GROWTH HORMONE (SOMATOTROPIN): STRUCTURE, FUNCTIONS - BIOLOGY - 2025

The somatotropin (STH) or growth hormone (GH for short) is a relatively small protein produced at the level of the adenohypophysis and involved in development processes, longitudinal growth of the organism and control of various metabolic processes.

It is a non-glandotropic hormone. The glandotropic hormones of the pituitary exert their effects through the modification in the synthesis and release of other hormones produced in other endocrine glands in the periphery of the organism.

Hormone modification in the pituitary gland (Source: Dubaele / Public domain, via Wikimedia Commons)

Glandotropic hormones are, for example, adrenocorticotropin (ACTH), gonadotropins (FSH and LH) and thyroid stimulating hormone (TSH).

Non-glandotropic hormones, for their part, and among which prolactin and growth hormone are included, act without the assistance of any other endocrine gland, since they exert their actions directly on the target cells whose activities they regulate.

Structure

Growth hormone is a relatively small protein that occurs in several isoforms. The major isoform is composed of about 191 amino acids, has a molecular weight of 22 kDa, and is derived from a longer precursor peptide (pre-GH) of 28 kDa, which is also secreted but lacks physiological functions.

In its structure, somatotropin appears evolutionarily homologous to prolactin and chorionic somatomamotropin (CS), the latter produced in the placenta. Such is the similarity that the three are considered to form a hormonal family.

Approximate structure of growth hormone (Source: Роман Беккер, via Wikimedia Commons)

The secondary structure of somatotropin shows 4 stabilized alpha helices with two disulfide bridges, the configuration of which is necessary for the interaction of the hormone with its receptor.

A fact in relation to the structure, and worth highlighting, is represented by the fact that despite the fact that the growth hormones of different species have remarkable similarities with the human, only the latter, and that of primates, exert effects significant in humans.

Features

The functions of somatotropin are usually described as those associated with the development and growth of the organism. Also those associated with metabolism, which include the changes in lipid and glucose metabolism promoted by the hormone.

Growth functions, however, can also be considered metabolic, since they involve anabolic functions associated with protein synthesis, which does not exclude some other functions without direct association with metabolism, such as cell proliferation.

Some of the functions or actions displayed by somatotropin are exerted by this hormone directly on its white tissues, but many of them are carried out by some other substances whose synthesis and release are stimulated by growth hormone.

IGF synthesis

The first line of action of somatotropin is precisely the synthesis of these substances that are known as insulin-like growth factors (IGF), of which types 1 and 2 have been identified. They are designated as IGF1 (the most important) and IGF2, according to their acronym in English.

These factors were initially known, and are still being designated, as mediators of the activity of somatotropin or somatomedins C (IGF1) and A (IGF2) or also as non-suppressible insulin-like activity (NSILA). They are synthesized by many cell types, but are produced primarily in the liver.

The actions of STH and IGF1 are very diverse. Some are exerted by each of these substances independently, sometimes in conjunction and synergistically, and sometimes they act antagonistically.

Growth induction

This is one of the most important actions promoted by somatotropin, but performed in conjunction with IGF1. Although both induce the growth of numerous body tissues, their most prominent effect is on skeletal growth.

This end result is produced by various effects induced by the hormone and IGF1. They include the increased protein deposition by chondrocytic and osteogenic cells, the higher rate of reproduction of these cells, and the conversion of chondrocytes into osteogenic cells; all of which leads to the deposit of new bone.

During the growth and development of the organism, and before the closure of the bony epiphyses, new cartilage is deposited in the epiphyses followed by its conversion into new bone, with which the diaphyses are lengthened and the epiphyses separate.

The progressive consumption of epiphyseal cartilage depletes it and the bone cannot continue to grow. In late adolescence, the diaphysis and epiphysis then fuse at each end, and the growth in length of the long bones slows and finally stops.

A second mechanism may explain the increased thickness of the bones. The periosteal osteoblasts deposit new bone on the old one, and the osteoclasts eliminate the old bone. If the deposition rate exceeds the removal rate, the thickness increases.

