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R Valero, S Vallette-Kasic, B Conte-Devolx, P Jaquet and T Brue

OBJECTIVE: Taking advantage of the over-expression of V3 receptors in adenomatous corticotroph cells, we evaluated the response to the vasopressin agonist desmopressin in 22 patients operated on for Cushing's disease, with a mean follow-up of 4.5 years. SUBJECTS AND METHODS: Twenty-two patients (17 women) operated on for Cushing's disease with a follow-up >2 years (median, 48; range, 24-141 months) underwent one desmopressin test (10 mug i.v. bolus) 3-6 months postoperatively. Twelve were in remission (R group), five had immediate failure (IF) after surgery and five had late recurrence (LR). RESULTS: Both ACTH and cortisol peaks after desmopressin were significantly lower in the R group than in the LR group (P=0.003 and P=0.013 respectively). The receiver operator characteristic curve method defined an ACTH peak threshold >/=22 pg/ml or ACTH rise >/=35%; cortisol peak >/=350 nmol/l or cortisol rise >/=14%. None of twelve patients in remission had ACTH or cortisol peaks above these thresholds vs three of five patients from the LR group and five of five in the IF group. DISCUSSION: On the basis of ACTH or cortisol peaks respectively, the desmopressin test was predictive of a later recurrence with a positive predictive value of 100% or 80% respectively, and a negative predictive value of 92%. Sensitivity and specificity were 80% and 100% respectively based on ACTH peak, and 80% and 92% respectively based on cortisol peak. CONCLUSION: In this first long-term study, a marked response of ACTH or cortisol to desmopressin was predictive of a later recurrence with good specificity and sensitivity.

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F Castinetti, I Morange, P Jaquet, B Conte-Devolx and T Brue

Context

Although transsphenoidal surgery remains the first-line treatment in Cushing's disease (CD), recurrence is observed in about 20% of cases. Adjunctive treatments each have specific drawbacks. Despite its inhibitory effects on steroidogenesis, the antifungal drug ketoconazole was only evaluated in series with few patients and/or short-term follow-up.

Objective

Analysis of long-term hormonal effects and tolerance of ketoconazole in CD.

Design

A total of 38 patients were retrospectively studied with a mean follow-up of 23 months (6–72).

Setting

All patients were treated at the same Department of Endocrinology in Marseille, France.

Patients

The 38 patients with CD, of whom 17 had previous transsphenoidal surgery.

Intervention

Ketoconazole was begun at 200–400 mg/day and titrated up to 1200 mg/day until biochemical remission.

Main outcome measures

Patients were considered controlled if 24-h urinary free cortisol was normalized.

Results

Five patients stopped ketoconazole during the first week because of clinical or biological intolerance. On an intention to treat basis, 45% of the patients were controlled as were 51% of those treated long term. Initial hormonal levels were not statistically different between patients controlled or uncontrolled. Ketoconazole was similarly efficacious as a primary or postoperative treatment. Among 15 patients without visible adenoma at initial evaluation, subsequent follow-up allowed identification of the lesion in five cases. No adrenal insufficiency was observed. Adverse effects were rare in patients treated long term.

Conclusions

Ketoconazole is a safe and efficacious treatment in CD, particularly in patients for whom surgery is contraindicated, or delayed because of the absence of image of adenoma on magnetic resonance imaging.

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F Castinetti, I Morange, H Dufour, P Jaquet, B Conte-Devolx, N Girard and T Brue

Corticotropin-releasing hormone (CRH)-stimulated petrosal sinus sampling is currently the gold standard method for the differential diagnosis between pituitary and ectopic ACTH-dependent Cushing’s syndrome. Our objective was to determine sensitivity and specificity of desmopressin test during petrosal sinus sampling.

Patients and methods: Forty-three patients had petrosal sinus sampling because of the lack of visible adenoma on magnetic resonance imaging (MRI) and/or because of discordant cortisol response to high-dose dexamethasone suppression test. ACTH sampling was performed in an antecubital vein, right and left petrosal sinuses, then at each location 5 and 10 min after injection of desmopressin. Diagnosis was based on the ACTH ratio between petrosal sinus and humeral vein ACTH after desmopressin test. Diagnosis was confirmed after surgery. A receiver operating characteristics curve was used to determine optimal sensitivity and specificity.

Results: Thirty-six patients had Cushing’s disease (CD) and seven had ectopic ACTH secretion. A ratio > 2 after desmopressin was found in 35 of the 36 cases of CD (sensitivity: 95%). A ratio ≤ 2 was found in the seven patients with ectopic ACTH secretion (specificity: 100%). Sinus sampling was ineffective in determining the left or right localization of the adenoma (sensitivity = 50%). No major adverse effects were observed during or after the procedure.

