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

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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Significant GH deficiency after long-term cure by surgery in adult patients with Cushing’s disease

Acta Endocrinologica ◽

10.1530/eje.1.02329 ◽

2007 ◽

Vol 156 (2) ◽

pp. 233-239 ◽

Cited By ~ 21

Author(s):

Francesca Pecori Giraldi ◽

Massimiliano Andrioli ◽

Laura De Marinis ◽

Antonio Bianchi ◽

Antonella Giampietro ◽

...

Keyword(s):

Replacement Therapy ◽

Cushing’S Disease ◽

Gh Deficiency ◽

Pituitary Surgery ◽

Male Gender ◽

Cushing's Disease ◽

Gh Secretion ◽

Wide Variability ◽

Acth Secreting

Objective: Impaired GH secretion usually accompanies Cushing’s syndrome and a variable proportion of patients reportedly fail to recover normal GH secretion after successful treatment. This wide variability is most probably due to differences in the treatment (i.e. surgery and/or radiotherapy), timing of patient re-evaluation after surgery and dynamic tests employed to challenge GH secretion, and hinders a precise assessment of risk of GH deficiency after cure. The aim of the present study is to evaluate GH secretory status after long-term cure of Cushing’s disease achieved by surgery alone. Design and methods: We studied 34 patients (27 females and 7 males, age range 21–68 years) formerly affected by Cushing’s disease. Patients were studied 2–20 years (median 3.3 years) following remission of hypercortisolism; all patients underwent transsphenoidal surgery with the removal of an ACTH-secreting adenoma; repeat pituitary surgery for relapse was performed in two patients while bilateral adrenalectomy was necessary in two patients. In all subjects, the GH response to GHRH+arginine stimulation was evaluated. At the time of testing, 13 patients were still on steroid replacement therapy. Results: In long-term surgical remission, 22 patients (65.0%) presented subnormal GH secretion; partial GH deficiency (GH peak <16.5 μg/l) was found in 11 patients and severe GH deficiency (GH peak <9 μg/l) in another 11. Male gender and length of hypercortisolism were risk factors for postsurgical GH deficiency. Conclusions: This study demonstrates the presence of GH deficiency in a high percentage of patients with Cushing’s disease after long-term remission of hypercortisolism obtained by surgery alone. Male gender and length of hypercortisolism are the most significant predictors of postsurgical GH deficiency. This finding is significant as it highlights that even the most favourable therapeutical course, i.e. remission achieved by surgery alone, is accompanied by impaired GH secretion. Assessment of GH secretion is therefore recommended for all patients cured from Cushing’s disease, even if not submitted to radiotherapy. Studies on the clinical impact of GH deficiency and the use of GH replacement therapy seem warranted in patients cured from Cushing’s disease.

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Effect of primary empty sella syndrome on pituitary surgery for Cushing's disease

Journal of Neurosurgery ◽

10.3171/2014.3.jns132012 ◽

2014 ◽

Vol 121 (3) ◽

pp. 518-526 ◽

Cited By ~ 11

Author(s):

Gautam U. Mehta ◽

Kamran D. Bakhtian ◽

Edward H. Oldfield

Keyword(s):

Pituitary Gland ◽

Cushing’S Disease ◽

Pituitary Surgery ◽

Empty Sella ◽

Cushing's Disease ◽

Csf Leak ◽

Empty Sella Syndrome ◽

Csf Leaks ◽

Primary Empty Sella

Object Primary empty sella syndrome (ESS) results from herniation of arachnoid mater into the pituitary fossa. It has been suggested to have a negative effect on pituitary surgery; however, outcomes in this cohort have not been defined. This study was performed to determine the effect of ESS on immediate and long-term biochemical outcome after pituitary surgery for Cushing's disease (CD). Methods Using a matched cohort study design, the authors followed patients treated with pituitary surgery for CD with and without ESS. Complete ESS was defined as pituitary gland height ≤ 2 mm, whereas partial ESS was defined as pituitary gland height > 2 mm but less than three-quarters of the total sellar depth. The primary end points were immediate and long-term biochemical outcome. Cerebrospinal fluid leaks were recorded as a secondary end point. Results Seventy-eight patients with CD and primary ESS were identified and matched with 78 patients with CD without ESS. After surgical management, immediate biochemical remission was achieved in 69 patients (88%) with ESS and 75 controls (96%, p = 0.10). Long-term remission was achieved in most patients in both groups (5-year cure: 85% vs 92%, p = 0.10). Among patients with ESS, the presence of complete ESS predicted a worse long-term outcome (p = 0.04). Intraoperative CSF leaks were significantly more frequent with ESS (54% vs 24%, p < 0.001), and despite sellar floor repair, the rate of postoperative CSF leaks was also increased (6% vs 3%, p = 0.27). Conclusions Biochemical outcome after pituitary surgery for CD was worse in patients with complete ESS, and the risk of a CSF leak was increased with both partial and complete ESS. However, as outcome remains superior to those following alternative therapies and the biology of these tumors is unchanged in the setting of ESS, pituitary surgery should remain the initial treatment of choice.

