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Resume Les traumatismes physiques et/ou psychiques pourraient participer au declenchement du diabete de type 1. Les specialistes de la reparation du prejudice corporel acceptent de reconnaitre l’existence de rares cas de diabetes post-traumatiques sur des criteres stricts de severite, de precession dans un laps de temps court et de l’absence de signes suggerant que le diabete ait pu etre anterieur. La litterature scientifique est ambigue, ne permettant ni d’affirmer, ni d’infirmer que des stress puissent faciliter l’apparition du diabete. Il existe en effet une grande heterogeneite des conclusions, non seulement dans la description d’un exces d’episodes de stress chez les gens qui vont devenir diabetiques, mais encore dans la date de survenue de celui-ci (dans les 12 mois precedant le diagnostic ou dans la periode perinatale). L’impression est que le role du stress recent n’est pas apparent dans des zones geographiques a forte prevalence de DT1 (Scandinavie), alors qu’il l’est dans d’autres moins touchees (Europe du sud). On serait tente de considerer au vu de ces donnees que si diabete post-traumatique il y a, le role propre du stress ne peut etre « qu’hypothetique, partiel et indirect » . Cette conclusion scientifique n’est cependant pas en accord avec la reponse attendue d’un expert, qui ne doit preter a aucune equivoque. L’expert diabetologue est ainsi ecartele entre un raisonnement base sur les preuves, parfaitement objectif mais probabiliste, et une decision fondee sur une intime conviction, mais forcement subjective.

Le capital folliculaire est constitue d’un stock definitif et genetiquement determine de cellules germinales formees au cours de la vie embryonnaire et fœtale pour la totalite de la vie reproductive. Ce capital folliculaire diminue progressivement des le cinquieme mois de developpement jusqu’a la menopause, par des phenomenes d’atresie et d’ovulation. Ainsi, la fonction ovarienne d’une femme depend a la fois du capital folliculaire initialement forme, mais aussi de la cinetique de l’atresie folliculaire. L’atresie folliculaire est la consequence d’actions entre des genes proapoptotiques et antiapoptotiques. Grâce aux etudes d’invalidation genetique sur modeles animaux et a celles menees chez des patientes atteintes de dysgenesie gonadique et d’insuffisance ovarienne prematuree, il a ete montre que la constitution de la reserve ovarienne folliculaire etait genetiquement determinee, et ce des la formation de la gonade. Bien qu’aucun gene-cle de la differenciation ovarienne, homologue a sex determining region Y (SRY) pour le testicule, n’ait ete decrit chez la femme, il existe cependant une cascade genetique comportant des genes antitesticulaires, ainsi que des genes pro-ovariens conduisant a la differenciation de la gonade bipotentielle en ovaire comme les genes WNT4, R spondine1 (RSPO) et DAX1. L’insuffisance ovarienne prematuree peut etre la consequence : soit d’un defaut initial de formation des follicules primordiaux par anomalie d’un des genes de la cascade genetique du determinisme gonadique, soit d’une atresie folliculaire acceleree, comme par exemple dans les anomalies de nombre ou de structure du chromosome X, soit d’un blocage de la maturation folliculaire, comme par exemple en cas de mutation du gene de recepteur a la follicle stimulating hormone (FSH). L’amelioration des connaissances concernant le controle genetique du capital folliculaire offre des pistes de recherche pour traiter les patientes atteintes ou a risque d’insuffisance ovarienne precoce du fait de traitements gonadotoxiques : utilisation de facteurs antiapoptotiques, therapie genique.

