ZonMw; COOK Medical.

More than half of the European population are overweight (body mass index (BMI) O25 and !30 kg/m 2 ) and up to 30% are obese (BMIR30 kg/m 2 ). Being overweight and obesity are becoming endemic, particularly because of increasing nourishment and a decrease in physical exercise. Insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatis, gastroesophageal reflux, obstructive sleep apnea, degenerative joint disease, gout, lower back pain, and polycystic ovary syndrome are all associated with overweight and obesity. The endemic extent of overweight and obesity with its associated comorbidities has led to the development of therapies aimed at weight loss. The long-term effects of diet, exercise, and medical therapy on weight are relatively poor. With respect to durable weight reduction, bariatric surgery is the most effective long-term treatment for obesity with the greatest chances for amelioration and even resolution of obesity-associated complications. Recent evidence shows that bariatric surgery for severe obesity is associated with decreased overall mortality. However, serious complications can occur and therefore a careful selection of patients is of utmost importance. Bariatric surgery should at least be considered for all patients with a BMI of more than 40 kg/m 2 and for those with a BMI of more than 35 kg/m 2 with concomitant obesity-related conditions after failure of conventional treatment. The importance of weight loss and results of conventional treatment will be discussed first. Currently used operative treatments for obesity and their effectiveness and complications are described. Proposed criteria for bariatric surgery are given. Also, some attention is devoted to more basic insights that bariatric surgery has provided. Finally we deal with unsolved questions and future directions for research. European Journal of Endocrinology 158 135-145

Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5-7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis-often mild and subclinical-can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism-as a sequel of postpartum thyroiditis-predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.

Tumor necrosis factor alpha (TNF alpha), a monokine produced by activated macrophages and monocytes, may be an essential mediator of the pathogenesis and of the hormonal response to endotoxic shock. It has been suggested that an elevated level of TNF alpha is a marker for morbidity and mortality during septic shock, and that treatment with antibodies against TNF alpha decreases mortality. Because monokines have been shown to interact at the hypothalamic-pituitary level, we have studied the effect of TNF alpha on basal and stimulated hormone release from normal rat anterior pituitary cells. After 3 days of incubation, primary cultures of rat anterior pituitary cells were stimulated with either 0.5 ng/ml CRF, 3 ng/ml AVP, 10 ng/ml angiotensin II (AII), 10(-6) M TRF, 10(-8) M LHRH, or 10(-8) M GHRH, alone or in the presence of 20 or 50 ng/ml human or murine recombinant TNF alpha. The culture media were analyzed for ACTH, GH, LH, and PRL content. Each experiment was performed in triplicate and was repeated 3 to 8 times. Time-course experiments (n = 3) demonstrated that TNF alpha inhibited CRF-stimulated ACTH production over a period of 8, 16, and 24 h, but had no effect before a period of 4 h. At doses ranging from 1 to 100 ng/ml, TNF alpha did not affect basal ACTH secretion but inhibited CRF-stimulated ACTH release in a dose-dependent manner (ED50 approximately 10 ng/ml). At a dose of 50 ng/ml, TNF alpha inhibited AVP-stimulated ACTH release by 30% and blocked the effect of AII. TNF alpha (20 and 50 ng/ml) completely prevented the CRF-AVP potentiation of ACTH release. Similarly, TNF alpha inhibited the stimulated release of GH (100% inhibition), LH (35% inhibition), and PRL (100% inhibition). TNF alpha had no effect on the basal secretion of GH or LH but inhibited basal PRL in a dose-dependent manner. The administration of the monokine did not cause any cellular damage because 48 h after removal of the TNF alpha treatment the cells showed normal basal and stimulated hormone levels in response to their specific stimuli. Incubation of TNF alpha solutions with antibody to TNF alpha reversed all TNF alpha actions. These data suggest that TNF alpha inhibits the secretion of pituitary hormones and particularly suppresses the response of the corticotroph cells. This inhibitory effect may contribute to the increased mortality observed in cases of severe septic shock with high circulating TNF alpha levels.

