Journal of the Royal Society of Medicine Volume 84 June 1991 363

The history of Cushing's disease: a controversial tale

V C Medvei MD FRCP 38 Westmoreland Terrace, London SWlV 3HL

Keywords: Harvey Cushing; Julius Bauer; Cushing's disease; pituitary

The history of Cushing's disease now goes back quitea long time. Yet no clear cut definition of the issuesinvolved has emerged. The pathogenesis of thecondition is still controoversial.Harvey Cushing (1869-1939) was one of the most

outstanding surgeons of the present century and, asGarrison put it, 'facile princeps in neurologicalsurgery, particularly surgery of the head and thepituitary body' (Figure 1).Born in Cleveland, Ohio, and educated at Yale and

Harvard Medical Schools, he worked, after spendingsome time in Europe, mainly at Johns-Hopkins inBaltimore and, finally, as Moseley Professor ofSurgery at the Harvard School of Medicine inBoston and Surgeon-in-Chief of the Peter BrentBrigham Hospital from 1912 to 1932. He gave hiscelebrated 'Oration in Surgery' on 'The HypophysisCerebri: Clinical Aspects ofHyperpituitarism and ofHypopituitarism' to the Section of Surgery of theAmerican Medical Association at the 16th AnnualSession, held at Atlantic City, in June 19091. At thattime he still worked in Baltimore.The subject here concerns, however, his publication

in 1932 ofa polyglandular syndrome: The basophilicadenomas of the pituitary body and their clinicalmanifestations (pituitary basophilism)'2. This was areview of 12 such patients, the first of whom wasa certain Minnie of New York. She developed thesyndrome at the age of 16. Cushing had mentionedher briefly in 19123 and thought that her clinicalpicture resembled those seen in some adrenaltumours. Later he changed his opinion and said, ifacromegaly was due to acidophil hyperpituitarism,

Figure 1. Harvey Cushing, 1869-1939

Paper read tojoint meetingof the Sectionsof Pathology andHistory ofMedicine,21 June 1988

Figure 2. Julius Bauer, 1887-1979

there was another form, due to excess ofthe basophilcells, involving sexual function (amenorrhoea inwomen, impotence in men). Minnie was still alive in1932. The late FM P Bishop and R G Close of Guy'sHospital, London, recognized and described such acase in the same year: 'A Case ofBasophil Adenomaof the Anterior Lobe of the Pituitary: Cushing'sSyndrome', thus giving it this name fur the firsttime4.My own involvement with the subject began

between 1932 and 1934, in Vienna. My then chief,Professor of Medicine Julius Bauer (1887-1979)(Figure 2) had published the case report of a patientin 1931. He had been diagnosed as adrenal tumour,operated on, but no tumour was found. He died afterthe operation. Postmortem exmination by ProfessorCarl Sternberg (of Stemnberg cells fame) compelled achange of diagnosis to hyperfimction of the totaladrenal system without anatomical basis5. Monthslater, Cushing advised Bauer to look at the pituitary,if still available. It was, and serial section revealeda basophil adenoma.

I was at that tima a Chief Assistant on Bauer'sMedical Profeorial Unit. Togete with my colleague,the late Dr Paul Wermer*, we observed in those years7 patients (including the Bauer-Sternberg case) inwhom we made the diagnosis of basophil adenoma

0141-0768/91/0603634)402.00/0

*Dr Paul Wermer (1898-1979) later descibed- the MEN © 1991(multiple endocrine neoplasia) type 1 yndrome (Wermer's The Royalsyndrome), when he worked at the College ofPhysicans and Society ofSurgeons, Columbia University, New York. Medicine

364 Journal of the Royal Society of Medicine Volume 84 June 1991

BASOPHILIC ADRENOCORTICALADENONA TUMOUR

+ I+ ++

+ +++

+++

+ ++

+ +4

+++

++

+(?)