As the growth hormone exerts an intense stimulation on the osteoblasts, under its effects the thickness of the bones can continue to increase, although their length no longer changes due to the closure of the epiphyses.

Enhancement of protein deposition in tissues

This effect can be achieved through different mechanisms: increased amino acid transport across cell membranes, increased RNA translation at the ribosome level, increased transcription from DNA to RNA in the nucleus, and reduced protein and amino acid catabolism.

Other metabolic actions

In fatty tissue, growth hormone promotes lipolysis and the release of fatty acids into the bloodstream, thereby increasing its concentration in body fluids. At the same time, it favors the conversion of fatty acids into acetyl coenzyme A and their use as an energy source in all tissues.

The stimulation of the use of fats, together with the accumulation of proteins due to its anabolic effect, lead to an increase in lean tissue.

The increase in fat mobilization can be so high that the liver produces large amounts of acetoacetic acid leading to ketosis and a fatty liver can develop.

In relation to carbohydrate metabolism, the effects of somatotropin include decreased glucose uptake in adipose and skeletal muscle tissue, increased hepatic glucose production, and increased insulin secretion.

All of these effects are called diabetogenic, and high growth hormone secretion can reproduce the metabolic disturbances that accompany non-insulin-dependent type II diabetes.

Other functions

The anabolic and mitogenic actions of GH and IGF1 are also manifested in the growth and function of the heart, liver, spleen, thyroid, thymus, and tongue. The hormone can contribute to skin thickening, sweat gland stimulation, and hair growth.

In the kidneys, it increases the glomerular filtration rate and the synthesis of calcitriol, which favors not only growth, but also bone mineralization. It also promotes erythropoiesis and fibrinogen synthesis and the immune response by stimulation of T lymphocytes and macrophages.

Receptors for somatotropin

The actions of somatotropin, including promoting the synthesis of insulin-like growth factors, are mediated through its binding to specific receptors expressed on target cell membranes.

There are two forms of these receptors, the second of which is a short (truncated) variant of the first; a truncated form that inhibits the function of the long receptor, and if it becomes overexpressed it would produce tissue insensitivity to the hormone.

The long receptor is made up of 638 amino acids and has an extracellular domain of 250, a transmembrane alpha helix of about 38, and an intracellular domain of 350 amino acids. Each somatotropin molecule ends up binding to two receptor molecules and causing what is called receptor dimerization.

This dimerization activates JAK2 protein kinases located at the intracellular ends of each receptor monomer, and these active kinases phosphorylate other substrates such as STAT5 and the somatotropin receptor itself.

Phosphorylated STAT5 molecules also undergo dimerization that makes them very precise regulators of gene expression and protein synthesis.

Production

Somatotropin is synthesized at the level of the somatotropic cells of the adenohypophysis. These cells are intensely stained with acidic substances, which is why they are also called acidophilic. Together they are the most abundant cell group in the gland since they represent 50% of the total of 5 different types.

There is a genetic complex of 5 genes on the long arm of human chromosome 17 that codes for the different isoforms of growth hormone and human chorionic somatomamotropin (hCS).

One of them is hGH-N or normal, which encodes the most abundant form of human growth hormone, which is the 22 kDa one mentioned and represents 75% of the total circulating growth hormone.

Its messenger RNA undergoes "splicing" to produce a smaller form of the hormone, 20 kDa, which lacks amino acid residues 32-46 and accounts for 10%.

A second gene (hGH-V) is expressed primarily in the placenta and encodes a variant form of hGH of which only significant amounts appear in the circulation during pregnancy. The other 3 genes encode isoforms of human chorionic somatomamotropin.

Release

Both the synthesis and the secretion or release of growth hormone are regulated by stimulating and inhibiting factors of these functions.

Stimulating influences

The main humoral influences that stimulate the synthesis and secretion of somatotropin include the peptides GHRH (growth hormone releasing hormone) and Ghrelin.

