ALBRIGHT, FULLER

(b. Buffalo, New York, 12 January 1900: d. Boston, Massachusetts, 8 December 1969)

medicine, endocrinology.

Albright was among a select group (including Herbert M. Evans, Edward C. Kendall. Robert Loeb. John P. Peters, and Lawson Wilkins) who forged the approach to clinical research in medicine and endocrinology during the middle third of the twentieth century. For more than twenty years he dominated the field of parathyroid physiology, until his career was terminated by illness in 1956. He held the rank of associate professor of medicine at Harvard Medical School and was physician in medicine at Massachusetts General Hospital at the time of his retirement. Albright was president of the American Society for Clinical Investigation (1943–1944) and the Association for the Study of Internal Secretions (1946–1947). He was elected to the National Academy of Sciences in 1955.

In 1897 Albright’s father. John Joseph Albright, an affluent widower with three children, married Susan Fuller, a Smith College graduate. Fuller Albright, the third of their five children, was reared in a happy, close-knit family amid the advantages of wealth. He attended the Nichols School in Buffalo (founded by his father) and entered Harvard at age sixteen, graduating cum laude three years later. He enrolled at Harvard Medical School in 1920 and was an “exceptionally good” student. In his final year he gave a paper to the Boylston Society titled “The Physiology and Physiological Pathology of Calcium,” with Joseph C. Aub as his sponsor. Aub’s patronage was fortunate, for aside from interests in lead poisoning ami calcium metabolism, he had trained in the Cornell division’s metabolism unit at Bellevue, a prototype for the future Ward 4 research unit at Harvard. Albright graduated in 1924 and interned at Massachusetts General Hospital in 1925, staying another year as Aub’s research fellow to work on calcium metabolism. Also in 1925, Ward 4 research opened and James B. Collip isolated parathormone, the principal ligand of calcium regulation.

Following a year as assistant resident at Johns Hopkins (1927), his interest in parathyroid function led Albright to join Jacob Erdheim in Vienna (1928–1929). Erdheim, a prolific investigator and brilliant bone pathologist, had noted tetany in parathyroidectomized animals as early as 1906. Albright frequently commented in later years that Erdheim “knew more about disease processes than any other living man.” Frdheim’s influence undoubtedly routed any thoughts of private practice, for in 1929 Albright joined the Harvard medical faculty and the staff of Massuchusetts General Hospital, where he remained until his retirement.

Albright’s marriage in 1933. to Claire Birdge of New York, was of significance to his professional life. In 1935 he developed signs of Parkinson’s disease, and it is doubtful that he could have maintained the strenuous pace of his later activities without her extraordinary courage, as well as the loyal support and physical care given by their sons, Birge and Reed. Though he was hampered by illness, his output was prolific in spite of the relatively short span of years in which he had to work.

In the late 1920’s endocrinology was still a descriptive area of medicine—something of a freak show. Albright’s work brought biochemical techniques and a rigorous scientific discipline into the field, compelling others to restructure their qualitative method of thought.

Albright began calcium balance studies with Walter Bauer and Aub in the new research unit (later renamed the Mallinckrodt Ward). Although the Cornell group originated the modern metabolic unit. Albright perfected it through his exploitation of the routine. The accuracy of his studies remained unchallenged until the cumbersome technique of that day yielded to newer methodology (isotopic dilution techniques). These 1929 balance studies with Aub, along with the first case report of idiopathic hypoparathyroidism, by Albright and his close friend Read Ellsworth, were the earliest analyses using controlled calcium diets. Clarifying parathormone’s action on calcium and phosphorus excretion (1930), Albright highlighted the role of bone as an available reserve supply of calcium and underscored total protein as a cardinal measurement in the assessment of serum calcium. In 1931 Albright, with J. R. Cockrill and Ellsworth. showed that the inverse relationship of serum calcium and phosphorus was coupled to parathormone activity, the former varying directly with parathormone levels and the latter inversely with increased renal excretion.

