Historical Background

The adrenal glands were first described in 1552 by Bartholomaeus Eustachius in his Opuscula Anatómica1 as "glandulae renis incumbentes" (glands lying on the kidney). His work was printed again in 1722 by Lancisus, long after Galen, da Vinci, and Vesalius failed to recognize their existence.2 In 1629, Jean Riolan of Paris introduced the term capsulae suprarenales, which persisted for many years.2 Their function remained controversial for the next 300 years. In 1716, the Academie des Sciences de Bordeaux offered a prize for the answer to the question "What is the purpose of the suprarenal glands?" but no progress was achieved. In the 18th century, Edward Home thought that they "form a reservoir in which some other substance is laid up in store, till wanted."3 In 1805, Cuvier defined the anatomic division into a cortex and a medulla4 without suggesting any functional role of the adrenals.

In 1855, Thomas Addison of Guy's Hospital5 published his clinicopathologic observations of 11 patients with destruction of both adrenal glands and described the eponymous clinical syndrome. The following year, Brown-Séquard6 performed unilateral and bilateral adrenalectomy in animals and provided the first experimental confirmation of Addison's theory that the adrenal glands were essential to life.

In 1895, the London physiologists George Oliver and Edward Sharpey-Schafer described the presence of a substance in the adrenal medulla that elevated the blood pressure in dogs and named it adrenaline.1 Their observation was confirmed in 1897 by John Abel, professor of pharmacology at the Johns Hopkins University School of Medicine, who isolated the active compound and named it epinephrine,8 In 1901, epinephrine was purified from the adrenal gland; subsequently, epinephrine and norepinephrine were first synthesized by Frank Stolz in Germany in 1904.9 In the 1940s, von Euler10 and Holtz and associates11 identified norepinephrine in nerve endings and the adrenal gland, and the a-adrenergic and P-adrenergic receptors were first described by Ahlquist in 1948.12

Surgery of the adrenal glands emerged as part of abdominal surgery at the end of the 19th century, when abdominal masses were found at operation or autopsy to be adrenal in origin. Slowly, different adrenal syndromes and tumors were distinguished. In 1865, DeCrecchio first reported congenital adrenal hyperplasia in a female pseudohermaphrodite. In 1886, Frankel13 described a type of tumor for which the pathologist Pick in 1912 proposed the name pheochromocy-toma,H from the Greek phaios (dark or dusky) and chroma (color). In 1912, Harvey Cushing described the classic features of his eponymous syndrome,15 and in 1955, Conn reported the first patient with primary hyperaldosteronism.16 In the early 1960s, Sipple17 and Werner18 described patients with multiple endocrine tumors (multiple endocrine neoplasia [MEN] syndromes).

Successful surgical treatment of adrenal disease evolved from 1889, when Knowsley-Thornton reported the removal of a large adrenal tumor.2 In 1926, Roux in Lausanne, Switzerland, and Charles Mayo in Rochester, Minnesota, successfully removed a pheochromocytoma.

Efforts to provide substitutive therapy in patients with adrenocortical insufficiency were made as early as 1856 by Brown-Sequard, and early attempts at adrenal transplantation were made by Pybus in 1924 in patients with Addison's disease.19 Introduction of cortisone replacement therapy in 1949 was preceded in the 1930s by the work of Reichtenstein and Shopper in Switzerland20 and Kendall21 of the Mayo Clinic, whose biochemical studies led to the understanding of the structure and synthesis of adrenocortical steroids. Their work resulted in the award of the Nobel Prize in physiology and medicine in 1950.

More recent advances have dramatically changed the understanding of adrenal physiology and pathology. The hypothalamic factor controlling the pituitary-adrenal axis (corticotropin-releasing hormone [CRH]) was characterized and synthesized by Vale and coworkers in 1981.22 The structure of corticotropin precursor—pro-opiomelanocortin (POMC), its messenger RNA, and its gene have been described. Specific intracellular location of the steroidogenic cytochrome P-450 enzymes and the genes that encode them have been identified. The elucidation of the structure of the steroid receptors and the genes that encode them provides insight into the mechanism by which the steroid-receptor complex interacts with specific DNA areas (called glucocorticoid response elements) to regulate transcription of target genes.

Therapeutic possibilities have increased significantly, from the first synthesis of corticosterone in 1949, to the first inhibitors of steroidogenesis in the 1960s, to the recent development of inhibitors of steroid receptors (as mifepristone [RU-486]).

Surgical intervention continues to play an important role in many diseases of the hypothalamic-pituitary-adrenal axis. An understanding of the embryology and anatomy of the adrenal glands is an essential prerequisite to successful and effective adrenal surgery.

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