Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa.

OBJECTIVE: To (i) compare fracture prevalence in adolescent females with anorexia nervosa (AN) versus normal-weight controls and (ii) examine whether reductions in areal bone mineral density (aBMD) predict fracture risk in females with AN. METHOD: Four-hundred eighteen females (310 with active AN and 108 normal-weight controls) 12- to 22-years-old were studied cross-sectionally. Lifetime fracture history was recorded by a physician during participant interviews. Body composition and aBMD measurements of the whole body, whole body less head, lumbar spine, and hip were assessed by dual-energy X-ray absorptiometry, and bone mineral apparent density (BMAD) was calculated for the lumbar spine. RESULTS: Participants with AN and normal-weight controls did not differ for chronological age, sexual maturity, or height. The lifetime prevalence of prior fracture was 59.8% higher in those with AN as compared to controls (31.0% vs. 19.4%, p = 0.02), and the fracture incidence rate peaked in our cohort after the diagnosis of AN. Lower aBMD and lumbar BMAD were not associated with a higher prevalence of fracture in the AN or control group on univariate or multivariate analyses. Compared to controls, fracture prevalence was significantly higher in the subgroup of girls with AN who had normal aBMD or only modest reductions of aBMD (Z-scores > -1 or -1.5). DISCUSSION: This is the first study to show that the risk of fracture during childhood and adolescence is significantly higher in patients with AN than in normal-weight controls. Fracture prevalence is increased in this cohort of participants with AN even without significant reductions in aBMD.

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.

Bone density characteristics and major depressive disorder in adolescents.

OBJECTIVE: Major depressive disorder (MDD) is common during adolescence, a period characterized by rapid bone mineral accrual. MDD has recently been associated with lower bone mineral density (BMD) in adults. Our objective was to determine whether MDD is associated with BMD, bone turnover markers, vitamin D, and gonadal steroids in adolescents. METHODS: Sixty-five adolescents 12 to 18 years of age (32 boys: 16 with MDD and 16 controls; 33 girls: 17 with MDD and 16 controls) were included in a cross-sectional study. BMD and body composition were obtained by dual-energy x-ray absorptiometry. Estradiol, testosterone, 25-hydroxy vitamin D levels, N-terminal propeptide of Type 1 procollagen (a marker of bone formation), and Type I collagen C-telopeptide (a marker of bone resorption) were measured. RESULTS: Boys with MDD had a significantly lower BMD at the hip (mean [standard deviation]=0.99 [0.17] g/cm2 versus 1.04 [0.18] g/cm2, body mass index [BMI] adjusted, p=.005) and femoral neck (0.92 [0.17] g/cm2 versus 0.94 [0.17] g/cm2; BMI adjusted, p=.024) compared with healthy controls after adjusting for BMI. This significant finding was maintained after also adjusting for lean mass and bone age (hip: p=.007; femoral neck: p=.020). In girls, there were no significant differences in BMD between the girls with MDD and the controls after adjusting for BMI (p>.17). CONCLUSIONS: Male adolescents with MDD have a significantly lower BMD as compared with healthy controls after adjusting for body mass and maturity. This association is not observed in girls.

Inhibition of Pref-1 (preadipocyte factor 1) by oestradiol in adolescent girls with anorexia nervosa is associated with improvement in lumbar bone mineral density.

OBJECTIVE: Adolescents with anorexia nervosa (AN) are amenorrheic and have decreased bone mass accrual and low bone mineral density (BMD). The regulation of mesenchymal stem cell differentiation is an important factor governing bone formation. Preadipocyte factor 1 (Pref-1), an inhibitor of adipocyte and osteoblast differentiation, is elevated in states of oestrogen deficiency. In this study, we aim to (i) investigate effects of transdermal oestradiol on Pref-1 in adolescent girls with AN, and (ii) examine associations of changes in Pref-1 with changes in lumbar BMD and bone turnover markers. DESIGN: Adolescent girls with AN and normal-weight controls were studied cross-sectionally. Girls with AN were examined longitudinally in a double-blind study and received transdermal oestradiol (plus cyclic medroxyprogesterone) or placebo for 12 months. PATIENTS: Sixty-nine girls (44 with AN, 25 normal-weight controls) 13-18 years were studied at baseline; 22 AN girls were followed prospectively. MEASUREMENTS: Pref-1 levels, bone formation and resorption markers, and BMD. RESULTS: Pref-1 levels decreased in girls with AN after treatment with transdermal oestradiol compared with placebo (-0·015 ± 0·016 vs 0·060±0·026 ng/ml, P = 0·01), although at baseline, levels did not differ in AN vs controls (0·246 ± 0·015 vs 0·267 ± 0·022 ng/ml). Changes in Pref-1 over 12 months correlated inversely with changes in lumbar BMD (r = -0·48, P = 0·02) and positively with changes in CTX (r = 0·73, P = 0·006). CONCLUSIONS: For the first time, we show that Pref-1 is negatively regulated by oestradiol in adolescent girls with AN. Inhibition of Pref-1 may mediate the beneficial effects of transdermal oestradiol replacement on BMD in girls with AN.

Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls.

Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal-weight controls) 13-18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r=0.67 and 0.53, p=0.0002 and 0.005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group.

Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls.

Amenorrhea is common in young athletes and is associated with low fat mass. However, hormonal factors that link decreased fat mass with altered gonadotropin pulsatility and amenorrhea are unclear. Low levels of leptin (an adipokine) and increased ghrelin (an orexigenic hormone that increases as fat mass decreases) impact gonadotropin pulsatility. Studies have not examined luteinizing hormone (LH) secretory dynamics in relation to leptin or ghrelin secretory dynamics in adolescent and young adult athletes. We hypothesized that 1) young amenorrheic athletes (AA) would have lower LH and leptin and higher ghrelin secretion than eumenorrheic athletes (EA) and nonathletes and 2) higher ghrelin and lower leptin would be associated with lower LH secretion. This was a cross-sectional study. We examined ghrelin and leptin secretory patterns (over 8 h, from 11 PM to 7 AM) in relation to LH secretory patterns in AA, EA, and nonathletes aged 14-21 yr. Ghrelin and leptin were assessed every 20 min and LH every 10 min. Groups did not differ for age, bone age, or BMI. However, fat mass was lower in AA than in EA and nonathletes. AA had lower LH and higher ghrelin pulsatile secretion and AUC than nonathletes and lower leptin pulsatile secretion and AUC than EA and nonathletes. Percent body fat was associated positively with LH and leptin secretion and inversely with ghrelin. In a regression model, ghrelin and leptin secretory parameters were associated independently with LH secretory parameters. We conclude that higher ghrelin and lower leptin secretion in AA related to lower fat mass may contribute to altered LH pulsatility and amenorrhea.

Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls.

CONTEXT: Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes. OBJECTIVE: We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight-bearing exercise. DESIGN AND SETTING: We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital. SUBJECTS AND OUTCOME MEASURES: We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15-21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. RESULTS: Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18-24% of the variability in tibial trabecular number and separation. CONCLUSION: In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA.

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.

Growth hormone is positively associated with surrogate markers of bone turnover during puberty.

BACKGROUND: Puberty is characterized by increases in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent with increased bone metabolism. OBJECTIVE: To determine the relationship between pubertal bone metabolism, GH and IGF-1. We hypothesized that bone turnover peaks at the time of greatest pubertal GH secretion. DESIGN AND SUBJECTS: Subjects included 86 girls and boys, 9-17 years-old (BMI 10th-90th percentiles). Because higher endogenous GH secretion is associated with a higher nadir following oral glucose, we used the GH nadir following a 2-h OGTT as indicative of GH status. Fasting serum IGF-1, aminoterminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal collagen crosslinks (CTX) were obtained. Subjects were grouped per expected timing of peak growth. Group 1: Tanner 1 girls and Tanner 1-2 boys (period preceding peak growth), Group 2: Tanner 2-3 girls and Tanner 3-4 boys (period of peak growth) and Group 3: Tanner 4-5 girls and Tanner 5 boys (period following peak growth). RESULTS: GH peaked at mid-puberty (Group 2) and IGF-1 in late puberty (Group 3). P1NP and CTX were highest in mid-puberty compared with early and late puberty (P = 0·0009 and 0·006 in girls and P = 0·005 and 0·04 in boys). GH, but not IGF-1, correlated with P1NP (r = 0·46 in both genders, P ≤ 0·008) and CTX (r = 0·37 and 0·38, P = 0·04 and 0·02 in girls and boys, respectively). Similarly, on regression modelling, GH (but not IGF-1) predicted both bone turnover markers in both genders. CONCLUSION: GH is strongly associated with pubertal bone metabolism, independent of systemic IGF-1 in girls and boys.

