Showing papers in "Annales D Endocrinologie in 2000"

Growth hormone-releasing peptides and the cardiovascular system.

Abstract: Growth Hormone (GH)-releasing peptides (GHRPs) and their non peptidyl analogues are synthetic molecules which exhibit strong, dosedependent and reproducible GH-releasing activity but also significant PRL- and ACTH/cortisol-releasing effects. An influence of these compounds on food intake and sleep pattern has been also shown. The neuroendocrine activities of GHRPs are mediated by specific receptors subtypes that have been identified in the pituitary gland, hypothalamus and various extra-hypothalamic brain regions with (125)I-Tyr-Ala-hexarelin, an octapeptide of the GHRP family. In addition, GHRP receptors were also present in different peripheral tissues such as heart, adrenal, ovary, testis, lung and skeletal muscle, with a density significantly higher than that found in the hypothalamo-pituitary -system. A remarkable specific (125)I-Tyr-Ala-hexarelin binding was observed in the human cardiovascular system where the highest binding levels were detected in ventricles, followed by atria, aorta, coronaries, carotid, endocardium and vena cava. The binding of the radioligand to cardiac membranes was inhibited by unlabeled Tyr Ala hexare lin and hexarelin as well as by GHRP-6, GHRP-1 and GHRP-2 but not by MK-677, a non peptidyl GHRP analog. In other experiments on H9c2 myocytes, a fetal cardiomyocytes-derived cell line, specific GHRP binding was found and hexarelin showed an anti-apoptotic activity. On the other hand, in vivo studies in animals and in humans showed that GHRPs possess direct cardiotropic actions. In fact, hexarelin protects from ischemia-induced myocardial damage in aged and GH deficient rats while hexarelin shows a positive inotropic effect in normal subjects as well as in patients with GH deficiency. In conclusion, GHRPs possess extra--neuroendocrine biological activity and, particularly, show direct GH-independent cardiotropic effects.

Vascular endothelial growth factors and angiogenesis.

Abstract: VEGF was discovered in 1989. Research -conducted over the past 10 years has -demonstrated that VEGF is a major regulator of angiogenesis and vasculogenesis. This paper reviews the molecular data on the multiple forms of VEGF, their signalling and accessory receptors. Five genes encoding VEGF-like proteins have been identified; the different isoforms of each VEGF molecule are generated by alternative splicing mechanisms. The different VEGF's recognize signalling tyrosine kinase receptors (Flt-1, Flk-1 and Flt-4) and accessory receptors. VEGF expression is stimulated by hypoxia-dependent and -independent mechanisms. Hypoxic responses are mediated by specific transcription factors that are expressed in a tissue dependent fashion and that are developmentally regulated. VEGF is thought to play a role in tumor angiogenesis and may contribute to cardioprotection in ischemic heart -diseases. Its role in pulmonary hypertension induced by chronic hypoxia is discussed. This review also stresses the difficulty of applying results from in vitro -studies to in vivo situations.

Aldosterone antagonists in hypertension and heart failure.

Abstract: Spironolactone, a competitive aldosterone receptor antagonist (ARA), has traditionally been the treatment of first choice in idiopathic hyperaldosteronism (IHA) and for preoperative management of aldosterone producing adenoma (APA). Spironolactone is partially absorbed, is extensively metabolized mainly by the liver and its therapeutic properties are attributable to active metabolite canrenone. At therapeutic doses of 25 to 400 mg per day, spironolactone effectively controls blood pressure and hypokalemia in the majority of cases. Endocrine side effect are often associated and mainly consist of gynecomastia, decreased libido and impotence in man and menstrual irregularities in women. Canrenone and the K+ salt of canrenoate are also in clinical use: they avoid the formation of intermediate products with anti-androgenic and progestational actions, resulting in a decreased incidence of side effects. Furthermore, a relatively new selective ARA compound (eplerenone) with reduced affinity for androgen and progesterone receptors, is currently undergoing clinical trials. In essential hypertension aldosterone can contribute to hypertension and increases the incidence of myocardial hypertrophy and cardiovascular events. On the other hand, inhibition of Renin-Angiotensin-Aldosterone System (RAAS) is associated with a decrease in blood pressure, with a regression of left ventricular hypertrophy and a reduction of target organ damage. Thus, ARA have been proposed as complementary treatment associated to ACE inhibitors and angiotensin receptor antagonists. Aldosterone is also known to play an important role in pathophysiolgy of congestive heart failure (CHF). In vitro and in vivo evidences suggest that aldosterone promotes myocardial fibrosis. This effect reflects direct, extra-epithelial actions of aldosterone via cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non potassium-sparing diuretics further stimulate the RAAS and cause hypokalemia. Thus, use of ARAs in CHF was first proposed to correct potassium and magnesium depletion. At present ARAs are indicated in the management of primary hyperaldosteronism, in oedematous conditions in patients with CHF, in cirrhosis of the liver accompanied by oedema and ascites, in essential hypertension and in hypokalemic states. Its indication as adjunctive therapy of heart failure is currently under investigation. In fact, it is well known that even high doses of ACE inhibitors may not completely suppress the RAAS; aldosterone 'escape' may occur through non angiotensin II dependent mechanisms. Addition of spironolactone to an ACE inhibitor causes marked diuresis and symptomatic improvement. During the last few years, the RALES study (Randomized Aldactone Evaluation Study) was organized to explore the efficacy of combination therapy with spironolactone and ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistically and clinically significant that it would be unethical to continue the trial. It is reported a 30 percent decrease in mortality and hospitalisation for cardiac causes in spironolactone-treated group vs placebo group.

