MiR-19 Family Impairs Adipogenesis by the Downregulation of the PPARγ Transcriptional Network.

microRNAs (miRNAs) are a class of small endogenous RNA that play pivotal roles in both the differentiation and function of adipocytes during the development of obesity. Despite this, only a few miRNA families have been identified as key players in adipogenesis. Here, we show the relevance of the miR-19 family, miR-19a and miR-19b, in lipid accumulation and the expansion of the adipose tissue in obesity. We observed that miR-19s were upregulated in the abdominal subcutaneous adipose tissue (aSAT) of human patients with morbid obesity, whereas after bariatric surgery, their expression was reduced. In vitro experiments identified miR-19a and b as crucial actors in adipogenesis and lipid accumulation. Overall, our results suggest a novel role of the miR-19 family in the regulatory networks underlying adipogenesis and, therefore, adipose tissue dysfunction.

Thyroid Function Alteration in Obesity and the Effect of Bariatric Surgery.

The most common endocrine disease in obesity is hypothyroidism and secondary endocrine alterations, including abnormal thyroid function, are frequent in obesity. It is unclear whether impaired thyroid function is the cause or the consequence of increased adiposity; furthermore, there are no clear data regarding the best way to dose levothyroxine for patients with both hypothyroidism and obesity, and the effect of bariatric surgery (BS). The aim of the present article is to review some controversial aspects of the relation between obesity and the thyroid: (1) Thyroid function in obesity and the effect of BS (2) Thyroid hormone treatment (THT) in obese patients with hypothyroidism and the effect of BS. In summary: In morbidly obese patients, TSH is moderately increased. Morbid obesity has a mild central resistance to the thyroid hormone, reversible with weight loss. In morbidly obese hypothyroid patients, following weight loss, the levothyroxine dose/kg of ideal weight did not change, albeit there was an increment in the levothyroxine dose/kg of actual weight. From a clinical practice perspective, in morbid obesity, diagnosing mild hypothyroidism is difficult, BS improves the altered thyroid function and THT can be adapted better if it is based on ideal weight.

Evaluation of Thyroid Hormone Replacement Dosing in Morbidly Obese Hypothyroid Patients after Bariatric Surgery-Induced Weight Loss.

The most frequent endocrine disease in obese patients is hypothyroidism. To date, there are no clear data regarding what happens to the dose of levothyroxine (LT4) after bariatric surgery (BS). The objective of the present study was to evaluate thyroid hormone replacement dose in morbidly obese hypothyroid patients after BS-induced weight loss. We explore the best type of measured or estimated body weight for LT4 dosing. We performed an observational study evaluating patients with morbid obesity and hypothyroidism who underwent BS. We included 48 patients (three men). In morbidly obese hypothyroid patients 12 months after BS-induced weight loss, the total LT4 dose or the LT4 dose/kg ideal body weight did not change, while there was a significant increase in LT4 dose/body surface area, LT4 dose/kg weight, LT4 dose/kg adjusted body weight, LT4 dose/kg body fat, and LT4 dose/kg lean body weight. There were no differences in LT4 dose and its variation between sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The present study strongly suggests that LT4 dosing in obese hypothyroid patients can be individually adapted more precisely if it is based on ideal body weight.

Metabolic recovery after weight loss surgery is reflected in serum microRNAs.

INTRODUCTION: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue. RESEARCH DESIGN AND METHODS: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up. RESULTS: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction. CONCLUSIONS: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.

Altered GH-IGF-1 Axis in Severe Obese Subjects is Reversed after Bariatric Surgery-Induced Weight Loss and Related with Low-Grade Chronic Inflammation.

