Growth hormone

Generally about growth hormone
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Structure, synthesis
Growth hormone (somatotropin, somatotropic hormone, STH, growth hormone, GH) is a linear polypeptide of 191 amino acids with two internal disulfide bridges and M r 21,500. Of the growth hormones of other mammals, only monkey STH is close to it immunologically and chemically. It is also the only one that is biologically effective in humans, the others are completely ineffective. Somatotropin arises from a larger precursor of M r 28,000, the so-called pre-STH (pre-GH), which is also secreted into the blood, but has no physiological effect. STH is synthesized and secreted in adenohypophyseal somatotropes, which make up approximately 50% of the cells of the adenohypophysis and (along with lactotrophs) are among the acidophilic secretory cells of the anterior lobe of the pituitary gland, staining with acid dyes (e.g. eosin).

Receptor pro STH
The growth hormone receptor is a protein of 620 amino acids with a large extracellular part, a transmembrane domain and a large part of the molecule in the cytoplasm, belonging to the family of cytokine receptors. STH has two receptor binding sites, i.e. when it binds to one receptor subunit, the other somatotropin binding site attracts the other receptor subunit. This creates a homodimer, which is necessary for the activation of the receptor and subsequently various intracellular cascades (primarily via the JAK2-Stat pathway of gene activation in the nucleus).

Transport STH
In plasma, STH binds to GHBP (GH binding protein), which is a large fragment of the extracellular domain of the receptor. GHBP is probably produced by cleavage of receptors for STH and its concentration is therefore proportional to the number of receptors for STH in tissues. About half of STH activity is bound, which creates a reserve of STH that can compensate for large fluctuations in its secretion. Free STH has a half-life in the blood of 20–50 min. Radioimmunoassay determines both the free and the bound form because the antibodies used have a higher affinity for the hormone than for the binding proteins.

Values
Endocrine regulation of growth


 * healthy adults secrete approximately 40 µg of STH per day (18.6 nmol/day);
 * adolescent young people secrete about 700 µg/day (32.5 nmol/day);
 * the daily output of the hormone in adults was calculated to be 0.2–1.0 mg/day;
 * in fasting adults, the morning concentration of STH in the blood is below 5 ng/ml (232 pm/l), sometimes even lower (2 ng/ml).

Genes
The gene for STH is located on the long arm of chromosome 17 in a cluster of five genes: STH-N encodes human STH, STH2 encodes a variant of STH produced in  the placenta, CSH1 and CSH2 encode prolactin, and CSHP1 , which encodes a variant of the prolactin molecule. STH, which is the product of the STH-N gene, is present in the greatest amount and represents about 75% of STH in the blood.

Gene for hCS
The STH2 gene is mainly expressed in  the placenta and its product is human chorionic somatomamotropin (hCS), which is also 191 amino acids long, but differs from "normal" STH by 13 amino acids. It is produced by the syncytiotrophoblast, it is found in large quantities in the maternal blood during pregnancy, but little passes into the blood of the fetus. In turn, it can reduce the secretion of STH from the pituitary gland in the mother. It is believed that hCS has a lactogenic effect (a positive effect on the growth of the mammary gland and on lactation) and most of the effects of growth hormone: it causes nitrogen, potassium and calcium retention, lipolysis and a decrease in glucose utilization in pregnancy, which helps the supply of glucose to the fetus. The amount of hCS produced is proportional to the size of the placenta.

Secretion of STH
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Control of secretion by the hypothalamus
STH secretion is controlled by two hypothalamic hormones, which are secreted into the portal pituitary blood:


 * 1) GHRH (STH-RH, GRH, somatoliberin) – has a stimulating effect.
 * 2) Somatostatin (GHIH) – has an inhibitory effect.

Since neither GRH nor somatostatin can be directly measured, it is necessary to consider the change in STH secretion as a manifestation of the sum of both of these hypothalamic hormones. In addition to this regulation, a number of other factors are involved in the regulation of STH secretion (see below).

GHRH
GRH stimulates the synthesis and secretion of STH in the somatotropes of the adenohypophysis (by the formation of cAMP ). GRH of 40 and 44 amino acids is present in the human hypothalamus. GRH-secreting neurons are located in  the nucleus arcuati and their axons terminate in the outer layer of the eminentia medialis. GRH is synthesized from a larger precursor of 107 or 108 amino acids (differs in the presence or absence of serine at position 103). Human GRH is highly similar to many gastrointestinal peptides, including secretin, gastrin, vasoactive intestinal peptide (VIP), and gastric inhibitory peptide. The half-life of GRH is 50 min. Administration of GRH leads to rapid secretion of STH (within minutes), peaks at 30 minutes and lasts for 60-120 minutes.

Somatostatin
Somatostatin inhibits the secretion of STH (reduces the formation of cAMP in somatotropes) and TSH (by increasing the direct inhibitory effect of thyroid hormones on adenohypophyseal thyrotropes). Cells secreting somatostatin are located in the periventricular region of the hypothalamus immediately above the optic chiasm, and their nerve endings are diffuse in the outer layer of the eminentia medialis. Somatostatin is a tetradecapeptide and, in addition to the hypothalamus, it is also found in the D-cells of the pancreatic islets of Langerhans, in the gastrointestinal mucosa, and in the parafollicular cells (C-cells) of the thyroid gland. The somatostatin precursor has 116 amino acids. Somatostatin-14 is the main one in the hypothalamus, somatostatin-28 is in the intestine. Somatostatin also has strong inhibitory effects on other hormones, including insulin and glucagon (paracrine in the islets of Langerhans), gastrin, secretin, and VIP (in the gastrointestinal mucosa). Somatostatin secretion increases with elevated STH and IGF-I levels (see below). A long-acting synthetic analogue of somatostatin (octreotide acetate) is used in therapy (for conditions of STH excess).

Shock secretion
STH is released into the blood in pulses. This irregular, intermittent secretion is associated with sleep and depends on age. It reaches its peak 1-4 hours after falling asleep (during sleep stages 3 and 4). These nocturnal secretion pulses amount to about 70% of the total amount secreted per day and are higher in children, decreasing with age. GRH secretion is episodic and its increase correlates with an increase in STH secretion. Somatostatin secretion is rather tonic.