Identification and role of aldosterone receptors in the cardiovascular system.

Abstract: The cardiovascular system is now recognized as an important mineralocorticoid target. All -components required for specific and selective aldosterone effects are present in the cardiovascular system. Mineralocorticoid receptors (MR) are expressed in the heart and large blood vessels together with the 11 B-hydroxysteroid dehydrogenase type II, which ensures the enzymatic protection of MR against glucocorticoids. The recent description of local vascular and cardiac aldosterone biosynthesis strongly supports an autocrine/paracrine hormonal action. Establishment of transgenic mice models of targeted overexpression of the mineralocorticoid receptor should facilitate new insights into the molecular and cellular mechanisms of aldo-sterone actions in the cardiovascular system.

The growth hormone and insulin-like growth factor 1 axis in heart failure.

Abstract: Les donnees experimentales indiquent que l'hormone de croissance et l'IGF-1 ont des effets benefiques sur la fonction cardiaque dans des modeles d'insuffisance cardiaque. Des donnees preliminaires suggerent qu'il existe une dysfonction de l'axe hormone de croissance/IGF-1 chez l'insuffisant cardiaque avec une resistance relative a l'hormone de croissance et des taux diminues d'lGF-1 circulant. Les effets benefiques potentiels de l'hormone de croissance et de l'IGF-1 incluent la vasodilatation peripherique, la stimulation de l'hypertrophie cardiaque, l'augmentation de la sensibilite au calcium des myofilaments cardiaques et la prevention de l'apoptose. Recemment, la cachexie cardiaque a ete demontree etre un facteur predictif negatif important dans l'insuffisance cardiaque. Les patients predisposes a la cachexie cardiaque ont des taux d'angiotensine II eleves. Des etudes effectuees chez le rat demontrent une interaction importante entre le systeme renine-angiotensine et l'IGF-1. En effet, l'infusion d'angiotensine induit une perte de poids chez l'animal qui est en partie due a un effet catabolique. Cet effet catabolique depend d'une augmentation de la degradation proteinique. Contrairement a son effet sur la musculature squelettique, l'angiotensine II augmente l'IGF-1 et le recepteur de l'IGF-1 au niveau cardiaque. Bien que les donnees cliniques soient tres limitees, quelques etudes suggerent un benefice de l'administration de l'hormone de croissance chez les insuffisants cardiaques. Des etudes supplementaires sont necessaires pour tester l'effet benefique potentiel de l'hormone de croissance et/ou de l'IGF-1 chez les insuffisants cardiaques.

Obésité : épidémiologie et santé publique

Abstract: L'obesite est devenue la pathologie nutritionnelle la plus frequente aussi bien dans les pays industrialises que dans le reste du monde. En France, on estime que 8 a 10 % de la population adulte presente une obesite. Sa prevalence augmente en particulier chez les jeunes et dans les populations en situation difficile. L'Organisation Mondiale de la Sante considere que l'epidemie actuelle justifie des actions de prevention et de prise en charge. Des « recommandations pour le diagnostic, la prevention et le traitement des obesites » ont ete publiees en France.

[Anti-TPO antibodies and screening of thyroid dysfunction in type 1 diabetic patients].

Abstract: The diagnosis of thyroid dysfunction is often late in type 1 diabetic population. So, the aims of this study were 1) to evaluate the prevalences of thyroperoxydase (TPO) and thyroglobulin (Tg) autoantibodies detected by highly sensitive radioimmunological method in a cohort of 258 adult type 1 diabetic patients without evidence of clinical thyroid disease; 2) to determine whether or not measurement of TPO and/or Tg antibodies can identify subjects at risk of clinical or infraclinical thyroid dysfunction by measuring TSH in the entire group. TPO antibodies were found in 45 of the 258 diabetic patients (17%). The prevalence of TPO antibodies was not influenced by the following factors: gender, duration of disease, age at screening and at diabetes diagnosis, positivity of familial history. Tg antibodies were found in 19 patients (7%), including 13 cases with TPO antibodies. All patients without TPO antibody (n=213), including Tg-positive patients displayed TSH values in normal range. Among the 45 TPO-positive patients, 11 patients displayed infraclinical thyroid dysfunction. At the end of the 5-year follow-up, only 2/45 patients became anti-TPO negative. Thirteen of the 45 patients developed subclinical or clinical thyroid diseases (4 Graves'disease and 9 thyroiditis with hypothyroidism). By contrast, none of 45 TPO negative patients, sex and age matched with the TPO-positive patients, developed during follow-up anti-TPO positivity and/or infraclinical thyroid dysfunction. In conclusion, the determination of TPO antibodies by a highly sensitive method allows identifying diabetic patients with thyroid autoimmunity and at risk of subsequent impaired thyroid function, whatever age at diagnosis and diabetes duration. By contrast, anti-Tg determination did not give further information about subsequent thyroid dysfunction. In TPO antibody positive patients repeated thyroid clinical examination and TSH determination could be recommended to detect infraclinical thyroid dysfunction.