Endocrine disorders are common in obesity, including altered somatotropic axis. Obesity is characterized by reduced growth hormone (GH) secretion, although the insulin-like growth factor-1 (IGF-1) values are controversial. The aim of this study was to evaluate the effect of weight loss after bariatric surgery in the GH-IGF-1 axis in extreme obesity, in order to investigate IGF-1 values and the mechanism responsible for the alteration of the GH-IGF-1 axis in obesity. We performed an interventional trial in morbidly obese patients who underwent bariatric surgery. We included 116 patients (97 women) and 41 controls (30 women). The primary endpoint was circulating GH and IGF-1 values. Circulating IGF-1 values were lower in the obese patients than in the controls. Circulating GH and IGF-1 values increased significantly over time after surgery. Post-surgery changes in IGF-1 and GH values were significantly negatively correlated with changes in C-reactive protein (CRP) and free T4 values. After adjusting for preoperative body mass index (BMI), free T4 and CRP in a multivariate model, only CRP was independently associated with IGF-1 values in the follow-up. In summary, severe obesity is characterized by a functional hyposomatotropism at central and peripheral level that is progressively reversible with weight loss, and low-grade chronic inflammation could be the principal mediator.

Central Resistance to Thyroid Hormones in Morbidly Obese Subjects Is Reversed after Bariatric Surgery-Induced Weight Loss.

Endocrine abnormalities are common in obesity, including altered thyroid function. The altered thyroid function of obesity may be due to a mild acquired resistance to the thyroid hormone. The aim of this study was to investigate the effect of weight loss after bariatric surgery (BS) on resistance to thyroid hormones in patients with extreme obesity compared with a control group. We performed an observational study evaluating patients with extreme obesity who underwent BS. We included 106 patients (83 women) and 38 controls (24 women). The primary endpoint was the thyrotroph thyroxine resistance index (TT4RI) and thyroid stimulating hormone (TSH) index (TSHRI). The parameters were studied before and after surgery. TSHRI and TT4RI were higher in the obese patients than in the control group. TT4RI and TSHI decreased significantly over time after surgery, with this decrease being associated with the excessive body mass index (BMI) loss and C-reactive protein (CRP). In extreme obesity, BS promotes a significant decrease in the increased TT4RI and TSHI. This decrease of TT4RI and TSHI is progressive over time after BS and significantly associated with excess BMI lost and CRP. Extreme obesity is characterized by a mild reversible central resistance to thyroid hormones.

Beneficial Effects of Bariatric Surgery-Induced by Weight Loss on the Proteome of Abdominal Subcutaneous Adipose Tissue.

Bariatric surgery (BS) is the most effective treatment for obesity and has a positive impact on cardiometabolic risk and in the remission of type 2 diabetes. Following BS, the majority of fat mass is lost from the subcutaneous adipose tissue depot (SAT). However, the changes in this depot and functions and as well as its relative contribution to the beneficial effects of this surgery are still controversial. With the aim of studying altered proteins and molecular pathways in abdominal SAT (aSAT) after body weight normalization induced by BS, we carried out a proteomic approach sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis. These results were complemented by Western blot, electron microscopy and RT-qPCR. With all of the working tools mentioned, we confirmed that after BS, up-regulated proteins were associated with metabolism, the citric acid cycle and respiratory electron transport, triglyceride catabolism and metabolism, formation of ATP, pyruvate metabolism, glycolysis/gluconeogenesis and thermogenesis among others. In contrast, proteins with decreased values are part of the biological pathways related to the immune system. We also confirmed that obesity caused a significant decrease in mitochondrial density and coverage, which was corrected by BS. Together, these findings reveal specific molecular mechanisms, genes and proteins that improve adipose tissue function after BS characterized by lower inflammation, increased glucose uptake, higher insulin sensitivity, higher de novo lipogenesis, increased mitochondrial function and decreased adipocyte size.

Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3.

Mkrn3, the maternally imprinted gene encoding the makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, as evidenced by central precocity caused by MKRN3 mutations in humans; yet, the molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that the microRNA, miR-30, with three binding sites in a highly conserved region of its 3' UTR, operates as repressor of Mkrn3 to control pubertal onset. Hypothalamic miR-30b expression increased, while Mkrn3 mRNA and protein content decreased, during rat postnatal maturation. Neonatal estrogen exposure, causing pubertal alterations, enhanced hypothalamic Mkrn3 and suppressed miR-30b expression in female rats. Functional in vitro analyses demonstrated a strong repressive action of miR-30b on Mkrn3 3' UTR. Moreover, central infusion during the juvenile period of target site blockers, tailored to prevent miR-30 binding to Mkrn3 3' UTR, reversed the prepubertal down-regulation of hypothalamic Mkrn3 protein and delayed female puberty. Collectively, our data unveil a novel hypothalamic miRNA pathway, involving miR-30, with a prominent role in the control of puberty via Mkrn3 repression. These findings expand our current understanding of the molecular basis of puberty and its disease states.

