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Pediatric Endocrine Society

Formerly Named in Honor of Lawson Wilkins

Historical Tidbits

Each month, the PES President's newsletter includes an historical tidbit that we have gathered here. If you have an interesting brief historical tidbit to share, please email and mention in your message Arlan Rosenbloom, chairman of the History Committee

May 2018 – submitted by Walter Miller
Treating CAH with cortisone

Lawson Wilkins had ameliorated salt loss in CAH with deoxycorticosterone, but his treatments with ACTH, testosterone and several androgen analogues failed. Wilkins’ preliminary report described suppressing one patient’s urinary 17KS with cortisone (Bull Johns Hopkins Hosp 86:249, 1950). Frederic Bartter’s contemporaneous abstract on treating CAH with cortisone concludes: “These findings suggest that the adrenogenital syndrome results, not from an abnormal pituitary stimulation of the adrenal, but from an abnormal adrenal response to a normal pituitary” (JCI 29:797,1950). They simultaneously published full papers; citing each other’s work (JCEM 11:1,1951;JCI 30:237,1951). Wilkins tried many steroids, eventually cortisone, whereas Bartter’s work was based on an early understanding of the pituitary-adrenal axis; they deserve equal credit for cortisone treatment, but Bartter understood the physiology.

April 2018 – submitted by Walter Miller
Two types of hypothalamic-pituitary connection

Stephen W. Ranson established that ADH was made in hypothalamic supraoptic nuclei, that the posterior pituitary (PP) was innervated by a supraoptico-hypophyseal tract; and that disruption of this innervation caused DI, thus establishing that the PP was under neural control (Bull NY Acad Med 13:241, 1937). Lieutaud reported circulation between brain and pituitary in 1742; Wislocki & King showed that blood flowed from hypothalamus to pituitary (Am J Anat 58:421, 1936). Geoffrey Harris noted the paucity of anterior pituitary innervation and that the hypophyseal portal system regenerated following stalk section but that nerve fibers from hypothalamus to PP did not, concluding that the PP was under neural control whereas the anterior pituitary was under humoral control (Physiological Rev 28: 139,1948).

March 2018 – submitted by Walter Miller
Philip E. Smith: The pituitary controls other glands

Smith established the central role of the pituitary. He showed that the pituitary controlled frog skin pigmentation (Science 44:280, 1916), the first evidence for melanocyte-stimulating hormone. He devised a pharyngeal hypophysectomy procedure in rats sparing the pars tuberalis and hypothalamus: the animals stopped growing; the liver, spleen and kidneys got smaller; pre-pubertal animals remained pre-pubertal; and the adrenals, thyroid and gonads atrophied (JAMA 88:158, 1927; Am J Anat 45:205, 1930). Pituitary transplants or injections of pituitary homogenates largely reversed these effects. Rats hypophysectomized by a temporal approach had a similar outcome but also became markedly obese. Smith correctly concluded that this was due to an injury of the hypothalamus, thus helping to establish the hypothalamic-pituitary axis.

February 2018 – submitted by Alan Rogol
Secretin: the defining moment for endocrinology

Claude Bernard coined the term “internal secretions” to describe the release of glucose from liver glycogen (Comptes Rendus 1853; 40:589). Starling and Bayliss investigated the innervation and movement of the small bowel, for Pavlov (The Physiology of Digestion, 1904) believed that exocrine pancreatic secretion was controlled by the vagus nerve. They dissected the nerves supplying the pancreas and duodenum in dogs. Acid added to the duodenum led to pancreatic enzyme secretion. They mixed duodenal scrapings with acid and administered the supernatant iv to a dog. Within seconds pancreatic enzyme secretion occurred. Their conclusion: a precursor, “pro-secretin” released secretin with acid (J Physiol (1902; 28:325). They called it a ‘hormone’ –Gr. “I arouse to act”.