In 1934, on the basis of a large series of patients with primary hype)athyroidism, Albright gave a detailed description of the complicating bony lesions (osteitis fibrosa generalisata) and nephrocalcinosis (Albright’s expression), further differentiating between “diffuse hyperplasia of all parathyroid glands rather than a solitary adenoma of one.” He organized the Stone Clinic—later dubbed “the quarry”—that uncovered eighty-nine cases of hype)athyroidism by 1947.

Albright in 1937 reported a nonheritable condition with seemingly unrelated findings: areas of cystic bone changes (without metabolic derangement), distinctive skin pigmentations, and the precocious onset of puberty in girls—now cataloged as “Albright’s syndrome.” His comment—“If pathological manifestations which at first seem to be totally disconnected are found to occur together in a sufficient series of patients, some relation between them is apparent”—forecast an eponymic kismet for Albright’s co-workers: Albright coauthored at least eight descriptions of new syndromes that were named for himself and various colleagues.

Between 1930 and 1945 Albright evolved a classification of metabolic bone disease (Albright’s coinage) that charted the differences between osteoporosis, osteomalacia, and osteitis fibrosa, and emphasized that osteoporosis was not a calcium derangement but rather a defect in protein metabolism resulting in decreased formation of bone matrix, Osteomalacia was characterized as a failure of mineralization, and osteitis fibrosa as bone destruction. Albright’s name became inseparable from the condition known as postmenopausal osteoporosis (his label) because he correctly related the osteopenia to estrogen withdrawal. Before 1940 neither physiological menopause nor artificial withdrawal of estrogen (oophorectomy) had been a recognized cause of decreased bone mass.

In 1942, with C. H. Burnett, P. H. Smith, and W. Parson, Albright reported a group of patients with short stature, hypocalcemia, ectopic calcifications, mental retardation, short metacarpal and metatarsal bones, and insensitivity to normal parathormone—a constellation Albright designated in his milestone paper “Pseudohypoparathyroidism [PHP]—An Example of Seabright-Bantam Syndrome” [sic]. In it he erected a theoretical scaffold based on four observations: (1) the Sebright bantam rooster has female feathering with normal androgen production; (2) the American male Indian is beardless with normal testosterone; (3) there existed “patients with low basal metabolic rates without other evidence of hypothyroidism”; and (4) patients with PHP were unresponsive to normal parathormone. Albright concluded that all four phenomena were examples of end organ failure and inferred that renal cell receptors in these patients were unresponsive to parathormone.

This was the first instance in which blunting of a normal response (hormonal resistance) had been contemplated. An accepted mechanism today, at the time this was an inspired orchestration of ideas. Albright assembled a new series of patients in 1952 (variations on a theme of PHP) with the same phenotypic findings but lacking calcium and phosphorus changes. He tagged the disorder “pseudopseudohypoparathyroidism,” theorizing that both conditions were expressions of different mutations of the same gene. Questions persist about these reciprocally related genetic conditions, and the specific gene awaits identification. Present data concerning end organ resistance in patients with PHP show a reduction of regulatory protein in the receptor cell memhranes coupled to the adenylate cyclase system of the kidney and other tissues. Albright’s analogy of the Sebright bantam reconciles with present data only insofar as it is an example of hormonal resistance—the defect in these cockerels is related to the conversion of androgen to estrogen (testosterone to estradiol) by their skin cells rather than an end organ defect, that is, the defect is proximal to the end organ.

In 1941 Albright hypothesized that a metastatic kidney tumor (nonendocrine) was capable of secreting a purathormone-like substance. More than an improvisational abstraction, this theory was monumentally prescient: at least a dozen or more polypeptide messengers have been involved with ectopic hormonal secretion. In 1948 Albright, with Kdward C. Reifenstein, published the monograph Parathyroid Glands and Metabolic Bone Disease. culminating more than twenty years of research on calcium metabolism. Encyclopedic in scope, it detailed many syndromes first described by Albright, including vitamin D-resistant rickets, milk-alkali syndrome, and osteomalacia secondary to steatorrhea. Its text still provides a footing for most of what is accepted about parathyroid physiology.