Effect of Weight Loss after Bariatric Surgery on Thyroid-Stimulating Hormone Levels in Euthyroid Patients with Morbid Obesity.

Obesity is associated with several endocrine abnormalities, including thyroid dysfunction. The objective of this study was to investigate the effect of weight loss after bariatric surgery on thyroid-stimulating hormone (TSH) levels in euthyroid patients with morbid obesity. We performed an observational study, evaluating patients with morbid obesity submitted to bariatric surgery. We included 129 patients (92 women) and 31 controls (21 women). Clinical, anthropometric, biochemical, and hormonal parameters were evaluated. The primary endpoint was circulating TSH (µU/mL). Fasting TSH levels were higher in the obese group (3.3 ± 0.2) than in the control group (2.1 ± 0.2). The mean excessive body mass index (BMI) loss (EBMIL) 12 months after bariatric surgery was 72.7 ± 2.1%. TSH levels significantly decreased in the obese patients after surgery; 3.3 ± 0.2 vs. 2.1 ± 0.2 before and 12 months after surgery, respectively. Free thyroxine (T4) (ng/dL) levels significantly decreased in the obese patients after surgery; 1.47 ± 0.02 vs. 1.12 ± 0.02 before and 12 months after surgery, respectively. TSH decreased significantly over time, and the decrement was associated with the EBMIL. In euthyroid patients with morbid obesity, weight loss induced by bariatric surgery promotes a significant decline of the increased TSH levels. This decrement of TSH is progressive over time after surgery and significantly associated with excess BMI loss.

Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications.

BACKGROUND: Ectopic pregnancy is a life-threatening condition for which novel screening tools that would enable early accurate diagnosis would improve clinical outcomes. Kisspeptins, encoded by KISS1, play an essential role in human reproduction, at least partially by regulating placental function and possibly embryo implantation. Kisspeptin levels are elevated massively in normal pregnancy and reportedly altered in various gestational pathologic diseases. Yet, the pathophysiologic role of KISS1/kisspeptin in ectopic pregnancy has not been investigated previously. OBJECTIVE: The purpose of this study was to evaluate changes of KISS1/kisspeptin levels in ectopic pregnancy and their underlaying molecular mechanisms and to ascertain the diagnostic implications of these changes. STUDY DESIGN: A total of 122 women with normal pregnancy who underwent voluntary termination of pregnancy and 84 patients who experienced tubal ectopic pregnancy were recruited. Measurements of plasma kisspeptins and KISS1 expression analyses in human embryonic/placental tissue were conducted in ectopic pregnancy and voluntary termination of pregnancy control subjects during the early gestational window (<12 weeks). Putative microRNA regulators of KISS1 were predicted in silico, followed by expression analyses of selected microRNAs and validation of repressive interactions in vitro. Circulating levels of these microRNAs were also assayed in ectopic pregnancy vs voluntary termination of pregnancy. RESULTS: Circulating kisspeptins gradually increased during the first trimester of normal pregnancy but were reduced markedly in ectopic pregnancy. This profile correlated with the expression levels of KISS1 in human embryonic/placental tissue, which increased in voluntary termination of pregnancy but remained suppressed in ectopic pregnancy. Bioinformatic predictions and expression analyses identified miR-27b-3p and miR-324-3p as putative repressors of KISS1 in human embryonic/placental tissue at <12 weeks gestation, when expression of microRNAs was low in voluntary termination of pregnancy control subjects but significantly increased in ectopic pregnancy. Yet, a significant repressive interaction was documented only for miR-324-3p, occurring at the predicted 3'-UTR of KISS1. Interestingly, circulating levels of miR-324-3p, but not of miR-27b-3p, were suppressed distinctly in ectopic pregnancy, despite elevated tissue expression of the pre-microRNA. A decision-tree model that used kisspeptin and miR-324-3p levels was successful in discriminating ectopic pregnancy vs voluntary termination of pregnancy, with a receiver-operating characteristic area under the curve of 0.95±0.02 (95% confidence interval). CONCLUSION: Our results document a significant down-regulation of KISS1/kisspeptins in early stages of ectopic pregnancy via, at least partially, a repressive interaction with miR-324-3p. Our data identify circulating kisspeptins and miR-324-3p as putative biomarkers for accurate screening of ectopic pregnancy at early gestational ages.

