History

DISCOVERY OF THE ADRENAL GLANDS

There have been numerous references to the existence of the adrenal glands ever since ancient times [1]. Probably the first account in the western world of the adrenal glands is to be found in the Bible. Professor R. B. Greenblatt in his work “Search the Scriptures” [2], cites the Biblical twins, Esau and Jacob, monozygotic twins, the first being described as exceptionally hairy and strong, possibly presenting the symptoms of congenital adrenal hyperplasia, whereas the other was completely normal. This author proposed that the ancient Hebrews knew about the adrenal glands and their disturbances. During Roman times, better documented descriptions are to be found on the adrenal glands as compiled by Claudius Galenus of Pergamum (130-201 AD), better known as Galen (Figure 1), who was an antique Greek physician. His views dominated European medicine for over a thousand years.

Figure 1. Claudius Galen (130-201 AD)

Figure 2. Claudius Galen of Pergamon. Libri Tres...De Facultatum Naturalium Substantia... Quod Animi Mores...De Propriorum Animi.... Paris: Simon Colinaeus, 1528.

Figure 3. Batholemeus Eustachius (1520-1574)

Although there is a debate as to their accuracy and several historians [3] believe that Galen’s description of the left adrenal vein is proof that he was the first to discover and describe the adrenal glands in mammals, while others [4] have not accepted this contention. Galen refers to a particular tissue as “loose flesh”—the assumption being that reference is being made to an accessory to renal tissue—and clearly describes the left adrenal vein connected to the left renal vein (Figure 2).

The credit for the discovery and description of the adrenal gland in the majority of the literature is given to Batholemeus Eustachius (1520-1574) (Figure 3).

Batholemeus Eustachius was a professor at the Collegio della Sapienza in Rome. He was the one who gave the first clear description including several accurate illustrations of the adrenal glands on a copper plates in 1552 [5, 22]. Batholemeus Eustachius was the anatomist who published his work “Opuscola Anatomica” at Venice in 1563-1564. After Eustachio’s death in 1574, his tabulae anatomicae were forgotten in the shelves of the Vatican Library until 1714 when Giovanni Maria Lancisi discovered them. Lancisi was the physician of Pope Clement XI and a successor to Eustachio in the chair of anatomy at the Sapienza. Lancisi appreciated the preciseness and the accuracy of the plates and went on to publish the entire series of forty-seven engravings under the title: “Tabulae Anatomicae Bartholomei Eustachi quas a tenebris tandem vindicatas” (Anatomical Illustrations of Bartholomeo Eustachi rescued from obscurity) (Figure 4, 5).

Figure 4. Batholemeus Eustachius. Tabulae Anatomicae, published in Rome in 1783

Figure 5. Batholemeus Eustachius. Tabulae anatomicae (Rome, 1783): Title page.

Figure 6. Bartholomeus Eustachius. The 47th plate of Tabulae anatomiae... Praefatione notisque illustravit ... J. Maria Lancisius ... Amsterdam: R. & G. Wetstenios, 1722.

The book was describing the kidneys in detail and referring to the adrenals as “Glandulae renibus incubentis” (“glands lying on the kidneys”), a term that implies an auxiliary renal role. The sixth chapter of his "Opuscula Anatomica" is entitled "De glandulis quae renibus incumbunt." It describes and pictures the adrenals as they occur in man (Figure 6).

His original description still holds true today: " Even if many will consider sufficient what we have said about the surface of the kidneys, somebody could well object that I have neglected something and I consider it indicated to say something of the glands, diligently overlooked [diligenter praetermissis] by other anatomists. Both kidneys are capped on the extremity towards the cava by a gland. Both are connected by a fold of the peritoneum in such a way that one, if he is not very attentive, does not really overlook them, as if they were not present. Their shape resembles that of the kidneys… sometimes one is bigger, sometimes another…" - translated by Lenard [16].

But these observations of Eustachio were not accepted by other anatomists of his time. Arcangelo Piccolomini [6] (1562-1605), who belonged to a noble, powerful, roman family and had named the glands the suprarenals, soon attacked Eustachio’s opinions. In 1587, Piccolomini published Anatomicae prelectiones with his own conclusions about adrenals, he wrote: “sometimes one may see two or more glands lying on the kidney, but we do not think they deserve special attention, because they are not to be found in every case and they have no flesh or parenchyma of their own, so that they might be considered renal excrescences. They form part of the renal parenchyma. Why do they exist in a few? The same way supra-abundance of material creates a sixth finger, they originate from a seminal surplus and that is the way they come out of the kidney” [6, 16]. Piccolomini was not the only one who had controversy with Eustachio’s conclusions: Andreé Du Laurens, physician of Henry IV of France, stated: “Eustachio claims to find a gland above the kidneys. Sometimes we saw that too; often however we notice that there was not such gland” [23].

