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

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.

Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress: a retrospective chart review.

BACKGROUND: Aromatase inhibitors (AIs) have been used off-label to increase adult height in short adolescent males. Studies have shown that AIs increase the predicted adult height (PAH) while delaying bone age (BA) maturation. We sought to determine whether AI therapy increases PAH in boys with short stature or rapid pubertal progression, and to evaluate any untoward effects. METHODS: The charts of 27 boys with BA ≥ 13 and short stature [height ≥ 2 standard deviation (SD) below the mean or ≥ 2 SD below mid-parental target height (MPTH)] or rapid pubertal progress, treated with anastrozole were reviewed. Outcome measures included anthropomorphic, hormonal, and metabolic data. RESULTS: The AI therapy averaged 21 months (range 14-30 months) for all, with Rx group 1 receiving <18 months therapy (n=7) and Rx group 2 receiving 18-30 months therapy (n=20). Post-therapy, in Rx group 1 and all subjects, there was no significant change in the PAH, height SDS, or BA/chronological age (CA). In Rx group 2, there was a small, nonsignificant increase in PAH, no change in height SDS, and a small decrease in BA/CA. Post-therapy PAH was different from MPTH in all and in both Rx groups 1 and 2, p<0.02. Eight of them achieved near-final height, averaging 6.73 ± 1.40 cm less than MPTH and 1.91 ± 0.86 cm less than the pre-therapy PAH. Post-therapy, the initially decreased estradiol did not persist but mildly increased testosterone and decreased high-density lipoprotein were noted, as was an increase in hematocrit, and decrease in growth velocity. CONCLUSIONS: We suggest that although bone age progression may be slightly delayed with longer duration of therapy, an overall short-term AI therapy does not lead to a final height that is greater than the predicted pre-therapy height.

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.

Vitamin D Deficiency Is Prevalent in Morbidly Obese Adolescents Prior to Bariatric Surgery.

BACKGROUND: Obese adults are frequently vitamin D deficient before bariatric surgery; whether similar abnormalities exist in morbidly obese adolescents is unknown. OBJECTIVE: To determine the prevalence of vitamin D deficiency in morbidly obese adolescents. METHODS: Cross-sectional study of preoperative laboratory measures from 236 adolescents evaluated for bariatric surgery. RESULTS: The group (N = 219 with 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) levels; 76 boys, 143 girls; 15.9 ± 1.2 years; 43% Caucasian, 35% Hispanic, and 15% African American) had mean BMI of 47.6 ± 8.1 kg/m2. 25OHD levels were deficient (<20 ng/mL) in 53%; 8% had severe deficiency (<10 ng/mL); only 18% of patients were replete (>30 ng/mL). 25OHD levels were inversely associated with BMI (r = -0.28, < 0.0001) and PTH levels (r = -0.24, P = 0.0003). Race was the strongest predictor of 25OHD (P < 0.002); 82% of African Americans, 59% of Hispanics, and 37% of Caucasians were deficient. African American race, BMI, and PTH explained 21% of the variance in 25OHD (P < 0.0001). CONCLUSIONS: Most adolescents presenting for bariatric surgery have suboptimal vitamin D levels, with African Americans and those with higher BMIs at greatest risk for vitamin D deficiency. All morbidly obese adolescents should be screened for vitamin D deficiency before bariatric procedures.

Pediatric pulmonary arterial hypertension and hyperthyroidism: a potentially fatal combination.

CONTEXT: Patients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death. CASES AND SETTING: We present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline. EVIDENCE SYNTHESIS: Aggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and ß-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation. CONCLUSIONS: Although the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.

Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury.

BACKGROUND: The beneficial effects of reperfusion therapies have been limited by the amount of ischemic damage that occurs before reperfusion. To enable development of interventions to reduce cell injury, our research has focused on understanding mechanisms involved in cardiac cell death after ischemia/reperfusion (I/R) injury. In this context, our laboratory has been investigating the role of the receptor for advanced-glycation end products (RAGE) in myocardial I/R injury. METHODS AND RESULTS: In this study we tested the hypothesis that RAGE is a key modulator of I/R injury in the myocardium. In ischemic rat hearts, expression of RAGE and its ligands was significantly enhanced. Pretreatment of rats with sRAGE, a decoy soluble part of RAGE receptor, reduced ischemic injury and improved functional recovery of myocardium. To specifically dissect the impact of RAGE, hearts from homozygous RAGE-null mice were isolated, perfused, and subjected to I/R. RAGE-null mice were strikingly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH, improved functional recovery, and increased adenosine triphosphate (ATP). In rats and mice, activation of the RAGE axis was associated with increases in inducible nitric oxide synthase expression and levels of nitric oxide, cyclic guanosine monophosphate (cGMP), and nitrotyrosine. CONCLUSIONS: These findings demonstrate novel and key roles for RAGE in I/R injury in the heart. The findings also demonstrate that the interaction of RAGE with advanced-glycation end products affects myocardial energy metabolism and function during I/R.

