Parat hormone in the blood

The reference concentration (norm) of parathyroid hormone in the blood serum of adults is 8-24 ng/l (RIA, N-terminal PTH); intact PTH molecule - 10-65 ng/l.

Parathyroid hormone is a polypeptide consisting of 84 amino acid residues, formed and secreted by the parathyroid glands as a high-molecular prohormone. After leaving the cells, the prohormone undergoes proteolysis to form parathyroid hormone. The production, secretion and hydrolytic cleavage of parathyroid hormone is regulated by the concentration of calcium in the blood. Its decrease leads to stimulation of synthesis and release of the hormone, and a decrease causes the opposite effect. Parathyroid hormone increases the concentration of calcium and phosphates in the blood. Parathyroid hormone acts on osteoblasts, causing increased demineralization of bone tissue. Not only the hormone itself is active, but also its amino-terminal peptide (1-34 amino acids). It is formed during the hydrolysis of parathyroid hormone in hepatocytes and kidneys in greater quantities, the lower the concentration of calcium in the blood. In osteoclasts, enzymes that destroy the intermediate substance of bone are activated, and in the cells of the proximal tubules of the kidneys, reverse reabsorption of phosphates is inhibited. In the intestine, calcium absorption is enhanced.

Calcium is one of the essential elements in the life of mammals. It is involved in a number of important extracellular and intracellular functions.

The concentration of extracellular and intracellular calcium is strictly regulated by targeted transport through the cell membrane and the membrane of intracellular organelles. Such selective transport leads to a huge difference in the concentrations of extracellular and intracellular calcium (more than 1000 times). Such a significant difference makes calcium a convenient intracellular messenger. Thus, in skeletal muscles, a temporary increase in the cytosolic concentration of calcium leads to its interaction with calcium-binding proteins - troponin C and calmodulin, initiating muscle contraction. The process of excitation and contraction in myocardiocytes and smooth muscles is also calcium-dependent. In addition, the intracellular concentration of calcium regulates a number of other cellular processes by activating protein kinases and phosphorylation of enzymes. Calcium is involved in the action of other cellular messengers - cyclic adenosine monophosphate (cAMP) and inositol-1,4,5-triphosphate and thus mediates the cellular response to many hormones, including epinephrine, glucagon, vasopressin, cholecystokinin.

In total, the human body contains about 27,000 mmol (approximately 1 kg) of calcium in the form of hydroxyapatite in bones and only 70 mmol in intracellular and extracellular fluid. Extracellular calcium is represented by three forms: non-ionized (or bound to proteins, mainly albumin) - about 45-50%, ionized (divalent cations) - about 45%, and in calcium-anion complexes - about 5%. Therefore, the total calcium concentration is significantly affected by the albumin content in the blood (when determining the concentration of total calcium, it is always recommended to adjust this indicator depending on the albumin content in the serum). The physiological effects of calcium are caused by ionized calcium (Ca++).

The concentration of ionized calcium in the blood is maintained in a very narrow range - 1.0-1.3 mmol/l by regulating the flow of Ca++ into and out of the skeleton, as well as through the epithelium of the renal tubules and intestine. Moreover, as can be seen in the diagram, such a stable concentration of Ca++ in the extracellular fluid can be maintained despite significant amounts of calcium coming with food, mobilized from the bones and filtered by the kidneys (for example, out of 10 g of Ca++ in the primary renal filtrate, 9.8 g is reabsorbed back into the blood).

Calcium homeostasis is a very complex, balanced and multicomponent mechanism, the main links of which are calcium receptors on cell membranes that recognize minimal fluctuations in calcium levels and trigger cellular control mechanisms (for example, a decrease in calcium leads to an increase in the secretion of parathyroid hormone and a decrease in the secretion of calcitonin ), and effector organs and tissues (bones, kidneys, intestines) that respond to calcium-tropic hormones by correspondingly changing the transport of Ca++.

