Parathyroid Glands And Parathyroid Hormone

The parathyroid glands arose relatively recently in vertebrate evolution, coincident with the emergence of ancestral forms onto dry land. They are not found in fish and are seen in amphibians such as the salamander only after metamorphosis to the land-dwelling form. The importance of the parathyroids in normal calcium economy was established during the latter part of the 19th century when it was found that parathyroidectomy resulted in lethal tetany. Diseases resulting from overproduction or underproduction of parathyroid hormone (PTH) are relatively uncommon.

Human beings typically have four parathyroid glands, but as few as two and as many as eight have been observed. Each gland is a flattened ellipsoid measuring about 6 mm in its longest diameter. The aggregate mass of the adult parathyroid glands is about 120 mg in men and about 140 mg in women. These glands adhere to the posterior surface of the thyroid gland or occasionally are embedded within thyroid tissue. They are well vascularized and derive their blood supply mainly from the inferior thyroid arteries. Parathyroid glands are comprised of two cell types (Fig. 6). The chief cells predominate and are arranged in clusters or cords. They are the source of PTH and have all of the cytological characteristics of cells that produce protein hormones: rough endoplasmic reticulum, prominent Golgi apparatus, and some membrane-bound storage granules. The oxyphil cells, which appear singly or in small groups, are larger than chief cells and contain a remarkable number of mitochondria. Oxyphil cells have no known function and are thought by some to be degenerated chief cells. Their cytological properties are not characteristic of secretory cells. Few oxyphil cells are seen before puberty, but their number increases thereafter with age.

FIGURE 6 Section through a human parathyroid gland showing small chief cells and larger oxyphil cells. The cells are arranged in cords surrounded by loose connective tissue. (From Borysenko, M., and Beringer, T. Functional histology, 2nd ed. Little, Brown, Boston, 1984, p 316.)

Biosynthesis, Storage, and Secretion of PTH

The secreted form of PTH is a simple straight-chain peptide of 84 amino acids. There are no disulfide bridges. As many as 50 amino acids can be removed from the carboxyl terminus without compromising biological potency, but removal of just the serine at the amino terminus virtually inactivates the hormone. All of the known biological effects of PTH can be reproduced with a peptide corresponding to amino acids 1-34. PTH is expressed as a larger ''preprohormone'' and is the product of a single-copy gene located on chromosome 11. Sequential cleavage forms first a 90-amino-acid prohormone and then the mature hormone. The larger, transient forms have little or no biological activity and are not released into the circulation even at times of intense secretory activity. Synthesis of PTH is regulated at both transcriptional and at post-transcriptional sites. Cyclic AMP, acting through the cyclic AMP response element binding protein (CREB) up-regulates PTH gene transcription, while vitamin D down-regulates transcription. Low plasma calcium concentrations prolong the survival time of the mRNA transcript, while low concentrations of plasma phosphate accelerate message degradation. PTH is synthesized continuously, but the glands store little hormone; only enough to sustain maximal secretion rates for about 90 min.

Parathyroid cells are unusual in the respect that hormone degradation as well as synthesis is adjusted according to physiologic demand for secretion. As much as 90% of the hormone synthesized may be destroyed within the chief cells, which break down PTH at an accelerated rate when plasma calcium concentrations are high. Proteolytic enzymes incorporated into secretory granules cleave the PTH molecules so that fragments are cosecreted with the intact 84-amino-acid PTH. Similar fragments are produced by degradation of PTH in liver and kidney and also enter the bloodstream. PTH fragments are cleared from blood by filtration at the glomeruli, but remain in the blood hours longer than intact hormone, which has a half-life of only about 2-4 min. The intact 84-amino-acid peptide is the only biologically active form of PTH in the blood.

A substance closely related to PTH, parathyroid hormone related peptide (PTHrP), is found in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcemia. The gene for PTHrP was isolated from some tumors and found to encode a peptide whose first 13 amino acid residues are remarkably similar to the first 13 amino acids of PTH; thereafter, the structures of the two molecules diverge. The similarities of the N-terminal primary sequence and presumably the secondary structure of subsequent segments allow PTHrP to bind with high affinity to

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