A History of Diabetes Insipidus: Paving the Road to Internal Water Balance
2010; Elsevier BV; Volume: 56; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2010.08.002
ISSN1523-6838
Autores Tópico(s)Neuroendocrine regulation and behavior
ResumoDiabetes insipidus is an ancient disease considered under the rubric of diabetes, the Greek descriptive term for polyuria, which was unrecognized even after the sweetness of urine was reported as a characteristic of diabetes mellitus in the 17th century. It would be another century before diabetes insipidus was identified from the insipid rather than saccharine taste of urine in cases of polyuria. After its increased recognition, pathologic observations and experimental studies connected diabetes insipidus to the pituitary gland in the opening decades of the 20th century. Simultaneously, posterior pituitary lobe extracts were shown to be vasoconstrictive (vasopressin) and antidiuretic (antidiuretic hormone). As vasopressin was purified and synthesized and its assay became available, it was shown to be released in response to both osmotic and volume stimuli that are integrated in the hypothalamus, and vasopressin thereby was essential to maintaining internal water balance. The antidiuretic properties of vasopressin to treat the rare cases of diabetes insipidus were of limited clinical utility until its vasoconstrictive effects were resuscitated in the 1970s, with the consequent increasing wider use of vasopressin for the treatment of compromised hemodynamic states. In addition, the discovery of antidiuretic hormone receptor blockers has led to their increasing use in managing hypo-osmolar states. Diabetes insipidus is an ancient disease considered under the rubric of diabetes, the Greek descriptive term for polyuria, which was unrecognized even after the sweetness of urine was reported as a characteristic of diabetes mellitus in the 17th century. It would be another century before diabetes insipidus was identified from the insipid rather than saccharine taste of urine in cases of polyuria. After its increased recognition, pathologic observations and experimental studies connected diabetes insipidus to the pituitary gland in the opening decades of the 20th century. Simultaneously, posterior pituitary lobe extracts were shown to be vasoconstrictive (vasopressin) and antidiuretic (antidiuretic hormone). As vasopressin was purified and synthesized and its assay became available, it was shown to be released in response to both osmotic and volume stimuli that are integrated in the hypothalamus, and vasopressin thereby was essential to maintaining internal water balance. The antidiuretic properties of vasopressin to treat the rare cases of diabetes insipidus were of limited clinical utility until its vasoconstrictive effects were resuscitated in the 1970s, with the consequent increasing wider use of vasopressin for the treatment of compromised hemodynamic states. In addition, the discovery of antidiuretic hormone receptor blockers has led to their increasing use in managing hypo-osmolar states. Shrouded in the origins of creation mythology, water has been considered a vital element since time immemorial. By the time Greek rational medicine emerged, water was incorporated into medical thought as a component of the 4 humors of Hippocratic medicine. Although water was recognized as being essential to life, the regulation of its internal balance remained a mystery well into the early 20th century, when insight into water homeostasis was provided from studies of diabetes insipidus, an ancient disease that had been unexplained before. In antiquity, it was a patient's presenting symptom of external glaring manifestations that defined an illness, and polyuria soon attracted attention and was recorded as a disease. As we know it today, polyuria is a manifestation of varied causes and it is difficult to discriminate to exactly which of these diseases the ancient authors were referring. Nevertheless, it generally is accepted that most clinical descriptions of polyuria given in ancient texts are consistent with diabetes mellitus, which together with the then other unknown causes of polyuria, such as diabetes insipidus, were classified under the generic term of diabetes.1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Hazard J. Perlemuter L. L'Homme Hormonal Une Histoire Illustrée.in: Hazan, Paris, France1995: 291-339Google Scholar, 3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar Demetrius of Apameia (1st-2nd century bce) is credited with introducing the term "diabetes," derived from the Ionic, meaning "to pass or run through," as in a siphon.4Gemmill C.L. The Greek concept of diabetes.Bull N Y Acad Med. 1972; 