Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) and functional hypothalamic amenorrhea (HA) are associated with low bone density, anxiety, and depression. Women with AN and HA have elevated cortisol levels. Significant hypercortisolemia, as in Cushing's disease, causes bone loss. It is unknown whether anxiety and depression and/or cortisol dysregulation contribute to low bone density in AN or HA. OBJECTIVE: Our objective was to investigate whether hypercortisolemia is associated with bone loss and mood disturbance in women with HA and AN. DESIGN AND SETTING: We conducted a cross-sectional study in a clinical research center. PARTICIPANTS: We studied 52 women [21 healthy controls (HC), 13 normal-weight women with functional HA, and 18 amenorrheic women with AN]. OUTCOME MEASURES: Serum samples were measured every 20 min for 12 h overnight and pooled for average cortisol levels. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at anteroposterior and lateral spine and hip. Hamilton Rating Scales for Anxiety (HAM-A) and Depression (HAM-D) were administered. RESULTS: BMD was lower in AN and HA than HC at all sites and lower in AN than HA at the spine. On the HAM-D and HAM-A, AN scored higher than HA, and HA scored higher than HC. Cortisol levels were highest in AN, intermediate in HA, and lowest in HC. HAM-A and HAM-D scores were associated with decreased BMD. Cortisol levels were positively associated with HAM-A and HAM-D scores and negatively associated with BMD. CONCLUSIONS: Hypercortisolemia is a potential mediator of bone loss and mood disturbance in these disorders.

Percentage extremity fat, but not percentage trunk fat, is lower in adolescent boys with anorexia nervosa than in healthy adolescents.

BACKGROUND: Anorexia nervosa (AN) is a condition of severe undernutrition associated with altered regional fat distribution in females. Although primarily a disease of females, AN is increasingly being recognized in males and is associated with hypogonadism. Testosterone is a major regulator of body composition in males, and testosterone administration in adults decreases visceral fat. However, the effect of low testosterone and other hormonal alterations on body composition in boys with AN is not known. OBJECTIVE: We hypothesized that testosterone deficiency in boys with AN is associated with higher trunk fat, as opposed to extremity fat, compared with control subjects. DESIGN: We assessed body composition using dual-energy X-ray absorptiometry and measured fasting testosterone, estradiol, insulin- like growth factor-1, leptin, and active ghrelin concentrations in 15 boys with AN and in 15 control subjects of comparable maturity aged 12-19 y. RESULTS: Fat and lean mass in AN boys was 69% and 86% of that in control subjects. Percentage extremity fat and extremity lean mass were lower in boys with AN (P = 0.003 and 0.0008); however, percentage trunk fat and the trunk to extremity fat ratio were higher after weight was adjusted for (P = 0.005 and 0.003). Testosterone concentrations were lower in boys with AN, and, on regression modeling, positively predicted percentage extremity lean mass and inversely predicted percentage trunk fat and trunk to extremity fat ratio. Other independent predictors of regional body composition were bone age and weight. CONCLUSIONS: In adolescent boys with AN, higher percentage trunk fat, higher trunk to extremity fat ratio, lower percentage extremity fat, and lower extremity lean mass (adjusted for weight) are related to the hypogonadal state.

Hormonal and nutritional effects on cardiovascular risk markers in young women.

