INTRODUCTION

Parathyroid hormone (PTH) is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-dihydroxyvitamin D) [1]. The minute-to-minute regulation of serum ionized calcium is exclusively regulated through PTH, maintaining the concentration of this cation within a narrow range, through stimulation of renal tubular calcium reabsorption and bone resorption [2,3]. On a more chronic basis, PTH also stimulates the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol in renal tubular cells, thereby stimulating intestinal calcium absorption. (See "Chapter 6F: Hormonal regulation of calcium and phosphate balance".)

PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells [4]. The receptor has a long amino terminus, seven transmembrane segments, and a shorter intracellular carboxyl terminus (figure 1). When activated by a small increase in serum ionized calcium, the calcium-receptor complex acts via one or more guanine nucleotide-binding (G) protein through second messengers such as intracellular calcium and inositol phosphates to inhibit PTH secretion. Conversely, the effect of deactivation of the receptor by a small decrease in serum ionized calcium is to stimulate PTH secretion.

NORMAL PTH SECRETION

PTH synthesis and degradation — PTH is synthesized as a 115- amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the N-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). The latter is the major storage, secreted, and biologically active form of the hormone [5,6]. The biosynthetic process is estimated to take less than one hour. The N-terminal cleaved pre-sequence is rich in hydrophobic amino acids that are necessary for transport into the endoplasmic reticulum, while the basic pro-peptide directs accurate cleavage of pro-PTH into the mature 1-84 molecule [6]. The C-terminal portion of PTH is also essential for the PTH secretory process [6]. PTH 1-84 is secreted by exocytosis within seconds after induction of hypocalcemia [5]. Calcium regulates not only the release but also the synthesis and degradation of PTH, in all its molecular forms as described below [7].

In addition to intact PTH, some inactive carboxyl-terminal fragments and small amounts of active amino-terminal fragments of PTH are present in the parathyroid glands. During hypocalcemia, intracellular degradation of PTH decreases, and mostly PTH 1-84 is secreted; in comparison, during hypercalcemia mostly biologically inactive carboxyl-terminal fragments of PTH are secreted [1,3,7]. These carboxy-terminal fragments include long, amino-terminally cleaved species, such as PTH 7-84, which possesses some biological activity. (See "Parathyroid hormone assays and their clinical use", section on 'PTH fragments'.)

Under normocalcemic conditions, PTH 1-84 constitutes 20 percent of total circulating PTH molecules. This proportion increases to 33 percent under hypocalcemic conditions, and decreases to 4 percent in the presence of hypercalcemia [7]. Once secreted, PTH is rapidly cleared from plasma through uptake principally by the liver and kidney, where PTH 1-84 is cleaved into amino- and carboxyl-terminal fragments that are then cleared by the kidney.