++

++

VIRILISING TUROURSOF THE OVARY

of the pituitary. Based on those observations, we

attempted to present a study on the differentialdiagnosis of basophil adenoma ofthe pituitary, whichwas published in 19346 (Table 1). The symptom ofdepression was, however, missing in our account.Cushing, who happened to hear about our paper,wrote to me in October 1934 and requested a reprint,which I sent him. He wrote again in April, 1939,unaware of the fact that since 1938, I had become a

medical student on a scholarship at the MedicalCollege of St Bartholomew's Hospital in London, I toldhim about it and he wrote to me again, but soon afterhe died of a sudden posterior coronary heart attackon 7 October 1939.In an independent investigation, I had found in

a consequential series of 100 apparently normalpituitaries histological evidence of basophil micro-adenomas in 6% ofthe glands examined in 1937, butthis remained unpublished as I left Vienna. Unknownto me, R T Costello, of the Mayo Clinic, had reportedin 1935 on 72 (7.2%) basophilic adenomas among1000 pituitaries examined in a routine manner,without any clinical signs, half as many as thechromophobe adenomas and three and a half timesmore numerous than eosinophil celled adenomas7.Susman (Manchester, England) found also in 1935,8% basophil adenomas in 260 pituitaries, rathermore frequent than other adenomas8. He, therefore,contested the anatomical basis ofCushing's pituitarybasophilism. Autopsy studies have shown, however,that 50-60% ofpatients with Cushing's disease havepituitary adenomas, about two-thirds ofwhich are ofthe minute basophilic variety. It seems that in a

recent follow-up of these investigations (CT andmagnetic resonance imaging scans in the UnitedStates) many patients are being found to havesymptomless abnormalities in their pituitaries - so-

called 'incidentalomas'. Neurosurgeons have concludedthat most of these lesions are benign and need notbe removed9.In 1950, Julius Bauer, who by then worked in Los

Angeles, California, published a paper 'The so-calledCushing's syndrome, its history, terminology, anddifferential diagnosis"'. In it he said: 'Cushing'sdisease, therefore, is the association of the knownclinical syndrome with pituitary basophilism. Henceit is this association of the known clinical syndrome,that should bear the eponym "Cushing's disease".I stuck to my conception of hyperfunction of theadrenals as sole explanation of the clinical picture... I presumed in 1933 that, besides the gonadotropic

and thyrotropic hormones, the pituitary must producean interrenotropic hormone, selectively stimulatingthe adrenal cortex.' 'A few months later, in 1933, thishormone was actually discovered and its existenceproved by Collip and his co-workers1". It is knownas adrenocorticotropic (pituitary) hormone (ACTH).There exist, therefore, in my opinion, two types ofinterrenalism: one (primary), produced by functioningtumours of the adrenal cortex, and another (secondary),produced by excessive stimulation of the adrenalcortex by a diseased pituitary. Only the latter deservesthe eponym "Cushing's Disease".' Although 'theessential features of primary and secondary hyper-corticism must be identical', according to Bauer,'quantitative rather than qualitative differences inthe clinical picture are to be expected, as was pointedout by my co-workers, Medvei and Wermer in 1934'6.Julius Bauer discussed since 1930 the fact that such

a small gland like the pituitary, containing only afew groups of different cells should produce morehormones than can be allocated to the histologicalgroups. He had a premonition that cells could producevarious hormones, perhaps what is now termed'hybrid hormones' like growth hormone and prolactin.He also suspected that many other organs mayproduce endocrine material. He said - when theBauer-Sternberg patient did not display anatomicalchanges in the suprarenals - that another endocrinegland, perhaps the pituitary might have caused thestimulation of the adrenals. His idea was that thepituitary might produce a general ('mother') hormoneacting as a stimulus on other endocrine glands, whichwould respond with an overproduction of their ownmanufacture. Accordingly, hypercorticalism of theadrenals may be primary or secondary, due to sucha general hormone of the pituitary or even otherorgans. As regards the role of the basophil cells, headmitted that they could act stimulating the adrenalcortex, but - he argued - who knows, how many otherendocrine and non-endocrine organs they couldstimulate. Bauer anticipated the discovery ofACTHbut more in the form ofa pituitary 'mother-hormone',acting on different endocrine and non-endocrineorgans. He used the pancreas as an example of amixed exocrine and endocrine organ and felt thatmany-more such combinations might exist. Incident-ally, Bauer was originally trained as a neurologist (hehad been Chief Assistant to Obersteiner) and hismethod of argumentation was influenced by theneurologist's approach and also by his other greatinterest as a geneticist.That Cushing's disease 'is due to excessive produc-

tion of the adrenocorticotropic hormone of thepituitary', was substantiated in 1935 by Jores12 andin 1941 by Albright and co-workers'3 and by Keplerin 194514. Albright also pointed out the presence ofa negative nitrogen balance - irrespective ofthe typeof Cushing's syndrome involved. According to him,Cushing's syndriome was the final result of excessiveproduction of 'si gar hormone' (glucocorticoid) by theadrenal cortex'5.Guthrie and d'Este Emery discussed precocious

obesity, premature sexual and physical developmentand hirsuties in relation to hypernephroma andother morbid conditions as early as 190716. (Sir)Gordon Holmes (London) published in 1924 'A caseof virilism asociated with a suprarenal tumour:Recovery after its removal' 17. It was the story ofa 24-year-old woman with hirsuties, masculine

