[Hyperthyroidism and an unexpected molar pregnancy]. / Hyperthyreoïdie en een onverwachte molazwangerschap.

BACKGROUND: A molar pregnancy is a rare complication of (non-viable) pregnancy and produces high levels of hCG-hormone. hCG has characteristics similar to TSH, and therefore (severe) hyperthyroidism can occur. The incidence of molar pregnancy is approximately 1 in 1000-1500 pregnancies. CASE DESCRIPTION: A 23-year-old woman had complaints of discomfort, nausea and vomiting. A urine pregnancy test was negative and laboratory tests showed a severe hyperthyroidism. After referral a molar pregnancy was diagnosed (hCG 1.7 million IU/L). She was treated by curettage. hCG levels insufficiently decreased in the following weeks, and gestational trophoblastic neoplasia was diagnosed. She needed several courses of methotrexate after which she completely recovered. CONCLUSION: Severe hyperthyreoidism can be caused by a molar pregnancy. A urine pregnancy test can be negative because of too high hCG-levels, also known as the hook effect. Early recognition and treatment are very important because of the risk of severe complications.

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

INTRODUCTION: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. METHODS: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6134; Pre-results.

Orally disintegrating and oral standard olanzapine tablets similarly elevate the homeostasis model assessment of insulin resistance index and plasma triglyceride levels in 12 healthy men: a randomized crossover study.

OBJECTIVE: Treatment with olanzapine is associated with obesity, diabetes mellitus, and dyslipidemia. Reports have indicated that orally disintegrating tablets (ODT) cause less weight gain than oral standard tablets (OST). The aim of this study was to compare the effect of short-term treatment with these 2 distinct olanzapine formulations on glucose and lipid metabolism in healthy men. METHOD: Twelve healthy men (mean ± SEM age: 25.1 ± 5.5 years) received olanzapine ODT (10 mg od, 8 days), olanzapine OST (10 mg od, 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, glucose, insulin, free fatty acids (FFA), and triglyceride concentrations were measured at 10-minute intervals from 30 minutes prior to 2 hours after ingestion of standard meals. Leptin and adiponectin concentrations were measured at 20- and 30-minute intervals, respectively, between 0000h-1200h. Physical activity was assessed with an accelerometer. Fuel oxidation was measured in fasting condition by indirect calorimetry. The study was conducted from April 2006 through September 2006. RESULTS: Treatment with olanzapine ODT and OST equally elevated the homeostasis model assessment of insulin resistance (HOMA-IR) (P = .005). At breakfast, both formulations equally increased fasting and postprandial triglyceride concentrations (P = .013 and P = .005, respectively) while decreasing fasting and postprandial FFA concentrations (P = .004 and P = .009, respectively). Body weight, body composition, physical activity, or fuel oxidation did not differ between treatment modalities. CONCLUSIONS: Eight days of treatment with both olanzapine formulations similarly increased HOMA-IR and triglyceride concentrations and decreased FFA concentrations in response to standard meals without affecting anthropometrics or physical activity. These data suggest that olanzapine hampers insulin action via mechanistic routes other than body adiposity or physical inactivity. TRIAL REGISTRATION: controlled-trials.com. Identifier: ISRCTN17632637.

Effects of olanzapine and haloperidol on the metabolic status of healthy men.

BACKGROUND: A large body of evidence suggests that antipsychotic drugs cause body weight gain and type 2 diabetes mellitus, and atypical (new generation) drugs appear to be most harmful. The aim of this study was to determine the effect of short-term olanzapine (atypical antipsychotic drug) and haloperidol (conventional antipsychotic drug) treatment on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS: Healthy normal-weight men were treated with olanzapine (10 mg/d; n = 7) or haloperidol (3 mg/d, n = 7) for 8 d. Endogenous glucose production, whole body glucose disposal (by [6,6-(2)H(2)]glucose dilution), lipolysis (by [(2)H(5)]glycerol dilution), and substrate oxidation rates (by indirect calorimetry) were measured before and after intervention in basal and hyperinsulinemic condition. RESULTS: Olanzapine hampered insulin-mediated glucose disposal (by 1.3 mg x kg(-1) x min(-1)), whereas haloperidol did not have a significant effect. Endogenous glucose production was not affected by either drug. Also, the glycerol rate of appearance (a measure of lipolysis rate) was not affected by either drug. Olanzapine, but not haloperidol, blunted the insulin-induced decline of plasma free fatty acid and triglyceride concentrations. Fasting free fatty acid concentrations declined during olanzapine treatment, whereas they did not during treatment with haloperidol. CONCLUSIONS: Short-term treatment with olanzapine reduces fasting plasma free fatty acid concentrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about without a measurable change of body fat mass.

