Relatively little PTH is stored in secretory granules within the parathyroid glands. In the absence of a stimulus for release, intraglandular metabolism occurs, causing complete degradation to its constituent amino acids or partial degradation to fragments (Figure 1). This has been postulated to occur through a specific calcium- regulated enzymatic mechanism. In the case of hypercalcaemia, the predominant hormonal entities released from the gland are fragments comprising midregion or COOH- terminal sequences. In response to hypocalcaemia, degradation of PTH within the parathyroid cell is minimized, and the major hormonal entity released is the bioactive PTH 1- 84 molecule. Thus, in the presence of hypocalcaemia, increased amounts of bioactive PTH are secreted, even in the absence of additional synthesis of hormone. Hormone stores are insufficient, however, to maintain secretion for more than a few hours in the presence of a sustained severe hypocalcaemic stimulus, and other mechanisms— transcriptional and posttranscriptional— come into play to increase hormone pro duction. For example, hypocalcaemia promotes stabilization of the preproPTH mRNA leading to increased PTH synthesis. In the presence of a sustained severe hypocalcaemic stimulus, additional PTH secretion depends on an increase in the number of parathyroid cells. Such an increase may also be stimulated by the reduction in circulating 1,25- dihydroxyvitamin D [1,25(OH)2D] that often ac companies hypocalcaemia. Normally, the sterol inhibits parathyroid cell proliferation by suppressing expression of immediate early response genes, such as the MYC proto- oncogene.
Fig1. Schema of the sites of regulation of parathyroid hormone (PTH) biosynthesis, intraglandular degradation, and secretion. Both extracellular fluid calcium and 1,25- dihydroxyvitamin D levels negatively regulate transcription of the PreproPTH gene. Hypercalcaemia increases PreproPTH mRNA turnover and PTH degradation while hypocalcaemia stabilizes PreproPTH mRNA and promotes the production and synthesis of mature PTH.
A circadian rhythm has been reported for PTH secretion, with increased blood levels occurring at night and small amplitude pulses of PTH secretion occurring at much shorter intervals. This suggests neural or central nervous system influences on PTH secretion, or reflects circadian alterations in the levels of extracellular calcium.