Multiple endocrine neoplasia type 2 (MEN2) is an hereditary disease with a prevalence of 1/5000. Three phenotypic variants have been identified: MEN2A associates medullary thyroid carcinoma (MTC) to pheochromocytoma in about 20–50% of cases and to primary hyperparathyroidism in 5-20% of cases; MEN2B associates MTC to pheochromocytoma in 50% of cases, to marphanoid habitus and to mucosal and digestive ganglioneuromatosis whereas in familial isolated medullary thyroid carcinoma (FMTC), the other components of the disease are absent. In MEN2, natural history of the disease and a common embryologic origin (neural crest) may explain the phenotypes observed in the organ involved, beginning from the stage of hyperplasia to adenoma and cancer. MEN2 is an inherited autosomal dominant disease with a complete penetrance, related to germline mutation in the proto-oncogene RET . MTC represent the most frequent circumstance of diagnosis. Pheochromocytoma and HPT may reveal the disease unfrequently and are systematically associated to undiagnosed MTC which is present yet. Analysis of the RET gene allows to confirm the diagnosis of MEN2 by identifying the causal germline mutation. Management of MEN2 patients include thyroidectomy associated to cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for HPT. Familial genetic screening detects at risk subjects who will develop the disease and allows to manage them at the earliest stage of the disease by perform early or prophylactic thyroidectomy such giving them the best chance of cure. Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC, thus pointing the necessity of a complete thyroid surgery for index cases with MTC and the earliest thyroidectomy for screened at risk subjects.

Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT). MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Diagnosis is usually made by a solitary nodule often associated to nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form and in about 30% of case as a familial form as a part of multiple endocrine neoplasia syndrome, an hereditary dominant inherited disease related to germline mutation of the proto-oncogene RET. Both biological (CT) and genetic (RET) markers allows the optimal diagnosis and treatment of MTC; the former allows screening and early diagnosis of MTC by routinely CT measurements in nodular thyroid diseases that make the adequate and complete surgery required to be performed. The former leads to diagnose familial MTC and to identify at risk subjects in whom early or prophylactic surgery may be performed. Treatment of MTC is based on the complete surgical resection: total thyroidectomy associated to central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be associated to other systemic treatments: as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appears as possible valuable therapeutic options for the future. Prognosis of MTC is mainly related to both the stage of the disease and the extend of the initial surgery. Ten-year survival is about 80% when the patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.

OBJECTIVE: To analyse trends in diagnostic practices of thyroid diseases and to relate them to the increase in thyroid cancer incidence in France over time. DESIGN: From 1980 to 2000, a French retrospective multicentric (three endocrinology and three nuclear medicine centres) study of thyroid diseases was conducted on 20 consecutive unselected patients' records, sampled every 5 years in each centre. METHODS: Characteristics of the population and diagnosis procedures (thyroid ultrasonography (US), radionuclide scan, cytology and hormonal measurements) were described over time. Changing trends in operated patients and in cancer prevalence were analysed as well as the impact of practices on cancer incidence. RESULTS: The study included 471 patients (82% female, mean age 46.7, range 9-84 years), referred for nodular thyroid diseases (66.7%) or thyroid dysfunctions (33.3%). A significant increase in US (3 to 84.8%) and cytological practices (4.5 to 23%), and a decrease (89.4 to 49.6%) in radionuclide scan procedures were observed over time. Although the proportion of patients undergoing surgery remained constant (24.8%), the prevalence of cancer increased among operated patients from 12.5 to 37% (P=0.006). In a Cox's proportional hazard model stratified on the clinical characteristics of patients, only the cytological practice, regardless of its results, was significantly associated with the occurrence of cancer: relative risk (RR)=4.4 (95% confidence interval (CI): 1.1-16; P=0.04). CONCLUSIONS: From 1980 to 2000, a major evolution in clinical practices has led to the increase in thyroid cancer reported in France. Such changes in medical, as well as in surgical and pathological, practices must be taken into account in incidence measurement.