Treatment with Growth Hormone for Adults with Growth Hormone Deficiency Syndrome: Benefits and Risks.

Pharmacological treatment of growth hormone deficiency (GHD) in adults began in clinical practice more than 20 years ago. Since then, a great volume of experience has been accumulated on its effects on the symptoms and biochemical alterations that characterize this hormonal deficiency. The effects on body composition, muscle mass and strength, exercise capacity, glucose and lipid profile, bone metabolism, and quality of life have been fully demonstrated. The advance of knowledge has also taken place in the biological and molecular aspects of the action of this hormone in patients who have completed longitudinal growth. In recent years, several epidemiological studies have reported interesting information about the long-term effects of GH replacement therapy in regard to the possible induction of neoplasms and the potential development of diabetes. In addition, GH hormone receptor polymorphism could potentially influence GH therapy. Long-acting GH are under development to create a more convenient GH dosing profile, while retaining the excellent safety, efficacy, and tolerability of daily GH. In this article we compile the most recent data of GH replacement therapy in adults, as well as the molecular aspects that may condition a different sensitivity to this treatment.

Oral glucose-stimulated growth hormone (GH) test in adult GH deficiency patients and controls: Potential utility of a novel test.

CONTEXT: The diagnosis of adult GH deficiency requires confirmation with a GH stimulation test. Oral glucose (OG) administration affects GH secretion, initially decreasing and subsequently stimulating GH secretion. OBJECTIVE: The aim of this study was to investigate the diagnostic efficacy and safety of a long OG test (LOGT) as a stimulus of GH secretion for the diagnosis of adult GH deficiency (AGHD). DESIGN: Prospective experimental cross-sectional study. SETTINGS: The study was conducted at the Endocrinology department of the University Hospital of a Coruña, Spain. PARTICIPANTS AND METHODS: We included 60 (40 women) AGHD patients (15) and controls (45) paired 1:3, of similar age, sex and BMI. The area under the curve (AUC) and peak were calculated for GH. The Mann-Whitney test was used to compare the different groups. ROC curve analyses were used. p-Values<0.05 were considered as statistically significant. INTERVENTIONS: The intervention consisted of orally administering 75g oral glucose administration; GH was obtained every 30min for a total of 300min. MAIN OUTCOME MEASUREMENT: Peak GH area under receiver operating characteristic curve (ROC-AUC) following LOGT. RESULTS: Peak GH (µg/L) levels were lower in the AGHD patients (0.26±0.09) than in the controls (4.00±0.45), p<0.001. After LOGT, with the ROC plot analysis the best peak GH cut-point was 1.0µg/L, with 100% sensitivity, 78% specificity, ROC-AUC of 0.9089 and 81.82% accuracy. There were no relevant adverse events during any of the LOGT. CONCLUSIONS: The LOGT could be a cheap, safe, convenient and effective test for the diagnosis of AGHD.

Niveles séricos de la adipomioquina irisina en pacientes con enfermedad renal crónica / Serum levels of the adipomyokine irisin in patients with chronic kidney disease