January 2018 – submitted by Walter Miller
JB Collip and the isolation of pituitary hormones

In 1933, James Bertram Collip, who had devised the insulin purification procedure that netted the Nobel Prize for Banting & MacLeod, prepared several anterior pituitary hormone fractions of varying purity (Lancet 222(5727): 1208-1209, 1933). As the pituitary extract was concentrated, the first material to precipitate was termed ‘Q extract’. Assaying fractions in the hypophysectomized rat model described by Philip E. Smith (Am J Anat 45:205-273, 1930), he showed that ‘Q extract’ was a powerful growth hormone free of gonadotropic, thyrotropic or adrenotropic activities. Once the Q extract was recovered, he removed prolactin by iso-electric precipitation, then prepared TSH by salt precipitation and fractionation with alcohol/acetone. ACTH was then precipitated at pH 5 in 75% acetone (Lancet 222(5237); 347-348, 1933).

December 2017 - submitted by Walter Miller
DNA Sequencing

The development of rapid, accurate DNA sequencing did for genetics what invention of the microscope did for cell biology. Maxam & Gilbert (PNAS 74:560-564,1977) and Sanger (PNAS 74:5463-5467,1977) devised the first viable DNA sequencing tactics. Insulin (Science 196:1313-1319,1977) and GH (Nature 270:486-494,1977) were among the first genes sequenced, and advances in the Sanger technology led to sequencing the human genome (Nature 409:860-921,2001; Nature 431:931-945,2004). Next-generation, massively parallel sequencing has delivered genome sequences of hundreds of living and extinct species, making sequencing a routine tool in biology, anthropology and medicine. Third generation, hand-held technologies will soon permit genome sequencing in the field or at the bedside. This 40-year history of DNA sequencing is celebrated in a 19 October review (Nature 550:345-353,2017).

November 2017 – submitted by Alan Rogol
Growth and the pituitary

The pituitary’s role in growth was established in 1886 by the association of acromegaly with pituitary tumor [P Marie, Rev Med (Paris) 6:297]. S Crowe, et al. associated the cessation of growth with hypophysectomy in puppies [Bull Johns Hopkins Hosp 21:127, 1910]. Evans and Long [Anat Red 21:62, 1921] and noted increased growth in rats following injection of an extract of anterior lobes. PE Smith showed that normal growth required the anterior pituitary [Am J Anat 45:205, 1930 (renamed Developmental Dynamics in 1992)]. Daily anterior pituitary homeotransplants restored normal growth in hypophysectomized rats; but intraperitoneal injections of aqueous pituitary extracts had no effect on the atrophied reproductive organs. Growth hormone is water-soluble, but gonadotropins are not.

October 2017 – submitted by Alan Rogol
The Ascheim-Zondek (A-Z) test for pregnancy

In 1927 Selmer Ascheim and Bernhard Zondek established the first bioassay to detect early human pregnancy by injecting a woman’s urine into an immature female mouse. The test was positive (pregnancy) if the mouse went into “heat”. Later modifications used rabbits and then frogs, but all relied on the biological activity of hCG, whose identity was not established until the 1960’s, even though its specific biological activity was known in the 1930’s. The first few thousand tests were deemed more than 98 % accurate with just a few false positives or negatives, a remarkable success rate! These bioassays have been supplanted by immunoassays, which quantitate hCG and can detect pregnancy at about 3 days post-implantation.

September 2017 – submitted by Walter Miller
Non-Classic Congenital Adrenal Hyperplasia (NCCAH) – A Common Disorder with Many Parents

Classical congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency has a worldwide incidence of 1 in 15-20,000, but NCCAH, the mild attenuated form, is seen in up to 1 in 1000 in some populations (Am J Hum Genet 37:650, 1985).  NCCAH was first described by Decourt et al. (Ann Endocrinol 18:416, 1957), but that paper was published in French, and was not widely read.  Describing NCCAH is typically credited to Maria New (13th PES President, 1985-86) (JCEM 48:356, 1979) and to Zev Rosenwaks & Claude Migeon (first PES President 1972-73) (JCEM 49:335, 1979), but Rosenwaks and Migeon cited nine previous reports from 1958-77!  About half of mutant CYP21A2 alleles in NCCAH carry V281L (NEJM 319:19, 1988; Clin Endocrinol 82:543, 2015).