Conclusion: Desmopressin test during petrosal sinus sampling is a safe and effective diagnostic procedure in ACTH-dependent Cushing’s syndrome. It thus represents a valuable alternative to CRH.

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F Castinetti, M Nagai, H Dufour, J-M Kuhn, I Morange, P Jaquet, B Conte-Devolx, J Regis and T Brue

Objective: Though transsphenoidal surgery remains the first-line treatment of Cushing’s disease, recurrence occurs frequently. Conventional radiotherapy and anticortisolic drugs both have adverse effects. Stereotactic radiosurgery needs to be evaluated more precisely. The aim of this study was to determine long-term hormonal effects and tolerance of gamma knife (GK) radiosurgery in Cushing’s disease.

Design: Forty patients with Cushing’s disease treated by GK were prospectively studied over a decade, with a mean follow-up of 54.7 months. Eleven of them were treated with GK as a primary treatment.

Methods: Radiosurgery was performed at the Department of Functional Neurosurgery of Marseille, France, using the Leksell Gamma Unit B and C models. Median margin dose was 29.5 Gy. Patients were considered in remission if they had normalized 24-h free urinary cortisol and suppression of plasma cortisol after low-dose dexamethasone suppression test.

Results: Seventeen patients (42.5%) were in remission after a mean of 22 months (range 12–48 months). The two groups did not differ in terms of initial hormonal levels. Target volume was significantly higher in uncured than in remission group (909.8 vs 443 mm3, P = 0.038). We found a significant difference between patients who were on or off anticortisolic drugs at the time of GK (20 vs 48% patients in remission respectively, P = 0.02).

Conclusion: With 42% of patients in remission after a median follow-up of 54 months, GK stereotactic radiosurgery, especially as an adjunctive treatment to surgery, may represent an alternative to other therapeutic options in view of their adverse effects.

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J Eroukhmanoff, I Tejedor, I Potorac, T Cuny, J F Bonneville, H Dufour, G Weryha, A Beckers, P Touraine, T Brue and F Castinetti

Objective

Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA.

Patients and methods

We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained.

Results

In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline.

Conclusion

No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

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F Castinetti, D Taieb, J F Henry, M Walz, C Guerin, T Brue, B Conte-Devolx, H P H Neumann and F Sebag

The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in MEN2 or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits <5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of the cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and the results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN2.

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S Vallette-Kasic, H Dufour, M Mugnier, J Trouillas, H Valdes-Socin, P Caron, S Morange, N Girard, F Grisoli, P Jaquet and T Brue

OBJECTIVE: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension. DESIGN: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome. METHODS: Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning. RESULTS: Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences. CONCLUSION: Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.

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R Reynaud, F Albarel, A Saveanu, N Kaffel, F Castinetti, P Lecomte, R Brauner, G Simonin, J Gaudart, E Carmona, A Enjalbert, A Barlier and T Brue

Background

Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause.

Objectives

i) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS.

Study design

We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes.

Results

PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS.

Conclusion

PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.

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F Maurice, A Dutour, C Vincentelli, I Abdesselam, M Bernard, H Dufour, Y Lefur, T Graillon, F Kober, P Cristofari, E Jouve, L Pini, R Fernandez, C Chagnaud, T Brue, F Castinetti and B Gaborit

Objective

Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a new mediator of bone metabolism. Cushing syndrome (CS) is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF.

Design

This was a cross-sectional study. Seventeen active and 17 cured ACTH-dependent CS patients along with 17 controls (matched with the active group for age and sex) were included.

Methods

The BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. Bone mineral density (BMD) was evaluated in patients using dual-energy X-ray absorptiometry.

Results

Active CS patients had higher BMF content both in the femur (82.5 ± 2.6%) and vertebrae (70.1 ± 5.1%) compared to the controls (70.8 ± 3.6%, P = 0.013 and 49.0 ± 3.7% P = 0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3 ± 2.9% (femur) and 46.7% ± 5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients.

Conclusions

Accumulation of BMF is induced by hypercortisolism. In remission patients, BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.

Free access

F Castinetti, M Fassnacht, S Johanssen, M Terzolo, P Bouchard, P Chanson, C Do Cao, I Morange, A Picó, S Ouzounian, J Young, S Hahner, T Brue, B Allolio and B Conte-Devolx

Objective

Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS).

Design

Retrospective study of patients treated in seven European centers.

Methods

Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200–1000). Median treatment duration was 2 months (0.25–21) for malignant CS, and 6 months (0.5–24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated.

Results

Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients.

Conclusion

Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.