Figure 7. Gaspar Bauchin (1550-1629)

Figure 8. Adriaan van den Spiegel (Adrianus Spigelius) (1578 – 1625)

Figure 9. Anatomische Tafeln... Frankfurt, 1656. Copperplate engraving. National Library of Medicine Giulio Casserio (ca. 1552-1616).

This clumsy frontispiece features five notable anatomists posed around a cadaver. In the center of the picture, the image of the Earth, with the continent of "America" visible, signifies that the anatomized body is a "New World," and dissection a voyage of discovery.

The existence of the adrenal glands was also mentioned several years later by Gaspar Bauchin (1550-1629) [7] (Figure 7), Adrianus Spiggelius (1578-1625) [9] (Figure 8) named them “Capsular renales” and  Giulio Casserio (1561-1616) [8] (Figure 9 and 10) termed them “Renes succentuari”.

Figure 10. Gaspar Bartholin (1586-1629)

Figure 11. Jean Riolan the younger (1538-1605),

Figure 12. Andreas Laurentius (1558-1609)

The anatomist Gaspar Bartholin (1586-1629) [10] (Figure 10) believed the adrenals to be hollow organs filled with “black bile” and named them Capsulae atrabiliarae, and Johan Vestling (1598-1649) in his treatise published in 1653 supported Bartholin’s view on the adrenals. However, several investigators including Dominicus de Merchetis (1526-1688), A. Molinetti [11], Nathaniel Higmore [12] and others, were detractors of Bartholin’s theory.

(Figure 11) Portrait of Jean Riolan from the frontispiece of his anatomy textbook, Encheiridium anatomicum et pathologicum, Paris, 1658. (Riolanus  J. Encheiridium anatomicum et pathologicum. Editio quarta, renovata Paris, France Apud Casparum Meturas1658;)

Jean Riolan (the Younger), of the Paris (15 February 1577 or 1580 – 19th February 1657) [13] (Figure 11) in 1629 introduced them as “capsulae suprarenales”, stated in 1655 that “… I have never seen a cavity in them. Should they have a cavity, no pea would find a place in it.” Jean Riolan (the Younger) was a French anatomist who was an influential member of the Medical Faculty of Paris. His father, Jean Riolan (the Elder) (1539–1605) was also a noted French anatomist, at one time was the dean of the Faculty of Medicine in Paris [24, 26]. Like his father, Jean Riolan was a rigorous defender of traditional medicine and a strong proponent of the views of Galen [25, 26]. He became a professor of anatomy and botany at the University of Paris and was appointed physician to kings Henry IV and Louis XIII and for 10 years was the personal physician to Marie de' Medici (1553–1642). He was one of the most authoritative anatomists of his time and, as a skilled dissector, added much to anatomical and embryological knowledge.

In 1640 Andre du Laurens [14] (Figure 12) doubt the existence of these organs, wrote, “Eustachius claims to have found a gland above the kidneys. Sometimes we have also noted this; often however we did not”. Marcus Aurelius Severinus (1580-1658) who first described an excretory duct issuing from the adrenal gland and connected to the left epididymis. Later on Antonio Maria Valsava [15] (1666-1723) also described a duct between the left adrenal gland and the left ovary in a woman. Valsava also indicated that the adrenals regulate the libido.