48: 1033-1036PubMed Google Scholar This descriptive term reflects the prevailing notion at the time that polyuria was caused by the passage of ingested fluids through the body unchanged, as if flowing through a tube or siphon, much as water does in the landmark Manneken-Pis statue in Brussels (Fig 1). It is under the term "diabetes" that Aretaeus of Cappadocia (2nd century ce) then recorded what is considered the first clinical description of diabetes mellitus: an affliction that is not very frequent … being a melting down of the flesh and limbs into the urine … life is short, disgusting and painful … thirst unquenchable … the kidneys and bladder never stop making water … it may be something pernicious, derived from other diseases, which attack the bladder and kidneys.5Areteus the Cappadocian.in: Adams F. The Extant Works. Sydenham Society, London, England1856: 338Google Scholar The subsequent story of diabetes mellitus has been told many times.1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Hazard J. Perlemuter L. L'Homme Hormonal Une Histoire Illustrée.in: Hazan, Paris, France1995: 291-339Google Scholar, 3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 6Sanders L.J. From Thebes to Toronto and the 21st century: an incredible journey.Diabetes Spectrum. 2002; 15: 56-60Crossref Google Scholar The less well-known story of diabetes insipidus is the subject of this article. With a license to interpret, diabetes insipidus also may be traced to Aretaeus, who in his comments mentions another rarer cause of diabetes due to the bite of a venomous snake, dipsas, which "kindles up an unquenchable thirst."5Areteus the Cappadocian.in: Adams F. The Extant Works. Sydenham Society, London, England1856: 338Google Scholar The story of this fabled serpent is told by several early Greek authors and in subsequent literature, came to be used as the name of enchanters, sibyls, and witches who inflicted various cravings in their victims. For our purposes, dipsas is the origin of the medical term "polydipsia," for excessive thirst. Whatever Aretaeus may have meant in his reference to dipsas as another cause of diabetes will forever be a mystery. For all practical purposes, reports of diabetes in the medical literature thereafter likely included cases of diabetes insipidus that were unrecognized well into the 17th century.7Henschen F. On the term diabetes in the works of Areteus and Galen.Med Hist. 1969; 13: 190-193Crossref PubMed Scopus (17) Google Scholar Throughout the rest of this article, the term diabetes, as defined by Demetrius, will be used interchangeably with polyuria to mean copious volumes of urine and qualified by its characteristics (saccharine, insipid, etc) in the specific diseases that came to be identified as a cause of polyuria. The foundation for differentiating the 2 principal forms of diabetes (mellitus and insipidus) was laid in the 1670s when Thomas Willis (1621-1675), professor of Natural Philosophy at Oxford, reported his observation that the residue of evaporated diabetic (polyuric) urine was "wonderfully sweet and tasted like honey (quasi melle)."1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 6Sanders L.J. From Thebes to Toronto and the 21st century: an incredible journey.Diabetes Spectrum. 2002; 15: 56-60Crossref Google Scholar, 8Willis T. Pharmaceutice Rationalis, or On Exercitation of the Operation of Medicines in Human Bodies.section IV, chapter III. T. Drink, C. Harper, and J. Leigh, London1679Google Scholar As important as this observation was, it was not a new one. Sweetness of the urine had been reported in the past, but attributed to the "siphoning" of ingested saccharine matter passed without change into the urine along with the water that had been drunk. This concept is vividly illustrated by the Manneken-Pis of Brussels, whose "urine" taste, color, and composition depends on the fluid pumped into its circulating system (Fig 1). The true importance of Willis's report was the argument that diabetes is not a disease of the kidneys, as it was considered before, but of the blood in which sweetness appears.9Eknoyan G. A history of diabetes mellitus—a disease of the kidneys that became a kidney disease.J Nephrol. 