Table 1

After MEDVEI and WERMER Med Klin 1934 N 3C

SIGN

OBESITY (MASCULINE DISTRIBUTION)

HIRSUTIESGONADAL DYS (HYPO) FUNCTION

MASCULINISATION OF EXTERNAL GENITALIA INWOMEN

PURPLE STRIAEOSTEOPOROSIS

HYPERTENSION

POLYCYTUE N IA

HYPERGLYCAENIADRY AND ROUGH SKIN

ENLARGERENT Of SELLAPALPABLE ABDOMINAL TUROURS

PALPABLE OVARIAN TUMOUR

Journal of the Royal Society of Medicine Volume 84 June 1991 365

appearance, amenorrhoea and virilism. In July 1914,Mr Percy Sargent removed a tumour, entirely outsidethe peritoneum, closely attached to the upper pole ofthe right kidney. The operation was successful. InAugust 1914 she had the firt period for 9 years. Thehirsuties disappeared. She was re-examined in 1920and in 1923 when she was 35 years old: she then hadnormal female characteristics. The histology of hertumour was that of the suprarenal zona reticularis.This and other similar patients, Sir Gordon Holmesdiscussed with Harvey Cushing, when the latter wasvisiting London in 1929.In January, 1926 F Parkes Weber (ndon) published

a case history 'Cutaneous striae, purpura, high bloodpressure, amenorrhoea and obesity, of the typesometimes connected with cortical tumours of theadrenal glands, occurring in the absence of any suchtumours - with some remarks on the morphogeneticand hormonic effects oftrue hypernephromata oftheadrenal cortex.'18. The patient was demonstrated atthe Section of Dermatology of the Royal Society ofMedicine in London on 18 June 1925. This wasundoubtedly a Cushing's syndrome which ParkesWeber discussed with Cushing. Parkes Weber alsoreferred to a similar (female) patient demonstrated andrecorded by Dr H G Turney in- 191319. She hadprecocious plethoric obesity, large purple striae,amenorrhoea, relatively thin legs and arms, a Systolicblood pressure of 200 mmHg, polycythaemia, spon-taneous fractures (osteoporotic); X-ray showed partialabsorption ofthe dorsum sellae. Apart from he ches,there were no obvious symptoms suggesting increasedintracranial pressure. She died in May 1914, aged 25.Postmortem examination showed the left suprarenalgland to be nearly twice as large as the right one,which was of normal size. Microscopically there werecortical 'islets' in which the cells were packed with'lipoid droplets'. Nothing abnormal was found in thepituitary and thyroid glands. The bones (including thesella turcica) were so soft that they could be cut easilywith scissors. Parkes Weber finally quotes the case,published by Dr John Anderson in Glasgow in191520, of a woman of 28 years, with amenorrhoea,obesity, hirsuties, redness of the face, headaches,exophthalmos and petechial haemorrhages. She died.Postmortem examination showed chronic interstitialnephritis, slightly hyperplastic suprarenal glands; inthe medulla of the left one was a small tumour,microscopically resembling the zona fasciculata. Theanterior lobe of the pituitary contained a smalladenoma, and in the rest of the anterior lobe thechromophobe cells were increased at the expenseof the eosinophil cells. The pars intermedia wasmarkedly cystic; the posterior lobe was normal.As regards the hyalinization with diminution or

disappearance of the granules of the basophiliccells in pituitary basophilism, described by Crooke2l,Bauer thought that it was more likely 'as a resultrather than as origin of the clinical syndrome, sincethe changes are associated with the clinical syndrome,whether it be due to primary or secondary hyper-adrenocorticism.' In rare cases22 thymus tumourscan cause the clinical syndrome of hypercorticism.For practical purposes, osteoporosis and purplishstriae are more common and pronounced in Cushing'sDisease, 'whereas virilisation of the female genitalia. . . bespeak an adrenal tumour' (Bauer). The17-ketosteroids in the urine are also more excessivein the latter.

