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X Bertagna

One of today’s challenges in endocrinology is the treatment of Cushing’s disease: Although pituitary surgery has the potential to ‘cure’ the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be ‘default options’. This ‘personal view’ tries to shed some light on the inescapable difficulties of the current treatments of Cushing’s disease and to provide some optimistic view for the future where the pituitary adenoma should be the ‘reasonable obsession’ of a successful therapeutist.

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M Messager, C Carrière, X Bertagna, and Y de Keyzer

Objective: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus.

Design: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome.

Methods: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms.

Results: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in <50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) γ2 were expressed in 50% of the tumours of each group whereas PPARγ1 was expressed in almost every tumour.

Conclusions: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.

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ML Raffin-Sanson, Y de Keyzer, and X Bertagna

Proopiomelanocortin (POMC) is the polypeptide precursor of ACTH. First discovered in anterior pituitary corticotroph cells, it has more recently been revealed to have many other physiological aspects. The fine molecular mechanisms of ACTH biosynthesis show that ACTH is but one piece of a puzzle which contains many other peptides. Present in various tIssues, among which are pituitary, hypothalamus, central nervous system and skin, POMC undergoes extensive post-translational processing. This processing is tIssue-specific and generates, depending on the case, various sets of peptides involved in completely diverse biological functions. POMC expressed in corticotroph cells of the pituitary is necessary for adrenal function. Recent developments have shown that POMC-expressing neurons in the brain play a major role in the control of pain and energy homeostasis. Local production of POMC-derived peptides in skin may influence melanogenesis. A still unknown function in the placenta is likely.POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities.

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B Zantour, B Guilhaume, F Tissier, A Louvel, X Jeunemaitre, AP Gimenez-Roqueplo, and X Bertagna

A 32-year-old asymptomatic female was diagnosed with an isolated thyroid nodule of 2.5 cm diameter. Fine needle aspiration suggested a medullary thyroid carcinoma. Consequently, a total thyroidectomy was performed. The nodule stained positive for chromogranin A, neurone-specific enolase and synaptophysin, but not for calcitonin. Finally, pathological analysis showed a thyroid paraganglioma. Although the tumour appeared to be sporadic in a patient with no personal or familial history of paraganglioma and/or pheochromocytoma, we have identified a new mutation (392delC) of the succinate dehydrogenase-B (SDHB) gene in the genomic DNA extracted from the leukocytes of the patient. That mutation induced a shift in the reading frame of the gene creating a premature stop codon (P131fsX135) which was predicted to result in a truncated SDHB protein of 135 amino acids.This report highlights the difficulties of this unexpected diagnosis of hereditary thyroid paraganglioma. It also discusses the clinical involvements in terms of familial screening and the necessary follow-up of the patient.

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A Bourdelot, J Coste, V Hazebroucq, S Gaillard, L Cazabat, X Bertagna, and J Bertherat

OBJECTIVE: Progress in the treatment of acromegaly with drugs is making it necessary to improve the prediction of the outcome of transsphenoidal surgery. DESIGN: We evaluated clinical, hormonal and radiologic predictors based on magnetic resonance imaging (MRI) of surgical outcome in patients with acromegaly. METHODS: This retrospective analysis included 125 consecutive patients investigated for acromegaly in a single endocrine unit since the use of MRI imaging began (1988). Eighty-three of these patients (50 women) underwent transsphenoidal surgery and were investigated before and after surgery in our department. A neuroradiologist unaware of the surgical outcome analyzed the results of pituitary gland MRI investigations. RESULTS: Surgical remission rates were 44%, 43%, 61% and 59% based on mean basal GH concentration under 2.5 microg/l, GH/oral glucose tolerance test (OGTT) of <1 microg/l, GH/OGTT of <2 microg/l or IGF-I concentration normal for age and sex respectively. In univariate logistic regression analysis with IGF-I concentration used as the criterion for cure, young age (P<0.001), high IGF-I concentration before surgery (P<0.01), high basal GH concentration before surgery (P<0.02), and high nadir GH/OGTT before surgery (P=0.03) were predictors of poor outcome. The following results in standardized MRI analysis were associated with a higher probability of not being cured: adenoma greater than 15 mm in diameter (P<0.02), infrasellar extension (P=0.04), suprasellar extension (P<0.005) and invasive adenoma (0.02) according to MRI staging. MRI analysis of the intracavernous extension showed that stages above B2 (possible sinus extension with sign of invasion of the space below the carotid artery) were associated with a lower probability of postoperative normal GH plasma levels (P=0.01). In multivariate analysis, age, preoperative hormonal levels and adenoma size remained the major predictors of surgical outcome. CONCLUSIONS: This report provides the first evidence that detailed MRI analysis of adenoma size, location and potential invasion, together with preoperative clinical and hormonal parameters, can be used for the prediction of hormonal outcome after transsphenoidal surgery for acromegaly.

