viral infection, had developed in several patients who had received preparations of somatropin in the late 1960s/early 1970s. This led to the withdrawal of these preparations in many countries. An international collaborative effort was maintained to identify newlydiagnosed cases. By 1990 a total of 30 such cases had been notified. More efficient purification procedures introduced during the 1970s greatly reduced the risk of viral contamination, but products containing pituitary-derived somatropin have been superseded by biosynthetically-manufactured preparations produced using recombinant techniques.

General Description

Somatropin for injection(Humatrope) is a natural-sequence human GH of rDNAorigin. Its composition and sequence of amino acids areidentical with those of human GH of pituitary origin. It isadministered intramuscularly or subcutaneously. Thedosage range is 0.05 to 0.1 IU.

Clinical Use

GHD is treated with purified and recombinant human GH. Recently, the effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been demonstrated in adult GHD. Acromegaly is treated with somatostatin analogs, dopamine antagonists, and GHR antagonists.

Clinical Use

Human Growth Hormone (Somatotropin) is a protein that is essential for normal growth and developmentin humans. Human Growth Hormone(hGH) affects many aspects of humandevelopment and metabolism including longitudinalgrowth, regulation (increase) of protein synthesis and lipolysis,and regulation (decrease) of glucose metabolism. Human Growth Hormone(hGH)has been used as a drug since the 1950s, and it has been extremelysuccessful in the treatment of classic growth hormonedeficiency, chronic renal insufficiency, Turner syndrome,failure to lactate in women, and Prader-Willisyndrome. In its long history, the hormone has been remarkablysuccessful and free of side effects.

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.