Context: GH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies.Objectives: Our objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults. Design:We conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods. Setting:The study was conducted at outpatient treatment facilities at four U.S. academic medical centers.Patients: Lean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations.Intervention: Human recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated. Main Outcomes Measures:Lean body mass and percent fat were measured by dual-energy x-ray absorptiometry.Results: Lean body mass increased from 42.65 Ϯ 2.25 (SE) to 45.47 Ϯ 2.31 kg (P Յ 0.0001), and percent fat decreased from 42.84 Ϯ 1.12 to 39.95 Ϯ 1.34% (P ϭ 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6 -12 months of GH. Mean fasting glucose of 85.3 Ϯ 3.4 mg/dl, hemoglobin A1c of 5.5 Ϯ 0.2%, fasting insulin of 5.3 Ϯ 0.6 U/ml, area under the curve for insulin of 60.4 Ϯ 7.5 U/ml, and homeostasis model assessment of insulin resistance of 1.1 Ϯ 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T 3 increased 26.7% from 127.0 Ϯ 7.8 to 150.5 Ϯ 7.8 ng/dl (P ϭ 0.021) with normalization in all subjects, including six (20%) with baseline T 3 values at least 2 SD below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients).Conclusions: This multicenter study demonstrates that GH improves body composition, normalizes T 3 , and is well tolerated without glucose impairment in PWS genotype adults.

Resumen El Síndrome de Prader-Willi es una alteración genética con grados variables de expresión que puede comprome-ter la vida del paciente y su desempeño en la sociedad. Su frecuencia de aparición es de 1/10.000 recién nacidos. El uso de la hormona del crecimiento en estos niños, a partir del año 2000, ha mejorado considerablemente las condiciones de salud de estos pacientes, siendo la hipoto-nía el mayor factor de riesgo para la vida de los mismos. Los efectos de la somatotropina recombinante sobre la tonicidad muscular de los casos que presentamos sugieren que es urgente su reconocimiento temprano y el uso de esta hormona en los afectados. Palabras clave: Prader-Willi; hormona del crecimiento; somatoprina. Summary Prader-Willi syndrome is a genetic disorder with varying degrees of expression that can compromise the patient's life and performance in society. It has a frequency of 1 / 10,000 newborns. The use of growth hormone in these children from the year 2000 has greatly improved the health conditions of these cases, being hypotonia the greatest risk factor for the lives of those affected. The effects of recombinant somatotropin on muscle tone in the cases we present suggest that it is an emergency its early recognition and the use of this hormone in them. Introducción El Síndrome de Prader-Willi (SPW) es una enfer-medad genética causada por diferentes mecanismos genéticos que resultan en la ausencia física o funcio-nal de genes que se expresan solo a partir del cromo-soma 15 paterno (15q11-q13), y que no pueden ser complementados al estar estos mismos genes silen-ciados en el cromosoma 15 materno 1-4. Ya sea por delección, disomía uniparental materna, defecto de impronta genética o translocación balanceada. La incidencia de este síndrome es de aproximada-mente 1 de cada 15.000-25.000 nacidos vivos y afecta por igual a hombres y mujeres. El SPW se caracteriza por presentar una hipoto-nía severa en el período neonatal que dificulta la

Hyperinsulinemia, a manifestation of insulin resistance, precursor of non-insulin dependent diabetes mellitus (NIDDM) and the hallmark of Syndrome X was assessed in 27 obese post-menopausal women. Insulin-like growth factor binding protein-1 (IGFBP-1), which had been shown previously to correlate inversely with insulin in animal and human studies, was evaluated as a diagnostic marker for abnormal glucose stimulated area under the curve (AUC) insulin (defined a priori as > or = 100 microU/ml). We performed analysis of variance and logistic regression to assess IGFBP-1 and other study covariates, including body mass index, blood pressure, lipids and measures of glucose and insulin in hyperinsulinemic vs. normal women and evaluated performance characteristics (sensitivity, specificity, positive and negative predictive values and accuracy rates). The mean IGFBP-1 was 6.1 ng/ml (95% confidence interval (CI) 3.1 to 8.9) for the hyper-insulinemic women compared to 33.5 ng/ml (CI 15.8 to 51.2) for normal women (P = .0027). At a cutoff point of 15ng/ml, which was selected to correspond to the lower 95% confidence limit for the normal study population, IGFBP-1 was abnormal in all 13 women with hyperinsulinemia and 4 women with normal insulin levels (sensitivity 100%, specificity 69%; positive predictive value 76%, negative predictive value 100%, diagnostic accuracy rate 85%). Logistic regression models indicated that, of all study covariates, IGFBP-1 was the best predictor variable for AUC-insulin as a binary dependent variable. These results suggest that IGFBP-1 may be a simple serum marker for hyperinsulinemia in a subpopulation of obese menopausal women.