Antecedentes: La irisina es una adipomioquina con posibles efectos antiobesidad y antidiabéticos. Esta hormona ha sido insuficientemente estudiada en pacientes con enfermedad renal crónica (ERC) avanzada. Objetivo: Realizar un análisis exploratorio de los niveles séricos de irisina en pacientes con diferentes modalidades de tratamiento de la ERC. Método: Según diseño transversal, estimamos niveles de irisina en 95 pacientes con ERC manejados conservadoramente (ERCA), con diálisis peritoneal (DP) o con hemodiálisis, comparándolos con un grupo control de 40 individuos sanos. También investigamos las correlaciones entre irisina sérica y variables demográficas, clínicas, metabólicas y de composición corporal. Resultados: Los niveles de irisina fueron más bajos en cualquier grupo de pacientes que en los controles. El análisis univariante desveló correlaciones moderadas entre irisina, por un lado, y masa grasa (pero no magra), filtrado glomerular (GFR) y albúmina y bicarbonato plasmático, por otro. El análisis multivariante confirmó que los pacientes con ERCA (diferencia 111,1ng/mL), en DP (25,9ng/mL) o hemodiálisis (61,4ng/mL) (todos p<0,0005) presentaban niveles ajustados más bajos de irisina que los controles. Asimismo, los pacientes en DP presentaban niveles más altos de la hormona que los de hemodiálisis (diferencia 39,4ng/mL; p=0,002) o ERCA (24,4ng/mL; p=0,036). El análisis multivariante también identificó bicarbonato plasmático (B=3,90 por mM/L; p=0,001) y GFR (B=1,89 por mL/min; p=0,003) como predictores independientes de los niveles de irisina. Por el contrario, no observamos correlación ajustada entre irisina y marcadores de composición corporal. Conclusiones: Los niveles de irisina son bajos en pacientes con ERC, y muestran correlación consistente con GFR y bicarbonato plasmático. Los pacientes en DP presentan niveles más altos de irisina que los manejados conservadoramente o con hemodiálisis. Nuestro estudio confirma una inconsistencia general en los análisis de asociación entre irisina sérica, por un lado, y marcadores metabólicos y de composición corporal, por otro (AU)

Background: Irisin is an adipomyokine with claimed anti-obesity and anti-diabetic effects. This hormone has been insufficiently studied in patients with advanced chronic kidney disease (CKD). Objective: To perform an exploratory analysis of serum irisin levels in patients undergoing different CKD treatments. Method: Following a cross-sectional design, we estimated serum levels of irisin in 95 patients with CKD managed conservatively (advanced CKD), with peritoneal dialysis (PD) or with haemodialysis, and compared our findings with a control group of 40 healthy individuals. We investigated the correlations between serum irisin and demographic, clinical, body composition and metabolic variables. Results: Irisin levels were lower in all the CKD groups than in the control group. The univariate analysis revealed limited correlations between irisin, on the one hand, and fat (but not lean) mass, glomerular filtration rate (GFR) and plasma albumin and bicarbonate, on the other. The multivariate analysis confirmed that advanced CKD patients managed conservatively (difference 111.1ng/ml), with PD (25.9ng/ml) or haemodialysis (61.4ng/ml) (all P<.0005) presented lower irisin levels than the control group. Furthermore, PD patients presented higher serum levels of irisin than those on haemodialysis (difference 39.4ng/ml, P=.002) or those managed conservatively (24.4 ng/ml, P=.036). The multivariate analysis also identified plasma bicarbonate (B=3.90 per mM/l, P=.001) and GFR (B=1.89 per ml/minute,P=.003) as independent predictors of irisin levels. Conversely, no adjusted correlation between irisin and body composition markers was found. Conclusions: Serum irisin levels are low in patients with CKD and show a consistent correlation with GFR and plasma bicarbonate levels. PD patients present higher levels of irisin than those managed conservatively or with haemodialysis. Our study confirms a general inconsistency of the association between serum irisin levels, on the one hand, and body composition and metabolic markers, on the other (AU)

Serum levels of the adipomyokine irisin in patients with chronic kidney disease. / Niveles séricos de la adipomioquina irisina en pacientes con enfermedad renal crónica.

