The history of pituitary surgery for Cushing disease

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Although he never performed a pituitary operation for the disease, Harvey Cushing was the first to describe and treat patients with Cushing disease (CD). Other surgeons at the time were reluctant to operate on the pituitary due to the normal sella on skull radiographs in CD and the unclear etiology of the disorder. To better define and understand factors influencing the history of pituitary surgery for CD, the authors analyzed historical texts related to CD biology, diagnosis, and treatment. Cushing's monograph on basophilic pituitary adenomas and cortisol excess appeared in 1932. One year later in 1933, Alfred Pattison performed the first successful pituitary operation for CD by implanting radon seeds in the sella. Resection of a pituitary adenoma for CD was attempted 1 month later in 1933 by Howard Naffziger, resulting in only transient improvement that corresponded to the lack of tumor in the resected tissue. Soon thereafter, Susman in 1935 and Costello in 1936 described pituitary basophilic adenomas at autopsy in patients without premorbid endocrinopathy. They concluded that the adrenal gland was the cause of CD, which resulted in a 3-decade abandonment of pituitary surgery for CD. Jules Hardy in 1963 used the operating microscope to perform the first selective removal of an adrenocorticotropic hormone (ACTH)–secreting microadenoma, which established a pituitary cause and defined the modern treatment of CD. Subsequent reports by Hardy, Laws, and Wilson resulted in widespread acceptance of pituitary surgery for CD. Initial reluctance to operate on the pituitary for CD was multifaceted and included general uncertainty surrounding the etiology of Cushing syndrome as well as a lack of early surgical success, both due to the small size of ACTH-secreting adenomas. Selective removal of ACTH-secreting adenomas identified the source of CD and ended the delay in acceptance of pituitary surgery for CD.

Abbreviations used in this paper: ACTH = adrenocorticotropic hormone; CD = Cushing disease; HPA = hypothalamic-pituitaryadrenal.

Article Information

Address correspondence to: Edward H. Oldfield, M.D., Department of Neurosurgery, University of Virginia Health System, University of Virginia, Charlottesville, Virginia 22901. email:

Please include this information when citing this paper: published online September 30, 2011; DOI: 10.3171/2011.8.JNS102005.

© AANS, except where prohibited by US copyright law.



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    Performing a craniotomy for placement of local radiation was the earliest form of pituitary surgery for CD. This lateral skull radiograph shows rods placed by Alfred Pattison after the first pituitary surgery for CD. Reprinted from The Lancet, Vol. 231, Pattison AR and Swan WG, Surgical treatment of pituitary basophilism, 1265–1269, 1938, with permission from Elsevier. The inset is an early portrait of Alfred Pattison. Reprinted from The Lancet, Vol. 235, Obituary: Alfred Richard Denis Pattison, 1142, 1940, with permission from Elsevier.

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    Illustrations depicting the technique for implantation of radon seeds in the pituitary gland. From Northfield DW, Proc R Soc Med 42:845–853, 1949. In 1935 Howard Naffziger (inset, photograph from 1918) used the same approach in the first attempt to remove a pituitary adenoma in CD.

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    Jules Hardy in 1963 (left). The use of the intraoperative microscope for transsphenoidal surgery pioneered by Jules Hardy in 1963 (center) permitted selective adenomectomy and sparing of normal gland (right, upper) and was a critical event in not only establishing treatment of CD, but also was a critical step in establishing pituitary adenomas as the etiology of CD. From Hardy J, J Neurosurg 34:582–594, 1971. Hardy successfully conveyed the concept of selective adenomectomy to surgeons and nonsurgeons using these images of the removal of a pimento from an olive (right, lower).

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    Photographs of the first patient treated by selective adenomectomy for CD by Jules Hardy. Patient pictured at the time of treatment in 1963 (A), in 1983 (B), and in 2010 (C). Used with permission of the patient.

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    Reports in 1978 of successful selective adenomectomy with consistent remission of CD in a series of patients by Edward R. Laws Jr. (left, 1979) and Charles B. Wilson (right, 1980s), combined with the reports of Hardy, established pituitary surgery as the initial treatment of choice for CD.

  • View in gallery

    Left: Photograph by Cushing of a basophilic pituitary adenoma from autopsy of a patient with clinical manifestations of pituitary basophilism. From Cushing H, Bull Johns Hopkins Hosp 50:137–195, 1932. Right: Photograph of a basophilic pituitary adenoma from autopsy of a patient without clinical symptoms of endocrinopathy. This article was published in Am J Pathol, Vol. 12, Costello RT: Subclinical adenoma of the pituitary gland, 205–216, Copyright Elsevier (1936).

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    Timeline of the treatment of CD. Pathophysiological advances (above the line) and treatment milestones (below the line) are listed by the scientists and surgeons who pioneered them.


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