Monique Martinie

Ketoconazole in Cushing's Disease: Is It Worth a Try?

BACKGROUND The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushings disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

A Combined Dexamethasone Desmopressin Test as an Early Marker of Postsurgical Recurrence in Cushing’s Disease

CONTEXT Recurrence of Cushings disease (CD) after transsphenoidal surgery (TSS) occurs in about 25% of cases. Twenty percent of patients with immediate postsurgical corticotroph deficiency will present late recurrence. OBJECTIVE The aim of the study was to evaluate a coupled dexamethasone desmopressin test (CDDT) as a predictor of recurrence of CD. DESIGN We conducted a prospective bicenter study (Marseille and Grenoble, France). PATIENTS We studied 38 patients treated by TSS for CD with a mean follow-up of 60 months. INTERVENTION(S) We evaluated 24-h urinary free cortisol, ACTH, and cortisol plasmatic levels and performed low-dose dexamethasone suppression test and CDDT 3 to 6 months after surgery and then yearly. MAIN OUTCOME MEASURES After CDDT, ACTH ratio (ACTHr) was defined as (PeakACTH - BaseACTH)/BaseACTH. Cortisol ratio (Cortisolr) was defined as (PeakCortisol - BaseCortisol)/BaseCortisol. Basal values were observed after low-dose dexamethasone suppression test. Receiver operator characteristics curve defined ACTHr and Cortisolr giving the best sensitivity and specificity associated with recurrence. RESULTS Ten patients presented recurrence. ACTHr and Cortisolr were superior or equal to 0.5 in all patients with recurrence and in three of 28 patients in remission (100% sensitivity, 89% specificity). The test became positive in eight of 10 patients with recurrence 6-60 months before classical markers of hypercortisolism. Six patients with immediate postsurgical corticotroph deficiency presented recurrence. All of them presented CDDT positivity during the 3 yr after surgery, and recurrence 6 to 60 months after CDDT positivity. CONCLUSIONS CDDT is an early predictor of recurrence of CD and could be of particular interest in the first 3 yr after surgery, by selecting patients at high risk of recurrence despite falsely reassuring classical hormonal markers.

Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

Cushings syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a beta-blocker-sensitive Cushings syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

Postoperative follow-up of Cushing's disease using cortisol, desmopressin and coupled dexamethasone-desmopressin tests: a head-to-head comparison.

Predicting the outcome of patients operated on for Cushings disease (CD) is a challenging task. Our objective was to assess the accuracy of immediate postsurgical plasma cortisol, desmopressin test and the coupled dexamethasone‐desmopressin test (CDDT) as predictors of outcome.

Évaluation du risque de récidive de la maladie de Cushing après chirurgie hypophysaire trans-sphénoïdale dans les centres français participant au registre national

La sous-unité régulatrice de la kinase AMPc-dépendante (PRKAR1A) présente des mutations dans deux maladies très différentes : le complexe de Carney (CNC) et l’acrodysostose avec multi-résistances hormonales (ADOH). Dans le CNC, les mutations créent classiquement une haploinsuffisance et dans ADOH, une insensibilité à l’AMPc. Certaines mutations faux-sens retrouvées dans le CNC (A213D ; G289W) touchent les mêmes acides aminés dans l’acrodysostose (A213T ; G289E). Nous avons voulu comprendre les différences fonctionnelles entre ces mutants. Méthodes.– Sept mutants faux-sens responsables d’ADOH et trois responsables de CNC ont été produits par mutagenèse dirigée et exprimés dans les cellules HEK293. Ont été analysées : – leur expression par Western Blot ; – leur dégradation en présence de cycloheximide ; – leur activité enzymatique par un système rapporteur Cre-luciférase ; – enfin leur affinité à la sous-unité catalytique et la liaison de l’AMPc par BRET. Résultats.– Les dix mutants sont exprimés. Ils ont tous une affinité comparable pour la sous-unité catalytique (BRET50 entre 0,4 et 0,6). Tous les mutants ADOH et un mutant CNC (G289W) présentent un défaut de liaison de l’AMPc (EC50 = 2 à 70 nM vs 1 nM pour WT). L’activité enzymatique est réduite pour les mutants ADOH et augmentée pour l’un des mutants CNC (D183Y). La comparaison des vitesses de dégradation entre les mutants CNC et ADOH est en cours. Discussion.– Les mutations faux-sens de l’acrodysostose sont toutes responsables d’une altération de la liaison de l’AMPc. Les anomalies fonctionnelles des mutants faux-sens du CNC sont différentes mais restent à identifier (dégradation accélérée ?).