Criteria of cure and remission in Cushing's disease: an update

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 µg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15% of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.

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Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing’s disease

BMC Endocrine Disorders ◽

10.1186/s12902-015-0055-9 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 11

Author(s):

Jon Ramm-Pettersen ◽

Helene Halvorsen ◽

Johan Arild Evang ◽

Pål Rønning ◽

Per Kristian Hol ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Short Term ◽

Postoperative Serum

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Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing's disease

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000800022 ◽

2007 ◽

Vol 51 (8) ◽

pp. 1355-1361 ◽

Cited By ~ 40

Author(s):

Guilherme Rollin ◽

Nelson Pires Ferreira ◽

Mauro A. Czepielewski

Keyword(s):

Diabetes Insipidus ◽

Cushing’S Disease ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Therapeutic Choice ◽

Remission Rates ◽

Transsphenoidal Pituitary Surgery ◽

Suppression Test

Transsphenoidal pituitary surgery (TSS) remains the treatment of choice for Cushing's disease (CD). Despite the widespread acceptance of this procedure as the first line treatment in CD, the indication of a second TSS in not cured or relapsed DC patients is not consensus. We report the results of TSS in 108 patients with CD (a total of 117 surgeries). The mean postoperative follow-up period was 6 years. Remission was defined as clinical and laboratorial signs of adrenal insufficiency, period of glucocorticoid dependence, serum cortisol suppression on oral 1-mg dexamethasone overnight suppression test and clinical remission of hypercortisolism. We evaluated 103 patients with CD by the time of the first TSS. Fourteen patients underwent second TSS (5 had already been operated in others centers; in 5 patients the first surgery was not curative; in 4 patients CD relapsed). Remission rates were 85.4% and 28.6% (p < 0.001) after first and second TSS, respectively. In microadenomas, remission rates were higher than macroadenomas (94.9% vs. 73.9%; p = 0.006). In patients with negative pituitary imaging remission rates were 71.4% (p = 0.003; vs. microadenomas). Postoperative complications were: transient diabetes insipidus, definitive diabetes insipidus, hypopituitarism, stroke and one death. Only hypopituitarism was more frequent after second TSS (p = 0.015). In conclusion, TSS for CD is an effective and safe treatment. The best remission rates were observed at the first surgery and in microadenomas. The low remission rates after a second TSS suggest that this approach could not be a good therapeutic choice when the first one was not curative.

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P34 Characteristics, diagnosis and management of Cushing’s disease - A systematic review and meta-analysis

BJS Open ◽

10.1093/bjsopen/zrab032.033 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

Author(s):

Chan Hee Koh ◽

Danyal Z Khan ◽

Ronneil Digpal ◽

Hugo Layard Horsfall ◽

Hani J Marcus ◽

...

Keyword(s):

Clinical Practice ◽

Cushing’S Disease ◽

Meta Analysis ◽

A Priori ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Cushing's Disease ◽

Diagnosis And Management ◽

Over Time

Abstract Introduction The clinical practice and research in the diagnosis and management of Cushing’s disease remains heterogeneous and challenging to this day. We sought to establish the characteristics of Cushing’s disease, and the trends in diagnosis, management and reporting in this field. Methods Searches of PubMed and Embase were conducted. Study protocol was registered a-priori. Random-effects analyses were conducted to establish numerical estimates. Results Our screening returned 159 papers. The average age of adult patients with Cushing’s disease was 39.3, and 13.6 for children. The male:female ratio was 1:3. 8% of patients had undergone previous transsphenoidal resection. The ratio of macroadenomas: microadenomas:imaging-undetectable adenomas was 18:53:29. The most commonly reported preoperative biochemical investigations were serum cortisol (average 26.4µg/dL) and ACTH (77.5pg/dL). Postoperative cortisol was most frequently used to define remission (74.8%), most commonly with threshold of 5µg/dL (44.8%). Average remission rates were 77.8% with recurrence rate of 13.9%. Median follow-up was 38 months. Majority of papers reported age (81.9%) and sex (79.4%). Only 56.6% reported whether their patients had previous pituitary surgery. 45.3% reported whether their adenomas were macroadenoma, microadenoma or undetectable. Only 24.1% reported preoperative cortisol, and this did not improve over time. 60.4% reported numerical thresholds for cortisol in defining remission, and this improved significantly over time (p = 0.004). Visual inspection of bubbleplots showed increasing preference for threshold of 5µg/dL. 70.4% reported the length of follow up. Conclusion We quantified the characteristics of Cushing’s disease, and analysed the trends in investigation and reporting. This review may help to inform future efforts in forming guidelines for research and clinical practice.