August 2017 – submitted by Alan Rogol
The Ascheim-Zondek (A-Z) test for pregnancy

In 1927 Selmer Ascheim and Bernhard Zondek established the first bioassay to detect early human pregnancy by injecting a woman’s urine into an immature female mouse. The test was positive (pregnancy) if the mouse went into “heat”. Later modifications used rabbits and then frogs, but all relied on the biological activity of hCG, whose identity was not established until the 1960’s, even though its specific biological activity was known in the 1930’s. The first few thousand tests were deemed more than 98 % accurate with just a few false positives or negatives, a remarkable success rate! These bioassays have been supplanted by immunoassays, which quantitate hCG and can detect pregnancy at about 3 days post-implantation.

July 2017 – submitted by Walter Miller
Growth hormone (GH): the first triumph of recombinant DNA technology

Bovine GH was isolated in 1944 (Li & Evans, Science 99:183), and incomplete amino acid sequences were obtained for bovine, rat and human GH by 1975, but it was slow work, and results were not always accurate. Recombinant DNA technology changed everything. Rat (Seeburg et al., Nature 270:486, 1977), human (Martial et al., Science 205:602, 1979) and bovine (Miller et al, JBC 255:7521,1980) GH were cloned; recombinant human and bovine GH were produced industrially. The discovery that clinically-used human cadaveric GH carried a substantial risk of Creutzfeld-Jacob disease (Koch et al., NEJM 313:731, 1985) overrode hysterical, non-scientific claims of the risks of biosynthetic proteins. Recombinant human GH was approved in 1985 and bovine GH (which promotes milk production) in 1995.

June 2017 – submitted by Walter Miller
Sulfation factor, Somatomedin-c, NSILA, and IGF-I

Administering GH to hypophysectomized rats restored growth and incorporation of 35S into chondroitin sulfate (“sulfation factor’ activity), but adding GH to cultured cartilage in vitro did not. Serum from normal animals stimulated 35S incorporation, serum from hypophysectomized animals did not, but serum from hypophysectomized animals treated with GH did, suggesting the ‘somatomedin’ hypothesis (Salmon & Daughaday, J Lab Clin Med 49:825, 1957). A non-suppressible insulin-like activity (NSILA) remained in plasma treated with anti-insulin antibodies (Froesch et al., JCI 42:1816, 1963). Rinderknecht & Humbel isolated a 7.5 kDa NSILA/insulin-like growth factor (IGF-I) with sequence similarity to pro-insulin (JBC 253:2769, 1978). Judson VanWyk (5th president of the LWPES, 1976-77) showed that IGF-I and somatomedin-c had identical amino acid sequences (Endocrinology 112:2215, 1983).

May 2017 – submitted by Arlan Rosenbloom

Abnormal hemoglobin in the red cells of diabetics was initially described in 1968 (S Rahbar, Clin Chem Acta 22:296-298), but it remained uncertain whether this was a marker for diabetes or a secondary phenomenon (LA Trivelli et al., NEJM 284:353-357, 1971; EP Paulsen, Metabolism 22; 269-271:1973). Measurements of HbA1c and the development of self-monitoring of blood glucose (Clements et al. Diabetes Care 4; 392-395, 1981) provided the means for monitoring intensified therapy, resulting in the landmark diabetes control and complications trial (DCCT) (NEJM 329:977-986, 1993; RD Lasker NEJM 329:1035-1036, 1993). The DCCT Research Group included about 700 investigators at 35 centers, including many prominent members of the Lawson Wilkins Pediatric Endocrine Society.

April 2017 – submitted by Alan Rogol and Walter Miller
Robert Blizzard and the National Pituitary Agency (NPA)

Bovine growth hormone (GH) was isolated in 1944 (Science 99:183), but growth-promoting effects were species-specific (Endocrinology 60:166, 1957), and only human GH could stimulate growth in GH-deficient children (Science 125:884, 1957; JCEM 18:901, 1958). To stimulate clinical and basic research, and pre-empt premature commercialization, a centralized mechanism was needed to collect pituitaries and extract the hGH. In 1960, Robert Blizzard (third President of the PES, 1974-75), the NIH, The College of American Pathologists, and others organized the NPA. From 1963 to 1985, when it became apparent that cadaveric hGH was a potential cause of Creutzfeld-Jacob disease, virtually all hGH in the USA was provided by the NPA. The history of hGH was reviewed by Frazier (J Pediatr 131:S1, 1997).