Figure 13. Thomas Wharton (1614-1673). In 'Adenographia' he gave the first thorough account of the glands of the human body

Figure 14. Thomas Wharton. Adenographia: sive, Glandularum Totius Corporis Descriptio ... London: Typis J. G., Impensis Authoris, 1656

In 1656 Thomas Wharton (1610-1673) [15] (Figure 13) published, at his own expense, Adenographia (Figure 14), "a description of the glands of the entire body," which became a foundational work. The text gave the first thorough account of the glands of the human body, which Wharton classified as either excretory, reductive, or nutrient. He described both the spleen and pancreas, and he differentiated the viscera from the glands; in addition, he discussed the abdominal and thoracic glands, those of the head, and the reproductive glands; he discovered the duct of the submaxillary salivary glands, the jelly of the umbilical cord, and gave the first thorough account of the thyroid. Thomas Wharton also associated the nearby nerve plexus with the function of the adrenal glands. He named adrenal glands as “glandulae renales”  [22]. Wharton was impressed with the large size of the plexus and with the large nerve supply to such a small organ and referred to the adrenals as glandulae ad plexum. He suggested that the adrenals received some substance from the nerves (which he assumed to be useless to the nerves); the adrenals absorbed this substance and passed it into the veins where it had some useful purpose. Although there is no direct evidence that Wharton supported his hypothesis with experimentation, to him goes the credit for being the first to associate the adrenal glands with a function of the nervous system. Indeed his description, published in 1656, of the adrenals taking a substance from nerves and transferring it to veins preceded the neuroendocrine concept of the adrenal medulla that we have only appreciated in the 20th century! [27]. Thomas Wharton was a physician at St Thomas’ hospital from 1657 and remained there for the majority of his career. Wharton was one of the few physicians not to flee London during the plague of 1665, remaining at St Thomas’ Hospital to treat patients, and his commitment was commended by the Royal College of Physicians. In addition to describing the duct of the submandibular salivary gland (Wharton’s duct) and the jelly of the umbilical cord (Wharton’s jelly), he also named the thyroid gland. All this was the fruit of careful dissection of human and animal bodies.

Jean Baptiste Senac (1693-1770) suggested that the adrenals secreted foetal mecomium, Jean Von Helmont (1577-1644) assumed that they secreted a juice which prevented the formation of renal calculi, while Giovanni Morgani (1622-1771) believed that these organs drained the lymph from the intestines during the life of the foetus, since the cisterna chili were observed not to be filled with lymph during this period.

Figure 15. Georges Chrétien Léopold Dagobert Cuvier or Jean Léopold Nicolas Frédéric Cuvier (August 23, 1769 – May 13, 1832), known as Georges Cuvier.

Figure 16. Emil Huschke (December 14, 1797 – June 19, 1858)

Figure 17. Alexander Ecker (1816-1887)

Baron George Cuvier (1769-1832) (Figure 15) , was a French naturalist and zoologist, he  described difference between the cortex and the medulla of the adrenal gland in 1805 [22] he was the first to recognize that the outer portion of the gland is morphologically distinct from that of the centre [16[. But these terms were first used by Emil Huschke of Jena in 1845 (Figure 16). Emil Huschke (December 14, 1797 – June 19, 1858) was a German anatomist and embryologist who was a native of Weimar. He studied medicine at the University of Jena, and spent most of his professional career at Jena. In 1827 he was appointed professor of anatomy and director of the anatomical institute. In 1846 Alexander Ecker (1816-1887) [18] (Figure 17), german anthropologist and anatomist, using new microscopes, pointed out that the adrenal medulla is remarkable for its brightness.

In 1836, N. Nage [17] for the first time used the terms cortical for the outer part and medulla for the inner part of the human adrenal glands and Improvement in microscope development in the first decades of the 19th century helped with accurate observations of the morphology of the adrenals.

Figure 18. Albert von Kölliker (6 July 1817–2 November 1905)


Figure 19. Johan Friedrich Meckel (1714-1774)

Figure 20. John Goodsir (1814-1867)

Credit, however, for the first complete microscopic description of the anatomy of the adrenals goes to R.A. Von Kölliker (1817-1905) [19] (Figure 18), a Swiss anatomist and physiologist, who in 1852 stated that “The cortical and medullary substances are physiologically distinct and have different functions …
It was not until the latter half of the 19th century that, by virtue of a large number of in-depth studies, it was unequivocally recognized that the adrenal medulla is functionally, histologically, embryologically and in many other respects separate from the cortex. It was found that the cortex to be of mesodermal origin and to be invaded by sympathetic neural elements, which formed the medulla and provided a rich nerve supply [22]. George Gulliver, (1804-1882), a London surgeon, suggested in 1840 that adrenal glands poured a peculiar mater into the blood, which has doubtless a special use [22].