Receptor for advanced glycation end products and its ligands: a journey from the complications of diabetes to its pathogenesis.

Many studies have suggested that the expression of RAGE (receptor for advanced glycation end products) is upregulated in human tissues susceptible to the long-term complications of diabetes. From the kidneys to the macrovessels of the aorta, RAGE expression is upregulated in a diverse array of cell types, from glomerular epithelial cells (podocytes) to endothelial cells, vascular smooth muscle cells, and inflammatory mononuclear phagocytes and lymphocytes. Although RAGE was first described as a receptor for advanced glycation end products (AGEs), the key finding that RAGE was also a signaling receptor for proinflammatory S100/calgranulins and amphoterin, led to the premise that even in euglycemia, ligand-RAGE interaction propagated inflammatory mechanisms linked to chronic cellular perturbation and tissue injury. Indeed, such considerations suggested that RAGE might even participate in the pathogenesis of type 1 diabetes. Our studies have shown that pharmacological and/or genetic deletion/mutation of the receptor attenuates the development of hyperglycemia in NOD mice; in mice with myriad complications of diabetes, interruption of ligand-RAGE interaction prevents or delays the chronic complications of the disease in both macro- and microvessel structures. Taken together, these findings suggest that RAGE is "at the right place and time" to contribute to the pathogenesis of diabetes and it complications. Studies are in progress to test the premise that antagonism of this interaction is a logical strategy for the prevention and treatment of diabetes.

Growth hormone therapy in children after cranial/craniospinal radiation therapy: sexually dimorphic outcomes.

Radiation therapy (RT) to the craniospinal region in childhood affects final height. The use of GH treatment (GHRx) in children after cranial or craniospinal RT results in variable improvement in final height. Nineteen children (12 males and 7 females) with tumors of the head, treated with cranial or craniospinal RT and subsequently with GHRx, were assessed for final height. Two outcome measures of efficacy of GHRx were used: Y1 = final height SD score (SDS) corrected for genetic potential, using midparental sex-adjusted target height (SATH) SDS, and Y2 = change in height SDS from predicted final height SDS pre-GHRx to actual final height SDS post-GHRx. The median age at diagnosis was 5.4 yr, the median RT to the hypothalamic-pituitary axis was 40 Gy, the median spinal RT dose in 13 of 19 of the subjects treated was 36 Gy, and the median years post-RT to GHRx was 4.8 yr. Adjuvant chemotherapy was used in 12 of 19 patients. All but one (optic glioma) had a lesion anatomically distant from the suprasellar region. The effects of age at diagnosis, sex, L-T4 or GnRH agonist use, conventional vs. hyperfractionated RT, spinal RT, dose of spinal or cranial RT, chemotherapy, peak stimulated GH, dose and duration of GHRx, age at GHRx, time interval between RT and GHRx initiation, bone age, and height SDS at the start of GHRx were also assessed. Y1girls best correlated with younger age at diagnosis and im vs. sc GHRx. Y2girls best correlated with delayed bone age and younger age at diagnosis [Y1girls = -9.95 + 0.38 (age in years at diagnosis) + 3.11[GH method (1 = i.m.; 2 = s.c.)]; r2 = 0.898; P = 0.02; Y2girls = -3.54 + 1.8 (bone age - age in years) + 0.334 (age at diagnosis in years); r2= 0.956; P = 0.02]. Both Y1boys and Y2boys were strongly associated with spinal RT and younger age at diagnosis or treatment [Y1boys = -11.22 + 4.65 [spinal RT (1 = yes; 2 = no)] + 0.396 (age in years at diagnosis); r2= 0.64, P = 0.01; Y2boys = -6.32 + 0.23 (age in years at GH start) + 1.75 [spinal RT (1 = yes; 2 = no)]; r2= 0.646; P < 0.01]. This small historical cohort underscores that final stature is significantly reduced when immature bones are exposed to ionizing radiation. Intramuscular vs. sc use of GHRx is likely to be simply a surrogate marker for earlier methods of treatment. Of note, spinal RT did not significantly impact girls' final heights, whereas in boys, spinal RT strongly predicted ultimate short stature and a reduced response to GHRx. This sexually dichotomous response may be due in part to the greater percentage of spinal growth remaining for boys vs. girls throughout childhood.