BACKGROUND: Irisin is an adipomyokine with claimed anti-obesity and anti-diabetic effects. This hormone has been insufficiently studied in patients with advanced chronic kidney disease (CKD). OBJECTIVE: To perform an exploratory analysis of serum irisin levels in patients undergoing different CKD treatments. METHOD: Following a cross-sectional design, we estimated serum levels of irisin in 95 patients with CKD managed conservatively (advanced CKD), with peritoneal dialysis (PD) or with haemodialysis, and compared our findings with a control group of 40 healthy individuals. We investigated the correlations between serum irisin and demographic, clinical, body composition and metabolic variables. RESULTS: Irisin levels were lower in all the CKD groups than in the control group. The univariate analysis revealed limited correlations between irisin, on the one hand, and fat (but not lean) mass, glomerular filtration rate (GFR) and plasma albumin and bicarbonate, on the other. The multivariate analysis confirmed that advanced CKD patients managed conservatively (difference 111.1ng/ml), with PD (25.9ng/ml) or haemodialysis (61.4ng/ml) (all P<.0005) presented lower irisin levels than the control group. Furthermore, PD patients presented higher serum levels of irisin than those on haemodialysis (difference 39.4ng/ml, P=.002) or those managed conservatively (24.4 ng/ml, P=.036). The multivariate analysis also identified plasma bicarbonate (B=3.90 per mM/l, P=.001) and GFR (B=1.89 per ml/minute, P=.003) as independent predictors of irisin levels. Conversely, no adjusted correlation between irisin and body composition markers was found. CONCLUSIONS: Serum irisin levels are low in patients with CKD and show a consistent correlation with GFR and plasma bicarbonate levels. PD patients present higher levels of irisin than those managed conservatively or with haemodialysis. Our study confirms a general inconsistency of the association between serum irisin levels, on the one hand, and body composition and metabolic markers, on the other.

Circulating Levels of Irisin in Hypopituitary and Normal Subjects.

CONTEXT: The recently identified myokine irisin conveys some of the benefits of exercise. Hypopituitarism with adult growth hormone deficiency (HP) is a situation characterized by decreased GH secretion and an altered body composition. OBJECTIVE: Our aim was to study the skeletal muscle hormone irisin in HP, and compare the results with a similar group of normal subjects. PARTICIPANTS AND METHODS: Seventeen HP patients and fifty-one normal subjects of similar age and sex were studied. The diagnosis of GH deficiency was confirmed by the presence of pituitary disease and a peak GH secretion below 3 µg/L after an insulin tolerance test. The patients were adequately treated for all pituitary hormone deficits, except for GH. Fasting serum irisin was measured with an enzyme immunoassay, and HOMA-IR, QUICKI and HOMA-ß were calculated. RESULTS: Fasting irisin levels (ng/ml) were similar in normal [208.42 (168.44-249.23)] and HP patients [195.13 (178.44-241.44)]. In the control group there were moderate significant positive correlations between irisin and BMI, waist circumference, leptin, fasting insulin, HOMA-IR, HOMA-ß, triglycerides, and cholesterol. In the control group there were moderate significant negative correlations between irisin and IGF-I and QUICKI. In the hypopituitary group there were moderate significant positive correlations between irisin and body fat and HOMA-ß. CONCLUSIONS: We found similar irisin levels in GH deficiency hypopituitary patients when compared with normal subjects. The correlation between irisin and adiposity related factors suggests that that in the case of this clinical model, irisin is regulated by adiposity and not by GH.

Cost-effectiveness analysis of preoperative treatment of acromegaly with somatostatin analogue on surgical outcome.

CONTEXT: There is no uniform standard of care for acromegaly. Due to the high costs involved, steps must be taken to ensure the cost-effective delivery of treatment. OBJECTIVE: Taking the results of an earlier meta-analysis as a starting point, this study aims to determine whether treatment with long-acting somatostatin analogue (SSA) prior to surgery improves the cost-effectiveness of the treatment of acromegaly. METHODS: The results are presented as an Incremental Cost Effectiveness Ratio (ICER) immediately after surgery, for the following year and over the next four decades. The cure rates percentage (95% CI) for the three randomized prospective controlled trials were 44.4% (34.2-54.7) and 18.2% (10.1-26.3) for preoperative treated and untreated patients respectively. The cost of pharmacological treatments was based on the number of units prescribed, dose and length of treatment. RESULTS: The mean (95% CI) ICER immediately after surgery was €17,548 (12,007-33,250). In terms of the postoperative SSA treatment, the ICER changes from positive to negative before two years after surgery. One decade after surgery the ICER per patient/year was €-9973 (-18,798; -6752) for postoperative SSA treatment and €-31,733 (-59,812; -21,483) in the case of postoperative pegvisomant treatment. CONCLUSIONS: In centres without optimal surgical results, preoperative treatment of GH-secreting pituitary macroadenomas with SSA not only shows a significant improvement in the surgical results, but is also highly cost-effective, with an ICER per patient/year one decade after surgery, of between €-9973 (-18,798; -6752) and €-31,733 (-59,812; -21,483) for SSA and pegvisomant respectively.