Facteurs de risque associés à l'obésité : le point de vue du métabolicien

Abstract: Obesity, especially visceral obesity, is associated with a cluster of metabolic complications increasing the risk of type 2 diabetes and coronary heart disease. It has been shown that obese patients characterized by a high accumulation of visceral adipose tissue have increased glycemic and insulinemic responses to an oral glucose load compared to normal weight individuals or to obese individuals with a low accumulation of visceral adipose tissue. Viscerally obese patients are also characterized by an unfavourable plasma lipid profile which includes elevated triglyceride and apolipoprotein B concentrations, reduced HDL-cholesterol levels as well as an increased proportion of small, dense LDL particles. Such alterations in the lipid profile are often observed even in the absence of elevated LDL-cholesterol concentrations. Our work has clearly shown that this cluster of metabolic abnormalities found among viscerally obese patients was associated with a substantial increase in coronary heart disease risk. Our work has also shown that the "metabolic triad" of non-traditional risk factors (hyperinsulinemia, elevated apolipoprotein B levels, increased proportion of small, dense LDL particles) was associated with a 20-fold increase in the risk of coronary heart disease. In this regard, we have been interested in developing simple tools which would allow clinicians to identify at an early stage and at low cost individuals who would be carriers of the atherogenic metabolic triad. We have noted that the measurement and interpretation of waist circumference and of fasting plasma triglyceride levels could allow the identification of a high proportion of carriers of the metabolic triad. Indeed, less than 10% of men with a waist circumference below 90 cm and triglyceride concentrations below 2 mmol/l were characterized by the features of the metabolic triad. However, more than 80% of individuals with a waist circumference above 90 cm and triglyceride levels above 2 mmol/l were carriers of the metabolic triad. Finally, an elevated visceral adipose tissue accumulation has also been associated with a thrombogenic and a pro-inflammatory metabolic profile which would be predictive of an unstable atherosclerotic plaque. Therefore, the stabilisation of the atherosclerotic plaque may represent a legitimate therapeutic objective to reduce the risk of coronary heart disease among patients with visceral obesity. It is proposed that a rather modest weight loss (approximately 10%) could contribute to substantially improve the risk profile of these patients.

Efficacy of quinagolide in resistance to dopamine agonists: results of a multicenter study. Club de l'Hypophyse.

Abstract: Dans une etude multicentrique francaise, portant sur 107 patients, l'efficacite du quinagolide (Norprolac®) a ete evaluee sur le volume tumoral et accessoirement sur le taux de prolactine (PRL) en presence d'adenomes a prolactine resistants a l'action de la bromocriptine a 15 mg par jour prescrite au minimum durant 3 mois La serie comprenait 80 macro-adenomes et 27 micro-adenomes De plus 55 patients ont eu un geste chirurgical partiel avant l'administration du quinagolide dont 17 une radiotherapie La PRL est revenue a la normale chez 44 % des patients en moyenne apres 9,8 mois avec des doses de quinagolide de 259 ± 32,7 μg par jour L'evolution tumorale sous quinagolide n'a ete evaluee que chez 82 patients apres avoir exclu 8 patients qui n'avaient pas de residu tumoral bien visible et les 17 qui ont eu une radiotherapie (13 avant et 3 sous quinagolide, et un traite exclusivement par radiotherapie) En definitive; 19,5 % des 82 patients ont eu une reduction tumorale de plus de 50 %; et 30,8 % des patients ont eu une reduction tumorale au moins partielle L'effet anti-tumoral a ete atteint en 16,8 ± 3,1 mois (3-78) avec une posologie de quinagolide de 255,4 ± 37,8 μg/jour (75-750) L'effet anti-tumoral a en fait ete observe en moins de 2 ans dans 80 % des cas a une dose de 300 μg par jour Enfin dans 17 % des cas le quinagolide a a la fois normalise le taux de PRL et reduit le volume tumoral Deux valeurs de PRL ont ete susceptibles d'indiquer l'efficacite therapeutique ulterieure: un taux de PRL de moins de 300 ng/ml avant quinagolide pendant la periode de wash-out a ete garant d'une normalisation de la PRL; et une decroissance moyenne des taux de PRL de 619 ng/ml (60,6 ± 7 %) apres 3 mois de quinagolide a ete le temoin de la reduction tumorale ulterieure Des effets secondaires, dependants de la posologie ont ete notes de facon mineure dans 47,6 % des cas Seuls 10,2 % des patients ont du arreter leur traitement pour des posologies en general superieures a 300 μg/jour

[Evaluation of corticosteroid replacement therapy and its effect on bones in Addison's disease].