Resume La neoplasie endocrinienne multiple de type 2 (NEM2) est une affection multiglandulaire hereditaire, autosomique dominante, associant un cancer medullaire de la thyroide, un pheochromocytome et une hyperparathyroidie, phenotype lie a une anomalie moleculaire du proto-oncogene RET. La NEM2 se caracterise par l'existence d'un marqueur biologique, la calcitonine plasmatique (CT) et son test de stimulation par la pentagastrine, et d’un marqueur genetique, le gene RET, accessibles en routine, qui sont a l'heure actuelle incontournables et indispensables au diagnostic et a la prise en charge de cette affection. La CT permet de poser le diagnostic du CMT, notamment par son dosage systematique en pathologie nodulaire thyroidienne, et de fait permet d'augmenter le nombre de CMT diagnostiques, le plus souvent a un stade precoce, curables chirurgicalement, tandis que l’analyse moleculaire systematique de RET devant tout CMT permet le depistage les formes familiales s'integrant dans une NEM2. Dans le cadre de la prise en charge familiale d’une NEM2, l'analyse moleculaire de RET identifie les sujets atteints d'une famille, la CT permettant ensuite de faire le diagnostic biologique de la maladie, lequel debouchera sur une prise en charge specifique.

Background. Struma ovarii is a rare ovarian germ-cell tumor containing thyroid tissue. We report an unusual case of incidental diagnosis of struma ovarii after thyroidectomy for thyroid cancer. Case. A 24-year-old woman presented with a papillary thyroid carcinoma (pT3N1). After 131 I administration for thyroid remnant ablation, whole-body scan showed a thyroid bed uptake and a right pelvic uptake corresponding to an ovarian cyst on ultrasonography. Preablation thyroglobulin was more elevated than usually found after total thyroidectomy. 18 F-FDG PET was normal. Histopathological analysis revealed a benign struma ovarii. At 6 months, after oophorectomy, serum-stimulated Tg returned to undetectable value and diagnostic WBS was negative. Conclusion. Only few cases of incidental scintigraphic diagnosis of struma ovarii have been described. To our knowledge, it is the first case revealed after remnant ablation for thyroid carcinoma. The distinction with ovarian metastasis is discussed.

We investigated the age-related changes in the tissular protein, cortico-releasing factor (CRF), somatostatin (SOM), neuropeptide Y(NPY), methionine enkephalin (M-ENK) and beta-endorphin (beta-END) levels in frontal cortex, hippocampus, striatum and hypothalamus of young (4-month-old), mature (18-month-old) and senescent (26-month-old) Wistar male rats, bred in a specific pathogen free environment. Between the age of 4 and 18 months, the tissular protein levels increased in all 4 structures studied. The CRF and SOM levels increased in the hippocampus, while the NPY levels decreased. During this time, the NPY content increased in the striatum, whereas the SOM and M-Enk striatal levels decreased. Concomitantly, the NPY and beta-End levels decreased in the hypothalamus. Interestingly, no significant variations were found to occur in the frontal cortex whatever the neuropeptide studied. Between the age of 18 and 26 months, no significant changes in the tissular protein levels were detected, except in the hippocampus. The changes in the neuropeptide concentrations observed during this period depended on the neuropeptide and the brain structure studied. The CRF and beta-End levels decreased in the frontal cortex and the hypothalamus, respectively. The NPY peptidergic systems seem to be preferentially affected by aging processes since 3 out of the 4 structures studied--the frontal cortex, the striatum and the hypothalamus--showed a decrease in their tissular NPY content. During the same period, none of the 5 neuropeptides studied were affected in the hippocampus.

Multiple endocrine neoplasia type 2 (MEN2) is an hereditary disease with a prevalence of 1/5000. Three phenotypic variants have been identified: MEN2A associates medullary thyroid carcinoma (MTC) to pheochromocytoma in about 20-50% of cases and to primary hyperparathyroidism in 5-20% of cases; MEN2B associates MTC to pheochromocytoma in 50% of cases, to marphanoid habitus and to mucosal and digestive ganglioneuromatosis whereas in familial isolated medullary thyroid carcinoma (FMTC), the other components of the disease are absent. In MEN2, natural history of the disease and a common embryologic origin (neural crest) may explain the phenotypes observed in the organ involved, beginning from the stage of hyperplasia to adenoma and cancer. MEN2 is an inherited autosomal dominant disease with a complete penetrance, related to germline mutation in the proto-oncogene RET. MTC represent the most frequent circumstance of diagnosis. Pheochromocytoma and HPT may reveal the disease unfrequently and are systematically associated to undiagnosed MTC which is present yet. Analysis of the RET gene allows to confirm the diagnosis of MEN2 by identifying the causal germline mutation. Management of MEN2 patients include thyroidectomy associated to cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for HPT. Familial genetic screening detects at risk subjects who will develop the disease and allows to manage them at the earliest stage of the disease by perform early or prophylactic thyroidectomy such giving them the best chance of cure. Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC, thus pointing the necessity of a complete thyroid surgery for index cases with MTC and the earliest thyroidectomy for screened at risk subjects.

Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT). MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Diagnosis is usually made by a solitary nodule often associated to nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form and in about 30% of case as a familial form as a part of multiple endocrine neoplasia syndrome, an hereditary dominant inherited disease related to germline mutation of the proto-oncogene RET. Both biological (CT) and genetic (RET) markers allows the optimal diagnosis and treatment of MTC; the former allows screening and early diagnosis of MTC by routinely CT measurements in nodular thyroid diseases that make the adequate and complete surgery required to be performed. The former leads to diagnose familial MTC and to identify at risk subjects in whom early or prophylactic surgery may be performed. Treatment of MTC is based on the complete surgical resection: total thyroidectomy associated to central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be associated to other systemic treatments: as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appears as possible valuable therapeutic options for the future. Prognosis of MTC is mainly related to both the stage of the disease and the extend of the initial surgery. Ten-year survival is about 80% when the patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.

All kind of stress produce an endocrine response. These hormonal responses can serve as stress indicators. The main peripheral endocrine responses to stress are the activation of adrenal corticoids, the stimulation of Growth Hormone (GH) and prolactin secretion, and the inhibition of insulin and gonadal secretion. Except for the inhibition of insulin release, all these hormonal variations depend on the adenohypophysis activity: stimulation of Adrenocorticotrophin hormone (ACTH), GH and prolactin, and inhibition of gonadotrophins (LH-FSH) secretions. Several lines of evidence demonstrate that specific hypothalamic Neuro-hormones stimulate or inhibit the hypophysial activity in response to stress. However, due to methodological difficulties, only measurements of peripheral hormones can be used as stress indicators.

FROM A CLINICAL POINT OF VIEW: Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant, inherited multiglandular disease with familial and individual age-related penetration and variable expression. A medullary thyroid carcinoma (MTC) is always concomitant to MEN2 and associated in varying proportion with pheochromocytoma (50%) and hyperparathyroidism (5 to 20%). PROGNOSTIC DATA: The prognosis of MEN2 is related to the carcinological evolution of MTC, which depends mainly on the stage of discovery and the quality of the first surgical treatment, emphasizing the need for early diagnosis. THE IMPORTANCE OF THE ERT GENE: The identification of mutations in proto-oncogene RET, responsible for the various forms of the disease allows subjects at risk in a family circle to be identified and early screening of various endocrine damage, notably MTC, should be performed. Biological explorations in all persons carrying this mutation would permit diagnosis and surgical treatment of the endocrine lesions, before their clinical manifestation.