March 2017 – submitted by Walter Miller
Contemporary pediatric endocrinologists will quickly suspect adrenocortical carcinoma (ACC) in a 3-6 year old girl with severe Cushingoid features, growth arrest and virilism. The first known published case of apparent ACC was that describing Hannah Taylor (1682-1688), a 6-year old whose autopsy was reported by Henry Sampson (Philosophical Transactions 19:80-82, 1697); this fascinating paper was reproduced and its historical context discussed recently (J Steroid Biochem Mol Biol 165:109-113, 2017). Fuller Albright’s mid-20th century perspective on ACC is seen in NEJM 241:874-877, 1949. Most pediatric ACC is caused by mutations in the p53 tumor-suppressor gene, usually in association with Li-Fraumeni syndrome (Endocr Rev 35: 282–326, 2014). Early diagnosis can permit surgical cure, but prognosis in metastatic disease remains poor.

February 2017 – submitted by Alan Rogol
Sir Charles Robert Harington was a classical organic chemist, who with George Barger completed the chemical structure of thyroxine (Biochem J 20:109, 1927). They devised an organic synthesis from tyrosine and proved its structure by comparing the composition of degradation fragments (some synthesized) with the compositions of the expected products. The mixed melting point of combined entities was the same as either individually for a number of these degradation products. They ended with: “Insofar, then, as the matter is susceptible of decision by chemical methods the identity of the synthetic product with natural thyroxine may be regarded as established”. Additionally, it raised the basal metabolic rate from about -40 % to around 0% (normal) in two profoundly myxedematous women.

January 2017 – submitted by Walter Miller
Hans Selye, who first described the hormonal stress response (Nature 138:32, 1936) and coined the terms ‘glucocorticoid’ and ‘mineralocorticoid’, observed that progesterone was a potent anesthetic agent that permitted abdominal surgery on rats (Proc Soc Exp Med Biol 46:116, 1941; Endocrinology 30:437, 1942). Research into the clinical use of steroidal anesthesia ended with the development of halothane (1956). Progesterone membrane receptors (Front Neurosci 7, Article 159, 2013) may mediate the anesthetic actions of progesterone. Allopregnanolone (3,5-tetrahydroprogesterone) is an endogenously produced neurosteroid progesterone metabolite with potent anesthetic, anxiolytic and anticonvulsant actions that acts via GABAa (and possibly other) receptors (similarly to barbituates and benzodiazepines). Allopregnanolone may play a role in stress disorders and has potential therapeutic uses, but is under-investigated.

December 2016 – submitted by Walter Miller
Bioassays for lactogenic and somatogenic activities were described in the 1930’s, but it took another 40 years to show that GH and Prl are distinct hormones. Frantz and Kleinberg showed that primate GH’s have low lactogenic activity via sensitive bioassays based on prolactin’s  ability to induce differentiation and milk secretion in cultured mouse breast tissue (Science 170:7745, 1970). Clinical observation suggested GH and Prl were distinct: men with acromegaly and high serum hGH had very low lactogenic activity; patients with galactorrhea lacked acromegaly; women with GH deficiency had normal lactation post-partum. Niall’s group reported prolactin’s amino acid sequence, ending the debate (Red Progr Horm Res 29:387-416, 1973); distinct, but related GH and Prl genes were cloned in the late 1970s.   