Abstract: Assessment of patients on steroid replacement therapy is important to avoid the consequences of overtreatment such as osteoporosis. The aim of this prospective study is to evaluate the severity and the etiology of osteopenia in 24 patients (15 women, 9 men) with Addison's disease receiving 30 mg hydrocortisone. Mean age of patients was 55 15 years. Osteoporosis, diagnosed by the measurement of bone mineral density (BMD) at the level of lumbar spine and right hip, was found in 58% of patients, i.e. in 10 women and 4 men. The latter had normal testosterone levels while seven women had an early menopause, the etiology of their Addison's disease being autoimmune. Three were on hormonotherapy. Correlations were found between BMD in the femoral neck and hip and the dose of hydrocortisone (mg/m(2)/day; mg/kg/day), the duration of treatment and 24 hr-cortisoluria/g creatinine. Multivariate analysis shows that 24-hr cortisoluria/g creatinine is a good predictor of BMD values. Thus, osteoporosis is frequent in Addison's disease and cortisoluria could be a useful tool to predict this complication.

[Ovarian endometriosis cyst with iodine 131 uptake : first case of false positive in the follow up for differentiated thyroid carcinoma].

Abstract: A whole body scan is performed after a radioiodine treatment in patients with differentiated thyroid carcinoma. This scan is useful coupled with thyroglobulin level for the patient's management. When unusual uptake is found, investigations have to be done to eliminate thyroid metastasis. A 28-year old woman underwent a total thyroidectomy for micro papillary carcinoma. Two years and a half after, ultrasonography of the neck showed a small lymph node in homolateral side of carcinoma. It was decided to begin treatment with iodine 131. The post-therapeutic scan showed an abnormal pelvic uptake. IRM found no osseous abnormality but an ovarian lesion. After surgery, histological diagnosis was an endometriosis cyst without thyroid or tumoral cells. Abdominal ou pelvic iodine false positive are rare. Ovarian cysts may be the cause of false positive radioiodine uptake. Endometriosis cyst was not previously described and the mecanism of iodine uptake is not clear.

Adénomes hypophysaires gonadotropes

Abstract: Initially, the distinction between "functional" and "non-functional" adenomas was a purely clinical notion. A "non-secreting" adenoma was not considered to cause acromegaly nor Cushing's syndrome nor amenorrhea-galactorrhea syndrome. The term "chromophobe adenoma" has been used since the advent Herlant tetrachrome. More recently immunocytochemistry methods have demonstrated that most of the "clinically non functional" adenomas (chromophobe with classical histology) are actually gonadotrophin secreting adenomas or gonadotroph adenomas. Due to progress in immunocytochemistry applied to operated adenomas, it is now known that gonadotroph tumors account for 15 to 20% of all pituitary adenomas. Gonadotroph adenomas are monoclonal but their pathogenesis, unlike somatotroph adenomas causing acromegaly and despite numerous molecular studies, remains unknown. Gonadotroph adenomas are most always discovered in patients presenting a pituitary syndrome (half to three-quarters consult for a visual field disorder). Pituitary imaging almost always demonstrates a macroadenoma: two-thirds of the macroadenomas are enclosed. Anterior pituitary insufficiency is much more frequent than gonad hyperstimulation whether testicular (macro-orchidia) or ovarian (ovarian hyperstimulation similar to that observed in ovulation induction). A careful analysis of hormone assay results shows that baseline concentrations of gonadotrophin or their free sub-units is elevated in 30 to 50% of cases (especially FSH in men, and the free a sub-unit in premenopausal women). Dynamic tests contribute little to diagnosis: the GnRH test is positive in 75 to 100% of cases, the TRH test in 60 to 70% for FSH (or alpha) and when there is already a baseline hypersecretion of FSH (or a) in 20 to 30% of the cases for the LH when the baseline LH concentration is high. The immunocytochemistry of gonadotroph adenomas is slightly different from that of other adenomas: generally, only 5 to 10% of the cells, grouped in islets of variable size, dispersed in the tumoral parenchyma, bind anti-FH, anti-LH and/or anti-sub-unit a antisera. Surgery is the primary treatment for gonadotroph adenomas. Complementary radiotherapy may be discussed in case of a postoperative remnant. It is probably effective against recurrence. Medical treatment (dopaminergic agonists, somatostatin analogs, GnRH agonists and antagonists) have given disappointing results.