Waist to hip ratio and trunk to extremity fat (DXA) are better surrogates for IMCL and for visceral fat respectively than for subcutaneous fat in adolescent girls.

BACKGROUND: Increased visceral adipose tissue (VAT) and intramyocellular lipids (IMCL) are associated with increased metabolic risk. Clinical and DXA body composition measures that are associated with VAT are generally even more strongly associated with subcutaneous adipose tissue (SAT) reflecting general adiposity, and thus are not specific for VAT. Measures more strongly associated with VAT than SAT (thus more specific for VAT), and predictors of IMCL have not been reported. SUBJECTS/METHODS: We studied 30 girls 12-18 years; 15 obese, 15 normal-weight. The following were assessed: (1) anthropometric measures: waist circumference at the umbilicus and iliac crest (WC-UC and WC-IC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), (2) DXA measures: total fat, percent body fat (PBF), percent trunk fat (PTF), trunk-to-extremity fat ratio (TEFR), (3) MRI and 1H-MRS: VAT and SAT (L4-L5), soleus-IMCL. RESULTS: Group as a whole: WC, trunk fat and PBF were more strongly associated with SAT than VAT; none were specific for VAT. In contrast, PTF and TEFR were more significantly associated with VAT (r = 0.83 and 0.81 respectively, p <0.0001 for both) than SAT (r = 0.77 and 0.75, p < 0.0001 for both). Strongest associations of S-IMCL were with WHR (r = 0.66, p = 0.0004). Subgroup analysis: In obese girls, WHR and WHtR were more strongly correlated with VAT (r = 0.62 and 0.82, p = 0.04 and 0.001) than SAT (r = 0.41 and 0.73, p not significant and 0.007), and for DXA measures, PTF and TEFR were more significantly associated with VAT (r = 0.70 and 0.72, p = 0.007 and 0.006) than SAT (r = 0.52 and 0.53, p = 0.07 and 0.06). In controls, PTF and TEFR were more strongly correlated with VAT (r = 0.79, p = 0.0004 for both) than SAT (r = 0.71 and 0.72, p = 0.003 for both). WHR was associated with IMCL in obese girls (r = 0.78, p = 0.008), but not controls. CONCLUSION: Overall, WHR (anthropometry), and PTF and TEFR (DXA) are good surrogates for IMCL and for visceral fat respectively in adolescent girls.

Peptide YY levels across pubertal stages and associations with growth hormone.

CONTEXT: Changes in appetite-regulating peptides may impact food intake during puberty and facilitate the pubertal growth spurt. Peptide YY (PYY) is an anorexigenic hormone that is high in anorexia nervosa and low in obesity, inhibits GnRH secretion, and is suppressed by GH administration. The relationship between PYY and GH has not been examined across puberty. OBJECTIVES: We hypothesized that PYY would be inversely associated with GH in adolescents and would be lowest when GH is highest. DESIGN AND SETTING: We conducted a cross-sectional study at a Clinical Research Center. SUBJECTS: We studied 87 children, 46 boys and 41 girls ages 9-17 yr at Tanner stages 1-5 of puberty (10th-90th percentiles for body mass index). OUTCOME MEASURES: We measured fasting PYY and nadir GH levels after administration of an oral glucose load. Leptin levels were also measured. RESULTS: Fasting PYY was lowest and nadir GH highest in boys in Tanner stages 3-4 (P = 0.02) and in girls in Tanner stages 2-3 (P = 0.02). Leptin levels were highest in early pubertal boys and late pubertal girls. For the group as a whole and within genders, even after controlling for body mass index, log nadir GH correlated inversely with log PYY (P = 0.003, 0.07, and 0.02). PYY levels did not correlate with leptin levels. CONCLUSIONS: During mid-puberty, at a time when GH levels are the highest, PYY is at a nadir, and these low PYY levels may facilitate pubertal progression and growth.

Visceral fat is a negative predictor of bone density measures in obese adolescent girls.