In 1806, Johan Friedrich Meckel (1714-1774) [20] (Figure 19), a German anatomist, associated the adrenal glands with sexual functions. Meckel stated that the basis for this relationship  was “… their simultaneous considerable development in several orders of mamallia…” and furthermore maintained that abnormalities of the adrenals were also connected with abnormalities of the sexual organs such as those, for example, in gestation or arising from syphilis.

John Goodsir (1814-1867) (Figure 20), a Scottish anatomist, published a paper in 1846 declaring that the adrenals, the thymus and the thyroid have embryologically the same origin and therefore may function similarly. Goodsir writes “[these glands]... elaborate the matter which has already been absorbed by other parts and is now circulating in the vessels of the more perfect individuals...” [28].

Figure 21. Thomas Addison (April 1793 – 29 June 1860)

Figure 22. Armand Trousseau (14 October 1801 — 27 June 1867)

Figure 23. Charles-Édouard Brown-Séquard (8 April 1817 – 2 April 1894)

The function was unknown and controversial until 1855, when Thomas Addison of Guy's Hospital, London, a renowned 19th-century English physician (Figure 21), presented a paper in 1849 and published a monograph “On the constitutional and local effects of disease of the suprarenal capsules” with his observations in eleven patients with destruction of both adrenal glands, and found out that the adrenal glands were essential to life. Those patients had anemia, debility, feebleness of the heart, irritability of the stomach, and “a peculiar changes of the color in the skin, occurring in connection with a diseased condition of the suprarenal capsules”. At the autopsy the adrenals showed gross disease. Addison felt that this association of clinical and pathological features must throw light on the function of the adrenal glands [22, 29]. He was right, after this finding the importance of these organs was realized, and scientists all over the world were attracted to research their function. In France, Armand Trousseau, an internist from Paris (Figure 22), saw similar patient with tuberculosis with involvement of sympathetic ganglia. He proposed the name “Addison’s disease” [22, 32].

Immediately after, Charles-Édouard Brown-Séquard (8 April 1817 – 2 April 1894), also known as Charles Edward, was a Parisian physiologist and neurologist (Figure 23), embarked on animal experiments, he was one of the first to postulate the existence of substances, now known as hormones, secreted into the bloodstream to affect distant organs. In particular, he demonstrated in animals (in 1856) that removal of the both adrenal glands resulted in death in a few hours, due to lack of essential hormones, but, surprisingly, removal of one adrenal was often fatal too, although the animals lived longer [22].

Walter Hadden of London thought that Addison’s disease resulted from deficiency of an internal secretion and in 1896, Sir William Osler of Baltimor prepared an extract of pigs’ adrenal gland (similar o George Murray’s thyroid extract for myxedema), and gave it by mouth for treatment of Addison’s disease with success in one case [22].

In 1893 two English physiologists, George Oliver and Edward Sharpey-Schafer of London showed that adrenal medulla contained a substance that caused constriction of the arteries and by that elevated the blood pressure, and caused rapid heart beats in dogs, when it was injected intavenously, and named this extract "adrenaline". Several years later, in 1897, John Abel, professor of pharmacology at Johns Hopkins University School of Medicine, U.S.A., purified the extract and named the active compound "epinephrine" [30, 32]. The closely related true product, “adrenaline” was purified in 1901, found to be a catecholamine and synthesized in 1904.

Word "Hormone" comes from the Greek word “hormao” - a substance that starts, urges on, initiates, irritates, stimulates and excites. The word hormone was first suggested by (Sir) William Bate Hardy, a Cambridge physiologist (Figure 24). Ernest Henry Starling introduced the term 'hormone' in his Croonian Lectures to the Royal College of Physicians, delivered on the 20th , 22nd , 27th and 29th June 1905

Figure 24. Ernest Henry Starling (1866-1927). He constructed a general scheme of the internal secretions, "hormones" as he called them

Figure 25. Edward Calvin Kendall (left), Tadeus Reichstein (middle), and Philip Showalter Hench (right).

The biochemical studies of the structure and synthesis of adrenocortical steroids in the 1930s by Reichtenstein in Switzerland and Kendall and Hench in the U.S.A. The Nobel Prize in Physiology or Medicine 1950 was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench "for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects" [22, 30, 31] (Figure 25).

DISCOVERY OF THE ADRENAL TUMORS.

In 1886 Felix Frankel was the first to describe a patient with an adrenal tumor, a pheochromocytoma (from the Greek phaios, dark, and chroma, color) in the adrenal medulla at autopsy [1, 2].