[Genetics of human obesity: results from genetic epidemiology studies].

Abstract: Obesity is a complex disease resulting from the interaction between a variety of genetic and environmental factors. Research conducted over the past 20 years in the field of genetic epidemiology has contributed to increase our understanding of the genetic basis of obesity. It is now clearly established that overweight and obesity aggregate in families. Studies have shown that the prevalence of obesity is 2 to 8 times higher in families of obese individuals than in the population at large and that the familial risk increases with the severity of obesity. The heritability of the various obesity phenotypes varies considerably depending on the phenotype under study, the nature of familial data and the methods used to compute heritability estimates. Heritability estimates tend to be highest when derived from twin studies (50% a 80%) while they are the lowest when derived from adoption studies (10% a 30%). Several studies have reported the presence of major gene effects for body mass index, body fat and abdominal visceral fat. Finally, there is increasing evidence that shared genetic factors could play a role in determining the covariation between obesity and its major co-morbidities, including blood pressure, insulin resistance, diabetes and dyslipidemia. This genetic covariation is however moderate and accounts for a smaller percentage of the variance compared to the genetic effects reported for each of the phenotypes studied independently.

Positive antithyroglobulin antibodies in patients with differentiated thyroid carcinoma. What significance

Abstract: Le but de ce travail retrospectif effectue sur 238 patients inscrits dans la serie institutionnelle des cancers thyroidiens de Champagne-Ardenne est de determiner la valeur a accorder a la presence d'anticorps antithyroglobuline (AcTg) chez les patients ayant un taux indetectable de Thyroglobuline (Tg) apres thyroidectomie totale pour cancer thyroidien differencie et administration d'une dose ablative d'iode 131. Trente de ces patients presentent sous defreination un taux de Tg indetectable avec presence d'AcTg. Parmi eux, 21 normalisent leur taux d'AcTg sans evenement clinique dans un delai variable de 3 a 84 mois (mediane 12 mois).Deux d'entre eux normalisent leur taux d'AcTg, des fixations pathologiques persistent a la scintigraphie. Chez les 7 autres patients, le taux d'AcTg demeure eleve 5 ans apres le diagnostic. Pour 3 d'entre eux, il s'agit d'une elevation secondaire du taux d'AcTg associee a une evolution clinique metastatique. Cette etude confirme la necessite d'associer au dosage de Tg sous defreination la recherche d'AcTg pour le suivi d'un cancer differencie de la thyroide. La persistance d'un taux eleve ou l'apparition d'AcTg au cours du suivi doit faire suspecter la persistance de tissu neoplasique.

Microsomal triglyceride transfer protein and abetalipoproteinemia

Abstract: Microsomal triglyceride transfer protein (MTP) is a dimeric protein complex consisting of protein disulfide isomerase and a unique 97 kDa subunit. In vitro, MTP accelerates the transport of triglyceride, cholesteryl ester, and phospholipid between vesicles. It was recently demonstrated that abetalipoproteinemia, a disease characterized as an inability to produce chylomicrons and very low density lipoproteins in the intestine and liver, respectively, is the result of a genetic absence of MTP. Downstream effects resulting from this defect, include very low plasma cholesterol and triglyceride levels, absence of plasma apolipoprotein B and a lipid malabsorption syndrome, leading to lipo-soluble vitamin deficiencies. A low fat diet is instituted to eliminate the diarrhea. In addition, a therapy with vitamins A and E is essential to prevent patients from developing secondary effects such as neuropathy, muscle weakness, and retinopathy.

Resistance to thyroid hormone in a family with no TRbeta gene anomaly: pathogenic hypotheses.

Abstract: Les syndromes de resistance aux hormones thyroidiennes (RHT) sont habituellement lies a une anomalie du gene codant le recepteur p de la triiodothyronine (TRβ). Seules six familles de RHT sans anomalie du gene TRβ ont ete decrites. Nous en rapportons une nouvelle et discutons les differents mecanismes pathogeniques possibles. Patients et methodes: Nous avons etudie quatre sujets apparentes presentant un phenotype de RHT typique. Nous avons amplifie l'ADN genomique et sequence le gene TRβ. Une analyse de liaison a ete effectuee a la recherche d'une liaison entre le gene TRβ et le phenotype de RHT. Resultats: Aucune anomalie du gene TRβ n'a ete mise en evidence malgre le sequencage direct de tous les exons codants. L'analyse de liaison a elimine dans cette famille toute liaison entre le phenotype de RHT et le gene TRβ. Conclusion: Les genes TRβ1 et TRβ2 sont normaux dans cette famille de RHT. Plusieurs mecanismes sont envisages pour expliquer cette situation, en amont, au niveau ou en aval des recepteurs thyroidiens. L'hypothese la plus probable est l'anomalie d'un cofacteur nucleaire implique dans le controle de la transcription genique dependante de la T3.

