The history of pituitary surgery for Cushing disease

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.

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Harvey Cushing and pituitary Case Number 3 (Mary D.): the origin of this most baffling problem in neurosurgery

Neurosurgical FOCUS ◽

10.3171/2016.2.focus1592 ◽

2016 ◽

Vol 41 (1) ◽

pp. E6 ◽

Cited By ~ 13

Author(s):

José María Pascual ◽

Ruth Prieto

Keyword(s):

Great Influence ◽

Pituitary Surgery ◽

Multiple Sources ◽

Tumor Registry ◽

Neurosurgical Procedure ◽

Harvey Cushing ◽

History Of ◽

Seminal Article ◽

Adamantinomatous Craniopharyngioma ◽

Case Number

From the very beginning of his career, Harvey Williams Cushing (1869–1939) harbored a deep interest in a complex group of neoplasms that usually developed at the infundibulum. These were initially known as “interpeduncular” or “suprasellar” cysts. Cushing introduced the term “craniopharyngioma” for these lesions, which he believed represented one of the most baffling problems faced by neurosurgeons. The patient who most influenced Cushing's thinking was a 16-year-old seamstress named “Mary D.,” whom he attended in December 1901, exactly the same month that Alfred Fröhlich published his seminal article describing an adiposogenital syndrome in a young boy with a pituitary cyst. Both Cushing's and Fröhlich's patients showed similar symptoms caused by the same type of tumor. Notably, Cushing and Fröhlich had met one another and became good friends in Liverpool the summer before these events took place. Their fortunate relationship led Cushing to realize that Fröhlich's syndrome represented a state of hypopituitarism and provided a useful method of diagnosing interpeduncular cysts. It is noteworthy that Cushing's very first neurosurgical procedure on a pituitary tumor was performed in the case of Mary D.'s “interpeduncular cyst,” on February 21, 1902. Cushing failed to remove this lesion, which was later found during the patient's autopsy. This case was documented as Pituitary Case Number 3 in Cushing's masterpiece, The Pituitary Body and Its Disorders, published in 1912. This tumor was considered “a teratoma”; however, multiple sources of evidence suggest that this lesion actually corresponded to an adamantinomatous craniopharyngioma. Unfortunately, the pathological specimens of this lesion were misplaced, and this prompted Cushing's decision to retain all specimens and documents of the cases he would operate on throughout his career. Accordingly, Mary D.'s case crystallized the genesis of the Cushing Brain Tumor Registry, one of Cushing's major legacies to neurosurgery. In this paper the authors analyze the case of Mary D. and the great influence it had on Cushing's conceptions of the pituitary gland and its afflictions, and on the history of pituitary surgery.

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Carbohydrate metabolism in patients with Cushing disease: a glance at the incretin system

Problems of Endocrinology ◽

10.14341/probl201662567-68 ◽

2016 ◽

Vol 62 (5) ◽

pp. 67-68

Author(s):

Lubov V. Matchekhina ◽

Ekaterina A. Shestakova ◽

Zhanna E. Belaya ◽

Marina V. Shestakova

Keyword(s):

