Rushika Conroy

Randomized double‐blind placebo‐controlled study of leptin administration after gastric bypass

Obese individuals have high levels of circulating leptin and are resistant to the weight‐reducing effect of leptin administration at physiological doses. Although Roux‐en‐Y gastric bypass (RYGB) is an effective weight loss procedure, there is a plateau in weight loss and most individuals remain obese. This plateau may be partly due to the decline in leptin resulting in a state of relative leptin insufficiency. The main objective of this study was to determine whether leptin administration to post‐RYGB patients would promote further weight reduction.

Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss.

The objective was to examine the effects of weight loss and leptin administration following weight loss on calciotropic hormones and bone turnover. This was a prospective, single-blinded study of 12 subjects (8 women, 4 men; 2 nonobese, 10 obese; age range, 19-46 years) who were studied on an inpatient basis while maintaining their usual weight [Wt(initial)] and during maintenance of 10% weight loss while receiving twice-daily injections of either a placebo [Wt(-10%P)] or replacement doses of leptin [Wt(-10%L)]. The main outcome measures were markers of bone formation (bone alkaline phosphatase and procollagen type 1 amino terminal propeptide) and resorption (N-telopeptide) as well as parathyroid hormone, calcium, and 25-hydroxy vitamin D measured from fasting morning serum. As expected, serum leptin declined with weight loss. Bone alkaline phosphatase decreased by 12.3% ± 3.9% between Wt(initial) and Wt(-10%P) and remained suppressed after leptin administration (both P < .01 compared with baseline). N-telopeptides increased by 37.2% ± 11.3% from Wt(initial) to Wt(-10%L) (P < .01). Procollagen type 1 amino terminal propeptide, parathyroid hormone, calcium, and 25-hydroxy vitamin D did not change. These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss.

Weight loss after bariatric surgery in morbidly obese adolescents with MC4R mutations.

To determine the frequency of Melanocortin 4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations.

Retinol binding protein 4 is associated with adiposity-related co-morbidity risk factors in children.

Abstract Objective: In adults, elevated levels of retinol binding protein 4 (RBP4) have been associated with biochemical markers of adiposity-related co-morbidities including insulin resistance, dyslipidemia, hypertension, and abdominal obesity. This study examined the relationship between RBP4 and risk factors for co-morbidities of adiposity in a population of ethnically diverse children in early- to mid-adolescence in the public school system of New York City. Materials/methods: We analyzed anthropometric (body mass index, % body fat, waist circumference), metabolic (lipids, glucose), and inflammatory (TNF-α, interleukin-6, C-reactive protein, adiponectin) markers for adiposity-related co-morbidities and serum alanine aminotransferase (ALT) in 106 school children (65 males, 41 females) 11–15 years of age (mean±SD=13.0±0.1 years) who were enrolled in the Reduce Obesity and Diabetes (ROAD) project. Insulin sensitivity was assessed by quantitative insulin sensitivity check index. Insulin secretory capacity was measured as acute insulin response and glucose disposal index. Results: Serum RBP4 was significantly correlated directly with ALT, triglycerides, and triglyceride z-score, and inversely correlated with adiponectin. Correlations with ALT and adiponectin remained significant when corrected for % body fat, age, and gender. There were significant ethnic differences in the relationship of RBP4 to ALT, glucose disposal index and adiponectin. Conclusions: In early- to mid-adolescents, circulating concentrations of RBP4 are correlated with multiple risk factors for adiposity-related co-morbidities. The observation that many associations persisted when corrected for % body fat, suggests that RBP4 can be viewed as an independent marker of adiposity-related co-morbidity risk in children.

Effect of laparoscopic adjustable gastric banding on metabolic syndrome and its risk factors in morbidly obese adolescents.

We examined the effect of laparoscopic adjustable gastric banding (LAGB) on weight loss, inflammatory markers, and components of the Metabolic Syndrome (MeS) in morbidly obese adolescents and determined if those with MeS lose less weight post-LAGB than those without. Data from 14–18 yr adolescents were obtained at baseline, 6 and 12 months following LAGB. Significant weight loss and improvements in MeS components were observed 6 months and one year following LAGB. The incidence of MeS declined 56.8% after 6 months and 69.6% after 12 months. There was no significant difference in amount of weight lost post-LAGB between those with and without MeS at either timepoint. Correlations between change in weight parameters and components of MeS in those with and without MeS at baseline were examined and found to vary by diagnostic category. LAGB is effective for short-term improvement in weight, inflammatory markers, and components of MeS in morbidly obese adolescents.