Figure 26. Harvey Williams Cushing, (April 8, 1869 - October 7, 1939)

Figure 27. Jerome W. Conn (September 24, 1907 - June 11, 1994)

Harvey Cushing (Figure 26) described the clinical features of hypercortisolism in 1912 [3]. In 1932 Harvey W. Cushing, a Boston neurosurgeon, defined a syndrome characterized by muscle weakness, obesity, abdominal stiae, diabetes, and adrenal hypertension. He called it “pituitary basophilism”, Since that time all conditions that cause glucocorticoid excess called Cushing’s, implying Cushing’s syndrome to the disease of adrenal gland (corticotrophin independed) or glands and Cushing’s disease to pituitary or ectopic origin (corticotrophin depended)

Jerome W Conn (Figure 27) described primary aldosteronism in 1955 [4].

Jerome Conn’s belief that adrenal adenomas are a common surgically correctable cause of “essential hypertension” may yet be proven correct. In 1954, two years after the discovery of aldosterone, Jerome Conn from Ann Arbor, Michigan, described the syndrome of primary aldosteronism. The first patient was a woman of 34 years who had intermittent tetany, paraesthesia, periodic muscular weakness and paralysis, polyuria, polydispsia, and mild hypertension, but no oedema. Laboratory tests showed severe hypokalaemic alkalosis, hypernatraemia, impaired renal tubular absorption of water, and an excess of aldosterone in the urine. Conn considered that total adrenalectomy, followed by substitution therapy, should abolish the metabolic abnormality and William Baum, a urologist, operated on December 14th, 1954. He found a cortical adenoma on the right and removed the whole gland, taking a biopsy from the left. The tumor was round, 4cm in diameter, 14.8 g in weight and deep yellow on its cut surface. Microscopy showed an encapsulated cortical adenoma and atrophy of the zona glomerulosa in the other gland. The tumor contained much aldosterone. All the symptoms were relieved, the metabolic abnormalities were corrected in ten days, and the blood pressure fell to normal in eighteen days. Within six weeks of the first report, four other patients with primary aldosteronism were found elsewhere, and three were cured by removal of adenomas. This led Conn to advise that the electrolytes should be measured in hypertensive patients and, if hypokalaemic alkalosis were present, the adrenal glands should be explored surgically. Conn predicted that up to 20% of hypertensive patients may have adrenal adenomas, and thus be potentially cured of their disorder by surgery. Such a figure was never realised in his lifetime with most series reporting less than a 1% incidence of Conn’s tumours in hypertensive populations. However, in recent years, primary screening of normokalaemic hypertensive pop-ulations with plasma renin-aldosterone ratio, has shown that possibly 10% may have an aldosterone secreting adenoma - Jerome Conn may yet be proven right [6].

HISTORY OF THE ADRENAL SURGERY

Figure 28. The first laparoscopic adrenalectomy described by Michael Gagner in 1992

The first successful adrenalectomy was carried out by Knowsley-Thornton who removed a large, 20-pound, adrenal tumor with the left kidney in 36-year-old woman in 1889 [1]. The history of adrenal surgery is longstanding, with the first planned adrenalectomy performed in 1914 by Perry Sargent [2]. The flank approach was used by Charles Mayo in 1927, he performed adrenalectomies for pheochromocytoma; and Roux in Switzeland [1]. Through the early to mid-1900s, multiple changes in surgical approaches to the adrenal gland were developed to augment several posterior and anterior approaches. For decades, little change to adrenal surgery was seen until first laparoscopic procedure of the adrenal gland was described by Michael Gagner in 1992 [3, 4] (Figure 28, 29). Since that time laparoscopic adrenalectomy became standard of care approach for majority of the benign adrenal tumors (Figure 30). Over the last decade trends to developed the least invasive approach resulted in dramatically new way of doing this procedure by laparoscopic posterior retroperitoneal adrenalectomy developed and modernized by Martin Walz, MD (Figure 31) 


Figure 29.  Michael Gagner, MD


Figure 30. Book of minimally invasive Endocrine Surgery by M Gagmer and W. Inabnet


Figure 31. Martin Waltz, MD


REFERENCES

DISCOVERY OF THE ADRENAL GLANDS

References

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DISCOVERY OF THE ADRENAL TUMORS.

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DISCOVERY OF THE ADRENAL GLANDS

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