Blood parathyroid hormone

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

Parathyroid hormone - a polypeptide consisting of 84 amino acid residues, is formed and secreted by parathyroid glands in the form of high-molecular prohormone. Progormone after exiting the cells undergoes proteolysis with the formation of parathyroid hormone. The production, secretion and hydrolytic cleavage of parathyroid hormone regulates the concentration of calcium in the blood. Reducing it leads to stimulation of synthesis and release of the hormone, and lowering causes the opposite effect. Parathyroid hormone increases the concentration of calcium and phosphate in the blood. Parathyroid hormone acts on osteoblasts, causing an increase in the demineralization of bone tissue. Active not only the hormone itself, but also its amino-terminal peptide (1-34 amino acids). It is formed by the hydrolysis of parathyroid hormone in hepatocytes and kidneys in the more quantity, the lower the concentration of calcium in the blood. In osteoclasts, enzymes that destroy the intermediate bone material are activated, and in the cells of the proximal tubules of the kidneys, the reverse reabsorption of phosphates is inhibited. Intestinal absorption of calcium is increased.

Calcium is one of the necessary elements in the life of mammals. It participates in the performance of a number of important extracellular and intracellular functions.

The concentration of extracellular and intracellular calcium is tightly regulated by directional 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 the skeletal muscles, a temporary increase in the cytosolic calcium concentration 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, intracellular calcium concentration regulates a number of other cellular processes by activating protein kinases and phosphorylation of enzymes. Calcium is also 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 a variety of hormones, among them epinephrine, glucagon, vasorepressin, cholecystokinin.

In total, about 27,000 mmol (about 1 kg) of calcium in the form of hydroxyapatite in bones and only 70 mmol in intracellular and extracellular fluids are found in the human body. Extracellular calcium is represented by three forms: non-ionized (or associated with proteins, mainly albumin) - about 45-50%, ionized (divalent cations) - about 45%, and about 5% in calcium-anionic complexes. Therefore, the total concentration of calcium is significantly influenced by the content of albumin in the blood (when determining the concentration of total calcium, it is always recommended to adjust this index 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 ++ in and out of the skeleton, and also through the epithelium of the renal tubules and intestines. Moreover, as can be seen on the diagram, such a stable concentration of Ca ++ in the extracellular fluid can be maintained despite significant amounts of calcium coming from the food mobilized from the bones and filtered by the kidneys (for example, from 10 g of Ca ++ in the primary renal filtrate is reabsorbed back into the blood 9.8 g).

Calcium homeostasis is a very complex balanced and multicomponent mechanism, the main links of which are calcium receptors on cell membranes, recognizing minimal calcium level fluctuations and triggering cellular control mechanisms (eg, calcium loss leads to increased secretion of parathyroid hormone and a decrease in calcitonin secretion), and effector organs and tissues (bones, kidneys, intestines) that react to calcium -otropic hormones by appropriate changes in the transport of Ca ++.

Calcium metabolism is closely related to the metabolism of phosphorus (mainly phosphate - -P04), and their concentrations in the blood are inversely related. This relationship is particularly relevant for inorganic calcium phosphate compounds, which pose an immediate danger to the body due to their insolubility in the blood. Thus, the product of the concentrations of total calcium and total blood phosphate is maintained in a very strict range, not exceeding in norm 4 (when measured in mmol / l), since at a value of this index above 5, active precipitation of calcium phosphate salts, causing vascular damage (and rapid development of atherosclerosis), calcification of soft tissues and blockade 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 bones, kidneys and intestines lead to an increase in calcium transport to the extracellular fluid and an increase in the calcium concentration in the blood.

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

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

Effect of parathyroid hormone on the kidneys

In the distal nephron, both parathyroid hormone receptors and calcium receptors are located, which allows extracellular Ca ++ to exert not only direct (through calcium receptors) but also mediated (via modulation of the parathyroid hormone level in the blood) effect on the renal component of calcium homeostasis. The intracellular mediator of parathyroid hormone action is c-AMP, the excretion of which in the urine is a biochemical marker of parathyroid gland activity. The kidney effects of parathyroid hormone action include:

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

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

[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]

Effect of parathyroid hormone on bone

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

The unique dual effect of parathyroid hormone on bone tissue was discovered back in the 30s of the XX century, when it was possible to establish not only resorptive, but also anabolic action of it on bone tissue. However, only 50 years later, on the basis of experimental studies with recombinant parathyroid hormone, it has become known that the long-term constant effect of excess parathyroid hormone exerts an osteorhypertensive effect, and pulse intermittent flow into the blood stimulates bone remodeling [87]. To date, only the preparation of synthetic parathyroid hormone (teriparatide) has a curative effect on osteoporosis (and not just suspends its progression) from among the US-approved FDA.