MRI diagnosis of cavernous sinus invasion by pituitary adenomas

Abstract: Several MRI signs are helpful for the preoperative MRI diagnosis of cavernous sinus invasion by an adenoma. The first step is to analyse the percentage of encasement of the intracavernous ICA by the adenoma. If this percentage is greater than or equal to 66%, the cavernous sinus is invaded. If the percentage of encasement of intracavernous CA is less than 25%, the cavernous sinus is not invaded. If the percentage of encasement is between 25 and 66%, the analysis of the cavernous venous compartment, the drawing of intercarotid lines and the analysis of the shape and venous compartments of the cavernous sinus are necessary. The cavernous sinus invasion remains very likely if the carotid sulcus venous compartment is obliterated, or if the lateral intercarotid line is crossed. Conversely, if the median intercarotid line is uncrossed, the superior venous compartment is visible, the cavernous sinus is of normal size, or there is no bulging of its lateral dural wall, invasion of the cavernous sinus space can reliably be excluded.

Growth hormone and cardiac function.

Abstract: Impaired cardiovascular function, which may reduce life expectancy, has recently been demonstrated both in GH deficiency and excess. Moreover, experimental and clinical studies support the evidence implicating GH and/or IGF-I in the regulation of heart development. The existence of a specific acromegalic cardiomyophathy characterized by myocardial hypertrophy with interstitial fibrosis, lympho-mononuclear infiltration and areas of monocyte necrosis which often result in biventricular concentric hypertrophy has been recenty demonstrated. By contrast, patients with childhood or adulthood-onset GH deficiency (GHD) present with abnormalities of structure and function of the left ventricle. In these patients, a significant increase in the vascular intima-media thickness and an increased number of atheromatous plaques have also been reported. The abnormalities of cardiovascular system could be partially reverted by suppressing GH and IGF-I levels in acromegaly or after GH remplacement therapy in GHD patients. The evidence that GH is able to increase cardiac mass suggested its use in the -treatment of chronic heart failure of diverse etiologies. GH administration was -demonstrated to induce an improvement in hemodynamics and clinical status in some patients. Although these data should be confirmed in double-blind placebo controlled studies in larger series, the promising results open new perspectives for GH treatment in humans.

Factors of variation and reference values for TSH in 45-70 year old women.

Abstract: Thyroid stimulating hormone (TSH) was measured in a sample of 4,403 women, aged 45-70 years in 11 Centers for health screening, to define the interest of this biological indicator for screening subclinical hypothyroidism. The aim of this work was to describe clinical signs, symptoms and medical history linked to TSH variations, to estimate the distribution of this hormone in a general population and reference limits in a selected subgroup. All the participating laboratories used the same third-generation immunoassay on fresh samples. In the general sample population (age mean: 55.2 6.9 yrs), 1.1% presented hyperthyroidism (TSH 12 mU/l). In the sub-sample of 151 women (3.4%) with TSH between 4-12 mU/l, 131 had subclinical hypothyroidism (FT4>8 ng/l). The TSH mean was significantly lower (- 10 to - 23%) in women presenting a nodular goiter. Inversely, TSH was higher in women with muscle cramps, asthenia, recent weight gain, morning eyelid edema and abnormal electrocardiogram. The reference limits for percentiles 2.5 and 97.5 were 0.43 and 3.71 mU/l on 1 348 subjects after excluding women having one of these symptoms or taking any drug treatment.

Large bilateral adrenal incidentalomas complicating untreated 11B hydroxylase deficiency in the third decade of life. A case report.

Abstract: Les auteurs rapportent un cas d'incidentalome surrenalien geant et bilateral revelateur d'un deficit en 11 β hydroxylase. Il s'agit d'un jeune homme de 22 ans chez qui l'echographie surrenalienne realisee dans le cadre d'une exploration d'une infection urinaire recidivante, a montre la presence de deux masses surrenaliennes droite et gauche, qui mesuraient respectivement 16 et 6 cm de diametre. A l'examen, le patient mesurait 145 cm et la TA etait a 19/10 cmHg. L'examen n'a pas trouve de testicules. Le bilan hormonal a montre un taux eleve de la 17 hydroxyprogesterone: > 50 ng/ml (n < a 1,1), du 11 desoxycortisol: 919 nmol/l (n < 30), de la testosterone: 19 ng/ml (n < 0,7), et de l'ACTH: 1 402 ng/l (n < 48). Le caryotype etait 46 XX. Le diagnostic d'hyperplasie des surrenales congenitale par bloc enzymatique en 11 beta hydroxylase a ete ainsi porte. Six mois apres le traitement par hydrocortisone, les deux masses ont nettement diminue de volume. Nous confirmons les recommandations anterieures sur la necessite des explorations hormonales de toute masse surrenalienne, a la recherche d'une hyperplasie des surrenales congenitale.