RationaleProgressive midlife weight gain is associated with multiple adverse health outcomes and may represent an early manifestation of insulin resistance in a distinct subset of women. Emerging data implicate hyperinsulinema as a proximate cause of weight gain and support strategies that attenuate insulin secretion.ObjectiveTo assess a previously reported novel hypocaloric carbohydrate modified diet alone (D), and in combination with metformin (M) and metformin plus low-dose rosiglitazone (MR), in diverse women with midlife weight gain (defined as >20lbs since the twenties), normal glucose tolerance, and hyperinsulinemia.Participants46 women, mean age 46.6±1.0, BMI 30.5±0.04 kg/m2, 54.5% white, 22.7% black, 15.9% Hispanic, at 2 university medical centers.MethodsA dietary intervention designed to reduce insulin excursions was implemented in 4 weekly nutritional group workshops prior to randomization.Main Outcome MeasureChange in 6-month fasting insulin. Pre-specified secondary outcomes were changes in body weight, HOMA-IR, metabolic syndrome (MS) measures, leptin, and adiponectin.ResultsSix-month fasting insulin declined significantly in the M group: 12.5 to 8.0 µU/ml, p = .026. Mean 6-month weight decreased significantly and comparably in D, M, and MR groups: 4.7, 5.4, and 5.5% (p’s.049, .002, and.032). HOMA–IR decreased in M and MR groups (2.5 to 1.6 and 1.9 to 1.3, p’s = .054, .013). Additional improvement in MS measures included reduced waist circumference in D and MR groups and increased HDL in the D and M groups. Notably, mean fasting leptin did not decline in a subset of subjects with weight loss (26.15±2.01 ng/ml to 25.99±2.61 ng/ml, p = .907. Adiponectin increased significantly in the MR group (11.1±1.0 to 18.5±7.4, p<.001) Study medications were well tolerated.ConclusionsThese findings suggest that EMPOWIR’s easily implemented dietary interventions, alone and in combination with pharmacotherapies that target hyperinsulinemia, merit additional investigation in larger, long-term studies.Trial RegistrationClinicalTrials.gov NCT00618072

Long-term weight reduction remains the ultimate objective and challenge of obesity management. Few long-term dietary or pharmacointervention studies have been conducted and there is a critical need for long-range treatment strategies that are effective, safe, and acceptable. The authors conducted a retrospective cohort analysis of 21 euglycemic, hyperinsulinemic women with progressive, refractory, midlife weight gain (Syndrome W) who had previously lost weight (> or =10% reduction from baseline) with a comprehensive 1-year treatment program that included metformin and a hypocaloric, carbohydrate-modified (low-glycemic index) diet, as well as, other lifestyle modifications. The goal of the analysis was to determine long-term efficacy of the composite intervention using NHLBI criteria for weight stabilization, weight regain < or =3 kg (6.6 lb) in 2 years. Of a total of 26 consecutive women with Syndrome W who achieved goal weight during a 3-year period (1998-2001), 21 women (mean [standard error] age, 55.2 [2.4] years; mean body mass index, 34.2 [1.3] kg/m(2)) continued metformin and returned for annual follow-up visits. Weight maintenance was observed at the final (2-4 year) follow-up visit in 19/21 (90.5%) of women. Mean final follow-up weight (77.5 [2.8] kg) correlated highly with mean weight at 1-year protocol completion (77.2 [2.7] kg), (correlation coefficients r(xy) and sigma(xy) = 0.96, P = 0.000), demonstrating long-term weight reduction in the surveillance phase. Significant and robust decrements in fasting insulin (-28.4% [8.1%] to -43.4% [3.7%]) were observed at all follow-up visits (P < or = 0.002). This preliminary case series suggests that metformin may be an effective long-term adjunct to dietary and other interventions in the treatment of obesity in hyperinsulinemic patients. A randomized clinical trial of the dual regimen should be considered in nondiabetic women with midlife weight gain and hyperinsulinemia (Syndrome W) and, quite possibly, in additional euglycemic overweight and obese subjects with documented hyperinsulinemia and other portentous features of the Metabolic Syndrome.