With the increasing availability of biochemical information in the 1930’s, Albright initiated studies on the pituitary-gonad and pituitary-adrenal axes. Pathophysiological information on menstrual dysfunction was sparse; however, by 1936 he had partially resolved the nature of amenorrhea in women of childbearing age, discriminating between primary ovarian failure and pituitary hypofunction His biological assay methods (crude by present standards) for measuring pituitary gonadotropins and, later, follicle-stimulating hormone (FSH) in the urine (1943), led to further study of menopause and of testicular dysfunctions. Using these estimations as “hormonal measuring sticks,” he defined menopause as a “primary condition in the ovary, and not secondary to hypofunction of the anterior pituitary,” with the demonstration of an increase in FSH after menopause, that is, “menopause is a physiological ovarian amenorrhea.”

Albright’s convincing evidence that menorrhagia was related to hypoprogesteronism ended an era of inappropriate hysterectomy for functional uterine bleeding. In 1938 he introduced the phrase “medical curettage” (suggested by J. S. L. Browne), advocating progesterone administration for five to six days even six weeks, thus restoring a normal menstrual cyle.

Albright’s classic description, written with his research fellow, Henry E. Klinefelter, Jr., and with E. C. Reifenstein (1942), of males with gynecomastia, aspermatogenesis, and increased secretion of FSH (Klinefelter’s syndrome) signaled a new generation of research (chromosomal mapping) directed to the study of genetic disorders. In 1956 the discovery of the presence of superfluous X-chromatin material in these patients (47XXY karyotype) clearly established a genetic transmission of the syndrome.

In 1943 Albright delivered his landmark Harvey Lecture “Cushing, s Syndrome: Its Pathological Physiology, Its Relationship to the Adrenogenital Syndrome, and Its Connection with the Problem of the Reaction of the Body to Injurious Agents (Alarm Reaction of Selye).” The conceptual fusion of ideas and their source, relating the rationale for appropriate corticosteroid therapy and its pitfalls, have been forgotten: however, the alpha lessons can be abstracted from this disquisition. Using elegant carbohydrate balance studies. Albright elaborated upon some of the fundamental distinctions between the “S” (sugar) hormone and the “N” (nitrogen-sparing, testosterone-like) hormone of the adrenal cortices. His theory, while oversimplified, is fundamentally correct; excess production of the former causes dishing’s syndrome, and excess secretion of the latter causes adrenogenital syndrome. Overabundant “S” hormone (glucocorticoid intoxication) was properly viewed by Albright as an antianabolic syndrome that was adrenal in origin, whether secondary to anterior pituitary stimulation (basophilic adenoma) or primary in the adrenals (cortical hyperplasia or adenoma).

As Albright anticipated, other ectopic hormonal syndromes have come to light. Adrenocorticotropic substances from both endocrine and nonendocrine tumors may produce a syndrome of hypercortisolism. The subtle paradigms relating female secondary sexual characteristics to adrenal origin, and the view that the counte)t (adrenogenital syndrome) to Cushing’s syndrome is overvirilization by the adrenal cortices, are Albrightian in origin. The endocrine rhetoric of hyper-this or hypo-that. The concatenation of circular diagrams bristling with modifying arrows— all shorthand expressions of hormonal circuitry— emanate from Albright’s chirographic style.

Convinced that he was a burden to those who loved him. Albright reached an agonizing decision in 1956—to undergo brain surgery (chemothalamectomy). The results were catastrophic. He hemorrhaged into his brain on the third postoperative day and spent the last thirteen years of his life an akinetic mute, bound to a wheelchair at Massachusetts General Hospital.

Acknowledged at the time of his death as the doyen of parathyroid physiology. Albright bequeathed a rich legacy. He left behind a dynamic model of bone resorption and remodeling that paired with a working conceptualization of the pituitary-ovarian and pituitary-adrenal axes, provided a rational approach to corticosteroid therapy and a solid foundation for clinical research in endocrinology. Of deep concern to Albright was the peril of segregating clinical practice from clinical investigation. He repeatedly stressed that the care of the sick was the primary objective of the clinical investigator, and “only secondarily, if at all, the study of laboratory animals.” Moreover, he was acutely aware that scientific theory ought not to be written in concrete, often making the point that each of his hypotheses was “subject to change tomorrow.”

BIBLIOGRAPHY

I. Original Works. All of Albright’s research papers and articles, including material relevant to the preceding text, as well as his appointments, honors, and awards, are listed in A. Leaf “Fuller Albright,” in Biographical Memoirs. National Academy of Sciences, 48 (1976), 3–22. Not included is the monograph written with Edward C. Reifenstein, The Parathyroid Glands and Metabolic Bone Disease (Baltimore, 1948). Albright’s remarks on ectopic hormonal (parathyroid hormone) production from a nonendocrine tumor are in “Case Records of the Massachusetts General Hospital (Case 27461),” in New England Journal of Medicine, 225 (1941), 789–791.

Albright’s presidential address to the American Society for Clinical Investigation (May 8, 1944). “Some of the Do’s and’ Do-Not’s in Clinical Investigation,” was printed in Journal of Clinical Investigation. 23 (1944), 921–926. His presidential address to the Association for the Study of Internal Secretions (June 6, 1947), “A Page out of the History of Hype)athyroidism,” is printed in Journal of Clinical Endocrinology, 8 (1948), 637–657. Both contain reproductions of his illustrations.

Albright’s extensive slide collection dealing with endocrine topics and metabolic studies has been restored and cataloged by his longtime associate Anne P. Forbes; copies are available by arrangement with the Countway Library of the Department of Medicine, Harvard Medical School.

II. Secondary Literature. No full-length biography of Albright has been published. For brief biographical sketches and panegyric materials, see Lloyd Axelrod, “Bones, Stones and Hormones: The Contributions of Fuller Albright,” in New England Journal of Medicine, 283 (1970), 964–970: C. Frederic Banter, “Fuller Albright,” in Birth Dejects, Original Article Series, 7 , no. 6 (1971), 3–4; S. Gilbert Gordan, “Fuller Albright and Postmenopausal Osteoporosis; A Personal Appreciation,” in Perspectives in Biology and Medicine. 24 (1981), 547–560; P. H. Henneman, “Fuller Albright (1900–1969),” in New England Journal of Medicine, 282 (1970), 280–281; and John E. Howard, “Fuller Albright: The Endocrinologists” Clinical Endocrinologist,’ in Perspectives in Biology and Medicine, 24 (1981), 374–381.

Photos and illustrations are in E. B. Pyle, “Fuller Albright”s Inimitable Style,’ in Harvard Medical Alumni Bulletin, 56 (1982), 46–51. An account of the circumstances surrounding Albright’s brain surgery is in Irving S. Cooper, The Vital Probe (New York, 1981), 161–170. Appraisals of Albright’s influence on twentieth-century clinical investigation and endocrinology are in James Bordley III and Abner M. Harvey, Two Centuries of American Medicine (Philadelphia, 1976), 223, 553–555; Abner M. Harvey. Science at the Bedside (Baltimore, 1981), 255–257; and in V. C. Medvei, A History of Endocrinology (Laneaster. England, 1982), 398–399, 486–489, 524–530, 700–701, 730, with page facsimiles of Albrights introduction to the chapter “Diseases of the Ductless Glands,” taken from Russell L. Cecil and Robert F. Loeb. eds., A Textbook of Medicine, 9th ed. (Philadelphia, 1955), and his address to the Society for Clinical Investigation cited above. A detailed history of the Mallinekrodt Ward, with commentaries on Albright’s work, is in James H. Means, Ward 4 (Cambridge. Mass., 1958).

Martin E. Fink