In a recent lecture, given in Hamburg by DrAP vanSeters of the Department of Endocrinology andMetabolic Diseases of the University Hospital Leiden,The Netherlands, entitled 'The History of Cushing'sSyndrome: Controversies Regarding Pathogenesis inthe -1930-1950s'23, van Seters was unaware of myhitherto unpublished lecture ou the same subject,given at the joint meeting ofthe Sections ofPathologyand History of Medicine of the Royal Society ofMedicine in London on the 21 June 1988. The generalsubject title for the afternoon was 'Pathology Thenand Now'. van Seters ended his lecture by saying:'. . it has become clear that the eponym 'Cushing-Bauer Syndrome' might have served a historicalpurpose.'In 1966, Gene G Hunder ofthe Mayo Clinic grappled

with the 'Pathogenesis of Cushing's Disease'29. Hecame to the conclusion that the hormonal excesswhich produces it, may result from the secretoryactivity of (1) hyperplastic adrenal cortices withoutany clinically evident endocrine lesion; (2) adrenalcortical adenoma or carcinoma; (3) ectopically locatedadrenal-like tumour, for example, of an ovary;(4) ACTH secreting tumour of the anterior pituitaryassociated with adrenal cortical hyperplasia, or(5) non-pituitary carcinoma, for example of lungsor the pancreas25, with secretion of an ACTH-likematerial which induces adrenal cortical hyperplasia.Besser and Edwards in London, arrived at a similar

grouping, when discussing Cushing's Syndrome in1972, calling pituitary dependent bilateral adreno-cortical hyperplasia (conventionally) Cushing'sdisease2. In an updated version, the authors came tothe conclusion, that 'Cushing's syndrome remainsone of the most challenging problems in clinicalendocrinology. Cushing's disease is caused in themajority of cases by basophil pituitary microadenomaswhich may be successully treated by transphenoidalhypophysectomy27.Bauer had already stressed the importance of the

differential diagnosis, because of the difference intreatment 'Adrenal tumours require surgical removal,Cushing's disease, X-ray treatment applied to thepituitary' (in 1950)10.In the 1940s there was an antipituitary lobby,

headed by Kepler. He thought (like Bauer) that theclinical picture was due solely to excess adrenalfunction and that the pituitary only provided theright milieu for adrenal hyperfimction; the adrenalbecame excessively sensitive to normal pituitarystimulation28.The diagnosis and management ofACTH-dependent

Cushing's syndrome are discussed by the same groupwith three additional authors, in a later paper-0. In10 out of 16 consecutive patients with ectopic ACTHsecreting tumour, that were completely occult toroutine and radiological investigation. No basal ordynamic investigation was able clearly to difTer-entiate these patients from those with Cushing'sDisease. Successful diagnosis and tumour localizationwas most frfequently achieved by a 'combination of CTscanning of the chest and abdomen and venouscatheter sampling for ACTH.'.... 'Occult ectopicACTH secetion ... may be impossible to distinguishfrom pituitary Cushing's disease'.In 1962, Liddle described the ectopic ACTH

syndromesO31. The intensity of the ACTH stimulusproduced by these non-pituitary tumours is sogreat that the clinical presentation can be one of

366 Journal of the Royal Society of Medicine Volume 84 June 1991

hypokalaemic alkalosis in the absence ofstigmata ofCushing's syndrome. According to Stuart Mason32' there is good reason for the use of "Liddle's

Syndrome" to describe all the clinical varieties ofcortisol excess caused by ACTH producing tnimoursoutside the pituitary.' 'Cushing's concept -of hyper-pituitarism has been completely vindicated by modernresearch.' Stuart Mason continues, 'That in honourigCushing's contribution tb-endocrinology, we shouldabandon the term "Cushing's syndrome" and use aclassification that expresses the disordero'f physiolog'.-Stuart Mason draws attention toa the fact thatpituitary Cushing's disease, although Iusually involv-.ing persistent disorder,'can end in spontaneous'cure:Cushing's Minnie was alive and better 29 years aftershe developed his disease. Another' confusing point,according to Stuart Mason, is the fact that menstrualfunction in patients with very high ACTH plasmalevels is usually normal and that they conceive easily.Finally, Stuart Mason introdlices' the term 'inappro-priate ACTH secretion' for'conditions in'which thesecretion ofACTH (from any source) is inappropriatefor the physiological demands of the body. 'Ourknowledge', he says,' 'of the' hypothalamic r6le incontrolling ACTH secretion makes it virtually certainthat corticotrophin releasing fotor(CRF) levels mustbe high to put an exceSsive output ofpituitary ACTHunless the pituitary has developed an autonomousACTH secreting tumour.'After adrenectomy the growth of a pituitary adenoma

may be prompted by strong stimulation from CRF.van Seters also pomits out that since the introduction

of ACTH and cortisone in 1950, all signs andsymptoms can be induced by their chronic admini-stration. Against this background, it seems to himappropriate to apply'the term 'Cushing's disease' onlyto patients with an evident pituitary tumour, or tothose patients with Cushings syndrome where ectopicor adrenal tumours have been excluded. He concluded:'We all realize that, even in- 1989, this distinction canoften not be made'.This paper highlights the complexity of the pro-

blems surrounding the term 'Cushing's disease',which Harvey Cushing and Julius Bauer so brilliantlyanticipated in the 1930s.