CONTEXT: Cardiovascular (CV) risk markers, including high-sensitivity C-reactive protein (hsCRP), are increasingly important in predicting cardiac events. A favorable CV risk profile might be expected in anorexia nervosa (AN) due to low body weight and dietary fat intake. However, women with AN have decreased IGF-I levels reflecting decreased GH action, and IGF-I deficiency is associated with elevated hsCRP. Moreover, oral estrogens, known to increase hsCRP in other populations, are commonly prescribed in AN. To date, hsCRP levels and their physiological determinants have not been reported in women with AN. OBJECTIVE: We examined the relationship between CV risk markers, undernutrition, IGF-I, and oral estrogens, specifically hypothesizing that in the setting of undernutrition, AN would be associated with low hsCRP despite low IGF-I levels and that those women taking oral contraceptive pills (OCPs) would have higher hsCRP and lower IGF-I levels. DESIGN AND SETTING: We conducted a cross-sectional study at a clinical research center. STUDY PARTICIPANTS: Subjects included 181 women: 140 women with AN [85 not receiving OCPs (AN-E) and 55 receiving OCPs (AN+E)] and 41 healthy controls [28 not receiving OCPs (HC-E) and 13 receiving OCPs (HC+E)]. MAIN OUTCOME MEASURES: We assessed hsCRP, IL-6, IGF-I, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). RESULTS: Despite low weight, more than 20% of AN+E had high-risk hsCRP levels. AN+E had higher hsCRP than AN-E. AN-E had lower mean hsCRP levels than healthy controls (HC+E and HC-E). IL-6 levels were higher in AN+E with elevated hsCRP (>3 mg/liter) than in AN+E with normal hsCRP levels. IGF-I was inversely associated with hsCRP in healthy women, suggesting a protective effect of GH on CV risk. However, this was not seen in AN. Few patients in any group had high-risk LDL or HDL levels. CONCLUSIONS: Although hsCRP levels are lower in AN than healthy controls, OCP use puts such women at a greater than 20% chance of having hsCRP in the high-CV-risk (>3 mg/liter) category. The elevated mean IL-6 in women with AN and high-risk hsCRP levels suggests that increased systemic inflammation may underlie the hsCRP elevation in these patients. Although OCP use in AN was associated with slightly lower mean LDL and higher mean HDL, means were within the normal range, and few patients in any group had high-risk LDL or HDL levels. IGF-I levels appear to be important determinants of hsCRP in healthy young women. In contrast, IGF-I does not appear to mediate hsCRP levels in AN.

Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa.

BACKGROUND: Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD). Adipokines and insulin play an important role in bone metabolism in healthy individuals. However, their association with bone metabolism in AN is unknown. OBJECTIVE: The aim of the study was to determine whether adipokines and insulin are independently associated with measures of BMD in adolescents with AN and controls. DESIGN/METHODS: Levels of adiponectin and insulin, fasting and after oral glucose, were evaluated in 17 AN patients and 19 controls (age, 12-18 yr), in whom hormonal parameters [GH, IGF-I, cortisol, estradiol, leptin, ghrelin, and peptide YY (PYY)] had been previously determined. Body composition, bone mineral content, and BMD at the lumbar spine, hip, femoral neck, and total body were assessed by dual energy x-ray absorptiometry. Two bone formation and bone resorption markers were examined. SETTING: The study was conducted at a General Clinical Research Center. RESULTS: Adiponectin differed between AN subjects and controls after controlling for fat mass and decreased in both after oral glucose (P = 0.02 and 0.07). On regression modeling, independent associations were observed of: 1) body mass index and adiponectin with lumbar spine bone mineral apparent density Z-scores (r(2) = 0.45); 2) lean mass, PYY, and ghrelin with hip Z-scores (r(2) = 0.55); 3) adiponectin and lean mass with femoral neck-bone mineral apparent density Z-scores (r(2) = 0.34); and 4) lean mass, PYY, GH, and ghrelin with total body-bone mineral content/height Z-scores (r(2) = 0.64), for the combined group. Adiponectin was also independently associated with BMD, and insulin was associated with bone turnover markers in the groups considered separately. CONCLUSIONS: Adiponectin contributes significantly to the variability of bone density, and insulin contributes to bone turnover markers in adolescent girls.

Cross-ethnic differences in eating disorder symptoms and related distress.

OBJECTIVE: This study investigated ethnic differences in the frequency of eating disorder symptoms and related distress in a U.S. college-based eating disorders screening program. METHOD: Responses to self-report questions and counselors' assessment were analyzed in an ethnically diverse sample (n = 5,435). RESULTS: The frequency of binge-eating, restrictive eating, vomiting, and amenorrhea did not differ significantly across ethnic groups. However, significant between-group differences were found with respect to modes of purging. Binge correlates (e.g., eating until uncomfortably full) were significantly more frequent among Caucasian than African American participants (p < .001). Binge eating was the best predictor of distress among Caucasians, African Americans, and Latinos, whereas vomiting was the best predictor of distress among Asians. Asian participants who used laxatives were significantly less likely to receive a recommendation for further evaluation than non-Asian participants. CONCLUSION: Ethnic diversity in symp tom prevalence and related distress was identified. Clinician recognition of this potential diversity may enhance culturally competent care for eating disorders.

Uncoupling of cardiovascular risk markers in adolescent girls with anorexia nervosa.