Drug Therapy ◽

Carbohydrate Metabolism ◽

Previous History ◽

Pituitary Surgery ◽

Underlying Disease ◽

Control Group ◽

Cushing Disease ◽

Free Cortisol ◽

History Of ◽

The Mean

Introduction. The relevance of carbohydrate metabolism studying in patients with Cushing disease can be explained by frequent occurrence of glucose metabolism disturbances on the one hand, and difficulties in glucose-lowering therapy in these patients on the other. The effectiveness of hyperglycaemia treatment may be reduced due to difficulties in remission / cure of the underlying disease, as well as to the use of specific drug-therapy, leading to the hyperglycaemia. There is a growing interest in research aimed at studying the role of incretin system in the pathogenesis of secondary hyperglycemia associated with neuroendocrine diseases recently.Methods. A total of 20 patients with Cushing disease were included, (19 female and 1 male), the mean age was 37.5 years (18-69). All of the patients were diagnosed with Cushing disease for the first time (using urinary free cortisol levels and MRI-data); none of them had a history of previous drug therapy, radiotherapy or pituitary surgery. The mean HbA1c level was 5,8% (5,3-6,2). All patients underwent OGTT, during which glucose, glucagon, GLP1, GLP2, GIP, ghrelin were measured at 0, 30 and 120 min respectively. The control group included 21 patients without previous history of carbohydrate metabolism disturbances. After OGTT 57% were presented without any carbohydrate metabolism disturbances, 28,57% presented with prediabetes and 14,43% were diagnosed with diabetes.Results. After glucose levels analyzing 40% of patients were diagnosed with early carbohydrate metabolism disturbances ,15% were diagnosed with diabetes. After glucose intake a slight inrease in glucagon levels with a peak by 30’ (p=0,001) compared to gradually decreasing levels in controls was observed . The levels of GIP during OGTT were not significantly different compared to control group. GLP-1 and GLP-2 levels were significantly higher compared to controls (p=0,017 and p<0,001 respectively) with peak levels at 30’. Ghrelin levels were also significantly higher compared to controls (p=0,013)Conclusion. Incretins levels can be possible markers of specific carbohydrate metabolism disturbances in patients with Cushing disease and presumably will help to differentiate steroid diabetes from T2DM. Further investigations needed to prove these speculations.

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Adrenal Adenoma Anarchy: A Case of an ACTH-Secreting Pheochromocytoma

Case Reports in Endocrinology ◽

10.1155/2020/4869467 ◽

2020 ◽

Vol 2020 ◽

pp. 1-4

Author(s):

Michelle N. Lee ◽

WingYee Wan ◽

Dianna C. Chormanski ◽

Maria I. Kravchenko

Keyword(s):

Cushing Syndrome ◽

Adrenal Adenoma ◽

Hot Flashes ◽

Adrenocorticotrophic Hormone ◽

Diagnostic Challenge ◽

Late Night ◽

History Of ◽

Biochemical Evaluation ◽

Plasma Metanephrines ◽

Acth Secreting

Introduction. Pheochromocytomas are rare neuroendocrine tumors that arise from sympathetic adrenomedullary chromaffin tissue. Depending on the amount of catecholamines they secrete, they have variable presentations. There have been reported cases of adrenocorticotrophic (ACTH) secreting pheochromocytomas that present with severe Cushing syndrome. Here, we present a pheochromocytoma with adrenocorticotrophic hormone (ACTH) cosecretion, which due to its rarity and variable presentation, may be a diagnostic challenge. Presentation. A 64-year-old woman with history of colon cancer presented with new-onset diabetes, worsening hot flashes, and hypertension. On CT imaging she had an enlarging right adrenal nodule (1.7 cm) with 60 Hounsfield units of attenuation and no PET avidity. Biochemical evaluation showed elevated urinary and plasma metanephrines, elevated plasma cortisol levels despite dexamethasone suppression, elevated late-night salivary cortisol, and high-normal adrenocorticotrophic hormone. The patient underwent laproscopic right adrenalectomy, and pathology confirmed pheochromocytoma. Her lab abnormalities and symptoms of hot flashes and hypertension improved postoperatively. Conclusion. This case demonstrates an unusual ACTH-secreting pheochromocytoma with subtle presentation and highlights the importance of obtaining a complete biochemical evaluation of incidental adrenal adenomas.

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Cushing disease: use of perioperative serum cortisol measurements in early determination of success following pituitary surgery

Neurosurgical FOCUS ◽

10.3171/foc.2007.23.3.8 ◽

2007 ◽

Vol 23 (3) ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

Armand Krikorian ◽

Dima Abdelmannan ◽

Warren R Selman ◽

Baha M Arafah

Keyword(s):

Sella Turcica ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Serum Cortisol Level ◽

Current Recommendation ◽

Cushing Disease ◽

Acth Deficiency ◽

Cortisol Levels ◽

Acth Secreting

✓Despite many recent advances, management of cases of Cushing disease continues to be challenging. After complete resection of ACTH-secreting adenomas, patients develop transient ACTH deficiency requiring glucocorticoid replacement for several months. The current recommendation by many centers, including ours, for patients with ACTH-secreting adenomas is to withhold glucocorticoid therapy during and immediately after adenomectomy until there is clinical or biochemical evidence of ACTH deficiency. A serum cortisol level of less than 2 μg/dl within the first 48 hours after adenomectomy is a reliable biochemical marker of ACTH deficiency and is associated with clinical remission of Cushing disease. Higher serum cortisol levels in the immediate postoperative period should be interpreted with caution. The decision to immediately reexplore the sella turcica should be individualized, taking into account the findings at surgery, the histopathological findings, and the changes in serum cortisol levels as well as the patient's wishes and concerns. Optimal diagnosis and therapy for patients with Cushing disease require thorough and close coordination and involvement of all members of the management team.