2006; 19: S71-S74PubMed Google Scholar In his writings, Willis merely highlighted the difference in taste of urine from polyuric compared with healthy individuals. He used the term diabetes in the generic sense, meaning polyuria, and did not comment on the occurrence of nonsaccharine-tasting urine in polyuric individuals. Nevertheless, it was his observation that led to the differentiation of diabetes mellitus from the rarer entity of diabetes insipidus a century later. In 1769, the Scottish physician and famed chemist William Cullen (1710-1790) of Glasgow and Edinburgh first called attention to diabetic (polyuric) urine that is insipid in taste and added the descriptive adjective "mellitus" to the disease described by Willis.1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Hazard J. Perlemuter L. L'Homme Hormonal Une Histoire Illustrée.in: Hazan, Paris, France1995: 291-339Google Scholar, 3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 10Cullen W. A Synopsis of Methodological Nosology. Parry Hall, Philadelphia1793: 115-116Google Scholar, 11Bostock J. Observations on diabetes insipidus.Med Chir Trans. 1812; 3: 107-122Crossref PubMed Google Scholar, 12Lindholm J. Diabetes insipidus: historical aspects.Pituitary. 2004; 7: 33-38Crossref PubMed Scopus (21) Google Scholar It is with some hesitation that Cullen described the case of polyuria he had encountered in which the urine taste was insipid rather than saccharine.11Bostock J. Observations on diabetes insipidus.Med Chir Trans. 1812; 3: 107-122Crossref PubMed Google Scholar Relevant are the contemporaneous studies of Matthew Dobson (1732-1784) of Liverpool of diabetes mellitus, who proved the postulates of Willis by showing that the sweetness of urine in diabetes mellitus is caused by sugar, which was preceded and accompanied by the same sweet residue in blood.1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 2Hazard J. Perlemuter L. L'Homme Hormonal Une Histoire Illustrée.in: Hazan, Paris, France1995: 291-339Google Scholar, 3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 6Sanders L.J. From Thebes to Toronto and the 21st century: an incredible journey.Diabetes Spectrum. 2002; 15: 56-60Crossref Google Scholar, 9Eknoyan G. A history of diabetes mellitus—a disease of the kidneys that became a kidney disease.J Nephrol. 2006; 19: S71-S74PubMed Google Scholar Dobson had consulted Cullen before reporting his observations of diabetes mellitus. In his response, Cullen, after commending Dobson for his studies, states … I have only to add that I wish you would examine both by taste and evaporation what might be called the Urina Potus or that copius limpid urine which runs in some people after drinking largely of water or watery liquors.6Sanders L.J. From Thebes to Toronto and the 21st century: an incredible journey.Diabetes Spectrum. 2002; 15: 56-60Crossref Google Scholar The urina potus to which Cullen refers is a medieval remnant of uroscopy in which the urine to be "looked at" was classified as that after eating (urina cibis), after sleep (urina sanguinis), and after drinking (urina potus). The reference to the Latin potus is to the vessels in which drinks were imbibed. The use of urina potus interchangeably with that of excessive urination (polyuria and diabetes) remained in use well into the 1930s, even after chemical analysis and osmometry of urine to diagnose diabetes insipidus had come into use.13Roehm H.R. Postvaccinal encephalitis associated with diabetes insipidus.Am J Dis Child. 1932; 44: 1293-1296Google ScholarPotus also is the origin of the clinical entity termed beer potomania that was to be described much later. In the report of his cases, Dobson recognizes Cullen's warning: On the other hand, a learned and justly celebrated professor, the very ingenious Dr. Cullen, assures me, that he has met some cases of the diabetes, in which the urine was not sweet, agreeable to what has been observed by foreign writers.14Dobson M. Experiments and observations of the urine in a diabetes.Med Observ Inquiries Soc Phys London. 1776; 5: 298-311Google Scholar The latter statement is in reference to the challenge on the Continent to the series of reports on diabetes mellitus from the British Isles, notably by Francois Boissier de Sauvages (1706-1767) of Montpellier, who termed diabetes mellitus a British disease (diabetes Anglicus) and declared that all cases of diabetes (polyuria) described in the past must have been cases of diabetes insipidus because the urine was tasted routinely as part of its examination, but its sweetness was not recorded; whereas all cases of diabetes being described from England had sweet-tasting urine.15de Sauvages F.B. Nosologie Methodique (French ed). J.-M. Bruyset, Lyon1772: 367-374Google Scholar Geopolitical objections notwithstanding, there followed in the literature an increasing number of clinical reports, mostly of individual cases, of diabetes insipidus, for which the definition was expanded and clarified in 1794 by Johann Peter Frank (1745-1821), while at the University of Pavia, as a "long continued abnormally increased secretion of non-saccharine urine which is not caused by a disease of the kidneys."16Frank J.P. Goudareau J.M.C. Double F.J. Traité de Medicine Pratique de Jean-Pierre Frank. Vol 1. J.B. Baillière, Paris, France1842: 394-412Google Scholar The latter part of the statement was to differentiate diabetes insipidus from diabetes mellitus, which then was considered a disease of the kidneys.1Eknoyan G. Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease.Adv Chronic Kidney Dis. 2005; 12: 223-229Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Frank, who further characterized diabetes insipidus as a rare entity, was at a loss as to its cause or treatment, and in deference to diabetes mellitus (verus, or true) called it spurious.16Frank J.P. Goudareau J.M.C. Double F.J. Traité de Medicine Pratique de Jean-Pierre Frank. Vol 1. J.B. Baillière, Paris, France1842: 394-412Google Scholar Other than diabetes spurious, synonymous terms of diabetes insipidus used over the years include hydriuria, hydruresis, paruria, incontinens aquosa, hyperuresis aquosa, hydrops ad matulam, urorrhea, polyuresis, and diarrhea urinosa.17Dunglison R. Increased Secretion of Urine in the Practice of Medicine: A Treatise on Special Pathology and Therapeutics. Vol 2. Lea & Blanchard, Philadelphia1844: 53-63Google Scholar This was to remain the general state of knowledge for another century, as summed in 1892 by William Osler (1869-1939) in the first edition of his textbook: The nature of the disease is unknown. It is doubtless of nervous origin. The most reasonable view is that it results from a vasomotor disturbance of the renal vessels … giving rise to continuous renal congestion.18Osler W. The Principles and Practice of Medicine.in: Classics of Medicine Library, Birmingham, AL1978: 305-307Google Scholar Osler's reference to diabetes insipidus as a disease of nervous origin derives from its reported occurrence in hysteria and individuals of "nervous temperament," reports of experimental "neurogenic polyuria" induced by needle injury of the brain, and the increasing number of reports that pathologic lesions at the base of the brain (tumors, syphilis, tuberculosis, and trauma) were associated with systemic (endocrine) abnormalities, including diabetes insipidus.12Lindholm J. Diabetes insipidus: historical aspects.Pituitary. 2004; 7: 33-38Crossref PubMed Scopus (21) Google Scholar His reference to the kidney is from reports of polyuria due to urina atonica, presumably caused by lower tone of the renal vasculature induced by renal denervation. The prevailing notion of a "nervous origin" of diabetes insipidus remained rather vague until a specific link to the pituitary was documented in 1912 by Alfred Eric Frank (1884-1957), then working on diabetes mellitus in the department of Oskar Minkowski (1858-1931) in Breslau.19Frank A.E. Ueber Beziehungen der hypophyse zum diabetes insipidus.Berliner Klin Wochenschr. 1912; 49: 393-397Google Scholar He reported on the onset of polyuria and polydipsia in a man who had survived after shooting himself in the temple, on whom radiography of the head revealed the bullet lodged in the posterior part of the sella turcica. Shortly thereafter, Morris Simmonds (1885-1925) of Hamburg reported the case of a woman with metastatic cancer of the breast with onset of diabetes insipidus, whose autopsy showed that the posterior lobe and infundibulum of the pituitary were destroyed by metastatic infiltrates, whereas the anterior lobe was intact.20Simmonds M. Hypophysis und diabetes insipidus.Münch Med Wochenschr. 1913; 60: 127-133Google Scholar The pituitary had been described by Galen of Pergamum (129-199). In the rather complex physiology of Galen, the "animal spirits" were said to be added in the brain to the circulating "vital spirits" generated in the heart, with the waste products of this reaction flowing to the base of the brain, down the pituitary stalk to the pituitary gland, which in turn discharged them through the cribriform plate of the ethmoid bone into the nasopharynx as nasal mucus, phlegm, or pituita; hence the names of pituitary (Latin for phlegmatic) gland and ethmoid (Greek for sieve) bone.21Widdess J.D.H. Some aspects of pituitary physiology.Irish J Med Sci. 1940; 15: 791-801Crossref Scopus (1) Google Scholar, 22Harris G.W. Humours and hormones.J Endocrinol. 1972; 53: ii-xxiiGoogle Scholar, 23Kaplan S.A. The pituitary gland: a brief history.Pituitary. 2007; 10: 323-327Crossref PubMed Scopus (6) Google Scholar This waste disposal function has been taken to belittle Galen's glandula pituitaria, but can be interpreted to the contrary as a herald of its greater importance documented in coming years, recalling that in the physiology of Galen the pituitary gland dealt with the control of 1 (phlegm) of the 4 (blood, yellow bile, black bile, and phlegm) body humors and therefore served a conceptually essential function in the maintenance of humoral balance vital to good health.21Widdess J.D.H. Some aspects of pituitary physiology.Irish J Med Sci. 1940; 15: 791-801Crossref Scopus (1) Google Scholar, 22Harris G.W. Humours and hormones.J Endocrinol. 