Les effets non-transcriptionnels des oestrogènes refont surface

Abstract: Les recepteurs des oestrogenes (RE) appartiennent a la superfamille des recepteurs nucleaires. Ils agissent classiquement comme des facteurs de transcription actives par leurs ligands pour reguler l'expression de genes cibles. Il existe cependant des effets rapides (quelques minutes) des oestrogenes dans differents tissus qui ne peuvent resulter de l'activation de la machinerie transcriptionnelle et de la synthese proteique. L'activation des voies classiques de transduction mettant en jeu des seconds messagers, telles que l'augmentation du calcium intracellulaire et l'accumulation d'AMP cyclique, a ete mise en evidence dans de nombreux modeles cellulaires. Des etudes recentes montrent que les oestrogenes peuvent aussi activer la voie de signalisation de la kinase MAP par l'intermediaire de leurs recepteurs. Ces differents effets non-genomiques sont retrouves dans divers tissus tels que l'os, le systeme nerveux, l'endothelium vasculaire et les cellules de cancer du sein. La mise en evidence des effets non-transcriptionnels des oestrogenes est une composante d'action supplementaire a integrer dans la modulation deja complexe des effets œstrogeniques. Ce mecanisme d'action pourrait aussi constituer une nouvelle cible therapeutique pour le traitement des maladies cardio-vasculaires, neurodegeneratives ou dans le cancer du sein.

Goitre multinodulaire et cancer de la parotide : un nouveau cas de maladie de Cowden.

Abstract: La maladie de Cowden (MC) est une genodermatose rare transmise sur le mode autosomique dominant associant des lesions de la thyroide, des seins et du tractus digestif. Nous rapportons une nouvelle observation de MC chez une femme de 23 ans, chez qui la maladie a ete diagnostiquee lors d'une consultation pour goitre multinodulaire. Le bilan d'extension a revele la presence de lesions du sein, de polypes gastriques et d'un cancer de la parotide. Il est important de reconnaitre la MC etant donne le risque de degenerescence de certaines lesions notamment : la thyroide et le sein. Les lesions cutanees restent les veritables marqueurs de risque de cancer dans cette pathologie.

Exploration de la fonction hypothalamo-hypophyso-surrénalienne au cours et au décours de la corticothérapie : revue critique et données récentes

Abstract: La corticotherapie prolongee est generalement consideree comme la cause la plus frequente d'insuffisance surrenalienne (IS). Elle est liee a une atrophie surrenalienne secondaire a l'inhibition de la secretion d' ACTH. Il n'y a pas de facteur de risque bien identifie de survenue d'une IS chez un malade sous corticoides. Les tests fonctionnels, au premier rang desquels le test au Synacthene 250 μg, mettent frequemment en evidence des anomalies de reponse chez les malades sous corticoides. Cependant, ces anomalies ne sont pas parfaitement correlees avec le risque de survenue d'une IS notamment lors d'un stress. Les tests plus recents (CRH, Synacthene « faible dose ») doivent encore etre evalues dans cette situation. Plusieurs etudes recentes ont montre que les besoins en glucocorticoides lors d'un stress chirurgical ont ete largement surestimes. Une revision a la baisse des recommandations de substitution a ete proposee recemment, la simple poursuite du traitement habituel chez un malade traite par corticoides etant le plus souvent suffisante pour prevenir la survenue d'une IS lorsqu'il s'agit d'une intervention mineure. De nouvelles evaluations paraissent necessaires pour des interventions plus importantes ou lors des stress lies a des affections medicales.

The pharmacology of endothelin and its antagonist bosentan

Abstract: Endothelin is one of the most potent vasoconstrictors known, but it also plays a role in inflammation, fibrosis and cellular hypertrophy. Endothelin is a key pathogenic factor in congestive heart failure, essential hypertension and pulmonary hypertension. Bosentan is a specific mixed antagonist of endothelin receptors. Preclinical and clinical data suggest that bosentan might become a new approach for the chronic treatment of these cadiovascular and pulmonary diseases.

Hypothalamic-pituitary Langerhans cell histiocytosis: a diagnostic challenge.

Abstract: Four cases of hypothalamic-pituitary Langerhans cell histiocytosis (LCH) are reported, highlighting the expanding spectrum of clinical and magnetic resonance imaging (MRI) features in adults. The diagnostic challenge of hypothalamic-pituitary LCH is emphasized in cases revealed as supra-sellar tumors with panhypopituitarism or as isolated central diabetes insipidus. Diagnosis is confirmed by histological examination showing infiltration with CD1a positive histiocytes. General guidelines for diagnosis procedure are drawn out, including the neurosurgical biopsy in particular cases.

Evaluation de la substitution par corticostéroïdes et de ses répercussions osseuses dans la maladie d'Addison.