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Endoscopic transsphenoidal pituitary surgery: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas

Acta Endocrinologica ◽

10.1530/eje-13-0325 ◽

2013 ◽

Vol 169 (3) ◽

pp. 329-337 ◽

Cited By ~ 48

Author(s):

M A E M Wagenmakers ◽

H D Boogaarts ◽

S H P P Roerink ◽

H J L M Timmers ◽

N M M L Stikkelbroeck ◽

...

Keyword(s):

Treatment Option ◽

Cushing’S Disease ◽

Remission Rate ◽

Pituitary Surgery ◽

Primary Treatment ◽

Endoscopic Technique ◽

Cushing's Disease ◽

Recurrence Rates ◽

Transsphenoidal Pituitary Surgery

ContextAlthough the endoscopic technique of transsphenoidal pituitary surgery (TS) has been widely adopted, reports on its results in Cushing's disease (CD) are still scarce and no studies have investigated long-term recurrence rates. This is the largest endoscopic series published till now.ObjectiveTo gain insight into the role of endoscopic TS as a primary treatment option for CD, especially in patients with magnetic resonance imaging (MRI)-negative CD and (invasive) macroadenomas.DesignRetrospective cohort study.Patients and methodsThe medical records of 86 patients with CD who underwent endoscopic TS were examined. Data on preoperative and postoperative evaluation, perioperative complications, and follow-up were collected. Remission was defined as disappearance of clinical symptoms with a fasting plasma cortisol level ≤50 nmol/l either basal or after 1 mg dexamethasone.ResultsThe remission rate in different adenoma subclasses varied significantly: 60% in MRI-negative CD (n=20), 83% in microadenomas (n=35), 94% in noninvasive macroadenomas (n=16), and 40% in macroadenomas that invaded the cavernous sinus (n=15). The recurrence rate was 16% after 71±39 months of follow-up (mean±s.d., range 10–165 months).ConclusionsEndoscopic TS is a safe and effective treatment for all patients with CD. Recurrence rates after endoscopic TS are comparable with those reported for microscopic TS. Our data suggest that in patients with noninvasive and invasive macroadenomas, the endoscopic technique of TS should be the treatment of choice as remission rates seem to be higher than those reported for microscopic TS, although no comparative study has been performed.

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Diagnosis and Multimodality Management of Cushing’s Disease: A Practical Review

International Journal of Endocrinology ◽

10.1155/2013/893781 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Gabriel Zada

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Disease ◽

Patient Survival ◽

Clinical Laboratory ◽

Management Strategies ◽

Serum Cortisol ◽

Cushing's Disease ◽

First Line ◽

Stepwise Approach

Cushing’s Disease is caused by oversecretion of ACTH from a pituitary adenoma and results in subsequent elevations of systemic cortisol, ultimately contributing to reduced patient survival. The diagnosis of Cushing’s Disease frequently involves a stepwise approach including clinical, laboratory, neuroimaging, and sometimes interventional radiology techniques, often mandating multidisciplinary collaboration from numerous specialty practitioners. Pituitary microadenomas that do not appear on designated pituitary MRI or dynamic contrast protocols may pose a particularly challenging subset of this disease. The treatment of Cushing’s Disease typically involves transsphenoidal surgical resection of the pituitary adenoma as a first-line option, yet may require the addition of adjunctive measures such as stereotactic radiosurgery or medical management to achieve normalization of serum cortisol levels. Vigilant long-term serial endocrine monitoring of patients is imperative in order to detect any recurrence that may occur, even years following initial remission. In this paper, a stepwise approach to the diagnosis, and various management strategies and associated outcomes in patients with Cushing’s Disease are discussed.

