New concepts in the formation, regulation of release, and metabolism of parathyroid hormone.

Abstract

New information has elucidated many of the biochemical pathways in the formation, release and metabolism of parathyroid hormone (PTH). The hormone is biosynthesized in the parathyroid cells from two distinct precursors, or prohormones, that are modified by specific enzymic cleavages during the synthesis and intracellular transport of the hormonal polypeptide. Release of the hormone from the gland inversely depends on the extracellular calcium concentration, but is regulated over a much narrower range of calcium concentration than was realized previously. This new information points to a pattern of regulation that is more appropriate for homeostasis than was the pattern indicated by earlier studies. The persistence of a basal level of PTH secretion, despite sustained hypercalcaemia, suggests a possible mechanism for the abnormal secretion seen in states of hyperparathyroidism. The discovery of a calium-dependent degradative pathway for PTH in the parathyroid cell indicates that changes in the turnover of PTH may be one means by which calcium regulates the amount of hormone available for secretion. Of the multiple immunoreactive forms of PTH present in the circulation of man and animals, the predominant form in blood appears to be a large biologically-inactive fragment consisting of the middle and carboxy two-thirds of the hormone sequence. At times, smaller biologically-active fragments of PTH may also appear in blood. Most circulating fragments of PTH probably arise from peripheral cleavage of the intact, secreted hormone in kidney and liver, but some forms of the hormone, including prohormones, may also be secreted from the parathyroid gland. The heterogeneity of circulating PTH and the concomitant uncertainties regarding its precise character have introduced difficulties in the interpretation of immunoassay measurements. A further delineation of the pathways and regulation of PTH biosynthesis, secretion and metabolism should lead to the development of more-specific immuno-assays and result in improved diagnosis and management of patients with disorders of the parathyroid glands.