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Julia Morera and Yves Reznik

The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA.

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Michael Joubert, Renaud Verdon and Yves Reznik

Design

We report the case of an incidental pituitary mass discovered in the context of bilateral cavernous sinus thrombosis due to a bacterial pansinusitis.

Conclusions

Magnetic resonance imaging features of the pituitary lesion, together with transient central hypogonadism and total regression of the mass after anticoagulation and antimicrobial therapy, suggest that this lesion is a pituitary oedema of vascular mechanism. Other possible causes of pituitary mass in such a situation are also discussed.

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Pierre C. Sizonenko, Yves Reznik and Michel L. Aubert

Abstract.

In order to compare the clinical effects of buserelin on central precocious puberty to its excretion in urine, as a parameter of metabolism or compliance, we have studied 52 patients treated either sc or intranasally. In girls with good control, urinary buserelin excretion represented 0.5 ± 0.1% of the daily intranasal dose vs 12.5 ± 2.3% of the daily sc dose. In boys, it represented 0.8 ± 0.2 and 9.9 ± 2.7%, respectively. In the sc treated group, 3 patients (2 girls and 1 boy) with poor control who exhibited excretion levels similar to those with good control were classified as resistant to therapy. Clinical control was poor in 4 intranasally treated girls: 2 had low excretion values suggesting poor compliance or failure of absorption by the nasal mucosa, and 2 appeared resistant to therapy, as urinary excretion levels of buserelin were similar to those of well-controlled patients. In addition, these data suggest that the small amount of buserelin absorbed by the nasal mucosa, as expressed by urinary excretion, is sufficient to desensitize the pituitary gonadotropes without any significant first-pass effect in the systemic circulation. This may explain the clinical effectiveness of the intranasal route for administration of small hormonal peptides acting on the pituitary gland.

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Anne Rod, Manuela Voicu, Laurence Chiche, Céline Bazille, Hervé Mittre, Estelle Louiset and Yves Reznik

Context

Ectopic ACTH syndrome (EAS) is principally associated with aggressive malignant tumors but also with neuroendocrine tumors of good prognosis. Recently, rare nonhepatocytic nested stromal and epithelial tumors (NSET) were characterized by their possible association with Cushing's syndrome of which biochemical and physiopathological features were still incompletely studied.

Objective

To describe the clinical and hormonal characteristics of an EAS originating from a liver NSET and further understand the mechanism of cortisol overproduction.

Design and setting

This is a clinical case report from the Endocrinology Department of Caen University Hospital, France.

Patient and intervention

A 17-year-old female patient was found to have a large liver NSET with mild Cushingoid clinical features and intense biological hypercortisolism but moderate ACTH secretion. Resection of the tumor was curative with a 30-month follow-up.

Results

The epithelial component of the tumor coexpressed ACTH mildly, corticotropin-releasing hormone (CRH) strongly, and 11β-hydroxysteroid dehydrogenase at a level comparable with normal human hepatocytes.

Conclusions

Liver NSET is a new cause of EAS, which may evoke hypercortisolism by multiple biochemical pathways.

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François Moreau, Hervé Mittre, Annie Benhaim, Camille Bois, Jérome Bertherat, Serge Carreau and Yves Reznik

Objective

The aromatase enzyme catalyzes the final stage of estrogen biosynthesis pathway from androgens. Its expression in the adrenal is poorly studied except for the rare estrogen-producing adrenocortical tumors. In order to further characterize aromatase expression in the adrenal, we evaluated the aromatase enzyme activity, Cyp19a1 gene expression level, and promoter utilization in normal adrenal tissues and in adrenocortical secreting tumors.