Effect of oral glucose administration on rebound growth hormone release in normal and obese women: the role of adiposity, insulin sensitivity and ghrelin.

CONTEXT: Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue. OBJECTIVE: The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity. PARTICIPANTS AND METHODS: We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed. RESULTS: The AUC of GH (µg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.

Perturbation of hypothalamic microRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance.

The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet-induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.

The Lin28/Let-7 system in early human embryonic tissue and ectopic pregnancy.

Our objective was to determine the expression of the elements of the Lin28/Let-7 system, and related microRNAs (miRNAs), in early stages of human placentation and ectopic pregnancy, as a means to assess the potential role of this molecular hub in the pathogenesis of ectopic gestation. Seventeen patients suffering from tubal ectopic pregnancy (cases) and forty-three women with normal on-going gestation that desired voluntary termination of pregnancy (VTOP; controls) were recruited for the study. Embryonic tissues were subjected to RNA extraction and quantitative PCR analyses for LIN28B, Let-7a, miR-132, miR-145 and mir-323-3p were performed. Our results demonstrate that the expression of LIN28B mRNA was barely detectable in embryonic tissue from early stages of gestation and sharply increased thereafter to plateau between gestational weeks 7-9. In contrast, expression levels of Let-7, mir-132 and mir-145 were high in embryonic tissue from early gestations (≤ 6-weeks) and abruptly declined thereafter, especially for Let-7. Opposite trends were detected for mir-323-3p. Embryonic expression of LIN28B mRNA was higher in early stages (≤ 6-weeks) of ectopic pregnancy than in normal gestation. In contrast, Let-7a expression was significantly lower in early ectopic pregnancies, while miR-132 and miR-145 levels were not altered. Expression of mir-323-3p was also suppressed in ectopic embryonic tissue. We are the first to document reciprocal changes in the expression profiles of the gene encoding the RNA-binding protein, LIN28B, and the related miRNAs, Let-7a, mir-132 and mir-145, in early stages of human placentation. This finding suggests the potential involvement of LIN28B/Let-7 (de)regulated pathways in the pathophysiology of ectopic pregnancy in humans.

Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis.

CONTEXT: Transsphenoidal neurosurgery is the accepted first-line treatment of acromegaly in the majority of patients. Previous studies addressing preoperative somatostatin analog (SSA) treatment and subsequent surgical cure rates are conflicting, reporting either benefits or no significant differences. OBJECTIVE: The aim of this study, based on a meta-analysis of all published reports, was to investigate whether treatment with SSA before surgery improves the surgical outcome of acromegaly. DATA SOURCES: All studies of preoperative treatment of acromegaly with SSA were systematically reviewed up to December 2011. We searched the Medline, Embase, Cochrane and Google Scholar electronic databases. STUDY SELECTION: The primary endpoint was the biochemical postoperative cure rate. We identified 286 studies, out of which 10 studies (3.49%) fulfilling the eligibility criteria were selected for analysis; five retrospective studies with a control group, two prospective non-randomized trials, and three prospective controlled trials. The meta-analysis was conducted using the random-effects model. DATA EXTRACTION: Data were extracted from published reports by two independent observers. DATA SYNTHESIS: A borderline effect was detected in the analysis of all of the trials with control groups, with a pooled odds ratio (OR) for biochemical cure with SSA treatment of 1.62 (95% CI, 0.93-2.82). In the analysis of the three prospective controlled trials, a statistically significant effect was identified OR: 3.62 (95% CI, 1.88-6.96). CONCLUSIONS: Preoperative treatment with SSA og GH-secreting pituitary adenomas shows a significant improvement on surgical results. This meta-analysis suggests that in centers without optimal results all patients with a GH-secreting pituitary macroadenoma should be treated with a long-acting SSA prior to surgical treatment.