OBJECTIVE: Cardiovascular (CV) risk begins in childhood, and low body weight should result in a favorable risk profile. However, adolescents with anorexia nervosa (AN) have alterations in many hormonal factors that mediate CV risk. We hypothesized that in AN, growth hormone (GH) resistance and hypercortisolemia would increase CV risk through effects on pro-inflammatory cytokines and lipid status despite low weight. STUDY DESIGN: We examined CV risk markers (high sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], apolipoprotein-B [Apo-B], and lipid profile) in 23 subjects with AN and in 20 control subjects 12 to 18 years of age, in whom GH, cortisol, leptin, and triiodothyronine (T3) had been previously determined. RESULTS: Subjects with AN had higher Apo-B (P < .0001), IL-6 (P = .03), Apo-B/high-density lipoprotien (HDL) (P = .01), and Apo-B/low-density lipoprotein (LDL) (P < .0001) and lower hsCRP (P = .01) than controls. Triglycerides were lower and HDL higher in subjects with AN. IGF-I predicted hsCRP in controls but not in AN. Log hsCRP correlated positively with GH and inversely with leptin. On regression modeling, the most significant predictor of log hsCRP was leptin; T3 predicted log IL-6, log Apo-B, log Apo-B/HDL, and Apo-B/LDL; and cortisol independently predicted log Apo-B. IL-6 decreased with weight gain. CONCLUSION: CV risk markers are uncoupled in AN, with increased Apo-B and IL-6 and decreased hsCRP, related to hormonal alterations. IL-6 normalizes with weight gain.

Nutrient intake in community-dwelling adolescent girls with anorexia nervosa and in healthy adolescents.

BACKGROUND: Adolescence is a common time for the onset of anorexia nervosa (AN), a condition associated with long-term medical and hormonal consequences. OBJECTIVE: The objective was to compare the nutrient intakes of community-dwelling girls with AN with those of healthy adolescents and to describe the associations between specific nutrient intakes and nutritionally dependent hormones. DESIGN: Nutrient intakes in 39 community-dwelling girls with AN and 39 healthy adolescents aged 12.1-18.7 y were determined by using 4-d food records. Fasting adiponectin, leptin, ghrelin, insulin, and insulin-like growth factor I (IGF-I) concentrations were measured. Indirect calorimetry was used to assess respiratory quotient and resting energy expenditure. RESULTS: In contrast with the control group, the AN group consumed fewer calories from fats (P < 0.0001) and more from carbohydrates (P = 0.0009) and proteins (P < 0.0001). Intake of individual fat components was lower and of dietary fiber higher in the AN group. No significant between-group differences were observed in dietary intakes of calcium, zinc, and iron; however, total intake was greater in the AN group because of greater supplement use (P = 0.006, 0.02, and 0.01, respectively). The AN group had greater intakes of vitamins A, D, and K and of most of the B vitamins, and significantly more girls with AN met the Dietary Reference Intake for calcium (P = 0.01) and vitamin D (P = 0.02) from supplement use. Fat intake predicted ghrelin, insulin, and IGF-I concentrations; carbohydrate intake predicted adiponectin. Resting energy expenditure was lower (P < 0.0001) and leisure activity levels higher in the AN group. CONCLUSIONS: Despite outpatient follow-up, community-dwelling girls with AN continue to have lower fat and higher fiber intakes than do healthy adolescents, which results in lower calorie intakes. Nutritionally related hormones are associated with specific nutrient intakes.

Elevated peptide YY levels in adolescent girls with anorexia nervosa.

BACKGROUND: Peptide YY (PYY) is an intestinally derived anorexigen that acts via the Y2 receptor, and Y2 receptor deletion in rodents increases bone formation. Anorexia nervosa (AN) is associated with a deliberate reduction in food intake and low bone density, but endocrine modulators of food intake in AN are not known. In addition, known regulators of bone turnover, such as GH, cortisol, and estrogen, explain only a fraction of the variability in bone turnover marker levels. HYPOTHESES: We hypothesized that PYY may be elevated in AN compared with controls and may contribute to decreased food intake and bone formation. METHODS: Fasting PYY was examined in 23 AN girls and 21 healthy adolescents 12-18 yr old. We also examined GH, cortisol, ghrelin, and leptin (overnight frequent sampling) and fasting IGF-I, estradiol, total T3, and bone markers. Macronutrient intake and resting energy expenditure (REE) were measured. RESULTS: AN girls had higher PYY levels compared with controls (17.8 +/- 10.2 vs. 4.8 +/- 4.3 pg/ml; P < 0.0001). Predictors of log PYY were nutritional markers, including body mass index (r = -0.62; P < 0.0001), fat mass (r = -0.55; P = 0.0003), and REE (r = -0.51; P = 0.0006), and hormones, including GH (r = 0.38; P = 0.004) and T3 (r = -0.59; P = 0.0001). Body mass index, fat mass, REE, GH, and T3 explained 68% of the variability of log PYY. Log PYY predicted percentage of calories from fat (r = -0.56; P = 0.0002) and independently predicted osteocalcin (r = -0.45; P = 0.003), bone-specific alkaline phosphatase (r = -0.46; P = 0.003), N-telopeptide/creatinine (r = -0.55; P = 0.0003), and deoxypyridinoline/creatinine (r = -0.52; P = 0.001) on regression modeling. CONCLUSION: Elevated PYY may contribute to reduced intake and decreased bone turnover in AN.

Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents.

CONTEXT: Anorexia nervosa (AN) in adolescents is associated with low bone mineral density (BMD) and increases in ghrelin secretion, an orexigenic GH secretagogue that stimulates osteoblast proliferation in vitro. OBJECTIVE: We hypothesized that ghrelin may have independent effects on bone in AN adolescents. STUDY DESIGN, SUBJECTS, AND OUTCOME MEASURES: Frequent sampling was performed overnight every 30 min for 12 h in 23 adolescent AN girls aged 12-18 yr and 21 controls of comparable maturity. Ghrelin, leptin, cortisol, and GH secretion were examined using Cluster and deconvolution. We measured BMD and body composition (dual-energy x-ray absorptiometry) and carboxy-terminal peptide of type I procollagen and N-telopeptide levels. RESULTS: In healthy adolescents, ghrelin secretion strongly predicted BMD; secretory burst mass being the strongest predictor of lumbar spine (LS) bone mineral apparent density (BMAD) (r = 0.66, P = 0.003), LS BMAD z-scores (BMAD-z) (r = 0.59, P = 0.01), hip BMD (r = 0.55, P = 0.02), and hip BMD-z (r = 0.52, P = 0.03). When body composition measures (body mass index, lean and fat mass), and hormonal predictors (GH, IGF-I, cortisol, leptin, and estradiol) were entered into a regression model with ghrelin secretion to determine independent BMD predictors, ghrelin was the strongest predictor of LS BMAD, BMAD-z, hip BMD, and hip BMD-z, contributing to 43, 30, 26, and 19% of the variability, respectively, independent of GH or cortisol effects. Conversely, in AN, ghrelin secretion did not predict LS BMAD or hip-z and weakly predicted LS BMAD-z and hip BMD. Ghrelin did not predict carboxy-terminal peptide of type I procollagen or N-telopeptide/creatinine, which were predicted by GH and cortisol. CONCLUSION: Ghrelin secretion predicts bone density independent of body composition, the GH-IGF-I axis, cortisol, or estradiol in healthy girls but not in those with AN.

Disclosure patterns of eating and weight concerns to clinicians, educational professionals, family, and peers.

OBJECTIVE: The current study investigated disclosure of eating and weight concerns to professionals, peers, and family. METHOD: Responses to a telephone questionnaire probing disclosure patterns were analyzed in a sample of 216 adult subjects with eating or weight symptoms, concerns, or problems. RESULTS: Nearly all of the sample (97.7%) had disclosed information about eating or weight symptoms or concerns to someone. Only 57% of the sample had disclosed this information to a health care professional. However, among subjects who had not otherwise volunteered information about their concerns, those who were queried were more likely than not to disclose them to health care professionals, counselors, and coaches. Disclosure to a health care professional or school counselor was associated with a higher likelihood of subsequent treatment seeking. DISCUSSION: These data suggest that individuals with disordered eating may be quite amenable to disclosing symptoms in clinical settings. Asking about an eating disorder may enhance detection and facilitate treatment in clinical settings.

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents.

Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.

Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents.

