Parathyroid hormone
Metabolism
Parathyroid hormone is synthesized by parathyroid glands from a polypeptide chain of 115 amino acids which, by successive hydrolyses, leads to active PTH formed of 84 amino acids.
The secretion of parathormone is controlled by the concentration of ionized calcium circulating through the parathyroid glands: when it is lowered, the secretion of PTH increases and conversely. Ionized calcium acts as a messenger on cell-surface receptors coupled to G proteins, called CaR, calcium receptor or CaSR, calcium-sensing receptor. Magnesium ions act in the same direction as calcium.
Certain compounds tend to increase the secretion of PTH: beta adrenergic agonists, dopamine, secretin, prostaglandin E and hyperkalemia. Others tend to decrease: alpha adrenergic agonist, prostaglandin F and chloride.
The plasma half-life of PTH is less than four minutes: it is degraded to inactive peptides which are eliminated in urine and bile.
Effects
PTH acts primarily on bone and kidneys by activating PTH1 receptors coupled to G proteins.
- Bone effects
The bone effects of PTH are complex and sometimes opposite. PTH, secreted in excess during hyperparathyroidism, increases bone resorption with phosphate and calcium release from bone, which tends to increase their plasma concentration. But, in low or pulsated doses, PTH increases the binding of calcium by bone and is used in these conditions for the treatment of osteoporosis.
- Renal effects
PTH increases the distal tubular reabsorption of calcium whose concentration tends to rise in plasma and decreases the reabsorption of phosphate whose concentration tends to decrease in plasma (its renal elimination is increased)
It reduces magnesium excretion and induces its rise in plasma.
It increases bicarbonate chloride and sulfate excretion.
- Intestinal effect
PTH, by inducing the conversion of calcifediol into calcitriol in the kidney, increases via calcitriol the intestinal absorption of calcium and phosphate.
- Plasma consequences
- Calcemia: PTH tends to increase calcemia by action on bone and kidney.
- Phosphatemia: PTH by increasing the renal elimination tends to reduce phosphatemia, but its effect on bone acts in the opposite direction. It is the renal effect which prevails.
- Vascular effect
PTH has vasodilator effect by stimulating PTH2 receptors.
Hypoparathyroidism is one of the causes of hypocalcemia which is generally treated with vitamin D and calcium. Parathyroid hormone is not used in the treatment of hypoparathyroidism.
Hyperparathyroidism results from a hypersecretion of PTH (hyperplasia, adenoma, carcinoma).
Therapeutic use
An analog of PTH, teriparatide, called rhPTH (1-34), rh for human recombinant and 1-34 because it is formed of the first 34 amino acids of PTH which contains 84, has the same biological properties as human natural PTH.
Teriparatide (Forteo*) is indicated for the treatment of osteoporosis in postmenopausal women at high risk of fractures. It is administered by subcutaneous route, once daily, at the dose of 20 micrograms. It increases transitorily after the injection calcemia and calciuria. Used during several months it increases bone density and reduces the frequency of fractures.
In male and female rats, teriparatide, in large and repeated doses, caused an increase of the incidence of osteosarcoma. Although this type of effect does not seem to have been observed in humans, this information must be taken into account until further data have been collected.
Modifiers of PTH secretion
The secretion of PTH increases when ionized calcium, Ca2+, decreases in plasma and conversely.
The compounds which act as extracellular calcium on the calcium receptors of the parathyroid gland or sensitize calcium receptors to calcium are called calcimimetic and those which have the inverse effect calcilytic.
Calcimimetic drug such as cinacalcet (Sensipar*, tablets) sensitize the CaSR receptors of the parathyroid gland to extracellular calcium and decrease the release of parathormone. The reduction of TPH is associated with a concomitant decrease in plasma calcium level. Cinacalcet is used in patients with hyperparathyroidism (abnormally high secretion of PTH) secondary to chronic kidney disease requiring dialysis, and in patients with parathyroid carcinoma.
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