Design and methods

Six normal adult adrenals (NA), 2 feminizing adrenal tumors (FT), 10 cortisol-producing adenomas with overt (CS, n=4) or sub-clinical Cushing syndrome (SCS, n=6) and 3 aldosterone-producing adenomas (APA) were studied. Tissue aromatase activity was determined by the tritiated (3H)-water method. Total aromatase mRNA were measured by a competitive RT-PCR. Promoter regions PII and PI.4-derived transcripts were also studied in NA, FT, and other steroid-producing tumors by a semi-quantitative comparative RT-PCR. Immunofluorescence analysis was performed in normal human adrenal tissues.

Results

Aromatase activity was detected in NA tissues and in all tumor subtypes, at high levels in both FT. In NA, aromatase immunofluorescence was detected in the cytoplasm of steroidogenic cells, mainly from zona reticularis. Compared with NA, aromatase transcript levels were similar in CS and APA, lower in SCS and similar or higher in FT. Promoter analysis suggested predominant PII utilization in NA, APA, and SCS, but similar PII and PI.4 utilization in CS tumors.

Conclusion

Aromatase is expressed at similar levels in normal adrenal and in adrenocortical tumors, but at variably high levels in FT. Different promoter utilization patterns are found among tumor subtypes.

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Anne Cailleux-Bounacer, Yves Reznik, Bruno Cauliez, Jean François Menard, Céline Duparc and Jean Marc Kuhn

Background

The functional testing of endocrine testis uses extractive human chorionic gonadotropin (ehCG). Recombinant human hCG (rhCG), avoiding any contamination, should replace ehCG. Moreover, a functional evaluation with recombinant human LH (rhLH) would be closer to physiology than a pharmacological testing with hCG.

Methods

The study was conducted in normal men. We first evaluated the dose–effect of ehCG on plasma testosterone and estradiol levels, before and after injection of either hCG or vehicle. Secondly, the responses to the optimal dose of ehCG were compared with those of rhCG. Thirdly, we investigated the dose–effect of rhLH, on steroid hormone secretion. LH, testosterone, and estradiol plasma levels were measured after the injection of either rhLH or placebo.

Results

ehCG induced dose-dependent increases in plasma estradiol and testosterone levels. They respectively peaked at 24 and 72 h after the injection. The most potent dose of ehCG (5000 IU) induced results similar to those observed with 250 μg (6500 IU) rhCG. By comparison with placebo, rhLH induced a significant and dose-dependent increase in plasma testosterone levels 4 h after the injection. Peak response of testosterone to rhLH and rhCG was significantly correlated. rhLH did not induce significant change in plasma estradiol level.

Conclusions

In normal men, a single i.v. injection of 150 IU rhLH induces a 25% rise in plasma testosterone levels by comparison with placebo. At the moment, the dynamic evaluation using hCG remains the gold standard test to explore the Leydig cell function. The use of 250 μg rhCG avoiding any contamination should be recommended.

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Mohamad Khalaf, Julia Morera, Antoine Bourret, Yves Reznik, Christine Denoual, Michel Herlicoviez, Hervé Mittre and Annie Benhaim

Background

The bone morphogenetic proteins (BMPs) are growth factors involved in the folliculogenesis. Alteration in their expression may compromise the reproductive process in disease such as the polycystic ovary syndrome (PCOS). This study investigated the expression and role of granulosa cell (GC) BMP from normal cycling and PCOS women.

Methods and results

This prospective study was performed in GCs obtained from 14 patients undergoing IVF: i) six women with normal ovulatory cycles and tubal or male infertility and ii) eight women with PCOS. BMP2, BMP4, BMP5, BMP6, BMP7, and BMP8A and their receptors BMPR1A, BMPR1B, and BMPR2 were identified by RT-PCR in GCs from normally cycling and PCOS women. BMP4, BMP6, and BMP7 expressions were confirmed by immunohistochemistry. Quantitative transcript analysis showed the predominant expression of BMP6. In GCs from PCOS women, an overexpression of BMP6 (P<0.01) and BMPR1A mRNA (P<0.05) was observed. GC culture experiments demonstrated that basal estradiol (E2) production was threefold higher but FSH-induced E2 increment was twofold lower in PCOS compared with controls. In PCOS, BMP6 and BMP7 exerted a stimulatory effect on basal E2 production while BMP4 and BMP6 inhibited FSH-induced E2 production. FSH receptor and aromatase expression were not different between both groups.