[27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]

The effect of parathyroid hormone on the intestine

Prat hormone has no direct effect on gastrointestinal absorption of calcium. These effects are mediated through the regulation of the synthesis of active (l, 25 (OH) 2D3) vitamin D in the kidneys.

Other effects of parathyroid hormone

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

Vitamin D3, already mentioned above, is the second strong humoral agent in the system of calcium homeostasis regulation. Its powerful unidirectional action, which causes an increase in calcium absorption in the intestine and an increase in Ca ++ concentration in the blood, justifies the other name of this factor - hormone D. Biosynthesis of vitamin D is a complex multi-stage process. In human blood, about 30 metabolites, derivatives or precursors of the most active 1,25 (OH) 2-dihydroxylated form of a hormone can be simultaneously located. The first step in the synthesis is the hydroxylation at position 25 of the carbon atom of the styrenic vitamin D ring, which either comes with food (ergocalciferol) or is formed in the skin under the influence of ultraviolet rays (cholecalciferol). At the second stage, the molecule is re-hydroxylated at position 1a with a specific enzyme of the proximal renal tubules - vitamin D-la-hydroxylase. Among the many derivatives and isoforms of vitamin D, only three have a 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 other variants of the vitamin. Acting on specific receptors of the enterocyte nucleus, vitamin Dg stimulates the synthesis of a transport protein that carries the transfer of calcium and phosphate through the cellular membranes into the blood. An inverse negative relationship between the concentration of 1,25 (OH) 2 vitamin Dg and the activity of l-hydroxylase provides autoregulation, which does not allow an overabundance of active vitamin D4.

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

Calcitonin is the third major component of the 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 in response to an increase in the concentration of extracellular Ca ++. Its hypocalcemic effect is achieved through inhibition of osteoclast activity and an increase in calcium excretion in the urine. So far, the physiological role of calcitonin in humans has not been fully established, since its effect on calcium metabolism is insignificant and 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 violations of calcium homeostasis.

Regulation of secretion of parathyroid hormone normal

The main regulator of the secretion rate of parathyroid hormone is extracellular calcium. Even a slight decrease in Ca ++ concentration in the blood causes an instant increase in the secretion of parathyroid hormone. This process depends on the severity and duration of hypocalcemia. The primary short-term decrease in Ca ++ concentration results in the release of the parathyroid hormone accumulated in the secretory granules within the first few seconds. After 15-30 minutes of the duration 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 matrix RNA of the parathyroid hormone is observed. Prolonged hypocalcemia stimulates hypertrophy and proliferation of parathyroid cells, which can be detected in a few days or weeks.

Calcium acts on the parathyroid glands (and other effector organs) through specific calcium receptors. For the first time he suggested the existence of similar structures of Brown in 1991, and later the receptor was isolated, cloned, its functions and distribution were studied. This is the first of the receptors found in a person who recognizes directly the ion, 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 allowed to explain the origin of familial hypocalciuric hypercalcemia (more than 30 different mutations of the receptor gene in carriers of this disease have been found). Activating Ca ++ - receptor mutations leading to familial hypoparathyroidism have also been established recently.

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

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

Among other modulators of the secretion of parathyroid hormone, mention should be made of magnesium. Ionized magnesium has an effect on the secretion of parathyroid hormone, similar to the action of calcium, but much less pronounced. A high level of Mg ++ in the blood (can occur with kidney failure) leads to oppression of the secretion of parathyroid hormone. At the same time, hypomagnesemia does not cause an increase in the secretion of parathyroid hormone, as one would expect, but a paradoxical decrease, which is obviously associated with intracellular suppression of the synthesis of parathyroid hormone with a deficiency of magnesium ions.

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

Other human hormones have a certain modulating effect on the synthesis and secretion of parathyroid hormone. So, catecholamines, acting mainly through the 6-adrenergic receptors, enhance 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 with hyperparathyroidism this effect is minimal due to a change in the sensitivity of parathyroid cells.

Glucocorticoids, estrogens and progesterone stimulate the secretion of parathyroid hormone. In addition, estrogens can modulate the sensitivity of parathyroid cells to Ca ++, affect stimulating 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. So, in addition to stable tonic secretion, a pulse discharge has been established, occupying a total of 25% of the total volume. With acute hypocalcemia or hypercalcemia, the first responds to the pulse component of secretion, and then, after the first 30 minutes, tonic secretion also reacts.