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Features of carbohydrate metabolism and incretin secretion in patients with Cushing disease and acromegaly

Diabetes Mellitus ◽

10.14341/dm8762 ◽

2017 ◽

Vol 20 (4) ◽

pp. 249-256

Author(s):

Lubov V. Matchekhina ◽

Ekaterina A. Shestakova ◽

Zhanna E. Belaya ◽

Lyudmila I. Astafieva ◽

Larisa V. Nikankina ◽

...

Keyword(s):

Carbohydrate Metabolism ◽

Direct Action ◽

Peak Level ◽

Glucagon Secretion ◽

Pituitary Surgery ◽

Cushing Disease ◽

Glucagon Receptor ◽

Glucose Levels ◽

Metabolism Disorder ◽

History Of

Aim. This study aims to analyse the rhythm and levels of incretins and neuropeptides secretion in patients with Cushing disease (CD) and acromegaly, and thus specify the pathogenesis of carbohydrate metabolism disturbances. Matherials and methods. In this study, 42 patients (mean age, 37.5 years) with CD and acromegaly were enrolled. All patients were newly diagnosed with CD and acromegaly, and none had a history of previous drug therapy, radiotherapy or pituitary surgery. All patients underwent OGTT, during which glucose, glucagon, GLP-1, GLP-2, GIP and ghrelin were evaluated at 0, 30 and 120 min, respectively. Results. During OGTT, glucose levels were not significantly different between the groups. The relevance of pre-diabetes was higher in patients with CD. In these patients, while glucagon levels were substantially higher at all cut-off points than those in controls (р = 0.001), GIP secretion was slightly lower. The acromegaly group was characterised by an inverse rhythm of GIP secretion with no peak level at 30 min. In addition, GLP-1 levels were significantly higher in patients with CD (р = 0.047). Similarly, GLP-2 levels were also significantly higher in patients with CD than in those with acromegaly and controls (p = 0.001). Finally, ghrelin levels were significantly higher in patients with CD (р = 0.013) and acromegaly (р = 0.023). Conclusion. More pleiotropic actions of glucocorticoids can explain the higher relevance of carbohydrate metabolism disturbances in patients with CD. This can also be explained by higher levels of glucagon secretion, which do not depend on the type of carbohydrate metabolism disorder and are stimulated by a direct action of glucocorticoids on the glucagon receptor. GIP and GLP-1 secretion in patients with CD and acromegaly are characterised by the inverse rhythm with no peak levels, implying that these hormones do not play a crucial role in the development of carbohydrate disturbances in these patients. In contrast, GLP-2 and ghrelin seem to influence and potentially regulate glucose homeostasis in patients with CD and acromegaly.

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Recovery of Adrenal Function after Pituitary Surgery in Patients with Cushing Disease: Persistent Remission or Recurrence?

Neuroendocrinology ◽

10.1159/000496846 ◽

2019 ◽

Vol 108 (3) ◽

pp. 211-218 ◽

Cited By ~ 1

Author(s):

Andreea Liliana Serban ◽

Elisa Sala ◽

Giulia Carosi ◽

Giulia Del Sindaco ◽

Claudia Giavoli ◽

...

Keyword(s):