Objectif L’objectif de cette etude etait d’evaluer la pertinence du test couple dexamethasone desmopressine (TCDD) comme facteur predictif de recidive de maladie de Cushing apres chirurgie trans-sphenoidale. Materiel et methodes Nous avons retrospectivement etudie 67 patients dans deux centres tertiaires (Marseille et Grenoble), en remission initiale apres chirurgie transsphenoidale et suivis au moins 18 mois. Nous avons evalue a 3 mois puis annuellement le cortisol libre urinaire sur 24 h, les taux d’ACTH et de cortisol plasmatiques, la reponse aux tests de freinage minute et a la desmopressine et le TCDD. Apres TCDD, un ratio d’ACTH (ACTHr) et de cortisol (cortisolr) etaient determines par la formule (pic – valeur basale)/valeur basale. Resultats Onze patients avaient recidive apres un suivi median de 52 mois (18–180). L’association ACTHr et cortisole superieur ou egal a 0,5 etait presente chez tous les patients ayant recidive et chez 14/56 patients en remission (sensibilite = 100 %, specificite = 75 %). La positivite du TCDD precedait de 6-76 mois les marqueurs classiques d’hypercorticisme chez 10/11 patients ayant recidive. Six patients avaient recidive malgre une cortisolemie a 8 h en postoperatoire immediat inferieur a 50 nmol/L : tous avaient un TCDD positif dans les 3 ans suivant la chirurgie. La reponse au TCDD etait reproductible au cours des evaluations chez 91 % des patients. Conclusion Le TCDD est un facteur predictif precoce et fiable de recidive de maladie de Cushing et a un interet majeur dans les 3 ans postoperatoire pour optimiser la surveillance a long terme.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder, predisposing to the development of central nervous system (CNS) and retinal hemangioblastomas, endolymphatic sac tumors, renal cell carcinoma and/or renal cysts, pheochromocytomas, pancreatic cysts and/or tumors. Incidence of the disease is 1/36,000. CNS hemangioblastomas and renal cell carcinoma are the main causes of death. The VHL gene, located on 3p25-26, is a tumor-suppressor gene which plays a major role in regulation of VEGF expression. Germline mutations of the VHL gene are identified in about 70-99% of the patients. Mutations associated with VHL type 2 (with pheochromocytoma) are mainly missense mutations with hot-spot at codon 167. Somatic mutations of the VHL gene are found in both sporadic central nervous system hemangioblastomas and sporadic renal cell carcinoma. For endocrinologists search for VHL disease (as for MEN) should be imperative in presence of a patient with pheochromocytoma and neuroendocrine pancreatic tumor.

PREMESSE: L’espressione del vascular endothelial growth factor (VEGF) e tipica dei carcinomi tiroidei differenziati ed e associata ad un comportamento aggressivo e ad una evoluzione sfavorevole. Il motesanib difosfato (AMG 706) e un nuovo inibitore orale dei recettori del VEGF, del recettore del platelet-derived growth-factor, E del KIT. METODI: E stato condotto un studio multicentrico di fase 2 in un gruppo di 93 pazienti con carcinoma tiroideo differenziato in progressione, con recidive locali o metastasi resistenti al radioiodio. I pazienti sono stati trattati con 125 mg/die di motesanib difosfato in unica somministrazione orale. L’obiettivo primario era la valutazione oggettiva della risposta mediante imaging. Obiettivi ulteriori erano la durata della risposta, la sopravvivenza in assenza di progressione di malattia, la sicurezza del trattamento e le variazioni della concentrazione sierica di tireoglobulina. RISULTATI: Dei 93 pazienti, 57 (61%) avevano un carcinoma papillare della tiroide. La frequenza di risposta positiva era del 14%. La malattia si stabilizzava nel 67% dei pazienti, e la stabilita veniva mantenuta per 24 o piu settimane nel 35% dei casi. L’8% dei pazienti presentava una progressione di malattia. La stima della durata mediana della risposta mediante Kaplan-Meier era di 32 settimane [il limite inferiore per un confidence interval (CI) del 95% era di 24 settimane; il limite superiore non poteva essere valutato a causa del numero insufficiente degli eventi]. La stima del periodo mediano senza progressione di malattia era di 40 settimane (95% CI, 32–50 settimane). Dei 75 pazienti in cui era stato effettuato il dosaggio della tireoglobulina, 1’81% mostrava una riduzione dei livelli sierici della stessa durante il trattamento, rispetto ai valori iniziali. I piu comuni effetti collaterali presentati dai pazienti erano diarrea (59%), ipertensione (56%), stanchezza (46%), e perdita di peso (40%). CONCLUSIONI: Il motesanib difosfato puo indurre una risposta parziale in pazienti con carcinoma differenziato della tiroide progressivo, in fase avanzata o con metastasi.

Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management.To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis.Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database.Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis.Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage.Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

In the multiple endocrine neoplasia (MEN) type 2A and in the familial medullary thyroid carcinoma (FMTC), the recent development of genetic testing has provided new methods of identifying disease gene carriers. The use of sensitive immunoradiometric calcitonin (CT) assays led us to evaluate reference ranges of plasma CT responses after pentagastrin in healthy subjects in order to discuss the place of pentagastrin testing in the management of hereditary MTC. Basal and pentagastrin-stimulated CT concentrations were measured in 71 healthy volunteers--aged 20-67 years--and 76 genetically unaffected members of families with hereditary MTC--aged 4-61 years. In healthy subjects, CT peak values were below 30 ng/l in 68 cases and below 50 ng/l in 3 cases. In the genetically unaffected patients, CT peak values were below 15 ng/l in young patients and below 30 ng/l in patients older than 19 year excepted 5 men with stimulated CT levels ranging from 36.5 to 52 ng/l. In 2 of these 5, thyroidectomy revealed C-cell hyperplasia. Borderline test results are not sufficient to establish diagnosis of MTC and in these familial syndromes, management has to be based on the results of genetic testing. However, the determination of the upper normal limit for stimulated CT concentrations in young patients (15 ng/l) may help to identify the optimal moment for surgery.

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. The emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the protooncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

Sporadic medullary cancer of the thyroid is often diagnosed late beyond the surgically curable stage. The aim of this work was to assess the capacity of routine calcitonin assay as an early diagnosis test for medullary cancer in patients with a thyroid lesion.Calcitonin was assayed (normal10 pg/ml) as a routine test from 1993-1995 in a series of 2975 patients seen for thyroid exploration. When baseline level was above 10 pg/ml, a pentagastrine test was performed (normal30 pg/ml). All patients with a calcitonin peakor = 100 pg/ml after pentagastrin underwent surgery for suspected medullary cancer. Surgery for suspected malignancy, hyperthyroidism or locoregional functional disorders was also performed in 1494 of the included patients, independent of calcitonin level. Patients with personal or familial history of multiple endocrine disease were excluded. Fine needle aspiration was done in all patients with an unique or predominant thyroid nodule.Medullary cancer of the thyroid was demonstrated in 14 patients (0.47%). Among 8 patients with clinically patent tumor, the diagnosis was established in 3 on the basis of cytology results and elevated calcitonin level; in the 5 other cases, initial cytology was incorrect (anaplastic, papillary, thyroiditis) but correct diagnosis was established on the basis of high calcitonin levels. Diagnosis was suspected preoperatively in the 6 others solely because of high calcitonin; these patients had microlesions measuring 1.2-9 mm. None of the 7 patients with a medullary cancer measuring10 mm had node extension at surgery and all 7 attained biological cure. Among the 7 other patients with a lesion10 mm, calcitonin level returned to normal level in 3 and remained high in 2; the 2 others died with distant metastasis.Routine assay of calcitonin in all patients with a thyroid nodule can improve preoperative diagnosis of medullary cancer of the thyroid and allows early diagnosis of latent infraclinical tumors.

Serum calcitonin (CT) assays are the most useful tumoral marker for the diagnosis and follow up of medullary thyroid carcinoma (MTC). Since 1988 the sensitivity and specificity of CT assays have been considerably improved. Normal basal and pentagastrin (Pg) stimulated CT ranges remain to be established and it appears necessary to determine the pathological circumstances which may be responsible for hypercalcitoninemia in addition to MCT. By reviewing literature and data from the "Groupe d'Etude des Tumeurs à Calcitonine": a/we compared basal and Pg stimulated CT values obtained with two commercially available immunometric CT assays and we observed that CT values measured by the CT-EASIA MEDGE-NIX kit were three fold the values obtained by suing the hGH ELSA CIS BIOINDUSTRIE Kit; b/we determined that hypercalcitoninemia may be observed in isolated C Cell Hyperplasia (HCC) surrounding either lymphocytic thyroiditis or follicular thyroid carcinoma loci, in chronic renal failure on maintenance hemodialysis, and in various neuroendocrine tumors. Surprisingly, the hypercalcitoninemia related to HCC has been found in genetically unaffected members (without any identified gene RET mutation) of both a Multiple Endocrine Neoplasia type 2A and isolated familial hereditary MTC.