CONTEXT: Regional fat is increasingly recognized as a determinant of bone mineral density (BMD), an association that may be mediated by adipokines, such as adiponectin and leptin, and inflammatory fat products. Chronic inflammation is deleterious to bone, and visceral adipose tissue (VAT) predicts inflammatory markers such as soluble intercellular adhesion molecule-1 and E-selectin, whereas sc adipose tissue (SAT) and VAT predict IL-6 in adolescents. OBJECTIVE: Our objective was to determine associations of regional fat mass and adipokines with BMD. We hypothesized that girls with greater VAT relative to SAT would have lower bone density mediated by inflammatory cytokines, adiponectin, and leptin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a clinical research center. SUBJECTS: SUBJECTS included 30 girls (15 obese, 15 normal weight) 12-18 yr old, matched for maturity (bone age), race, and ethnicity. OUTCOME MEASURES: We assessed regional fat (SAT, VAT) using magnetic resonance imaging, total fat, and BMD using dual-energy x-ray absorptiometry. Fasting leptin, adiponectin, IL-6, soluble intercellular adhesion molecule-1, and E-selectin were obtained. RESULTS: Mean body mass index sd score was 3.7 +/- 1.5 in obese subjects and 0.1 +/- 0.4 kg/m(2) in controls. VAT was a negative predictor of spine BMD and bone mineral apparent density, whole-body BMD and bone mineral content/height in obese girls and whole-body BMD and bone mineral content/height for the group as a whole after controlling for SAT, as was the ratio of VAT to SAT. In a regression model that included VAT/SAT, adipokines, and cytokines, E-selectin and adiponectin were negative predictors of BMD and leptin a positive predictor. CONCLUSION: VAT is an independent inverse determinant of bone density in obesity. This association may be mediated by adipokines and a chronic inflammatory state.

Use of SSRIs may Impact Bone Density in Adolescent and Young Women with Anorexia Nervosa.

OBJECTIVES: Alterations in serotonin impact bone metabolism in animal models, and selective serotonin reuptake inhibitors (SSRI) have been associated with increased fracture risk in older adults. SSRIs are commonly used in anorexia nervosa (AN), a condition that predisposes to low bone mineral density (BMD). Our objective was to determine whether SSRI use is associated with low BMD in AN. METHODS: We examined Z-scores for spine, hip and whole body (WB) BMD, spine bone mineral apparent density and WBBMC/height (Ht) in females with AN 12-21 years old who had never been on SSRIs, on SSRIs for <6 months (<6M) or >6 months (>6M). RESULTS: Subjects on SSRIs for >6M had lower spine, femoral-neck and WBBMD Z-scores than those on SSRIs for <6M. Hip BMD and WBBMC/Ht Z-scores were lowest in subjects on SSRIs for >6M. Duration of SSRI use, duration since AN diagnosis and duration of amenorrhea inversely predicted BMD, whereas BMI was a positive predictor. In a regression model, duration of SSRI use remained an independent negative predictor of BMD. DISCUSSION: Duration of SSRI use >6M is associated with low BMD in AN. CONCLUSION: It may be necessary to monitor BMD more rigorously when duration of SSRI use exceeds 6M.

Increased carbohydrate induced ghrelin secretion in obese vs. normal-weight adolescent girls.

Orexigenic and anorexigenic pathways mediate food intake and may be affected by meal composition. Our objective was to determine whether changes in levels of active ghrelin and peptide YY (PYY) differ in obese vs. normal-weight adolescent girls following specific macronutrient intake and predict hunger and subsequent food intake. We enrolled 26 subjects: 13 obese and 13 normal-weight girls, 12-18 years old, matched for maturity (as assessed by bone age) and race. Subjects were assigned a high-carbohydrate, high-protein, and high-fat breakfast in random order. Active ghrelin and PYY were assessed for 4 h after breakfast and 1 h after intake of a standardized lunch. Hunger was assessed using a standardized visual analog scale (VAS). No suppression in active ghrelin levels was noted following macronutrient intake in obese or normal-weight girls. Contrary to expectations, active ghrelin increased in obese girls following the high-carbohydrate breakfast, and the percent increase was higher than in controls (P = 0.046). Subsequent food intake at lunch was also higher (P = 0.03). Following the high-fat breakfast, but not other breakfasts, percent increase in PYY was lower (P = 0.01) and subsequent lunch intake higher (P = 0.005) in obese compared with normal-weight girls. In obese adolescents, specific intake of high-carbohydrate and high-fat breakfasts is associated with greater increases in ghrelin, lesser increases in PYY, and higher intake at a subsequent meal than in controls. Changes in anorexigenic and orexigenic hormones in obese vs. normal-weight adolescents following high-carbohydrate and high-fat meals may influence hunger and satiety signals and subsequent food intake.