November 2016 – submitted by Walter Miller
Nathan B. Talbot (1909-94) created one of America’s first pediatric endocrine programs at the Massachusetts General Hospital (MGH) in 1942. He published a textbook of pediatric endocrinology in 1952, preceded only by Lawson Wilkins’ 1950 text. Talbot’s early work centered on adrenal steroids, refining the colorimetric assay of corticosteroids (J Biol Chem 160:535, 1945) and describing the growth-inhibitory effects of cortisone (NEJM 254:636, 1956). He first described what was later termed ‘the maternal deprivation syndrome’ (NEJM 236: 783, 1947) and with his fellow, Juan Sotos, described cerebral gigantism (NEJM 271:109, 1964). When Talbot became Chief of Pediatrics at MGH (1962-77), he designated John D. Crawford (1920-2005) as chief of pediatric endocrinology (1963-90), who grew the program to international prominence.

October 2016 – submitted by Walter Miller
Stress can inhibit growth. Talbot at MGH reported poor growth secondary to grief or maternal rejection (Am J Dis Child 72:450, 1946; NEJM 236: 783, 1947). Twenty years later, Powell, Brasel and Blizzard at Johns Hopkins expanded on these observations, calling it the ‘maternal deprivation syndrome,’ characterized by ravenous appetite, foraging from garbage cans, drinking from toilets and disordered sleep cycles (NEJM 276:1271, 1967). With Raiti, they noted transiently failed secretion of growth hormone with rapid growth when the child was removed from the dysfunctional environment (NEJM 276:1279, 1967). Such ‘reversible GH deficiency’ in children >2yo is now distinguished from true maternal deprivation syndrome in infancy; both disorders highlight the interactions of stress, hormones and behavior.

September 2016 – submitted by Walter Miller
Cushing syndrome results from glucocorticoid excess from any source, whereas Cushing Disease results from ACTH-producing pituitary adenomas. Harvey Cushing (1869-1939) famously described his eponymous disorder as “The Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations: Pituitary Basophilism” (Bull Johns Hopkins Hosp 50:137-195, 1932), but failed to appreciate the role of the adrenal. Fuller Albright correctly deduced that ‘hyperadrenocorticism’ caused Cushing syndrome, hypothesizing that ‘’those patients with Cushing’s syndrome, who do not have adrenal cancer, have hyperadrenocorticism because of over-production of some pituitary corticotropic hormone’ (J Clin Endocrinol 1:375-384, 1941). ACTH was purified and sequenced by CH Li (Nature 176 687–689, 1955) and shown to derive from a large precursor (POMC) by Nakanishi (Nature 278 423–427, 1979)

August 2016 – submitted by Walter Miller
The most important discovery in biology since the discovery of cells by Robert Hooke (1665) was the discovery that DNA is the genetic material. Watson and Crick famously discovered the double helical structure and base-pairing of DNA (Nature 171:737, 1953; Nature 171:964, 1953), but credit for the discovery that DNA conveyed genetic information belongs to Oswald T. Avery (1877-1955). Frederic Griffith reported in 1928 that the pneumococcal serotypes could be ‘transformed’ by dead bacteria. Avery, MacLeod and McCarty showed that the transforming fraction was DNA (prepared by ethanol precipitation, still used today), and not proteins (J Exp Med 79:137, 1944). Avery is arguably the most deserving medical scientist not to receive a Nobel Prize, despite multiple nominations.

July 2016 - submitted by Walter Miller
In 1865, Luigi De Crecchio, a forensic pathologist in Naples, described the autopsy of Giuseppe Marzo, who lived as a man and had Tanner IV genitalia, but had female internal reproductive organs and massively enlarged adrenals (Il Morgagni 7:151, 1865). De Crecchio dismissed the adrenal hyperplasia as being unrelated, and considered that Marzo had a disorder of puberty. De Crecchio interviewed people who knew Marzo to understand his life, emphasizing his social difficulties functioning as a male. This first report of congenital adrenal hyperplasia illustrates that despite advances in the endocrinology and genetics of CAH, the psycho-social aspects have advanced less. A complete translation and discussion of De Crecchio’s paper was published last year by Delle Piane et al. (Endocrinology 156:1210, 2015).