Conclusion

The BMP system is expressed in human GCs from normal cycling and PCOS women. The BMP may be involved in reproductive abnormalities found in PCOS.

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Stéphane Bardet, Elodie Malville, Jean-Pierre Rame, Emmanuel Babin, Guy Samama, Dominique De Raucourt, Jean-Jacques Michels, Yves Reznik and Michel Henry-Amar

Objective

Whether lymph-node dissection (LND) influences the lymph-node recurrence (LNR) risk in patients with papillary thyroid cancer remains controversial. The prognostic impact of macroscopic and microscopic lymph-node involvement at diagnosis is also an unresolved issue. A retrospective study was conducted to assess the influence of various LND procedures and to search for LNR risk factors.

Methods

Overall 545 patients without distant metastases prior to surgery and main tumour ≥10 mm were included. A total thyroidectomy was performed in all patients with either no LND (Group 1, n=161), bilateral LND of the central and lateral compartments (Group 2, n=181) or all other dissection modalities (Group 3, n=203). Post-operative radioiodine was given to 496 (91%) patients. The 10-year cumulative probability of LNR was assessed and a prognostic study using multivariate analysis was performed.

Results

Macroscopic lymph-node metastases were present in 118 patients, 57 diagnosed before surgery and 61 only at surgery (including 81% in the central compartment). Overall, the 10-year cumulative probability of LNR was 7%. Macroscopic lymph-node metastases (P=0.001), extra-thyroidal invasion (P=0.017) and male gender (P=0.05) were independent risk factors, while bilateral LND of the central and lateral compartments was protective (P=0.028). In patients with macroscopic lymph-node metastases, the 10-year probability was lower in Group 2 than in Group 3 (10% vs 30%, P<0.01). In patients without macroscopic lymph-node metastases (n=427), no significant differences were observed between the three LND groups.

Conclusions

Patients with macroscopic, but not microscopic, lymph-node involvement have a major LNR risk and need an optimal LND at primary surgery.

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Hélène Lasolle, Christine Cortet, Fréderic Castinetti, Lucie Cloix, Philippe Caron, Brigitte Delemer, Rachel Desailloud, Christel Jublanc, Christine Lebrun-Frenay, Jean-Louis Sadoul, Luc Taillandier, Marie Batisse-Lignier, Fabrice Bonnet, Nathalie Bourcigaux, Damien Bresson, Olivier Chabre, Philippe Chanson, Cyril Garcia, Magalie Haissaguerre, Yves Reznik, Sophie Borot, Chiara Villa, Alexandre Vasiljevic, Stephan Gaillard, Emmanuel Jouanneau, Guillaume Assié and Gérald Raverot

Objectives

Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.

Design

Multicenter retrospective study by members of the French Society of Endocrinology.

Methods

Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.

Results

The median treatment duration was 6.5 cycles (range 2–24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0–72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0–57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.

Discussion

Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Free access

Hélène Bihan, Arnaud Murat, Marinos Fysekidis, Abdallah Al-Salameh, Claire Schwartz, Eric Baudin, Philippe Thieblot, Françoise Borson-Chazot, Pierre-Jean Guillausseau, Catherine Cardot-Bauters, Isabelle Raingeard, Elisabeth Requeda, Jean Louis Sadoul, Yves Reznik and Régis Cohen for the French Group of Endocrine Tumours (GTE)

Objective

Due to a strong genotype–phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis.

Subjects and methods

We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene.

Results

The average age at diagnosis was 35.6 years±20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4–82 years). The mean follow-up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x-Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5–78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2–24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months.

Conclusions

This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism.