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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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P. Corvol, X. Bertagna, and J. Bedrossian

ABSTRACT

The control of plasma aldosterone level depends on the secretion rate and on the metabolic clearance rate (MCR) of the hormone. The rate of aldosterone metabolism was measured in 6 anephric patients in comparison with normal volunteers. Unexpected high aldosterone MCR's were found in the anephric patients: 2700 ± 265 1/24 h (M ± sem), as compared to the normals (1600 ± 57). Passive 45° tilting did not significantly change aldosterone MCR's in both the normal and anephric patients. This increase in aldosterone MCR might be explained by a high hepatic plasma flow due to a high cardiac output. The haemodynamic condition of these patients could also explain the high testosterone MCR found in 3 male anephric patients, although testosterone-oestradiol binding globulin was in the high normal male range.

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Y de Keyzer, F Lenne, and X Bertagna

GH-releasing peptides are a new class of potent GH secretagogs (GHS) in vivo and in vitro. In normal man GHS also elicit low but definite ACTH and prolactin secretion. Recently it was shown that patients with pituitary corticotrope adenomas respond to GHS with a dramatic rise in ACTH secretion, and it has been suggested that GHS may provide a diagnostic tool to differentiate Cushing's disease from the ectopic ACTH syndrome. GHS actions are mediated by a G protein-coupled receptor recently characterized and cloned in man and rat. In this study we analyzed GHS receptor (GHS-R) expression in various types of pituitary adenoma and in endocrine and non-endocrine lung tumors by RT-PCR. GHS-R transcription was detected in all normal pituitaries and GH-secreting adenomas as expected. The receptor was also transcribed in some prolactin-secreting adenomas and non-functioning adenomas, and, more strikingly, in all 18 ACTH-secreting pituitary adenomas studied. Furthermore, it was frequently expressed in endocrine bronchial tumors, especially carcinoids, whereas it was not found or barely detectable in non-endocrine bronchial tumors. Again ACTH-secreting carcinoids of the lung were all positive for GHS-R expression. These results show that GHS-R transcription is a common feature of endocrine tumors independent of their type and origin.

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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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X. Bertagna, M. Donnadieu, D. Seurin, M. Binoux, and F. Girard

ABSTRACT

In order to characterize more accurately the relationship between immunoreactive β-MSH ("β-MSH") and the lipotrophins (LPH) we attempted to investigate the gel filtration and the immunological characteristics of "β-MSH" in the plasma of patients with Nelson's syndrome and Addison's disease as well as in the culture medium from a human corticotrophic adenoma using a sensitive radioimmunoassay from human β-MSH.

When added either to hormone free plasma or to a plasma from a patient with Nelson's syndrome all the human β-MSH (hβ-MSH) elutes from a Sephadex G-50 column as a single peak in a volume corresponding to its molecular weight. In contrast plasma "β-MSH" in 3 patients with Nelson's syndrome and one patient with Addison's disease almost completely elutes in a volume corresponding to a molecular weight range of 6000– 10 000; no "β-MSH" can be detected in its normal elution volume. Drastic pH change (8.2 to 2.3) does not significantly alter the elution pattern. Chromatography of a corticotrophic adenoma culture medium gave a similar pattern of "β-MSH" with a main peak in the molecular weight range of 6000–10 000. In our radioimmunoassay the culture medium and purified hβ-LPH gave parallel displacement curves for [125I]hβ-MSH. It is suggested that hβ-LPH or a closely related substance is the main material responsible for "β-MSH" immunoactivity.

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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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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.