1972; 53: ii-xxiiGoogle Scholar, 23Kaplan S.A. The pituitary gland: a brief history.Pituitary. 2007; 10: 323-327Crossref PubMed Scopus (6) Google Scholar, 24Eknoyan G. Emergence of the concept of endocrine function and endocrinology.Adv Chronic Kidney Dis. 2004; 11: 371-376Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 25Wilson J. The evolution of endocrinology.Clin Endocrinol. 2005; 62: 389-396Crossref PubMed Scopus (14) Google Scholar This speculative functional interpretation of the role of the pituitary based on its anatomic position was held for the next 15 centuries after Galen and perpetuated by Andreas Vesalius (1514-1564) of Brussels, who in his De Humani Corporis Fabrica provides the first illustrations of the hypothalamic-pituitary structural and circulatory relationships.26Saunders JB de C. O'Malley C.D. The Anatomical Drawings of Andreas Vesalius.in: 7th book. Bonanza Books, New York1982: 199Google Scholar Although Leonardo da Vinci (1452-1519) made a drawing of the base of the brain showing the rete mirabilis surrounding the pituitary sometime between 1508 and 1509, the drawing was in his personal notebook and was unpublished for several centuries thereafter. Thus, it is the work of Vesalius, published in 1543 and publicly available, that affected medical thought in general and the pituitary function in particular. In the second half of the 17th century, the structural basis of presumed pituitary function was eroded by the anatomic studies of Conrad Victor Schneider (1614-1680) of Wittenburg in 1655 and the injection studies of Richard Lower (1631-1691) of Oxford in 1670, which failed to show a connection of the sella turcica to the nasopharynx.3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 21Widdess J.D.H. Some aspects of pituitary physiology.Irish J Med Sci. 1940; 15: 791-801Crossref Scopus (1) Google Scholar, 27Rolleston H. The history of endocrinology.Br Med J. 1937; 1: 1033-1036Crossref PubMed Scopus (5) Google Scholar In 1778, the German anatomist Samuel Thomas Sömmering (1755-1830) of Mainz labeled the pituitary by its anatomic position as hypophysis cerebri to replace that of glandula pituitaria of Galen, now deprived of its phlegmatic function and degraded to the pituitary "body."2Hazard J. Perlemuter L. L'Homme Hormonal Une Histoire Illustrée.in: Hazan, Paris, France1995: 291-339Google Scholar, 3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar The abbreviated term hypophysis entered the medical lexicon thereafter and came to be used interchangeably with pituitary. Deprived of a role in maintaining humoral balance, the pituitary gland then was relegated to near obscurity. Of the sundry speculative roles attributed to the pituitary during the ensuing years (ganglion, lymph node, cerebellar replica, etc), one that stands out for its vision is that of the Swedish polymath, mystic, and theologian Emanuel Swendenborg (1688-1772). In his quest for the seat of the soul, Swendenborg studied brain function, and in his notes published posthumously, wrote the following: The pituitary is the last of the organs of the chymical laboratory of the brain. It is their complement and crown … and even carries out here some sublime and grand work which concerns the whole kingdom, and on which its whole welfare depends. On this account the pituitary gland may deservedly be styled the gland of life, or the arch gland, which receives the whole spirit of the brain and communicates it to the blood.28Gross C.E. Emanuel Swendenborg: a neuroscientist before his time.Neuroscientist. 1997; 3: 142-147Crossref Scopus (18) Google Scholar This prescient declaration had to wait 2 centuries before it could be made as an evidence-based statement in 1935 by Walter Langdon-Brown (1870-1946) of Cambridge that the pituitary is "the leader of the endocrine orchestra."29Langdon-Brown W. Integration of the endocrine system.Br Med J. 1935; 2: 1061-1063Crossref PubMed Google Scholar What follows is the story of one lead player in Langdon-Brown's orchestra, vasopressin, the hormone essential to maintaining internal water balance and by extension fundamental to maintaining the "internal milieu" of Claude Bernard (1813-1878). However, these future developments were yet to come. In 1890, the pituitary was flatly declared as being "probably the rudiment of an archaic sense organ" by Alexander Macalister (1844-1919), Professor of Anatomy at Cambridge,27Rolleston H. The history of