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
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.
