OBJECTIVE:Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up.DESIGN AND PATIENTS:Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille.METHODS:Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.RESULTS:Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients.CONCLUSION:Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.

OBJECTIVE:Predicting the outcome of patients operated on for Cushing's 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. DESIGN AND PATIENTS:Sixty-seven patients with initial remission and a minimal postsurgical follow-up greater than 18 months were included in this retrospective bicentre study. MEASUREMENTS:Follow-up included 3-6 months followed by yearly 24-h urinary-free cortisol, ACTH and cortisol plasmatic levels, a 1-mg overnight dexamethasone suppression test (1-mg DST), desmopressin test and the CDDT. ROC curves were performed to define the optimal threshold of immediate postsurgical cortisol level and 3- to 6-month desmopressin test and CDDT, as predictors of final outcome in comparison with classical biological markers of recurrence. RESULTS:Eleven patients presented recurrence. The patient's median follow-up was 52 months (range, 18-180). As early predictors of outcome, immediate postsurgical plasma cortisol level <35 nmol/l predicted the lack of recurrence with 93% negative predictive value (NPV), whereas predictive positive value (PPV) was 25%. During the follow-up, the CDDT was more precise than the desmopressin test in predicting the lack of recurrence (100% NPV) when performed in the first 3 years after surgery. Positivity of the CDDT was defined based on ROC curves by ACTH and cortisol increments >50%. The CDDT was highly reproducible, as the same response was observed every year in 91% of the patients. CONCLUSIONS:Adding the CDDT the first 3 years after surgery to immediate postsurgical cortisol evaluation should allow obtaining an optimal follow-up management of patients operated for Cushing's disease.

Background. - Patients suffering from adrenal insufficiency, whether primary (PAI) or secondary (SAI) have an increased mortality risk and increased morbidity. There are no guidelines on hydrocortisone replacement therapy and little is known on patients' management in current practice. We described patients' profiles and treatment in a tertiary referral centre. Methods. - Data were collected retrospectively from medical charts. PAI and SAI patients were described and compared. Results. - Two hundred and one patients (79 PAI + 122 SAI) were included. They had a mean duration of disease of 11.2 years. Main causes of PAI were autoimmune diseases (31%) and adrenalectomy (26%). SAI was caused primarily by pituitary tumors (61%) and irradiation (20%). Mean dose of daily hydrocortisone (HC) was 27.5 and 19.9 mg/day in PAI and SAI patients respectively, with a majority of patients dividing the dose into 2 intakes (46.8 and 72.2% in PAI and SAI groups, respectively). SAI patients exhibited more cardiovascular risk factors than PAI patients. The HC daily dose was slightly higher in patients with dyslipidemia (in both PAI and SAI groups) and in those with high blood pressure (in the SAI group only). One third of patients were out of work, due to unemployment, sick leaves, or disability. Conclusions. - The management of AI is far from standardized, and individual tailorization is difficult with currently available means of treatment. Under- and overdose of hydrocortisone likely leads to complications, and altered quality of life reflected by a high rate of "out of work" patients. (C) 2015 Elsevier Masson SAS. All rights reserved.

BACKGROUND:The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2.METHODS:This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy.FINDINGS:1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent.INTERPRETATION:The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.

INTRODUCTION Focused parathyroidectomy is the treatment of choice for patients with concordant positive imaging. Bilateral cervical exploration is performed for cases with discordant imaging, yet more than 70% of those cases are the result of a single-gland disease. As focused parathyroidectomy is generally costless and harmless, for cases with discordant imaging, we tried to determine whether preoperative characteristics can lead to a diagnosis of single-gland disease. METHODS This study included 182 patients treated for primary hyperparathyroidism by bilateral exploration from 2009 to 2012 at La Timone Hospital, Marseille, France. We classified patients based on preoperative images and pathological results (single-gland or multiglandular disease). We then compared the demographical, laboratory and imaging results. We also asked a senior nuclear medicine practitioner who was blind to the ultrasound and pathological results to perform a second reading. RESULTS Of the total number of patients, 15.4% had negative, 54.4% discordant and 30.2% concordant imaging. After reviewing the scintigraphy results, 8% of the cases with discordant imaging would have been classified as concordant with ultrasound. Subtraction scintigraphy obtained better results than dual-phase scintigraphy (concordance with ultrasound in 50 vs 31% with classical scintigraphy). For the cases of discordant imaging, no predictive factors of single-gland disease could be identified. Ultrasound and scintigraphy were similarly effective in determining the correct location of the abnormal gland. CONCLUSION Discordant results of preoperative imaging modalities do not discriminate between uniglandular and multiglandular diseases in hyperparathyroidism. Diagnostic differentiation between the different causes of hyperparathyroidism requires improvements in imaging techniques and might benefit from subtraction scintigraphy.

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 Cushing's 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.

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 Cushing's 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.

The depictions of Akhenaten have long interested medicine and above all endocrinology because of the eunuch gynoid morphology of this haraoh. These depictions call to mind various diagnostic hypotheses that have been successively considered as endocrinology progresses, with mphasis on the three diseases recently identified (gynecomastia family, Kennedy’s disease, and fertile eunuch syndrome), which are compatible ith the now proven fertility of Akhenaten. 2013 Elsevier Masson SAS. All rights reserved.