Gonadal dysfunction in Morbidly Obese Adolescent Girls

OBJECTIVE To describe gonadal dysfunction and evaluate polycystic ovary syndrome (PCOS) and its association with metabolic syndrome (MeS) among girls in a morbidly obese adolescent population. DESIGN In a cross-sectional study of 174 girls, height, weight, waist circumference, Tanner stage, reproductive hormones, carbohydrate and lipid markers, drug use, and menstrual history were obtained at baseline. Exclusion criteria were menarcheal age <2 years, hormonal contraceptive or metformin use, Tanner stage <4, and incomplete data on PCOS or MeS classification. SETTING University medical center outpatient clinic. PATIENT(S) Ninety-eight girls ages 13-19.6 years, Tanner 5, average body mass index of 46.6 kg/m(2), menarche at 11.4 years, and average menarcheal age of 5 years. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Polycystic ovary syndrome and MeS. RESULT(S) Ninety-eight girls were divided into four groups: PCOS by National Institutes of Health criteria (PCOSN, n = 24), irregular menses only (n = 25), elevated T (≥55 ng/dL) only (n = 6), and obese controls (n = 43). Metabolic syndrome by modified Cook criteria affected 32 girls or 33% overall: 6 of 24 PCOSN, 7 of 25 irregular menses only, 4 of 6 elevated T only, and 15 of 43 obese controls. Polycystic ovary syndrome by National Institutes of Health criteria and its individual components were not associated with MeS after adjusting for body mass index. CONCLUSION(S) Unlike obese adults, PCOSN and its individual components were not associated with MeS in the untreated morbidly obese adolescent population.

Metabolic Syndrome in Children and Adolescents.

1. Chrystal Wittcopp, MD* 2. Rushika Conroy, MD, MS* 1. *Department of Pediatrics, Baystate Children’s Hospital, Tufts University School of Medicine, Boston, MA. Metabolic syndrome in obese children is associated with increased risk for the development of type 2 diabetes and cardiovascular disease. Currently, no unifying definition exists and the impact of metabolic syndrome on other obesity-related comorbidities continues to be poorly understood. After completing this article, the reader should be able to: 1. Describe the relationship between obesity and metabolic syndrome (MetS). 2. Recognize the difficulty in defining MetS in the pediatric population. 3. Recognize the multiple risk factors associated with MetS in the pediatric population. 4. Describe the importance of various clinical features associated with MetS. 5. Initiate screening for MetS in appropriate patients and develop treatment strategies for those patients. As the prevalence of obesity in adults and youth continues at historically high rates, so does the occurrence of obesity-related comorbidities. Many chronic diseases that were once believed to be conditions of adults alone are now being seen commonly in the pediatric population. The combination of dyslipidemia, abnormal glucose regulation, central adiposity, and hypertension, known collectively as metabolic syndrome (MetS), has long been recognized in the obese adult population and is associated with an increased risk for the development of cardiovascular disease (CVD) and type 2 diabetes (T2D). The definitive criteria for MetS have not been firmly established; many criteria have small differences that can alter the risk stratification for progression to CVD and T2D. (1)(2) What is clear is that the risk of developing CVD or T2D increases substantially in the presence of MetS, with a twofold increase for the former and fivefold increase for the latter in adult populations. (3) In the pediatric population, only 1 set of criteria is …

Recombinant human leptin does not alter gut hormone levels after gastric bypass but may attenuate sweet cravings.

Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05 mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was 53 ± 2.3 months; mean BMI was 34.6 ± 0.2 kg/m2. At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P < 0.05). No other differences were observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women.

Luteoma of pregnancy associated with nearly complete virilization of genetically female twins.

OBJECTIVE To describe a pregnancy that was complicated by the virilization of the mother and two 46XX infants. METHODS We outline the clinical presentation and diagnosis of the virilization of a mother and her twins, reviewing pertinent literature. RESULTS We report the case of a 40-year-old Caucasian female who conceived a trichorionic triplet pregnancy through in vitro fertilization (IVF) but underwent cytoreduction at 13 weeks of gestation, leaving a diamniotic dichorionic twin pregnancy. At 16 weeks of gestation the mother experienced increasing acne, facial hair, and deepening of her voice. Due to preeclampsia, the twins were delivered via caesarean section at 33 weeks of gestation. The infants had male-appearing external genitalia (Prader score IV-V) but no palpable gonads. Congenital adrenal hyperplasia was ruled out for both twins and they were both found to have a uterus and a 46XX karyotype. Maternal testosterone level was elevated at birth (1,981 ng/dL), but the infants had normal levels. Maternal testosterone levels returned to normal after delivery, consistent with a luteoma of pregnancy, although imaging was negative for a mass. CONCLUSION This is the second reported case of complete virilization associated with a luteoma of pregnancy. Whether or not IVF and related procedures increase the risk for a luteoma and whether or not fetal reduction procedures disrupt placental aromatases and increase the risk of virilization in the face of elevated androgen levels are questions that require further research.

Long-term follow-up of gonadal dysfunction in morbidly obese adolescent boys after bariatric surgery.

Abstract Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m2) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 <350 ng/dL. Sixteen had long-term hormonal data for analysis at baseline (T0), 1 year (T1) and 2 years (T2) post-surgery. T-tests, chi-squared (χ2) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 μIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=−0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.