We studied lumbar bone mineral densities (BMD) using a dual photon absorptiometer in 18 women with anorexia nervosa (AN). Results were compared with data from a control group of 36 healthy women. We found significantly reduced mean bone densities as compared with control group (0.814 +/- 0.072 g/cm2 hydroxy-apatite equivalent vs 1.011 +/- 0.023; p0.01). Only one patient developed vertebral compression fracture. BMD was negatively correlated with duration of amenorrhoea (r = -0.68; p0.01) but not significantly with duration of AN. We found no correlation between BMD and estradiol blood levels, age of onset, body mass index and daily calorie intake. The correlation between BMD and duration of amenorrhoea may indicate that long standing estrogen deficiency is a major factor in the osteoporosis (OP) observed in AN.

A case of thyrocalcitonin-secreting endocrine tumour of the pancreas is reported. Endocrine pancreatic tumours are neoplasias evolving over a long period; most of them are multisecreting, usually with a predominant secretion responsible for clinical symptoms. In this particular case the retrospective diagnosis of a thyrocalcitonin-secreting tumour of the pancreas was made by immunocytochemical study of the pancreatectomy specimen. One year after pancreatectomy, the persistence of clinical signs and a plasma thyrocalcitonin level higher than 25,000 pg/ml led to the discovery of a liver metastasis. An immunocytochemical study of the segmental hepatectomy specimen showed a single population of thyrocalcitonin-secreting cells identical with those found in the pancreatic tumour. In this context, radioimmunological assays of peptides and immunocytochemistry seem to be the best diagnostic methods.

Sulfonylureas act as hypoglycemic agents by stimulating insulin secretion and improving insulin sensibility by a post-receptor mechanism. Their long term results mainly depend on extra-pancreatic mechanisms. Moreover they indirectly decrease triglyceridemia. Glipizide and gliclazide enhance fibrinolysis. Gliclazide also inhibits platelet aggregation and adhesion. The best indication of sulfonylureas is non insulin dependent diabetes with normal weight.

Thyrotoxicosis may be held responsible for osteoporosis. The question is whether a very slight subclinical hyperthyroidism, as is desirable in the post-operative treatment of differentiated thyroid carcinoma, can in the long run be detrimental to bone tissue. In a series of 37 patients, aged 50.9 +/- 11.1 years, presenting with the features of subclinical hyperthyroidism of 8.0 +/- 4.8 years duration, the authors have been unable to find any change in paraclinical parameters of bone and calcium-phosphate metabolism. Thirty-six of these 37 patients showed no abnormal decrease of vertebral bone density measured by dual photon absorptiometry.

Resume Ni la biologie (honnis la calcitonine pour le diagnostic des cancers medullaires), ni l’imagerie ne permettent dans la majorite des cas de distinguer les nodules thyroidiens benins (90 a 95 % des nodules) des cancers thyroidiens. La cytoponction est a l’heure actuelle la methode de depistage la plus performante parce que rapide, accessible au plus grand nombre, peu invasive, peu couteuse, reproductible et qui possede la meilleure sensibilite et specificite. Elle est recommandee par le rapport de l’ANDEM en 1995 et par le consensus international : « la cytoponction a l’aiguille fine est recommandee pour tous les nodules palpables isoles ou dominants, independamment de leurs taille » (in Thyroid 2003, 13 : 80-86 et Endocrine Reviews 2003, 24 : 102-132). Il n’est pas necessaire de realiser systematiquement les cytoponctions a l’aide de l’echographie, mais cette aide permet de reduire le nombre des ponctions non significatives. La cytoponction doit etre effectuee avec une aiguille de 25-27G, avec ou sans aspiration a la seringue et 2 a 6 ponctions par nodule ; l’etalement sur lame est seche a l’air ou fixe par ether-alcool (ou spray), puis achemine au laboratoire dans les 2 jours ou conserve a moins 20° jusqu’a la lecture.