Calcium metabolism is closely interconnected with phosphorus metabolism (mainly phosphate - PO4), and their concentrations in the blood are inversely related. This relationship is especially relevant for inorganic calcium phosphate compounds, which pose a direct danger to the body due to their insolubility in the blood. Thus, the product of the concentrations of total calcium and total phosphate in the blood is maintained in a very strict range, not exceeding 4 in the norm (when measured in mmol/l), since when this indicator is above 5, active precipitation of calcium phosphate salts begins, causing vascular damage (and rapid development of atherosclerosis ), calcification of soft tissues and blockage of small arteries.

The main hormonal mediators of calcium homeostasis are parathyroid hormone, vitamin D and calcitonin.

Parathyroid hormone, produced by the secretory cells of the parathyroid glands, plays a central role in calcium homeostasis. Its coordinated actions on bone, kidney, and intestine lead to increased calcium transport into the extracellular fluid and increased blood calcium concentrations.

Parathyroid hormone is an 84-amino acid protein weighing 9500 Da, encoded by a gene located on the short arm of chromosome 11. It is formed as a 115-amino acid pre-pro-parathyroid hormone, which, upon entering the endoplasmic reticulum, loses a 25-amino acid region. The intermediate pro-parathyroid hormone is transported to the Golgi apparatus, where the hexapeptide N-terminal fragment is split off and the final hormone molecule is formed. Parathyroid hormone has an extremely short half-life in circulating blood (2-3 min), as a result of which it is split into C-terminal and N-terminal fragments. Only the N-terminal fragment (1-34 amino acid residues) retains physiological activity. The direct regulator of parathyroid hormone synthesis and secretion is the concentration of Ca++ in the blood. Parathyroid hormone binds to specific receptors on target cells: renal and bone cells, fibroblasts, chondrocytes, vascular myocytes, fat cells and placental trophoblasts.

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The effect of parathyroid hormone on the kidneys

The distal nephron contains both parathyroid hormone receptors and calcium receptors, which allows extracellular Ca++ to exert not only a direct (via calcium receptors) but also an indirect (via modulation of blood parathyroid hormone levels) effect on the renal component of calcium homeostasis. The intracellular mediator of parathyroid hormone action is cAMP, the excretion of which in the urine is a biochemical marker of parathyroid gland activity. Renal effects of parathyroid hormone include:

1. increased reabsorption of Ca++ in the distal tubules (at the same time, with excessive secretion of parathyroid hormone, excretion of Ca++ in urine increases due to increased calcium filtration as a result of hypercalcemia);
2. increased phosphate excretion (acting on the proximal and distal tubules, parathyroid hormone inhibits Na-dependent phosphate transport);
3. increased excretion of bicarbonate due to inhibition of its reabsorption in the proximal tubules, which leads to alkalization of the urine (and with excessive secretion of parathyroid hormone - to a certain form of tubular acidosis due to the intensive removal of alkaline anion from the tubules);
4. increasing the clearance of free water and, thus, the volume of urine;
5. increase in the activity of vitamin D-la-hydroxylase, which synthesizes the active form of vitamin D3, which catalyzes the mechanism of calcium absorption in the intestine, thus affecting the digestive component of calcium metabolism.

According to the above, in primary hyperparathyroidism, due to excessive action of parathyroid hormone, its renal effects will manifest themselves in the form of hypercalciuria, hypophosphatemia, hyperchloremic acidosis, polyuria, polydipsia and increased excretion of the nephrogenic fraction of cAMP.