RU 486 is a synthetic steroid hormone antagonist which acts at the receptor level. It has both intrinsic antiprogesterone and antiglucocorticosteroid properties in animals. We investigated the antiglucocorticosteroid activity in humans by evaluating the pituitary-adrenal response to RU 486 in men and in pregnant and nonpregnant women. In nonpregnant women, RU 486 (-1 mg/kg of body weight per day) produced an interruption of the luteal phase without affecting the pituitary-adrenal axis, thereby indicating a more potent antiprogesterone than antiglucorticosteroid effect. In the course of pregnancy interruption by RU 486 (-4 mg/kg per day), there was a significant increase in plasma corticotropin, f-lipotropin, and cortisol concentrations. In normal men, RU 486 administration led to a dose-dependent stimulation of plasma corticotropin, -endorphin, and cortisol. This disinhibition of the pituitary-adrenal axis was only observed during the morning hours of the circadian rhythm. When administered concomitantly with 1 mg of dexamethasone at midnight, 6 mg of RU 486 per kg completely suppressed the dexamethasone inhibitory effect on the pituitary-adrenal axis. These results indicate that RU 486 is an antiglucocorticosteroid that disrupts the negative pituitary feedback of both the morning cortisol rise and administered dexamethasone. Furthermore, they demonstrate the possibility of optimizing the antiprogestational effect of the compound and its potential use for human fertility control by modifying the dose and the time of administration of the drug and thereby minimizing the antiglucocorticosteroid effect.RU 486 [17p8-hydroxy-11,-(4-dimethylaminophenyl)-17a-(prop-1-ynyl)-estra-4,9-dien-3-one] is a synthetic 19-nor-steroid with high binding affinity for progesterone and glucocorticosteroid receptors (1-4). In vitro and in vivo experiments in animals have established that RU 486 displays no agonist activity but is an antagonist to both progesterone and endogenous (cortisol) or synthetic (dexamethasone) glucocorticosteroids. In vitro, it antagonizes the inhibitory effect of dexamethasone on uridine incorporation in rat thymocytes and the dexamethasone induction of tyrosine aminotransferase by rat hepatoma cells (D. Philibert and R. Deraedt, personal communication); it also suppresses the inhibition of corticotropin (ACTH) secretion induced by corticosteroids in rat pituitary cells (5) and the dexamethasone action on cultured L-929 mouse fibroblasts (2). In rats in vivo, it antagonizes the effects of corticosteroids on liver glycogen and tryptophan pyrrolase, thymolysis, and diuresis (1) and the inhibition of ACTH secretion induced by dexamethasone (5).RU 486 was first used in humans to interrupt the luteal phase of the menstrual cycle and early pregnancy (6). In women who received RU 486 to induce abortion during weeks 6-8 of pregnancy, an increase in blood cortisol was observed. The present work was undertaken to investigate the possible antiglucocorticosteroid effect of RU 486 on the pituitary-adrenal axis in h...

Objectives: In humans, fasting leads to elevated serum GH concentrations. Traditionally, changes in hypothalamic GH-releasing hormone and somatostatin release are considered as the main mechanisms that induce this elevated GH secretion during fasting. Ghrelin is an endogenous ligand of the GH secretagogue receptor and is synthesized in the stomach. As ghrelin administration in man stimulates GH release, while serum ghrelin concentrations are elevated during fasting in man, this increase in ghrelin levels might be another mechanism whereby fasting results in stimulation of GH release. Design and subjects: In ten healthy non-obese males we performed a double-blind placebo-controlled crossover study comparing fasting with and fasting without GH receptor blockade. GH, ghrelin, insulin, glucose and free fatty acids were assessed. Results: While ghrelin levels do not vary considerably in the fed state, fasting rapidly induced a diurnal rhythm in ghrelin concentrations. These changes in serum ghrelin concentrations during fasting were followed by similar, profound changes in serum GH levels. The rapid development of a diurnal ghrelin rhythm could not be explained by changes in insulin, glucose, or free fatty acid levels. Compared with fasting without pegvisomant, fasting with pegvisomant did not change the ghrelin rhythm. Conclusions: These data indicate that ghrelin is the main driving force behind the enhanced GH secretion during fasting.

The goals of the MELANIE project are to determine if disease-associated patterns can be detected in high resolution two-dimensional polyacrylamide gel electrophoresis (HR 2D-PAGE) images and if a diagnosis can be established automatically by computer. The ELSIE/MELANIE system is a set of computer programs which automatically detect, quantify, and compare protein spots shown on HR 2D-PAGE images. Classification programs help the physician to find disease-associated patterns from a given set of two-dimensional gel electrophoresis images and to form diagnostic rules. Prototype expert systems that use these rules to establish a diagnosis from new HR 2D-PAGE images have been developed. They successfully diagnosed cirrhosis of the liver and were able to distinguish a variety of cancer types from biopsies known to be cancerous.

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