Abstract: Assessment of patients on steroid replacement therapy is important to avoid the consequences of overtreatment such as osteoporosis. The aim of this prospective study is to evaluate the severity and the etiology of osteopenia in 24 patients (15 women, 9 men) with Addison's disease receiving 30 mg hydrocortisone. Mean age of patients was 55 15 years. Osteoporosis, diagnosed by the measurement of bone mineral density (BMD) at the level of lumbar spine and right hip, was found in 58% of patients, i.e. in 10 women and 4 men. The latter had normal testosterone levels while seven women had an early menopause, the etiology of their Addison's disease being autoimmune. Three were on hormonotherapy. Correlations were found between BMD in the femoral neck and hip and the dose of hydrocortisone (mg/m(2)/day; mg/kg/day), the duration of treatment and 24 hr-cortisoluria/g creatinine. Multivariate analysis shows that 24-hr cortisoluria/g creatinine is a good predictor of BMD values. Thus, osteoporosis is frequent in Addison's disease and cortisoluria could be a useful tool to predict this complication.

Maladie de Wegener et diabète insipide central

Abstract: Les vascularites compliquees de diabete insipide central sont une association rare qui doit etre connue en raison de ses implications therapeutiques specifiques. A partir d'une observation de maladie de Wegener associee a un diabete insipide central, nous avons repris les donnees de la litterature concernant les caracteristiques cliniques et radiologiques de l'atteinte hypophysaire et l'effet therapeutique du Cyclophosphamide sur le diabete insipide. Le diabete insipide est inaugural dans 46 % des cas. La maladie de Wegener ne comporte pas de caracteristique specifique. L'elargissement de la posthypophyse en imagerie par resonance magnetique (IRM) est observe dans 100 % des cas. Le Cyclophosphamide entraine une remission complete ou partielle du diabete insipide dans 80 % des cas. Au cours de la maladie de Wegener, les lesions de vascularite peuvent concerner l'hypophyse posterieure L'IRM est l'examen de reference. Le Cyclophosphamide est le traitement de choix des lesions de vascularite au cours de la maladie de Wegener.

[Prolactinoma in man: clinical and histological characteristics].

Abstract: Prolactinoma usually occurs a small intrasellar tumor in women or as a large tumor in men. To determine whether the predominance of macroprolactinomas in men is due to a delay in diagnosis as has been suggested, or whether there is a sex-related difference in growth rate we conducted a retrospective study in 45 men and 51 women with prolactinomas. Preoperative prolactin level (PRL) was 2,789 573 ng/ml and mean tumor size was 26 2 mm. Prolactin levels and tumor size were significantly higher in women (292 74 ng/ml and 10 1 mm; p<0.01). There was no correlation with age at diagnosis or duration of symptoms. Giant tumors were only observed in men (n=8). Frequency of resistance to bromocriptine (30% vs 5%, p<0.01) and invasive tumors (52% vs 27%, p<0.001) were significantly higher in men than in women. Likewise, proliferation rate was higher for the prolactinomas in men (Ki-67: 2.6 1.1% positive nuclei vs 0.4 0.2%; p=0.08; PCNA: 5.0 2.3% vs 3.7 1.1%). In conclusion, prolactinomas in men are more aggressive than in women. They grow rapidly, often invade the cavernous sinus and are resistant to bromocriptine; proliferation rates can be increased.

[Monogenic forms of obesity: from mice to human].

Abstract: The cloning of five rodent obesity genes has constituted a major advance in our understanding of body weight homeostasis. Breakthroughs in human molecular genetics have identified mutations disrupting either rodent homologue/analogue genes or genes involved in the same pathways in obese patients. Three rare cases of human morbid obesity of early onset associated with hypogodatropic hypogodanism are due to mutations in the leptin and the leptin receptor genes. These studies have confirmed that leptin plays not only a crucial role in the control of body weight in the human but also in several endocrine functions. Other Human obesity syndromes are linked to mutations in the genes encoding brain-expressed targets of leptin, particularly some key components of the melanocortin system. Patients compound heterozygous for mutations in the POMC gene display severe obesity of early onset, congenital adrenal insufficiency and red hair. Another genetic cause of obesity is due to mutation in the Proconvertase gene (PC1), the enzyme required for the cleavage of POMC into ACTH and alpha MSH, and also of Proinsulin to insulin. The subject compound heterozygous for the PC1 mutation displays besides obesity, a partial ACTH deficiency, elevated POMC and late post absorptive hypoglycemia due to the accumulation of high pro-insulinemia. Contrasting largely with these rare syndromic forms of obesity, several mutations located in the melanocortin 4 receptor gene have been showed to cause an early onset dominant form of obesity with no other associated abnormalities indifferent populations. These mutations in MC4-R could represent a "frequent" cause of common monogenic forms of obesity in human. More generally, these researches into human obesity have opened new exciting understandings in some of the pathways regulating body fat mass.