Compared with other secretory systems, the parathyroid cell contains minimal amounts of hormone stored in the granules. Consequently, regulation of secretion occurs at the gene level and by cell proliferation. PTH is initially synthesized as pre–pro-PTH, a large precursor peptide of 115 amino acids. During translation from its messenger ribonucleic acid (mRNA), the initial “pre” sequence directs the growing peptide across the membrane of the endoplasmic reticulum and is then cleaved before synthesis of the entire hormone is completed. The 90-amino-acid pro-PTH is then transported through membrane channels to the Golgi apparatus where the hexapeptide extension of pro-PTH is removed. PTH is stored in the secretory vesicles until secretion occurs. Once secreted it is metabolized to inactive products composed of fragments from the carboxyl (C)-terminal end. Modern-day assays for PTH recognize the intact molecule and do not measure the inactive C-terminal fragments.

The regulation of PTH secretion is more complex than previously recognized. Its secretion is controlled not only by serum calcium and phosphorus but also by the active form of 1,25-dihydroxyvitamin D (1,25-DHVD) and by fibroblastic growth factor-23 [FGF23] and its membrane receptor Klotho.

Serum calcium and phosphorus have a post-transcriptional effect on gene PTH expression. Hypocalcemia increases mRNA levels and PTH secretion. Chronic low-calcium states also induce cell proliferation. Increased serum phosphorus has opposite effects. It decreases secretion of PTH via a regulatory step at the mRNA level where specific proteins stabilize or destabilize the concentration of PTH mRNA.

FGF23 is a regulatory protein of phosphorus. It is a skeletal protein that acts on the kidney to decrease synthesis of 1,25-DHVD and increase phosphorus excretion through binding to a renal membrane protein called Klotho. The parathyroid cell also has this Klotho receptor protein. The binding of FGF23 to parathyroid cell Klotho receptor causes an activation of specific intracellular kinases that suppress PTH gene expression and subsequent secretion of the hormone.