Bone metabolism in adolescent boys with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a condition of severe undernutrition associated with low bone mineral density (BMD) in adolescent females with this disorder. Although primarily a disease in females, AN is increasingly being recognized in males. However, there are few or no data regarding BMD, bone turnover markers or their predictors in adolescent AN boys. HYPOTHESES: We hypothesized that BMD would be low in adolescent boys with AN compared with controls associated with a decrease in bone turnover markers, and that the gonadal steroids, testosterone and estradiol, and levels of IGF-I and the appetite regulatory hormones leptin, ghrelin, and peptide YY would predict BMD and bone turnover markers. METHODS: We assessed BMD using dual-energy x-ray absorptiometry and measured fasting testosterone, estradiol, IGF-I, leptin, ghrelin, and peptide YY and a bone formation (aminoterminal propeptide of type 1 procollagen) and bone resorption (N-telopeptide of type 1 collagen) marker in 17 AN boys and 17 controls 12-19 yr old. RESULTS: Boys with AN had lower BMD and corresponding Z-scores at the spine, hip, femoral neck, trochanter, intertrochanteric region, and whole body, compared with controls. Height-adjusted measures (lumbar bone mineral apparent density and whole body bone mineral content/height) were also lower. Bone formation and resorption markers were reduced in AN, indicating decreased bone turnover. Testosterone and lean mass predicted BMD. IGF-I was an important predictor of bone turnover markers. CONCLUSION: AN boys have low BMD at multiple sites associated with decreased bone turnover markers at a time when bone mass accrual is critical for attainment of peak bone mass.

Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls.

Although body composition, insulin sensitivity, and lipids are markedly altered in overweight adolescents, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. We hypothesized that low-peak GH on the GH-releasing hormone (GHRH)-arginine stimulation test and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance, and lipids. We examined the following parameters in 15 overweight and 15 bone age-matched control 12- to 18-yr-old girls: 1) body composition using dual-energy X-ray absorptiometry and MR [visceral and subcutaneous adipose tissue at L(4)-L(5) and soleus intramyocellular lipid ((1)H-MR spectroscopy)], 2) peak GH on the GHRH-arginine stimulation test, 3) mean overnight GH and cortisol, 4) 24-h urinary free cortisol (UFC), 5) fasting lipids, and 6) an oral glucose tolerance test. Stepwise regression was the major tool employed to determine relationships between measured parameters. Log peak GH on the GHRH-arginine test was lower (P = 0.03) and log UFC was higher (P = 0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with subcutaneous adipose tissue and, with body mass index standard deviation score, accounted for 92% of its variability, whereas log peak GH and body mass index standard deviation score accounted for 88% of visceral adipose tissue variability and log peak GH for 34% of the intramyocellular lipid variability. Log mean cortisol was independently associated with log homeostasis model assessment of insulin resistance, LDL, and HDL and explained 49-59% of the variability. Our data indicate that lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance, and lipids.

Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study.

OBJECTIVES: Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids. DESIGN: Cross-sectional. SUBJECTS AND MEASUREMENTS: We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12-18 years old. Fasting blood was drawn for active ghrelin, leptin, E(2) and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI). RESULTS: AA girls had lower BMI than EA and controls (P = 0.003). Log ghrelin was higher in AA than in EA and controls (P < 0.0001), and remained higher after controlling for BMI Z-scores. Leptin was lower in AA than in the other groups (P < 0.0001), however, the differences did not persist after controlling for BMI Z-scores. Testosterone was lower in AA than in EA and controls (P = 0.002) and log E(2) trended lower in AA (P = 0.07). We observed inverse associations of log active ghrelin with testosterone (P = 0.01), and positive associations of leptin with testosterone and log E(2) (P = 0.02 and 0.009). CONCLUSION: Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.