In order to elucidate the physiological role of the 41 amino-acid residue corticotropin-releasing factor (41-CRF) on the secretion of ACTH, B-Endorphin and alpha-MSH, plasma levels of these peptides were measured by radioimmunoassay in intact and adrenalectomized rats, two hours after the injection of either 41-CRF antiserum (CRF-AS) or normal rabbit serum for controls. The administration of CRF-AS strikingly lowered the plasma ACTH levels in both intact and adrenalectomized rats. A statistically significant reduction of plasma levels of B-Endorphin was also observed in the same rats. However, the effect of CRF-AS on B-Endorphin release was less pronounced than the effect on ACTH release. No changes in plasma alpha-MSH levels were observed after passive immunization with CRF-AS. We conclude that, in the rat, 41-CRF plays a physiological role in the regulation of ACTH and B-Endorphin secretion, but is not involved in the regulation of alpha-MSH release from the pituitary gland.

A 21-year-old female was first seen in 1974 for periodic hypersomnia. It had started at 13 years of age and was characterized by 4-6 days of drowsiness with megaphagia and some light psychic disorders. The attacks usually occurred at approximately 5-6 days after menstruation. Later, after an interval of oral contraception, they appeared during ovulation and increased in duration. During the periods of contraception, these attacks disappeared completely. At present (1980), the episodes are characterized by periodic hypersomnia, seen in a nocturnal polygraphic study; megaphagia has decreased, but the patient appears uncommunicative, sub-active and inexpressive when awaking in the course of the periods of somnolence. Several EEG recordings were made between 1974 and 1980, which showed few or no abnormalities during the attacks and which were normal with in the inter-ictal periods. Hormonal investigations failed to show any striking abnormality or correlation with continuous polygraphic studies. Similarity of this syndrome with the 'periodic hypersomnia and megaphagia in adolescent males' syndrome (Kleine-Levin) is discussed.

Rat hypophysial portal blood, collected from the pituitary stalk, was extracted and enkephalins were assayed by different RIA. Met-Enk-IR and Leu-Enk-IR levels were1635 ± 470pg/ml and125 ± 50pg/ml, respectively. Using HPLC characterization, the presence in portal blood of Met-Enk, Leu-Enk, proenkephalins fragments and dynorphinJ-17 has been demonstrated. An unidentified Met-Enk-IR peptide has also been found.

Plasma DHA, DHAS and cortisol levels were measured by R.I.A. before and after intravenous and intramuscular injection of beta 1-24 ACTH. In 7 normal adult women, plasma cortisol and DHA levels rose sharply in response to beta 1-24 ACTH (0,25 mg) i. v injection; in opposition, plasma DHAS levels did not change significantly 30 and 120 minutes after the injection. In 9 normal adults women, the i. m injection of Zn beta 1-24 ACTH (1 mg) caused a significant increase in both plasma cortisol, DHA and DHAS levels 8 and 24 hours after the injection.

A peptide with 41-residue having CRF activity both in vivo and in vitro has recently been isolated from ovine hypothalami (41-CRF). Passive immunization of Sprague-Dawley Rats with an antiserum against this peptide is followed by a significant decrease in plasma ACTH and cortisosterone levels under basal conditions as well as after ether-stress and adrenalectomy. These data demonstrate that 41-CRF plays a major role in the physiological regulation of ACTH secretion.

Dopamine exerts an inhibitory or stimulant action on some of the hormones produced by the anterior pituitary gland. The dopamine content of the hypothalamus is considerably reduced in patients with Parkinson's disease. We have tested the anterior pituitary endocrine function in such patients to evaluate the repercussions on this function of the dopaminergic deficiency: the secretion of pituitary stimulins was found to be unaltered both at baseline level and after pharmacological stimulation.