June 2016 - submitted by Arlan Rosenbloom
Since the first demonstrations that purified GH from human pituitaries possesses lactogenic activity in 1961, efforts had been made to isolate a human prolactin separate from GH. Frantz and Kleinberg reported their highly sensitive bioassay differentiating GH and prolactin in unextracted human plasma in Science in 1970 (Prolactin: evidence that it is separate from growth hormone in human blood. 170:745-7)

May 2016 - submitted by History Committee
'Sex chromatin';, first described by ML Barr (Nature 163:676, 1949), became known as the 'Barr body'; and was used to establish sex via buccal smear cytology. Independent studies by Mary Lyon (Nature 190:372, 1961) and by Mel Grumbach & Akira Morishima (Acta Cytologica 6:46, 1962) showed that sex chromatin was an inactivated X chromosome. Grumbach';s paper, contributed to the proceedings of a Symposium on Sex Chromatin, is listed as having been received on October 25, 1960, but publication was delayed for over a year. Morishima, Grumbach and Taylor showed that the inactivated X replicated after the active one (PNAS 48:756, 1962). Inactivation of an X chromosome became known as 'Lyonization';, in part because no one could say 'Grumbachianization';.

April 2016 - submitted by History Committee
The growth promoting activity of crude anterior pituitary extract was first reported in 1921, by Evans and Long from the University of California (Anat Record 21:62-63). They injected the extract into the peritoneal cavity of 38 rats, at an undisclosed frequency beginning at 14 days of age. The animals were followed for 60 days with weight measurements every five days. Weight at 75 days for the experimental animals was 228 g and for the littermate controls 183 g. Twenty-four years later Li and associates (including Evans) isolated and characterized the hormone responsible for this effect  (J Biol Chem 159:353-366).

March 2016 - submitted by History Committee
That chlorothiazide could increase the urine concentration of normal subjects in the midst of a sustained water diuresis was reported in 1958 (Laragh et al. Effect of chlorothiazide on electrolyte transport in man JAMA 166:145-152). The effective application of this observation to 2 subjects with diabetes insipidus, one central and one nephrogenic, was described the following year in Nature (Crawford JD, Kennedy GC: Chlorothiazide in diabetes insipidus. 183:891-2).

February 2016 - submitted by History Committee
In 1958, before the development of radioimmunoassay for GH, Laron and colleagues evaluated 3 siblings with marked growth retardation from a recently immigrated consanguineous Yemenite Jewish family. When GH assay became available in 1963, the children were found to have, apparently paradoxically, elevated GH levels, reported in 1966. (Z. Laron, A. Pertzelan, S. Mannheimer. Genetic pituitary dwarfism with high serum concentration of growth hormone. A new inborn error of metabolism? Isr. J. Med. Sci., 2, pp. 153-155)

January 2016 - submitted by History Committee
The initial attempt to determine the frequency of congenital adrenal hyperplasia (CAH) in the US was by Child, Grumbach, and Van Wyk in 1956 (Virilizing adrenal hyperplasia; a genetic and hormonal study. JCI 1956; 35:213-222). Assuming that all CAH came to Hopkins, and comparing to all live births from Maryland during the years the patients were born, they estimated the frequency of 1/67,000. Using a comparable assumption for the referral area to the University of Wisconsin, Rosenbloom and Smith calculated a minimal incidence of 1/15,000 live births (Lancet 1966;1:660), very similar to subsequent incidence rates based on infant screening programs.

December 2015 - submitted by History Committee
2015 is the 100th anniversary of the discovery of the lowly bacteriophage, the semi-living viral entities that infect bacteria (FW Twort, Lancet 186:1241-1243, 1915). Phage studies yielded the principles of genetic recombination, DNA and RNA polymerases, restriction endonucleases, ligases and other enzymes, providing the 'toolbox'; for the 20th century molecular genetics that revolutionized medicine and endocrinology. All contemporary molecular genetic diagnostics derive directly from studies of bacteriophages. 2015 is also the 100th anniversary of the General Theory of Relativity, which is related to endocrinology only in that both are beautiful.