Short-term treatment with olanzapine does not modulate gut hormone secretion: olanzapine disintegrating versus standard tablets.

BACKGROUND: Treatment with olanzapine (atypical antipsychotic drug) is frequently associated with various metabolic anomalies, including obesity, dyslipidemia, and diabetes mellitus. Recent data suggest that olanzapine orally disintegrating tablets (ODT), which dissolve instantaneously in the mouth, might cause less weight gain than olanzapine standard oral tablets (OST). DESIGN AND METHODS: Ten healthy men received olanzapine ODT (10 mg o.d., 8 days), olanzapine OST (10 mg o.d., 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, blood samples were taken for measurement of pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin (CCK) concentrations. RESULTS: With the exception of pre- and postprandial concentration of ghrelin at dinner and preprandial CCK concentrations at breakfast, which were all slightly increased (respectively P=0.048, P=0.034 and P=0.042), olanzapine did not affect gut hormone concentrations. Thus, olanzapine ODT and OST had similar effects on gut hormone secretion. CONCLUSION: Short-term treatment with olanzapine does not have major impact on the plasma concentration of gut hormones we measured in healthy men. Moreover, despite pharmacological difference, gut hormone concentrations are similar during treatment with olanzapine ODT and OST. The capacity of olanzapine to induce weight gain and diabetes is unlikely to be caused by modulation of the secretion of gut hormones measured here. We cannot exclude the possibility that olanzapine's impact on other gut hormones, to impair insulin sensitivity and stimulate weight gain, exists.

Olanzapine shifts the temporal relationship between the daily acrophase of serum prolactin and cortisol concentrations rhythm in healthy men.

Treatment with the atypical antipsychotic drug olanzapine is frequently associated with development of obesity and insulin resistance. Treatment-induced weight gain has been suggested to be the main contributing factor of diminished insulin sensitivity. This study evaluated the effects of short-term treatment with olanzapine on 12h plasma prolactin and cortisol concentrations in healthy men. The effects of two distinct olanzapine formulations were investigated; the oral standard tablets (OST) and the orally disintegrating tablets (ODT). Recent reports indicate that treatment with the ODT formulation may be less harmful in terms of weight gain than the OST. 12 healthy men (age: 25.1+/-5.5 y) received olanzapine OST (10mg QD, 8 days), olanzapine ODT (10mg QD, 8 days) or no intervention in a randomized cross-over design. On day 8, blood samples were taken every 10min between 0000 and 1200h for determination of cortisol and prolactin concentrations. Treatment with olanzapine OST and ODT similarly increased the 12h mean PRL concentrations and the secreted PRL mass. Both drugs similarly shifted the maximal PRL concentration approximately 3-4h backwards in time. Cortisol secretions rates were lower, but the timing of the cortisol acrophase did not change. Both drugs significantly elevated HOMA index for insulin resistance. In conclusion olanzapine OST and ODT equally elevated the prolactin concentration and significantly shifted its acrophase, thus dissociating PRL and cortisol, while both formulations induced similar insulin resistance as evidenced by the elevated HOMA-IR. Notably, these alterations occurred without a measurable effect on body adiposity.

Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes.

OBJECTIVE: The hypothalamus plays a critical role in the regulation of energy balance and fuel flux. Glucose ingestion inhibits hypothalamic neuronal activity in healthy humans. We hypothesized that hypothalamic neuronal activity in response to an oral glucose load would be altered in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, single blind, case-control study, 7 type 2 diabetic men (BMI 27.9 +/- 2.0 kg/m(2)) and 10 age-matched healthy men (BMI 26.1 +/- 3.2 kg/m(2)) were scanned twice for 38 min on separate days using functional magnetic resonance imaging. After 8 min, they ingested either a glucose solution (75 g in 300 ml water) or water (300 ml). RESULTS: Glucose ingestion resulted in a prolonged significant blood oxygen level-dependent signal decrease in the upper and lower hypothalamus in healthy subjects but not in diabetic patients. CONCLUSIONS: Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Failure of neural circuits to properly adapt to nutrient ingestion may contribute to metabolic imbalance in type 2 diabetic patients.

Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion.

We previously showed that hypothalamic neuronal activity, as measured by the blood oxygen level-dependent (BOLD) functional MRI signal, declines in response to oral glucose intake. To further explore the mechanism driving changes in hypothalamic neuronal activity in response to an oral glucose load, we here compare hypothalamic BOLD signal changes subsequent to an oral vs. an intravenous (iv) glucose challenge in healthy humans. Seven healthy, normal-weight men received four interventions in random order after an overnight fast: 1) ingestion of glucose solution (75 g in 300 ml) or 2) water (300 ml), and 3) iv infusion of 40% glucose solution (0.5 g/kg body wt, maximum 35 g) or 4) infusion of saline (0.9% NaCl, equal volume). The BOLD signal was recorded as of 8 min prior to intervention (baseline) until 30 min after. Glucose infusion was associated with a modest and transient signal decline in the hypothalamus. In contrast, glucose ingestion was followed by a profound and persistent signal decrease despite the fact that plasma glucose levels were almost threefold lower than in response to iv administration. Accordingly, glucose ingestion tended to suppress hunger more than iv infusion (P < 0.1). We infer that neural and endocrine signals emanating from the gastrointestinal tract are critical for the hypothalamic response to nutrient ingestion.

Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation.

OBJECTIVE: STAT5b is a component of the GH signaling pathway. Recently, we described a 31-year-old male patient (height, -5.9 SDS) with a novel homozygous inactivating mutation in the STAT5b gene. The purpose of this study is to describe the phenotype in detail, including GH secretion and immunological function. In addition, we report four family members of this patient, all heterozygous carriers of the mutation. DESIGN AND METHODS: Twenty-four hour GH and prolactin secretion characteristics were assessed by blood sampling at 10-min intervals. An IGF-I generation test was performed. Monocyte function was tested by stimulation of whole blood with lipopolysaccharide (LPS) in the presence or absence of Interferon-gamma (IFN-gamma). In addition, T cell function was determined by measuring proliferative responses of peripheral blood mononuclear cells (PBMC) after stimulation by various polyclonal activators and Interleukin-2 (IL-2). Clinical and biochemical characteristics were determined in the carriers of the mutation. RESULTS: GH secretory parameters were comparable with that of healthy male controls (mean fat percentage 25), but likely increased in relation to the patient's 40% body fat. The regularity of GH secretion was diminished. Prolactin secretion was increased by sixfold. The IGF-I generation test showed a small increase in IGF-I and IGF-binding protein-3 on lower GH doses and an increase in IGF-I to -2.4 SDS on the highest dose of GH. In vitro, IL-12p40, IL 10, and tumour necrosis factor-alpha (TNF-alpha) production rates by PBMC increased to values within the normal range upon stimulation of LPS. Heterozygous carriers of the mutation did not show abnormalities, although the height of the males was below the normal range. CONCLUSIONS: This report shows that GH and prolactin secretion were increased in this patient homozygous for a new STAT5b mutation. Although STAT5b plays a role in signaling within immune cells, clinical immunodeficiency is not an obligatory phenomenon of STAT5b deficiency per se. Heterozygous carriers of a STAT5b mutation show no signs of GH insensitivity.

Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation.

CONTEXT: GH insensitivity can be caused by defects in the GH receptor (GHR) or in the postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary and immunological problems were described with a defect in STAT5b, a critical intermediary of downstream GHR signaling. OBJECTIVE: The objective was to determine the functional characteristics of a novel STAT5b mutation and describe the phenotype. PATIENT: We describe an adult male patient with short stature [-5.9 sd score (SDS)], delayed puberty, and no history of pulmonary or immunological problems. GH-binding protein level as well as GH secretion characteristics were normal. Plasma prolactin level was elevated. Extremely low levels of IGF-I (-6.9 SDS), IGF-binding protein-3 (-12 SDS), and acid-labile subunit (-7.5 SDS) were found. RESULTS: We found a homozygous frameshift mutation in the STAT5b gene (nucleotide 1102-3insC, Q368fsX376), resulting in an inactive truncated protein, lacking most of the DNA binding domain and the SH2-domain. CONCLUSIONS: This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommended.