Effect of Transdermal Estradiol and Insulin-like Growth Factor-1 on Bone Endpoints of Young Women With Anorexia Nervosa.

CONTEXT: Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. OBJECTIVE: To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes. DESIGN: Double-blind, randomized, placebo-controlled 12-month longitudinal study. PARTICIPANTS: Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study. INTERVENTION: Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. MAIN OUTCOME MEASURES: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. RESULTS: Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. CONCLUSIONS: We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.

Cyberbullying and Adolescents.

PURPOSE OF REVIEW: Cyberbullying is an aggressive behavior involving a type of electronic communication intending to harm a victim that can have profound effects on adolescents. This review examines the epidemiology, issues from cyberbullying, presentation to care of its victims and proposed interventions to this behavior. RECENT FINDINGS: There are a variety of physical and psychological effects on victims of cyberbullying that can include recurrent abdominal pain, headaches and difficulty with sleep. In addition, victims have higher rates of anxiety, depression, suicidal ideation and a lower level of well-being. Unfortunately, victims may remain silent, so screening for cyberbullying is encouraged in a variety of settings. Interventions can be designed at the level of the victim (and perpetrator), family, school and other support networks. Prevention of cyberbullying can be a focus for providers of healthcare. SUMMARY: Cyberbullying can have profound biopsychosocial effects on its victims. There are strategies currently in use and under development to identify and intervene on behalf of those affected by these behaviors.

Suboptimal bone microarchitecure in adolescent girls with obesity compared to normal-weight controls and girls with anorexia nervosa.

BACKGROUND: Despite their higher areal bone mineral density (aBMD), adolescents with obesity (OB) have an increase in fracture risk, particularly of the extremities, compared with normal-weight controls. Whereas bone parameters that increase fracture risk are well characterized in anorexia nervosa (AN), the other end of nutritional spectrum, these data are lacking in adolescents with obesity. OBJECTIVE: Our objective was to compare bone parameters in adolescent girls across the nutritional spectrum, to determine whether suboptimal bone adaptation to increased body weight may explain the increased fracture risk in OB. METHODS: We assessed bone endpoints in 153 adolescent girls 14-21 years old: 50 OB, 48 controls and 55 AN. We used (i) DXA to assess aBMD at the lumbar spine, proximal femur and whole body, and body composition, (ii) high resolution peripheral quantitative CT (HRpQCT) to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and (iii) finite element analysis to assess failure load (a strength estimate) at the distal radius and tibia. All aBMD, microarchitecture and FEA analyses were controlled for age and race. RESULTS: Groups did not differ for age or height. Areal BMD Z-scores at all sites were highest in OB, intermediate in controls and lowest in AN (p < 0.0001). At the radius, cortical area and thickness were higher in OB compared to AN and control groups (p = 0.001) while trabecular area did not differ across groups. Compared to controls, OB had higher cortical porosity (p = 0.003), higher trabecular thickness (p = 0.024), and higher total, cortical and trabecular vBMD and rod BV/TV (p < 0.04). Plate BV/TV did not differ in OB vs. controls, but was higher than in AN (p = 0.001). At the tibia, total, cortical, and trabecular area and cortical thickness were higher in OB vs. controls and AN (p < 0.005). OB also had higher cortical porosity (p < 0.007) and lower trabecular thickness (p < 0.02) than the other two groups. Trabecular number, total and trabecular vBMD, and rod BV/TV were higher in OB vs. controls and AN (p < 0.02), while cortical vBMD and plate BV/TV did not differ in OB vs. the other two groups. Finally, failure load (a strength estimate) was higher in OB at the radius and tibia compared to controls and AN (p < 0.004 for all). However, after adjusting for body weight, failure load was lower in OB vs. controls at both sites (p < 0.05), and lower than in AN at the distal tibia. CONCLUSION: Not all bone parameters demonstrate appropriate adaptation to higher body weight. Cortical porosity and plate BV/TV at the radius and tibia, and cortical vBMD and trabecular thickness at the tibia are particularly at risk. These effects may contribute to the higher risk for fracture reported in OB vs. controls.

Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial.

OBJECTIVE: Anorexia nervosa is characterized by low weight, aberrant eating attitudes, body image distortion, and hypogonadism. Anxiety is a common comorbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in anorexia nervosa. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes without affecting body image in anorexia nervosa. METHOD: Girls 13-18 years old with anorexia nervosa (DSM-IV) were randomized to transdermal estradiol (100 µg twice weekly) with cyclic progesterone or placebo patches and pills for 18-months, between 2002 and 2010. The State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory-2 (EDI-2), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these measures at baseline (n=38 [girls receiving estrogen] and n=34 [girls receiving placebo]) and 37 at 18 months (n=20 [girls receiving estrogen] and n=17 [girls receiving placebo]). The primary outcome measure was the change in these scores over 18 months. RESULTS: Estrogen replacement caused a decrease in STAIC-trait scores (-3.05 [1.22] vs. 2.07 [1.73], P=.02), without impacting STAIC-state scores (-1.11 [2.17] vs. 0.20 [1.42], P=.64). There was no effect of estrogen replacement on EDI-2 or BSQ-34 scores. Body mass index (BMI) changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (P=.03). Increases in serum estradiol were significantly associated with decreases in STAIC-trait scores (Spearman ρ = -0.45, P=.03). CONCLUSIONS: Estrogen replacement improved trait anxiety (the tendency to experience anxiety) but did not impact eating attitudes or body shape perception. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00088153.