November 2015 - submitted by History Committee
The Society for Internal Secretions (which later became The Endocrine Society), was founded in 1917 by a charlatan who specialized in selling glandular extracts by mail order. Harvey Cushing was elected without his knowledge to the Society? presidency in 1920. He accepted, hoping to reform a field that he termed ''endo-criminology,'' consisting largely of ''poppycock.'' (Bliss M. Harvey Cushing: a life in surgery. New York: Oxford University Press; 2003. pp. 382-3.)

October 2015 - submitted by History Committee
The initial appreciation of the disadvantageous Ca/P ratio and buffering capacity in cows milk formulas contributing to neonatal tetany in non-breast-fed infants, which led to recommending adding calcium gluconate supplementation was by a pioneering pediatric endocrinologist Lytt Gardner when he was a research fellow with Allan Butler. His superb study published 65 years ago led to changes in formulas and the disappearance of the problem. (Gardner LI, McLachlan EA, Pick W, Terry ML, Butler AM. Etiologic factors in tetany of newly born infants. Pediatrics 1950;5;228-240)

September 2015 - submitted by History Committee
In 1928, Cammidge described cases of what he thought was a dominantly inherited form of mild hyperglycemia (Diabetes mellitus and heredity. Br Med J 2:738). It was not until 1974 that Tattersall noted a distinct dominant pattern of inheritance among subjects with mild diabetes occurring in the 2nd and 3rd decade of life (Mild familial diabetes with dominant inheritance. QJ Med 43:339-57).

August 2015 - submitted by History Committee
The correct determination of the human diploid chromosome number as 46 occurred 60 years ago at the University of Lund, Sweden with the historic photograph by Tijo that he labeled "Human cell with 46 chromosomes observed 1955 on December 22nd at 2.00 am"; the finding was published in April 1956 (Tjio J-H, Levan A. The chromosome number of man. Hereditas 42:1-6), ending a period of more than 30 years when the number had been thought to be 48. Their methods laid the foundation for the analysis of chromosome disorders beginning with trisomy 21 and sex chromosomal abnormalities in 1959. [Harper PS. The discovery of the human chromosome number in Lund, 1955-1956. Hum Genet 2006;119:226-32]

July 2015 - submitted by History Committee
It was 62 years ago that Pickering and Fisher validated the efficacy of sodium-L thyroxine treatment of thyroid ablated infant rhesus monkeys and two years later that Fisher, Hammond, and Pickering reported the efficacy of L-thyroxine therapy in the hypothyroid infant and child which led to the eventual supplanting of animal thyroid extract as the treatment of choice.

Pickering D E, Fisher DA. Growth and metabolism following L-thyroxine administration in thyroid ablated infant Rhesus monkeys. Am J Dis Child 86: 1-10,1953

June 2015 - submitted by Jennifer Yee and Constantine Polychronakos
Eleanor Colle was one of the first women to establish a career in the developing field of pediatric endocrinology. She and Robert Ulstrom at UM published the first description of ketotic hypoglycemia [J Peds, May 1964; 64:632-51] reporting metabolic features of 8 pediatric subjects.

May 2015 - submitted by History Committee
Half a century ago, on October 9, 1965, a paper was received by the Israel Journal of Medical Sciences titled "Genetic pituitary dwarfism with high serum concentration of growth hormone: a new inborn error of metabolism?" authored by Zvi Laron, Athalia Pertzelan, and Shoshana Mannheimer. Published in spring 1966, this was the initial report of GH insensitivity that became known as Laron syndrome, describing 3 siblings of a consanguineous Yemeni Jewish family.

April 2015 - submitted by Del Fisher
2015 marks the 60th anniversary of the paper by Grumbach,Van Wyk, and Wilkins characterizing male chromosomal sex patterns in 20 patients with ovarian agenesis (Turner syndrome) using Barr body analysis of skin biopsies. They likened the syndrome to the castrated fetus in animal models and proposed a classification of ambisexual development in chromosomal males based on varying degrees of fetal testicular insufficiency. Barr body analysis subsequently became a routine approach to diagnosis. [Grumbach MM, Van Wyk JJ, Wilkins L. Chromosomal Sex in Gonadal Dysgenesis (Ovarian Agenesis): Relationship to Male Pseudohermaphroditism and Theories of Human Sex Differentiation. J Clin Endocrinol Metab 1955; 15:1161-1193]

February 2015 - submitted by Arlan Rosenbloom
In 1957, the uptake of 35S-sulfate by costal cartilage from hypophysectomized rats showed response to normal rat serum, but no response to GH at high dosage [Salmon JR, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825-36]. Ergo, normal rat serum contained GH-dependent "sulfation factor." The reason that the other assays were able to observe an effect of GH and these investigators were not had to do with the conditions of incubation. Later studies would show a delayed and lesser response of GH on uptake of 35S-sulfate and 3 H-thymidine (the expanded somatomedin hypothesis).

January 2015 - submitted by Walter Miller
"Thyroxine at 100:" John Kendall shared the 1950 Nobel Prize with Philip Hench and Tadeus Reichstein for isolating and characterizing several steroids, notably cortisol. 2014 marks the 100th anniversary of his earlier isolation of thyroxine. Kendall reported purifying 100 mg of thyroxine in 1914, and in 1919 he detailed the purification and crystalization of 33 grams of thyroxine from 6500 pounds of pig thyroids (J Biol Chem 19:251-256; J Biol Chem 40: 265-334), but he failed to determine its chemical structure, which was reported by Charles Harrington in 1927. (Biochem J 21: 169-183)

November 2014 - submitted by Del Fisher
John Eager Howard, Lawson Wilkins, and Walter Fleischmann reported early attempts to stimulate growth in adolescent "pituitary dwarfs" via daily oral or parenteral administration of 25 mg of methyltestosterone for "over one year." They observed increased sexual development, increased growth rate, elevated BMR, and marked creatinuria. A similar effect was observed in two females given testosterone along with 1 mg diethylstilbestrol daily. ["The metabolic and growth effects of various androgens in sexually premature dwarfs" -Transactions of the Association of American Physicians, Volume LVII , 212-215, 1942]

October 2014 - submitted by Alan Rogol
The 1947 Nobel prizes in physiology and medicine went to Carl and Gerty Cori (née Radnitz) 'for their discovery of the course of the catalytic conversion of glycogen' [Cori cycle] and to Bernardo Houssay, an Argentinian physician who began his studies in various combinations of pancreatectomized, hypophysectomized, adrenalectomized, and hormone-treated dogs in 1924 'for his discovery of the part played by the hormones of the anterior pituitary lobe in the metabolism of sugar.

September 2014 - submitted by History Committee
Two years after Yalow and Berson described the first hormone radioimmunoassay, for insulin, in 1960 (JCI 39:1157), Utiger, Parker, and Daughaday reported in the same journal their successful radioimmunoassay for human growth hormone. [Studies of human growth hormone. I. A radioimmunoassay for human growth hormone (1962; 41:254-61)]

August 2014 - submitted by Del Fisher
The last paper describing the outcome of children with congenital hypothyroidism before the introduction of newborn screening in 1975, was by Salvatore Raiti and George Newns (Early diagnosis and its relation to mental prognosis, Arch Dis Childhood 1971; 46:692-694). They were able to measure IQ in 56 of 141 cases. Three fourths of those treated before 3 months of age, but only ~40% of those treated later had IQ's above 90, consistent with the report from Hopkins in 1957 in the largest series up to that time. [Smith DW, Blizzard RM, Wilkins L., The mental prognosis of hypothyroidism of infancy and childhood: A review of 128 cases - Pediatrics 1957; 19:1011-22]

July 2014 - submitted by Jadranka Popovic
The first description of a Turner Syndrome karyotype and correlation with phenotype (including the absence of secondary sexual characteristics and being "backward in school") and other laboratory analyses was by CE Ford et al. in: A Sex-Chromosome Anomaly in a Case of Gonadal Dysgenesis (Turner's Syndrome) Lancet 1959;1:711-713.

June 2014 - submitted by Arlan Rosenbloom
The first description of precocious puberty with hypothyroidism (including regular menses beginning at age 5 years) was an elegant case report in 1905. [FW Kendle; Case of precocious puberty in a female cretin; Brit Med J 1905; 1:245]