Parathyroid hormone (PTH) is a single-chain peptide hormone composed of 84 amino acids. It is produced in the parathyroid gland in a precursor form of 115 amino acids, the excess 31 amino terminal amino acids being cleaved off before secretion.
Within the gland is a calcium-sensitive protease capable of cleaving the intact hormone into fragments, thereby providing one mechanism by which calcium limits the production of PTH. A second mechanism involves the calcium-sensing receptor (CaSR) which, when stimulated by calcium, reduces PTH production and secretion. The parathyroid gland also contains the vitamin D receptor (VDR) and the enzyme, CYP27B1, that produces 1,25(OH)2D, thus enabling circulating or endogenously produced 1,25(OH)2D to suppress PTH production. 1,25(OH)2D also induces the CaSR, making the parathyroid gland more sensitive to suppression by calcium. Biologic activity resides in the amino terminal region of PTH such that synthetic PTH 1-34 (available as teriparatide) is fully active. However, a full length form of PTH (rhPTH 1-84, Natpara) has recently been approved for treatment of hypoparathyroidism, as has an analog of PTHrP (abaloparatide). Loss of the first two amino terminal amino acids eliminates most biologic activity.
The metabolic clearance of intact PTH is rapid, with a half-time of disappearance measured in minutes. Most of the clearance occurs in the liver and kidney. The inactive carboxyl terminal fragments produced by metabolism of the intact hormone have a much lower clearance, especially in renal failure. In the past, this accounted for the very high PTH values observed in patients with renal failure when the hormone was measured by radioimmunoassays directed against the carboxyl terminal region. Currently, most PTH assays differentiate between intact PTH 1-34 and large inactive fragments, so that it is possible to more accurately evaluate biologically active PTH status in patients with renal failure.