Surgical Intervention ◽

Pituitary Surgery ◽

Disease Recurrence ◽

Adrenal Function ◽

Surgical Removal ◽

Cushing Disease ◽

Adult Age ◽

First Line Therapy ◽

Acth Secreting

Background: Cushing disease (CD) represents the principal cause of endogenous hypercortisolism. The first-line therapy of CD is surgical removal of the ACTH-secreting pituitary adenoma, which is generally followed by adrenal insufficiency (AI). Objective: To analyze the recovery of AI in patients with CD after pituitary surgery in relation with recurrence and persistent remission of CD. Patients and Methods: We performed a retrospective analysis of patients with CD who met the following inclusion criteria: adult age, presence of AI 2 months after the surgical intervention, and a minimum follow-up of 3 years after the surgical intervention. Results: Sixty-one patients were followed for a median of 6 years. Ten (16.4%) patients recurred during follow-up. The patients who restored adrenal function did so after a median time of 19 months, with a significantly shorter time in the recurrence group (12.5 vs. 25 months, p = 0.008). All 10 patients who recurred recovered their adrenal function within 22 months. The recovery rate of AI in the persistent remission group was 37.3% (19/51) at 3 years and 55.8% (24/43) at 5 years. In all patients the duration of AI was negatively associated with disease recurrence. Conclusion: The duration of postsurgical AI in patients with recurrent CD is significantly shorter than that in patients with persistently remitted CD, and this parameter may be a useful predictor of recurrence. Patients showing a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored as they are at higher risk of disease relapse.

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PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex

Acta Endocrinologica ◽

10.1530/eje-17-0227 ◽

2017 ◽

Vol 177 (2) ◽

pp. K7-K12 ◽

Cited By ~ 15

Author(s):

Florian W Kiefer ◽

Yvonne Winhofer ◽

Donato Iacovazzo ◽

Márta Korbonits ◽

Stefan Wolfsberger ◽

...

Keyword(s):

Cushing Syndrome ◽

Pituitary Tumour ◽

Carney Complex ◽

Regulatory Subunit ◽

Loss Of Function ◽

Cushing Disease ◽

First Case ◽

Acth Secreting ◽

Inactivating Mutation

Context Carney complex (CNC) is an autosomal dominant condition caused, in most cases, by an inactivating mutation of the PRKAR1A gene, which encodes for the type 1 alpha regulatory subunit of protein kinase A. CNC is characterized by the occurrence of endocrine overactivity, myxomas and typical skin manifestations. Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine disease observed in CNC. Case description Here, we describe the first case of a patient with CNC and adrenocorticotropic hormone (ACTH)-dependent Cushing disease due to a pituitary corticotroph adenoma. Loss-of-heterozygosity analysis of the pituitary tumour revealed loss of the wild-type copy of PRKAR1A, suggesting a role of this gene in the pituitary adenoma development. Conclusion PRKAR1A loss-of-function mutations can rarely lead to ACTH-secreting pituitary adenomas in CNC patients. Pituitary-dependent disease should be considered in the differential diagnosis of Cushing syndrome in CNC patients.

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Percutaneous Bilateral Adrenal Radiofrequency Ablation in Severe Adrenocorticotropic Hormone-dependent Cushing Syndrome

Journal of Clinical Imaging Science ◽

10.25259/jcis_98_2020 ◽

2020 ◽

Vol 10 ◽

pp. 60

Author(s):

Grzegorz Rosiak ◽

Krzysztof Milczarek ◽

Dariusz Konecki ◽

Maciej Otto ◽

Olgierd Rowinski ◽

...

Keyword(s):

Radiofrequency Ablation ◽

Adrenocorticotropic Hormone ◽

Clinical Symptoms ◽

Cushing Syndrome ◽

Vena Cava ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Endocrine Tumor ◽

Adrenergic Blockade ◽

Cushing Disease

Objectives: The objectives of the study were to evaluate adrenal radiofrequency ablation (RFA) as a method of treatment in patients with severe adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, among whom bilateral adrenalectomy is not a suitable option. Material and Methods: Five patients with ACTH-dependent Cushing syndrome underwent RFA of both adrenal glands. Four of them presented with Cushing disease unsuccessfully treated with pituitary surgery and medical therapy, while one patient had ACTH-dependent Cushing syndrome due to pancreatic endocrine tumor with liver metastases. All patients were disqualified from adrenalectomy due to morbid obesity or lack of consent. Results: A technical success was obtained in all cases, with only one re-intervention necessitated by a cooling effect of the inferior vena cava. Despite pre-procedural adrenergic blockade, severe hypertension was noted during the procedure in three cases, this being treated immediately using direct-acting vasodilators. No complications occurred otherwise. In all cases, significant improvement of clinical symptoms was observed, as well as marked decreases in levels of serum cortisol, free urine cortisol, and dehydroepiandrosterone sulfate. Conclusion: Bilateral RFA under CT-guidance is technically feasible and clinical improvement can be achieved using the method. In patients disqualified from adrenal surgery, RFA might be considered as an alternative method of ACTH-dependent Cushing syndrome treatment.

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