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Endogenous ACTH Concentration-Cortisol Secretion Dose Analysis Unmasks Decreased ACTH Potency in Cushing's Disease with Restoration after Successful Pituitary Adenomectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1878 ◽

2011 ◽

Vol 96 (12) ◽

pp. 3768-3774 ◽

Cited By ~ 8

Author(s):

Ferdinand Roelfsema ◽

Daniel M. Keenan ◽

Johannes D. Veldhuis

Keyword(s):

Surgical Treatment ◽

Cushing’S Disease ◽

Pituitary Surgery ◽

Pulse Frequency ◽

Cushing's Disease ◽

P Value ◽

Cortisol Secretion ◽

Acth Concentration ◽

Active Disease

Background: The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known. Hypothesis: Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion. Subjects: Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls. Outcomes: ACTH and cortisol secretion rates and analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were evaluated. Results: Both basal and pulsatile secretion of ACTH and cortisol were increased in patients with active disease but normal in cured patients. ACTH, but not cortisol pulse frequency, was amplified in patients and restored after successful surgical treatment. ACTH EC50, an inverse measure of potency, was higher during pulse onset in Cushing's disease (59 ± 7.4 ng/liter) than in controls (20 ± 3.7 ng/liter) (P < 0.0001) and remitted patients after surgery [15 ± 3.2 ng/liter, P value not significant (NS) vs. controls] and during pulse recovery phases [128 ± 18 (P <0.0001), 70 ± 8.4, and 67 ± 17 ng/liter (NS vs. controls), respectively]. Efficacy was increased in active disease and normalized after surgical treatment [patients, 38 ± 8.3 nmol/liter · min, vs. controls, 21 ± 2.3 nmol/liter · min (P <0.0001), and cured patients, 15 ± 3.2 nmol/liter · min (NS vs. controls)]. Sensitivity to endogenous ACTH did not differ among the three groups. Conclusion: The adrenal gland in Cushing's disease exhibits decreased responsiveness to submaximal ACTH drive and amplified efficacy, with unchanged sensitivity. These target-gland abnormalities are reversible in long-term remission after pituitary surgery.

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Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance

Clinical Endocrinology ◽

10.1111/j.1365-2265.2005.02380.x ◽

2005 ◽

Vol 63 (5) ◽

pp. 549-559 ◽

Cited By ~ 182

Author(s):

A. Brew Atkinson ◽

Adele Kennedy ◽

M. Ivan Wiggam ◽

David R. McCance ◽

Brian Sheridan

Keyword(s):

Cushing’S Disease ◽

Pituitary Surgery ◽

Cushing's Disease ◽

Remission Rates

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Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000100004 ◽

2010 ◽

Vol 54 (1) ◽

pp. 17-23 ◽

Cited By ~ 17

Author(s):

Ricardo Santos de Oliveira ◽

Margaret de Castro ◽

Sonir Roberto Rauber Antonini ◽

Carlos Eduardo Martinelli Júnior ◽

Ayrton Custódio Moreira ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Pediatric Patients ◽

Serum Cortisol ◽

Plasma Cortisol Level ◽

Hormone Deficiency ◽

Cushing's Disease ◽

Specialized Center ◽

Biochemical Cure

OBJECTIVE: The aim of this study was to review the results of surgery for pediatric patients with Cushing's disease who were less than 18 years old and underwent transsphenoidal surgery in a specialized center during a 25-year period. SUBJECTS AND METHODS: Retrospective study, in which the medical records, histology and pituitary imaging of 15 consecutive pediatric patients with Cushing's disease (mean age: 13 years) were evaluated by the same team of endocrinologists and a neurosurgeon from 1982 to 2006. Patients were considered cured when there was clinical adrenal insufficiency and serum cortisol levels were below 1. 8 µg/dL or 50 nmol/L after one, two, three, or seven days following surgery; they therefore required cortisone replacement therapy. Follow-up was for a median time of 11.5 years (range: 2 to 25 years). RESULTS: Clinical and biochemical cure was achieved in 9/15 patients (60%) exclusively after transsphenoidal surgery. Hypopituitarism was observed in four patients; growth hormone deficiency, in two; permanent diabetes insipidus, in one case. CONCLUSIONS: Cushing's disease is rare in children and adolescents. Transsphenoidal surgery is an effective and safe treatment in most of these patients. Plasma cortisol level < 1. 8 µg/dL following surgery is the treatment goal and is a good predictive factor for long-term cure of Cushing's disease.

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