The history of parathyroid endocrinology.

The parathyroid glands are now recognized as being essential for life. Their structure and function is well delineated, and their disease and dysfunction, well characterized. Diagnosis and management of parathyroid disease has improved in the past few decades. The path of parathyroid science, however, has been far from smooth. This paper describes the early history of parathyroid endocrinology. In doing so, it focuses on major events and discoveries, which improved the understanding and practice of our specialty. Contribution in anatomy, physiology, pathology, medicine, surgery and biochemistry are reviewed.

INTRODUCTION

The nineteenth century witnessed the boom of endocrinology as a clinical science. Innovations in research, diagnosis and therapeutics stimulated interest in this young branch of medicine.[1]

In 1805, Cuvier defined the medulla and cortex of the adrenal gland. A few years late, Alibert described acromegaly (1822), while Rathke described the formation of the pituitary gland (1838). In 1860, Von Luschka was able to describe the pituitary portal circulation.

Maximum attention, however, was focused on reproductive endocrinology. In 1824, Prevost and Dumas described ovulation, and in 1827, von Baer discovered the human ovum. The first suggestion for artificial insemination in man came from John Hunter in 1790. Berthold, in 1849, conducted elegant experiments on testicular transplants in birds, and Brown- Sequard tried organotherapy, using testicular extracts on himself. In such a rapidly evolving, exciting period of scientific discovery, the parathyroids took back seat. The choice of their name itself was unfortunate, as they were considered thyroid appendages, and were not given their due physiological significance too easily.

ANATOMY

In 1852, the parathyroids were described in the rhinoceros by Sir Richard Owen in London. He noted a small compact yellow, glandular body, attached to thyroid, in an Indian rhinoceros cadaver, preserved in London. Virchow described the human parathyroids in 1963, but credit for the first complete description goes to the Swedish doctor Sandstroem, in 1980. He identified two parathyroid bodies in 43 out of 50 autopsies.

In 1890, Anton Woelfler described areas of “young tissue” or “foetal rests” which might have been intrathyroid, as parathyroid glands.[1] Though the anatomy of the parathyroids had been reasonably well described, their physiology was not understood until much later.

EARLY STUDIES ON PHYSIOLOGY

Eugene Gley studied the parathyroid glands (he thought there were two in each animal) in rabbits, and performed parathyroidectomy, without causing death (1891). He thought that the parathyroids were potential thyroid tissue, as they grew hypertropic after thyroidectomy.[2] Others opposed him, including Giulio Vassale and Francesco Generali. They demonstrated the occurrence of tetany and myxedema after parathyroid and thyroid removal, in 1895 and 1986, respectively.[1] At the same time, Walter Edmunds proved that the parathyroids did not convert to thyroid tissue after thyroidectomy.[1] A few years later, Kohn was able to establish that the parathyroids were anatomically independent from the thyroid. He coined the name ‘epithel koer perchen’ for the glands.[1] Later workers showed fatal tetany after complete removal of all parathyroid tissue, proving that the glands are essential for life, in the first decade of the twentieth century.[1]

In spite of this research, however, scientists such as Noel Paton and Findlay continued to assert that the function of the parathyroid was to detoxify guanidine (1917).[1]

CLINICAL MEDICINE

Though the study of anatomy and physiology of the parathyroids proceeded slowly, clinical medicine had recognized the symptoms of parathyroid disease quite early. Tetany in the pediatric age group was described by John Charke in 1815, and carpopedal spasm and glottis spasm by George Kellie in 1816. Steinheim, working in German, described tetany as “acute rheumatism” in 1830. Trousseau's sign was described in 1862, Erb's sign in 1873, and Chvostek's sign in 1876. Though organotherapy had been in vogue as far as testicular and thyroid extracts were concerned, for quite some time, the first account of parathyroid hormone replacement was given in 1898. G. Moussu injected on aqueous extract of 12- 20 equine glands and successfully treated post- parathyroidectomy tetany in canine models. In 1909, Berkeley and Beebe[3] described correction of hypo- calcemic tetany, with parathyroid extract, in man. In the same year, Mac Callum and Vogetlin demonstrated a much simpler method of managing tetany with intravenous calcium chloride.[4]

SURGERY

While experimental parathyroidectomies had been carried out by early researchers in the ninetieth century, the first parathyroid transplant was attempted by WS Halsted in 1909, in Baltimore. He transplanted canine parathyroids into thyroid tissue and under the abnormal skin, trying both iso- and auto- transplantation.[5] His auto- transplants had a success rate of 61 5. Mandl was the first surgeon to include the small parathyroid glands in the ambit of endocrine surgery. He successfully treated a case of osteitis fibrosa by surgical removal of a parathyroid adenoma in 1925.[1]

PARATHORMONE

The first report of isolation of an effective parathyroid extract is by Hanson, who reported his work in cattle in 1923. Yet he is not credited with the discovery of parathromone. This honour goes to the Canadian James Bertram Collip.[1] Parathromone was discovered by Collip in 1925, and used to treat tetany successfully, by Leitch and him, in the same year. It was named as parathyrin.[67] It is surprising that Collip is remembered more for his role in the discovery of insulin (though the Nobel Prize committee did not feel him worthy of the prize), than for his role in the discovery of parathyroid hormone, an equally important feat. The parathyroid hormone was isolated and purified by Ramussen and Craig in 1959, and its polypeptide structure defined by them in 1962.[89] Bovine parathyroid tissue was used by all researchers initially.

The actions of the parathyroid hormone were discovered slowly. Greenwald identified its phosphaturic action in 1911,[10] while Barnicot noted its resorptive effect on bone in 1948.[11] The anti calciuric and anti magnesiuric action were described by Jahan and Pitts in the same year.[12] Another ten years passed before Talage and Elliott observed an increase in calcium absorption form the small intense parathormone.[13]

The effectiveness of vitamin D in parathyroidectomized animals was reported by Hanson in 1935.[1] It has taken many years for scientists to understand the actual relationship between vitamin D and parathormone.

In 1962, a new hormone, calcitonin, was discovered, and was initially thought to be secreted from the parathyroid gland. Its thyroid origin and significance was understood later.[14]

PATHOLOGY

Gerhard Engel described the clinical condition of osteitis fibrosa in 1864. Von Recklinghausen gave a complete description of the disease in 1891. In 1904, Askanasy discovered a parathyroid adenoma while performing a post- mortem on a patient with skeletal disease, and postulated a connection between parathyroid tumour and osteitis fibrosa cystic. In 1907, Erdheim described hyperplasia of the parathyroids in osteomalacia in humans, while in 1914; he found the same finding in rachitic rats. This is the first report of secondary hyperparathyroidism.[1]

The most extensive work on hyperparathyroidism was done by Fuller Albright in the 1930s. He described parathyroid hyperplasia, and differentiated between primary, secondary and tertiary hyperparathyroidism.[151617] He and his team also described pseudohyperparathyroidism in 1942.[18] The pathophysiology of the parathyroids was put in perspective by Greep RO, in 1963, who studied the comparative endocrinology of the glands. He suggested that as amphibians migrated from calcium- rich marine environment to calcium- poor terrestrial surroundings, and the need for a calcium homeostasis mechanism occurred. This then led to the development, and functioning of the parathyroid glands.[18]

CONCLUSION

The endocrinology of the parathyroids has grown slowly over the nineteenth and early twentieth centuries. Advances in anatomy, physiology, medicine, surgery and biochemistry have contributed to effective modalities of diagnosis and treatment which are in use today. This brief article pays homage to the pioneers of our specialty, while offering tribute to their acumen and perseverance.