Hyperthyroidism due to Graves’ disease is autoimmune in origin. The initiation of dysimmunity responsible for the disease is still poorly understood. Numerous population studies show that genetic factors have a major role, but the environment and any kind of stress also contribute to the onset of the disease. There remains the recurring question for medical experts of the accountability of stress in the onset of Graves’ disease. To date, it is impossible to establish a direct link between this disease and a specific stress. The relationship can only be hypothetical, indirect and partial.

SummaryIntroductionGiven the new therapeutic options in acromegaly, it seemed important to evaluate the outcome of operated acromegalic patients today.ObjectiveTo analyse the characteristics and short‐ and long‐term surgical outcome of patients who underwent transsphenoidal surgery for a growth hormone (GH)‐secreting adenoma in our centre and to determine predictive factors of remission.Design and patientsThis retrospective 10‐year study included 115 newly diagnosed acromegalic patients operated on at Timone University Hospital, Marseille, France, between 1997 and 2007.MeasurementsInitial and long‐term outcomes were evaluated using stringent and current remission criteria, associating GH nadir after oral glucose tolerance test <0·4 μg/l and normal insulin‐like growth factor‐1 (IGF‐1) at 3 months, and a normal IGF‐1 at the end of follow‐up (52·4 ± 36·8 months, median 41 months, range 6·7–135·4 months, n = 99).ResultsAt the end of follow‐up, 90·9% of patients had controlled disease. Overall, 49·5% of patients were in long‐term remission after surgery alone, and only 2·0% of patients experienced recurrent disease. Multivariate predictors of 3‐month remission included mean GH at diagnosis (P = 0·033), tumour invasion (P = 0·013) and surgeon report of incomplete or uncertain macroscopic resection (P = 0·003 and P = 0·047, respectively). Multivariate predictors at diagnosis of long‐term remission included mean GH level (P = 0·048), adenoma size (P = 0·007) and absence of pituitary deficit (P = 0·026).ConclusionsIn long‐term follow‐up after surgery of acromegaly, half of the patients achieved remission after surgery alone and more than 90% had their disease controlled. With stringent 3‐month remission criteria, recurrence was rare.

The depictions of Akhenaten have long interested medicine and above all endocrinology because of the eunuch gynoid morphology of this pharaoh. These depictions call to mind various diagnostic hypotheses that have been successively considered as endocrinology progresses, with emphasis on the three diseases recently identified (gynecomastia family, Kennedy's disease, and fertile eunuch syndrome), which are compatible with the now proven fertility of Akhenaten.

Hyperthyroidism due to Graves’ disease is autoimmune in origin. The initiation of dysimmunity responsible for the disease is still poorly nderstood. Numerous population studies show that genetic factors have a major role, but the environment and any kind of stress also contribute o the onset of the disease. There remains the recurring question for medical experts of the accountability of stress in the onset of Graves’ disease. o date, it is impossible to establish a direct link between this disease and a specific stress. The relationship can only be hypothetical, indirect and artial. 2013 Elsevier Masson SAS. All rights reserved.

Abstract Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.

Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.

We report here a rare case of a young male patient presenting with a Multiple Endocrine Neoplasia Type 1 - prolactin-secreting pituitary carcinoma, controlled long-term after temozolomide withdrawal. Initial presentation was pituitary apoplexy leading to surgery. Dopamine agonists and radiotherapy allowed control of prolactin secretion and pituitary remnant. Metastasis appeared 10 years after initial presentation, leading to the diagnosis of pituitary carcinoma. At that time, dopamine agonists were no more effective; temozolomide, an oral alkylating agent, was administered for 24 cycles, and allowed decrease of the volume of the pituitary lesion and metastases. The patient is still currently followed in our department, 3 years after temozolomide withdrawal: prolactin level and pituitary tumor volume remain controlled without any chemotherapy. To our knowledge, this is the first case of MEN1 prolactin secreting pituitary carcinoma controlled long-term after temozolomide discontinuation.

PURPOSE OF REVIEW:Mifepristone is the first and only available glucocorticoid receptor antagonist. Cushing's syndrome is a rare disease, responsible for increased morbidity and mortality. The treatment of Cushing's syndrome is far from perfect. The aim of this review is to better define the merits and pitfalls of mifepristone in treating Cushing's syndrome, and try to determine its potential roles in the treatment of hypercortisolism. RECENT FINDINGS:Only case reports or series based on a low number of patients had been reported in the literature. A recent retrospective European Study based on about 20 patients with Cushing's syndrome gave more precise data about mifepristone. Coupled with the 20 previously reported patients in various studies, these results determine the profile of patients who could benefit from mifepristone. SUMMARY:High clinical efficacy of mifepristone is counterbalanced by the lack of available biological monitoring data during treatment, and the risk of worsening of hypokalemia and blood pressure levels. However, its rapid efficacy and the fact that the drug uses a mechanism that is different from all currently available treatment should make mifepristone a valuable treatment in particular cases of uncontrolled hypercortisolism despite classical methods.