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I Belmihoub, S Silvera, M Sibony, B Dousset, P Legmann, X Bertagna, J Bertherat, and G Assié

New European guidelines for the management of adrenal incidentalomas were recently released. One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically, he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT scan, it was a 6 cm heterogeneous tumor. On hormonal work-up, there was no secretion. The patient was operated of an adrenalectomy, and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge, this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma.

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D Guiban, JF Massias, MA Dugue, J Coste, X Bertagna, and ML Raffin-Sanson

OBJECTIVE: Measurement of plasma ACTH is a key step for the exploration of hypothalamic-pituitary-adrenal disorders. To further improve ACTH recognition a new generation of ACTH IRMA was developed using antibodies directed towards succinylated ACTH (sACTH IRMA). DESIGN: The usefulness of this assay was compared with that of another commercially available ACTH IRMA assay using intact ACTH (ELSA-ACTH) in various pathophysiological situations: patients with low ACTH plasma levels, high ACTH plasma levels with normal or tumoural pituitaries, or ectopic ACTH syndrome, and pregnant women with high proopiomelanocortin (POMC) plasma levels. METHODS: All plasma samples were assayed simultaneously with the two different IRMAs. Comparisons were assessed by plotting the results along the theoretical line of identical values, and by the graphical method of Bland and Altman. RESULTS: In the ELSA-ACTH IRMA, CLIP (or ACTH18-39) showed true cross-reactivity, and alpha-melanocyte-stimulating hormone and purified POMC both interfered and induced falsely lower ACTH results; in the sACTH IRMA no peptide showed any cross-reactivity, and only extremely high values of CLIP (50 000 pg/ml) interfered and induced falsely lower ACTH results. In ACTH hypersecretory syndromes, of tumoural (Cushing's disease, ectopic ACTH secretion) or non-tumoural (Addison's disease, congenital adrenal hyperplasia) origins a good agreement between the two assays was observed except for very high ACTH plasma values (above 1000 pg/ml) and in some tumours where the sACTH IRMA yielded lower results; in some cases, the presence of circulating CLIP, demonstrated by HPLC studies, may contribute to this discrepancy. It is also likely that the calibration of the ELSA-ACTH kit itself generates higher ACTH values. In normal pregnant women both IRMAs gave highly correlated values, yet lower results were obtained with the sACTH IRMA. CONCLUSION: These data show that the sACTH IRMA has improved qualities of specificity and usefulness for rapid assessment of ACTH plasma levels.

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ML Raffin-Sanson, F Ferre, J Coste, C Oliver, D Cabrol, and X Bertagna