endocrinology.Br Med J. 1937; 1: 1033-1036Crossref PubMed Scopus (5) Google Scholar and in 1909 was defined by Harvey Cushing (1869-1939) as "a small bilobed body of unknown function attached to the infundibulum at the base of the brain."30Cushing H. Papers Relating to the Pituitary Body, Hypothalamus and Parasympathetic Nervous System. C.C. Thomas, Springfield, IL1932: 10Google Scholar It was just about this time that interest in pituitary function, stimulated by the steady accumulation of cases of diabetes insipidus associated with pituitary lesions, prompted experimental studies of pituitary function in various medical disciplines, progressing in parallel but independently of each other, which were to unravel the importance of the pituitary. To recognize individually the contributors who made this possible is beyond the scope of this article, which will mention only pioneering lead investigators, whose steadfast work provided the breakthroughs that allowed for others to expand the field. Prompted by the studies of Claude Bernard's successor to the Chair of Experimental Medicine at the Collège de France, Charles-Édouard Brown-Séquard (1817-1894), on the adrenals and testicles, organotherapy was in full swing in the 1890s.24Eknoyan G. Emergence of the concept of endocrine function and endocrinology.Adv Chronic Kidney Dis. 2004; 11: 371-376Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 25Wilson J. The evolution of endocrinology.Clin Endocrinol. 2005; 62: 389-396Crossref PubMed Scopus (14) Google Scholar In 1895, George Oliver (1841-1915) and Edward Albert Schafer (1850-1935) from University College London first reported experiments on the endocrine functions of the pituitary.31Oliver G. Schafer E.A. On the physiological actions of pituitary body and certain other glandular organs.J Physiol. 1895; 18: 277-279Crossref PubMed Scopus (178) Google Scholar Oliver, a Harrogate practitioner who had invented a "haemodynameter, intended to read variations in blood pressure," and an "arteriometer, for measuring with exactness the lumen of the radial artery," convinced Schafer to let him use them in his laboratories to study adrenal function. Following their successful demonstration of vasoconstriction caused by injection of adrenal extracts, they were the first to report that injecting a water extract of the pituitary also results in vasoconstriction.3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 25Wilson J. The evolution of endocrinology.Clin Endocrinol. 2005; 62: 389-396Crossref PubMed Scopus (14) Google Scholar, 27Rolleston H. The history of endocrinology.Br Med J. 1937; 1: 1033-1036Crossref PubMed Scopus (5) Google Scholar, 32Schafer E.A. Herring P.T. The action of pituitary extracts upon the kidney.Phil Trans R Soc London Series B. 1908; 199: 1-29Crossref Google Scholar In subsequent studies, Schafer and Herring reported that the increase in blood pressure was associated by diuresis, whereas the adrenal extract caused a mark diminution of the kidney and complete stoppage of the secretion of urine, extract of pituitary generally produces after a short period of latency, a remarkable and long-continued expansion of the organ, accompanied by a decided and often prolonged diuresis.32Schafer E.A. Herring P.T. The action of pituitary extracts upon the kidney.Phil Trans R Soc London Series B. 1908; 199: 1-29Crossref Google Scholar The effect of the extract was shortly located to the posterior pituitary, but its reported diuretic effect was challenged.3Rolleston H.D. The Endocrine Organs in Health and Disease With an Historical Review.in: Oxford University Press, London, England1936: 419-434Google Scholar, 25Wilson J. The evolution of endocrinology.Clin Endocrinol. 2005; 62: 389-396Crossref PubMed Scopus (14) Google Scholar, 27Rolleston H. The history of endocrinology.Br Med J. 1937; 1: 1033-1036Crossref PubMed Scopus (5) Google Scholar There followed a series of conflicting reports of differing results caused by: (1) variation in pituitary extraction methods, dose used, and route of administration; (2) the experimental animals studied, their state of hydration, and method of anesthesia; (3) duration of the experimental observation; and (4) sterile techniques used. In a summary statement of the confusion in the field, Homer Smith (1895-1962) stated that "the subject got off to a bad start and has been marked by many contradictory results."33Smith H.W. The Kidney Structure and Function in Health and Disease.in: Oxford University Press, New York, NY1951: 246-257Google Scholar To explain the divergent results (diuretic, antidiuretic) being reported, Schafer argued for the presence of 2 pituitary substa
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