Adolescent girls with anorexia nervosa have impaired cortical and trabecular microarchitecture and lower estimated bone strength at the distal radius.

CONTEXT: Adolescents with anorexia nervosa (AN) have low areal bone mineral density (aBMD) at both cortical and trabecular sites, and recent data show impaired trabecular microarchitecture independent of aBMD. However, data are lacking regarding both cortical microarchitecture and bone strength assessment by finite element analysis (FEA) in adolescents with AN. Because microarchitectural abnormalities and FEA may predict fracture risk independent of aBMD, these data are important to obtain. OBJECTIVE: Our objective was to compare both cortical and trabecular bone microarchitecture and FEA estimates of bone strength in adolescent girls with AN vs normal-weight controls. DESIGN, SETTING, AND SUBJECTS: We conducted a cross-sectional study at a clinical research center that included 44 adolescent girls (21 with AN and 23 normal-weight controls) 14 to 22 years old. MAIN OUTCOME MEASURES: We evaluated 1) aBMD (dual-energy x-ray absorptiometry) at the distal radius, lumbar spine, and hip, 2) cortical and trabecular microarchitecture at the ultradistal radius (high-resolution peripheral quantitative computed tomography), and 3) FEA-derived estimates of failure load at the ultradistal radius. RESULTS: aBMD was lower in girls with AN vs controls at the lumbar spine and hip but not at the distal radius. Girls with AN had lower total (P < .0001) and trabecular volumetric BMD (P = .02) and higher cortical porosity (P = .03) and trabecular separation (P = .04). Despite comparable total cross-sectional area, trabecular area was higher in girls with AN (P = .04), and cortical area and thickness were lower (P = .002 and .02, respectively). FEA-estimated failure load was lower in girls with AN (P = .004), even after controlling for distal radius aBMD. CONCLUSIONS: Both cortical and trabecular microarchitecture are altered in adolescent girls with AN. FEA-estimated failure load is decreased, indicative of reduced bone strength. The finding of reduced cortical bone area in girls with AN is consistent with impaired cortical bone formation at the endosteum as a mechanism underlying these findings.

Nonfocal renal biopsies: adequacy and factors affecting a successful outcome.

PURPOSE: The purpose of this study was to evaluate factors affecting the success of ultrasound-guided core biopsy of kidneys and determine the optimum number of passes. METHODS: This retrospective study evaluated 484 nonfocal renal biopsies performed with 18-gauge side-notch biopsy needles. Number of biopsy passes, serum creatinine, body mass index, needle type, transplant age, kidney size, diabetic status, and operator were evaluated as predictors of the number of biopsy passes. RESULTS: Four hundred seventy-four biopsies (338 transplant, 136 native) were included with mean number of passes 2.87 (3.1 native vs 2.78 transplant; P = 0.002). Mean number of glomeruli yielded per pass was 6.9 (7.2 transplant vs 6.1 native; P = 0.0002) with 3 passes adequate for histological diagnosis in 84% of biopsies. Native kidney, increasing serum creatinine level, trainee biopsy operator, and use of a Temno needle were found to be independent predictors of having more than 3 biopsy passes on multivariate analysis. Age, sex, body mass index, diabetic status, and kidney size were not associated with the number of biopsy passes. CONCLUSIONS: The success of a nonfocal renal biopsy has many influencing variables, and in the absence of an on-site electron microscopy technologist to immediately evaluate biopsy samples, 3 passes with an 18-gauge needle would be adequate in 84% of kidneys to achieve a histological diagnosis, with 2 passes needed for transplant kidneys to meet the Banff 97 criteria.

Detection of urothelial tumors: comparison of urothelial phase with excretory phase CT urography--a prospective study.

PURPOSE: To compare contrast material-enhanced computed tomographic (CT) urography 60 seconds after injection of contrast material (urothelial phase [UP]) after intravenous administration of a diuretic with the standard 5-minute delayed excretory phase (EP) in a high-risk population for upper tract tumors. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Eighty CT urographic examinations in 77 patients known to have or at high risk for urothelial malignancy were included. After intravenous administration of a diuretic, dual-phase CT urography was performed at 60 seconds (UP) and 5 minutes (EP) after intravenous administration of contrast material. Two experienced abdominal radiologists independently interpreted each phase more than 1 month apart to minimize recall bias. Urinary tract distention and location and size of all lesions suspected of being urothelial tumors were recorded. Standard of reference was obtained from prospective study interpretation and surgical histopathologic findings. Generalized estimating equations for logistic regression were used to compare performance measures and adjust for the correlation of repeated measures within patients. RESULTS: There were 23 upper and 61 lower urinary tract tumors confirmed in 15 and 32 patients, respectively. For detection of bladder tumors, there was higher sensitivity for the UP than the EP (89.3% [109 of 122] vs 70.5% [86 of 122], respectively; P<.0001). For detection of upper tract tumors, there was higher sensitivity for the UP than the EP (82.6% [38 of 46] vs 69.6% [32 of 46], respectively; P=.0194). Distention of all upper urinary tract segments was better during the EP than the UP (P<.0001). CONCLUSION: UP CT urography after injection of a diuretic has a higher lesion detection rate than the EP for both upper and lower urinary tract tumors, which suggests its possible use as a single-phase protocol for evaluation of the entire urinary tract in patients at high risk for urothelial tumors.

Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.

Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including hypogonadism and low estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high estrogen doses given as an oral contraceptive do not improve BMD. The impact of physiologic estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] ≥15 years, n = 96) were randomized to 100 µg of 17ß-estradiol (with cyclic progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low-dose oral ethinyl-estradiol (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, 11.25 µg from 12 to 18 months) to mimic pubertal estrogen increases or placebo for 18 months. All BMD measures assessed by dual-energy X-ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to estrogen (AN E + ) did not differ from those randomized to placebo (AN E-) for age, maturity, height, BMI, amenorrhea duration, and BMD parameters. Spine and hip BMD Z-scores increased over time in the AN E+ compared with the AN E- group, even after controlling for baseline age and weight. It is concluded that physiologic estradiol replacement increases spine and hip BMD in girls with AN.

Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa.

BACKGROUND: Adolescents with anorexia nervosa (AN) have low bone density and low levels of surrogate markers of bone formation. Low bone density is a consequence of hormonal alterations that include hypogonadism and decreases in IGF-1, a bone trophic factor. Although IGF-1 is key to pubertal bone accretion, and effects have been demonstrated in adults, there are no data regarding the effect of recombinant human (rh) IGF-1 administration in adolescents with AN. OBJECTIVES: We hypothesized that rhIGF-1 would cause an increase in PINP, a bone formation marker, in girls with AN, without any effect on CTX, a bone resorption marker. SUBJECTS AND METHODS: RhIGF-1 was administered at a dose of 30-40 mcg/k twice daily to 10 consecutive girls with AN 12-18 years old for 7-9 days. Ten age-matched girls with AN were followed without rhIGF-1 for a similar period. IGF-1, PINP and CTX levels were measured. RESULTS: RhIGF-1 administration caused an increase in IGF-1 from day-1 to day-4/5 (p<0.0001) and day-1 to day-8/9 (p<0.0001). Simultaneously, PINP increased from day-1 to day-4/5 (p=0.004) and day-1 to day-8/9 (p=0.004), with a smaller increase from day-4/5 to day-8/9 (p=0.048). CTX levels did not change with rhIGF-1 administration. No changes occurred in IGF-1 or PINP levels in girls not receiving rhIGF-1; however, CTX levels increased significantly (p=0.01). Percent change in PINP was significantly higher (p=0.02) and percent change in CTX was significantly lower (p=0.006) in girls who received rhIGF-1 compared to those who did not receive any intervention. RhIGF-1 was well tolerated without hypoglycemia. CONCLUSION: Short-term administration of rhIGF-1 causes an increase in a surrogate bone formation markers in girls with AN without significant side effects.

Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects.

OBJECTIVE: We hypothesized that, despite increased activity, bone density would be low in athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, because of associated hypogonadism and would be associated with a decrease in bone formation and increases in bone-resorption markers. METHODS: In a cross-sectional study, we examined bone-density measures (spine, hip, and whole body) and body composition by using dual-energy radiograph absorptiometry and assessed fasting levels of insulin-like growth factor I and bone-turnover markers (N-terminal propeptied of type 1 procollagen and N-telopeptide) in 21 athletes with amenorrhea, 18 athletes with eumenorrhea, and 18 control subjects. Subjects were 12 to 18 years of age and of comparable chronologic and bone age. RESULTS: Athletes with amenorrhea had lower bone-density z scores at the spine and whole body, compared with athletes with eumenorrhea and control subjects, and lower hip z scores, compared with athletes with eumenorrhea. Lean mass did not differ between groups. However, athletes with amenorrhea had lower BMI z scores than did athletes with eumenorrhea and lower insulin-like growth factor I levels than did control subjects. Levels of both markers of bone turnover were lower in athletes with amenorrhea than in control subjects. BMI z scores, lean mass, insulin-like growth factor I levels, and diagnostic category were important independent predictors of bone mineral density z scores. CONCLUSIONS: Although they showed no significant differences in lean mass, compared with athletes with eumenorrhea and control subjects, athletes with amenorrhea had lower bone density at the spine and whole body. Insulin-like growth factor I levels, body-composition parameters, and menstrual status were important predictors of bone density. Follow-up studies are necessary to determine whether amenorrhea in athletes adversely affects the rate of bone mass accrual and therefore peak bone mass.