Growth hormone releasing hormone (GHRH) is a hypothalamic peptide that exists in two variants of 40 and 44 amino acids respectively. It leads in somatotrophic cells to the synthesis of cAMP and the activation of the transcription factor PIT1 specific for growth hormone.

Ghrelin is an endogenous growth hormone secretagogue. It is a peptide of about 28 amino acids synthesized at the level of the hypothalamus and in the stomach. It acts synergistically with GHRH whose release it promotes, at the same time that it inhibits that of somatostatin. It works through receptors that activate phospholipase C.

Some metabolic parameters such as hypoglycemia, low levels of free fatty acids in the blood and high concentrations of amino acids are important stimuli for the secretion of growth hormone.

Other stimulant factors that count include acute stress, body strain, pain, sex steroids (puberty), dopamine, α2 receptor stimulation, acetylcholine, galanin, serotonin, and β-endorphin.

Inhibitory influences

These include somatostatin or growth hormone release inhibitor hormone (GHRIH) and negative feedback.

Somatostatin is a 14 amino acid hypothalamic peptide that inhibits the secretion, but not the synthesis, of growth hormone. A long variant, of 28 amino acids, is synthesized in the gastrointestinal tract. Both variants bind to the same receptor and inhibit cyclic AMP synthesis.

Regarding negative feedback, released GH, through autocrine action, inhibits its own subsequent release. IGF1 inhibits growth hormone-releasing hormone in the hypothalamus and stimulates somatostatin, while it inhibits GH synthesis in the pituitary.

Some metabolic parameters such as hyperglycemia, high plasma levels of free fatty acids, and low levels of amino acids are inhibitors of somatotropin secretion.

Inhibitors are also cold, chronic stress, adiposity, progesterone, thyroid hormone deficiencies, cortisol deficits or excesses, and β2 adrenergic receptor stimulation.

Dose

The therapeutic use of biosynthesized growth hormone is indicated for the treatment of conditions in which a deficiency in its secretion has been shown, in pituitary dwarfism and in short children due to Turner syndrome.

Administration is made in the form of an injectable solution reconstructed from a vial containing a lyophilisate with 40 IU of the biosynthetic hormone, and to which the accompanying 2 ml of 0.9% sodium chloride solution are added.

In growth hormone deficiency in children, between 0.07 and 0.1 IU / kg of body weight per day is recommended. In Turner syndrome 0.14 IU / kg of body weight per day. For growth hormone deficiency in adults: 0.018 to 0.036 IU / kg of body weight per day.

Effects edit

The therapeutic administration of growth hormone can be accompanied by some adverse side effects such as overt hypersensitivity through generalized urticaria, fasting hypoglycemia, inflammation at the injection site, and temporary headache.

The development of a certain benign intracranial hypertension has been described, more frequent in children and less in adults.

Regarding carbohydrate metabolism, the development of diabetes mellitus has been reported in patients receiving growth hormone treatment.

In relation to the musculoskeletal system there is evidence of inflammatory myositis with myalgia and muscle weakness, produced not by the hormone, but perhaps by the metacresol used as a preservative in the formula.

Gynecomastia, anemia, and acute pancreatitis have been reported.

References

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2. Guyton AC, Hall JE: Pituitary Hormones and Their Control by the Hypothalamus, in Textbook of Medical Physiology, 13th ed, AC Guyton, JE Hall (eds). Philadelphia, Elsevier Inc., 2016.
3. Lang F, Verrey F: Hormone, in Physiologie des Menschen mit Pathophysiologie, 31 th ed, RF Schmidt et al (eds). Heidelberg, Springer Medizin Verlag, 2010
4. Voigt K: Endokrines System, in Physiologie, 6th ed; R Klinke et al (eds). Stuttgart, Georg Thieme Verlag, 2010.
5. Widmaier EP, Raph H and Strang KT: The Endocrine System. The Hypothalamus and Pituitary Gland, in Vander's Human Physiology: The Mechanisms of Body Function, 13th ed; EP Windmaier et al (eds). New York, McGraw-Hill, 2014.