OBJECTIVE: The human placenta normally expresses the pro-opiomelanocortin (POMC) gene. The pattern and secretory kinetics of POMC and/or POMC-derived peptides by the placenta during gestation is still debated. We recently demonstrated that full length POMC was a normal product of the human placenta. The aim of our study was to establish its normal secretory kinetics and to explore its physiological relevance. DESIGN: In a prospective, longitudinal study, thirty normal pregnant women had monthly measurements of plasma POMC. In a cross-sectional study of 128 healthy pregnant women, plasma POMC and human chorionic gonadotrophin (hCG) were concomitantly measured to assess their correlation. Finally, POMC levels were assessed in venous and arterial cord blood samples, in amniotic fluid and in retroplacental blood. METHODS: Plasma POMC was measured by a specific IRMA in unextracted blood or biological fluid. RESULTS: Plasma POMC became detectable by the 8th week of pregnancy and reached its maximum at around the 20th week, remaining stable thereafter. The relationship between POMC and gestation time (weeks) best fitted with a third degree polynomia curve. A significant negative correlation (P=0.01) was observed between plasma levels of POMC and hCG after adjustment for gestation time to take into account the dependence of both hormones on this parameter. POMC was not secreted into the fetal circulation at term, but was present in very high levels in amniotic fluid. The highest levels of POMC were present in the retroplacental blood where the values were 35 times higher than in maternal blood; by comparison, corticotrophin releasing hormone and ACTH values in this compartment were twice or equal to those in the maternal blood. CONCLUSION: Placental POMC secretion increases during the first half of pregnancy and reaches a plateau from the 20th week to delivery. The inverse correlation between POMC and hCG plasma levels, and very high POMC levels at the feto-maternal interface suggest a physiological role for this precursor during pregnancy.

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C Vincent-Dejean, L Cazabat, L Groussin, K Perlemoine, G Fumey, F Tissier, X Bertagna, and J Bertherat

Objective

The cAMP/protein kinase A (PKA) pathway plays an important role in endocrine tumorigenesis. PKA is a heterotetramer with two regulatory subunits (four genes: PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B) and two catalytic subunits. Inactivating PRKAR1A mutations have been observed in Carney complex and a subset of adrenocortical tumors (ACT). This study was designed to search for other alterations of PKA in ACT, and to establish their correlation with the clinical characteristics.

Methods

In this study, 35 ACT (10 non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S), and 12 malignant s (ACC)) were studied. PKA subunits were studied by western blot and RT-qPCR. The PKA activity was measured.

Results

A subgroup of ACA-S with a 96% R2B protein decrease by comparison with normal adrenal (4.1%±4 vs 100%±19, P<0.001) was identified, ACA-S2 (6/13). By contrast, no differences were observed in ACC and ACA-NS. The level of R1A mRNA was decreased in ACA-S (P<0.001), but not the level of R2B mRNA. No mutation of the R2B gene was detected in ACA-S2. The ACA-S2 group with loss of R2B protein showed a threefold higher basal PKA activity than the ACA with normal R2B protein (3.37±0.31 vs 1.00±0.20, P<0.0001). The ACA-S2 tumors with the loss of the R2B protein presented a homogenous phenotype and were all small benign cortisol-secreting tumors.

Conclusion

This loss of PRKAR2B protein due to a post-transcriptional mechanism in ACA-S is a new mechanism of cAMP pathway dysregulation in adrenocortical tumorigenesis. It defines a new subtype of secreting adenomas with high basal PKA activity presenting a homogenous clinical phenotype.

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L Amar, L Guignat, F Tissier, B Richard, O Vignaux, Y Fulla, P Legmann, X Bertagna, and P Bonnichon

OBJECTIVE: To present first-line thoracic surgery made possible by localization studies in three patients with ectopic parathyroid adenomas. DESIGN AND METHODS: Three patients with ectopic parathyroid tissue in the mediastinum were examined by ultrasound, technetium-99m sestamibi scintigraphy, computed tomography (CT), and venous catheterization with measurement of parathyroid hormone. Without previous cervical exploration, video-assisted thoracic surgery (VATS) was used in all cases to avoid the need for thoracic open surgical procedures. RESULTS AND CONCLUSIONS: The mediastinal parathyroid glands were all detected at scintigraphy, and CT and venous catheterization were helpful in anatomic and functioning characterization. All pathologic glands were successfully resected, with only one minor complication. VATS can safely remove a deep mediastinal parathyroid adenoma and avoid more aggressive open approaches. In an experienced referral center, systematic and sophisticated imaging studies may accurately identify and localize rare ectopic parathyroid adenomas, and avoid cervical surgery.