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Action of parathyroid hormone on bones

Parathyroid hormone has both anabolic and catabolic effects on bone tissue, which can be distinguished as an early phase of action (mobilization of Ca++ from bone for rapid restoration of balance with extracellular fluid) and a late phase, during which the synthesis of bone enzymes (such as lysosomal enzymes) is stimulated, promoting bone resorption and remodeling. The primary site of application of parathyroid hormone in bone is osteoblasts, since osteoclasts apparently do not have parathyroid hormone receptors. Under the influence of parathyroid hormone, osteoblasts produce a variety of mediators, among which a special place is occupied by the proinflammatory cytokine interleukin-6 and osteoclast differentiation factor, which have a powerful stimulating effect on osteoclast differentiation and proliferation. Osteoblasts can also inhibit osteoclast function by producing osteoprotegerin. Thus, osteoclast bone resorption is stimulated indirectly via osteoblasts. This increases the release of alkaline phosphatase and the urinary excretion of hydroxyproline, a marker of bone matrix destruction.

The unique dual action of parathyroid hormone on bone tissue was discovered back in the 1930s, when it was possible to establish not only its resorptive, but also its anabolic effect on bone tissue. However, only 50 years later, based on experimental studies with recombinant parathyroid hormone, it became known that the long-term constant effect of excess parathyroid hormone has an osteoresorptive effect, and its pulsed intermittent entry into the blood stimulates bone tissue remodeling [87]. To date, only a synthetic parathyroid hormone preparation (teriparatide) has a therapeutic effect on osteoporosis (and does not simply stop its progression) of those approved for use by the US FDA.

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Action of parathyroid hormone on the intestines

PTH does not have a direct effect on gastrointestinal calcium absorption. These effects are mediated through regulation of the synthesis of active (l,25(OH)2D3) vitamin D in the kidneys.

Other effects of parathyroid hormone

In vitro experiments have also revealed other effects of parathyroid hormone, the physiological role of which is not yet fully understood. Thus, the possibility of changing blood flow in intestinal vessels, increasing lipolysis in adipocytes, and increasing gluconeogenesis in the liver and kidneys has been established.

Vitamin D3, already mentioned above, is the second strong humoral agent in the calcium homeostasis regulation system. Its powerful unidirectional action, causing increased calcium absorption in the intestine and an increase in the concentration of Ca++ in the blood, justifies another name for this factor - hormone D. The biosynthesis of vitamin D is a complex multi-stage process. About 30 metabolites, derivatives or precursors of the most active 1,25(OH)2-dihydroxylated form of the hormone can be simultaneously present in human blood. The first stage of synthesis is hydroxylation in position 25 of the carbon atom of the styrene ring of vitamin D, which either comes with food (ergocalciferol) or is formed in the skin under the influence of ultraviolet rays (cholecalciferol). At the second stage, repeated hydroxylation of the molecule in position 1a occurs by a specific enzyme of the proximal renal tubules - vitamin D-la-hydroxylase. Among the many derivatives and isoforms of vitamin D, only three have pronounced metabolic activity - 24,25(OH)2D3, l,24,25(OH)3D3 and l,25(OH)2D3, but only the latter acts unidirectionally and is 100 times stronger than other vitamin variants. By acting on specific receptors of the enterocyte nucleus, vitamin Dg stimulates the synthesis of a transport protein that carries calcium and phosphate through cell membranes into the blood. The negative feedback between the concentration of 1,25(OH)2 vitamin Dg and the activity of lа-hydroxylase ensures autoregulation, preventing an excess of active vitamin D4.

There is also a moderate osteoresorptive effect of vitamin D, which manifests itself exclusively in the presence of parathyroid hormone. Vitamin Dg also has an inhibitory dose-dependent reversible effect on the synthesis of parathyroid hormone by the parathyroid glands.

Calcitonin is the third of the main components of hormonal regulation of calcium metabolism, but its effect is much weaker than the previous two agents. Calcitonin is a 32-amino acid protein that is secreted by parafollicular C-cells of the thyroid gland in response to an increase in the concentration of extracellular Ca++. Its hypocalcemic effect is realized through inhibition of osteoclast activity and an increase in calcium excretion in urine. The physiological role of calcitonin in humans has not yet been fully established, since its effect on calcium metabolism is insignificant and is overlapped by other mechanisms. Complete absence of calcitonin after total thyroidectomy is not accompanied by physiological abnormalities and does not require replacement therapy. A significant excess of this hormone, for example, in patients with medullary thyroid cancer, does not lead to significant disturbances in calcium homeostasis.

Regulation of parathyroid hormone secretion is normal

The main regulator of the rate of parathyroid hormone secretion is extracellular calcium. Even a small decrease in the concentration of Ca++ in the blood causes an immediate increase in parathyroid hormone secretion. This process depends on the severity and duration of hypocalcemia. The initial short-term decrease in the concentration of Ca++ leads to the release of parathyroid hormone accumulated in the secretory granules during the first few seconds. After 15-30 minutes of hypocalcemia, the true synthesis of parathyroid hormone also increases. If the stimulus continues to act, then during the first 3-12 hours (in rats) a moderate increase in the concentration of the parathyroid hormone gene matrix RNA is observed. Long-term hypocalcemia stimulates hypertrophy and proliferation of parathyroid cells, which is detected after several days to weeks.

Calcium acts on the parathyroid glands (and other effector organs) through specific calcium receptors. The existence of such structures was first proposed by Brown in 1991, and the receptor was later isolated, cloned, and its function and distribution studied. It is the first receptor discovered in humans that recognizes an ion directly, rather than an organic molecule.

The human Ca++ receptor is encoded by a gene on chromosome 3ql3-21 and consists of 1078 amino acids. The receptor protein molecule consists of a large N-terminal extracellular segment, a central (membrane) core, and a short C-terminal intracytoplasmic tail.

The discovery of the receptor has made it possible to explain the origin of familial hypocalciuric hypercalcemia (more than 30 different mutations of the receptor gene have already been found in carriers of this disease). Mutations that activate the Ca++ receptor, leading to familial hypoparathyroidism, have also been recently identified.

The Ca++ receptor is widely expressed in the body, not only in organs involved in calcium metabolism (parathyroid glands, kidneys, thyroid C-cells, bone cells), but also in other organs (pituitary gland, placenta, keratinocytes, mammary glands, gastrin-secreting cells).

Recently, another membrane calcium receptor has been discovered, located on parathyroid cells, placenta, and proximal renal tubules, the role of which still requires further study of the calcium receptor.

Among other modulators of parathyroid hormone secretion, magnesium should be noted. Ionized magnesium has an effect on parathyroid hormone secretion similar to that of calcium, but much less pronounced. High levels of Mg++ in the blood (can occur in renal failure) lead to inhibition of parathyroid hormone secretion. At the same time, hypomagnesemia does not cause an increase in parathyroid hormone secretion, as one would expect, but a paradoxical decrease, which is obviously associated with intracellular inhibition of parathyroid hormone synthesis due to a lack of magnesium ions.

Vitamin D, as already mentioned, also directly influences parathyroid hormone synthesis through genetic transcriptional mechanisms. In addition, 1,25-(OH) D suppresses parathyroid hormone secretion at low serum calcium and increases intracellular degradation of its molecule.

Other human hormones have a certain modulating effect on the synthesis and secretion of parathyroid hormone. Thus, catecholamines, acting mainly through 6-adrenergic receptors, increase the secretion of parathyroid hormone. This is especially pronounced in hypocalcemia. Antagonists of 6-adrenergic receptors normally reduce the concentration of parathyroid hormone in the blood, but in hyperparathyroidism this effect is minimal due to changes in the sensitivity of parathyroid cells.

Glucocorticoids, estrogens and progesterone stimulate the secretion of parathyroid hormone. In addition, estrogens can modulate the sensitivity of parathyrocytes to Ca++, and have a stimulating effect on the transcription of the parathyroid hormone gene and its synthesis.

The secretion of parathyroid hormone is also regulated by the rhythm of its release into the blood. Thus, in addition to stable tonic secretion, a pulsating release of it has been established, occupying a total of 25% of the total volume. In acute hypocalcemia or hypercalcemia, the pulsating component of secretion is the first to react, and then, after the first 30 minutes, the tonic secretion also reacts.