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hyperpituitarism and of hypopituitarism. (Oration onSurgery, given to the Sedtion ofSurgery ofthe AmericanMedical Association held in Atlantic City in June, 1909).JAMA 1909;53:24945 '

2 Cushing HW. The basophilic adenQmas ofthe pituitprybody and their clinical qmnaiestations (pituitary bay -

philism). Bull John HopI,ins Hosp 1932;P:188-953 Cushing HW. The pituitary body and its disorders.

Philadelphia: Lippincott, 1912:2174 Bishop PMF, Close HG.'A'Case ofBasophil Adenoma of

the Anterior Lobe ofthe Pituitay: 'Cushing's Syndroie".Guy's Hosp Rep 1932;82:143-53

5 Bauer J. Ueberfunktiond gestnten Nebennierensystemsohne anatomischen Befund. WIen Klin W- heInsehr1930;43:582-5

6 Medvei VC, Wermer P. Zur ,Differentialdiagnose desbasophilen Adenoms der Hypoph,yse.-Med Klinik 1934;No. 30:992-4

7 Costello RT. Subcli,nical adeno,mnas of the pituitary body.Mayo Clin Proc 1935;1O:449-5,3,

8 Susman Win. Adenom'ata of pituitary: -with specialreference to pituitary basophiIi'sm of Cushing. Br JSurg1935;22:539-44

9 Reincke M, Allolio B, Saeger W, Menzel J, WinkelmannW. The= 'incidentaloma' of the pituitary gland. Isneurosurgery required? JAMA 1990;263:2772-6^

10 Bauer J. The so-called Cushing'sj syndrome, its history,terminology and differental diagnosis Acta Med Scand1950;137:412-16

11 CoUip JE, Anderson E, Thompson DL. The adrenotropichormone ofthe anterior pituitary. Lancet 1933;ii:347-50

12 Jores A. Ueber Hormonuntersuchungen bei MorbusCushing. Klin Wochenschr 1945;14:1348-52

13 Albright F. Cushing's syndrome. Harvey Lecture Series1942-1943;38:123-86

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15 Albright F, Parson W, Bloomberg E. Cushing's syndromeinterpreted as hyperadrenocorticism leading to hyper-gluconeogenesis; results oftreatment with testosteronepropionate. J Clin Endocrinol 1941;1:375-81

16 Guthrie L, d'Este Emery W. Precocious obesity,premature sexual and physical development and hirsutiesin relation to hypernephroma and other morbid condi-tions. Trans Clin Soc Lond 1907;40:175-202

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19 Turney HG. Discussion on disease ofthe pituitary body.Proc R Soc Med 19121136-69

20 Anderson J. A case of polyglandular syndrome withadrenal hypernephroma and adenoma ofthe pituitarygland - both of small size., Glasgow Med J 1915;newseries;133:178-92

.1 Crooke AC. A change in the basophilic cells of thepituitary gland common to conditions which exhibit thesyndrome- attributed to basophilic adenoma. J PatholBacteriot 1935;41:339-49

22 Hubble D. Cushing's syndrome and thymic carcinoma.Q J Med 1949;18:193-5

23 van Seters AP. The history of Cushing's syndrome:controversies regarding pathogenesis in the 1930-1950s.In: Luedecke DK, Chrous GP, Tolis G, eds. ACTH,Cushing's syndrome and other hypercortisolemic states.New York. Raven Press, 1991

24 Hunder QG. Pathogenesis of Cusbing's disease. MayoClin Proc 1966;41:29-39

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29 Howlett TA, Drury PL, Perry L, Doniach I, Rees LH,Besser GM. Diagnosis and management of ACtH-dependent Cushing's syndiome: comparison of thefeatures in ectopic and pituitary ACTH production. Clin

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32 Stuart Mason A. Reflections on GushinDg's syndrome.Proc R Soc Med 1971;64:749-52

(Accepted 2 July 1990)