The Discovery of Parathyroid Hormone

Overview

Parathyroid hormone (PTH) is an 84-amino-acid peptide secreted by the parathyroid glands in response to low blood calcium. It was first purified in 1925 by James Bertram Collip, the same biochemist who had purified insulin for clinical use with Banting, Best, and Macleod a few years earlier. Collip's PTH work at the University of Alberta showed that parathyroid extracts could rescue tetany in parathyroidectomized animals and raise calcium in normal ones.

The clinical significance of the parathyroid glands had been recognized earlier. Ivar Sandström had described them as four small glands near the thyroid in 1880; Eugène Gley and William Stewart Halsted had shown in the 1890s that their removal caused tetany. However, a biochemically active extract that could be characterized, standardized, and used as a therapy was not available until Collip's work.

PTH acts primarily on bone and kidney to increase blood calcium. In bone, it stimulates osteoclast activity indirectly through osteoblasts, releasing calcium. In the kidney, it increases calcium reabsorption and activates 1-alpha-hydroxylation of vitamin D, increasing intestinal calcium absorption via calcitriol. Paradoxically, intermittent low-dose PTH has an anabolic effect on bone, a property now exploited therapeutically.

Key People

• Ivar Sandström (1852–1889): Swedish medical student who first described the parathyroid glands.
• Eugène Gley and William Stewart Halsted: Demonstrated the essential role of parathyroid glands.
• Adolph M. Hanson and James B. Collip: Independently prepared active parathyroid extracts in the early 1920s.
• John Potts and colleagues: Determined the amino acid sequence of PTH in the 1970s.

Timeline

• 1880: Sandström describes the parathyroid glands.
• 1891: Gley shows thyroparathyroidectomy causes tetany.
• 1909: MacCallum and Voegtlin link hypocalcemia to parathyroid deficiency.
• 1925: Collip and Hanson independently prepare active PTH extracts.
• 1970: Sequence of bovine PTH is established.
• 1971: Human PTH sequence is determined.
• 1984: Recombinant PTH fragment (1-34) is synthesized.
• 2002: Teriparatide (PTH 1-34) is approved for osteoporosis.

Background

PTH is synthesized as a preproparathyroid hormone, processed to proparathyroid hormone, and finally secreted as the mature 84-amino-acid peptide. Once in circulation, it binds to the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor expressed in bone and kidney. A related peptide, parathyroid hormone-related protein (PTHrP), shares the N-terminal sequence of PTH and acts through the same receptor; it is crucial in fetal calcium regulation and is responsible for the hypercalcemia of malignancy in some cancers.

The regulation of PTH secretion by extracellular calcium through the calcium-sensing receptor (CaSR), cloned in 1993, provided a molecular basis for the long-known inverse relationship between serum calcium and PTH. Calcimimetic drugs such as cinacalcet, which activate CaSR, are now used to treat secondary hyperparathyroidism.

Modern Relevance

Clinically, PTH is central to the diagnosis and management of calcium disorders. Measurement of intact PTH is a standard test in the workup of hypercalcemia and hypocalcemia, and intraoperative PTH assays guide parathyroidectomy.

Therapeutic PTH has become important in osteoporosis. Teriparatide (PTH 1-34) and abaloparatide (a PTHrP analog) are given as daily subcutaneous injections and, uniquely among osteoporosis drugs, strongly stimulate new bone formation. They are often reserved for patients at very high fracture risk. Recombinant full-length PTH (1-84) is also approved in some markets for chronic hypoparathyroidism as a replacement therapy.

Related Compounds

• Parathyroid hormone
• Teriparatide
• Abaloparatide
• Calcitonin
• Vitamin D / Calcitriol