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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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Surgical outcomes and multidisciplinary management strategy of Cushing’s disease: a single-center experience in China

Neurosurgical FOCUS ◽

10.3171/2020.3.focus2067 ◽

2020 ◽

Vol 48 (6) ◽

pp. E7 ◽

Cited By ~ 1

Author(s):

Keyi Zhang ◽

Ming Shen ◽

Nidan Qiao ◽

Zhengyuan Chen ◽

Wenqiang He ◽

...

Keyword(s):

Cushing’S Disease ◽

Surgical Outcomes ◽

Management Strategy ◽

Remission Rate ◽

Pituitary Surgery ◽

Multivariate Regression Analysis ◽

Cushing's Disease ◽

Endoscopic Endonasal ◽

Remission Rates

OBJECTIVEThe primary aim of this study was to investigate the value of multidisciplinary team (MDT) management in treating patients with Cushing’s disease (CD). The secondary aim was to assess the concordance of bilateral inferior petrosal sinus sampling (BIPSS) lateralization with intraoperative observations.METHODSThe authors recruited 124 consecutive patients (128 procedures) who had undergone endoscopic endonasal resection of adrenocorticotropic hormone–secreting pituitary adenomas from May 2014 to April 2018 and assessed their clinical characteristics, surgical outcomes, and adjuvant therapies. The criteria for surgical remission were normalized serum and urinary cortisol levels, which could be suppressed by a low-dose dexamethasone suppression test at 3-months’ follow-up without adjuvant treatment.RESULTSThe remission rates of the 113 patients with long-term follow-up (20.3 ± 12.2 months) were 83.2% after surgery alone and 91.2% after adjuvant therapy. The surgical remission rates of macroadenomas, MRI-visible microadenomas, and MRI-negative tumors were 66.7% (12/18), 89.3% (67/75), and 75% (15/20), respectively (p = 0.039). The surgical remission rates had a trend of improvement during the study period (87.5% in 2017–2018 vs 76.5% in 2014, p = 0.517). Multivariate regression analysis showed that a history of previous pituitary surgery (OR 0.300, 95% CI 0.100–0.903; p = 0.032) and MRI-visible microadenoma (OR 3.048, 95% CI 1.030–9.019; p = 0.044) were independent factors influencing surgical remission. The recurrence rate was 3.2% after a mean of 18 months after surgery. The remission rate of postoperative MDT management in patients with persistent disease was higher than non-MDT management (66.7% vs 0%, p = 0.033). In cases with preoperative BIPSS lateralization, 84.6% (44/52) were concordant with intraoperative findings.CONCLUSIONSMRI-visible microadenoma and primary surgery were independent predictors of surgical remission in CD. The MDT management strategy helps to achieve a better overall outcome. BIPSS may help to lateralize the tumor in MRI-negative/equivocal microadenomas.

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

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000800023 ◽

2007 ◽

Vol 51 (8) ◽

pp. 1362-1372 ◽

Cited By ~ 23

Author(s):

Mauro A. Czepielewski ◽

Guilherme A.F.S. Rollin ◽

Alessandra Casagrande ◽

Nelson P. Ferreira

Keyword(s):

Cushing’S Disease ◽

Previous Treatment ◽

Pituitary Surgery ◽

Serum Cortisol ◽

Normal Subjects ◽

Cushing's Disease ◽

Biochemical Tests ◽

Transsphenoidal Pituitary Surgery ◽

Cortisol Levels

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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Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery

Acta Endocrinologica ◽

10.1530/eje-11-0424 ◽

2011 ◽

Vol 165 (5) ◽

pp. 729-737 ◽

Cited By ~ 33

Author(s):

Roula Bou Khalil ◽

Camille Baudry ◽

Laurence Guignat ◽

Carmen Carrasco ◽

Jean Guibourdenche ◽

...

Keyword(s):

Cushing’S Disease ◽

Positive Response ◽

Pituitary Surgery ◽

Cushing's Disease ◽

Hormonal Changes ◽

Long Term Follow Up ◽

Mean Time ◽

Midnight Cortisol

ObjectiveTo describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS).DesignRetrospective study in a single center.Patients and methodsWe studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined ‘overt recurrence’, as presence of two classical parameters of excess cortisol (increased midnight – either serum or salivary – and 24 h urinary cortisol (UC)), leading to further specific therapeutic action, and ‘mild recurrence’, as presence of a single classical parameter, leading to simple surveillance.ResultsOf the 101 patients, 21 (20.8%) presented with recurrence, ‘mild’ or ‘overt’, during long-term follow-up (median 50.4 months, range 7–99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7–94 vs mean 21.5 months, median 17, range 3–61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively.ConclusionA positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.

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