Ghrelin is an orexigenic peptide and a growth hormone (GH) secretagogue. Secretory dynamics of ghrelin have not been characterized in adolescents with anorexia nervosa (AN). We hypothesized that, compared with healthy adolescents, girls with AN would have increased ghrelin concentrations measured over 12 h of nocturnal sampling from increased basal and pulsatile secretion, and endogenous ghrelin would independently predict GH and cortisol. We examined ghrelin concentration and secretory dynamics in 22 girls with AN and 18 healthy adolescents 12-18 yr old. Associations between ghrelin, various hormones, and measures of insulin resistance were examined. On Cluster analysis, girls with AN had higher ghrelin concentrations than controls, including total area under the curve (AUC) (P = 0.002), nadir (P = 0.0006), and valley levels (P = 0.002). On deconvolution analysis, secretory burst amplitude (P = 0.03) and burst mass (P = 0.04) were higher in AN, resulting in higher pulsatile (P = 0.05) and total ghrelin secretion (P = 0.03). Fasting ghrelin independently predicted GH burst frequency (r = 0.44, P = 0.005). The nutritional markers body mass index and body fat predicted postglucose and valley ghrelin but not fasting levels. Ghrelin parameters were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and IGF-I. HOMA-IR was the most significant predictor of most ghrelin parameters. Valley ghrelin independently predicted cortisol burst frequency (52% of variability), and ghrelin parameters independently predicted total triiodothyronine and LH levels. Higher ghrelin concentrations in adolescents with AN are a consequence of increased secretory burst mass and amplitude. The most important predictor of ghrelin concentration is insulin resistance, and ghrelin in turn predicts GH and cortisol burst frequency.

Interpretation and use of weight information in the evaluation of eating disorders: counselor response to weight information in a National Eating Disorders Educational and Screening Program.

OBJECTIVE: Eating disorders are frequently undetected and inadequately treated in clinical settings. The current study investigated whether weight data were used appropriately in making recommendations for further care in the first National Eating Disorders Screening Program (NEDSP). METHOD: Accuracy of counselors' assessment of appropriateness of weight for height and adherence to an algorithm using weight to determine need for further evaluation were assessed for the 5,684 adult participants in a two-stage screening program held on college campuses. RESULTS: In 95% of cases, the counselors correctly used the algorithm developed for the NEDSP to assign participants to weight categories ranging from normal to extremely underweight. However, counselors were poorly adherent to an algorithm directing them to recommend urgent evaluation to all extremely underweight participants--that is, those with a weight at or below 75% of expected weight. Of the extremely underweight participants (n = 32), only 25.0% (n = 8) received an appropriate recommendation for urgent evaluation, whereas 59.4% (n = 19) received a recommendation for further (but nonurgent) evaluation, and 15.6% (n = 5) did not receive a recommendation to seek any evaluation. DISCUSSION: Clinicians appeared not to use weight data appropriately to make clinical recommendations for extremely underweight individuals. These results suggest that further specific emphasis on the health risks of extreme underweight may be helpful in training clinicians to manage patients with eating disorders.

Hormonal determinants of regional body composition in adolescent girls with anorexia nervosa and controls.

We have previously demonstrated that girls with anorexia nervosa (AN) have higher levels of GH and cortisol and lower levels of estradiol than healthy adolescents. The effects of endocrine alterations on regional body composition in AN, however, have not been reported. We, therefore, enrolled 23 adolescent girls with AN and 20 healthy girls of comparable maturity in a study examining regional body composition. Levels of estradiol and IGF-I, as well as measures of GH and cortisol concentration (using cluster analysis of data obtained from frequent sampling q30' for 12 h overnight) were examined to determine hormonal determinants of regional body composition in adolescent girls with AN and controls. Girls with AN were followed for 1 yr and examined again at weight recovery (10% increase in body mass index) (n = 11). Percent trunk fat and trunk to extremity fat ratio (T/E fat) were significantly reduced in girls with AN compared with healthy adolescents (P = 0.001 and 0.01, respectively). Percent trunk lean mass and trunk to extremity lean mass ratio (T/E lean) were higher in AN than in controls (P = 0.01 and 0.009); percent extremity lean mass was lower in AN (P = 0.009). In healthy controls, total area under the curve (AUC) for GH correlated inversely with percent trunk fat and T/E fat (r = -0.66, P = 0.002 and r = -0.62, P = 0.003). Similar correlations were observed between other measures of GH concentration (mean and nadir) and percent trunk fat and T/E fat. No relationship was observed between GH concentration and regional lean mass or between cortisol concentration and regional body composition. In contrast, GH concentration did not predict regional body composition in adolescents with AN on regression analysis. However, nadir cortisol concentration correlated inversely with percent extremity lean mass (r = -0.49; P = 0.02) and positively with percent trunk lean mass and T/E lean (r = 0.48, P = 0.03; and r = 0.49, P = 0.02) in girls with AN. A similar trend was observed between other measures of cortisol concentration (mean cortisol and AUC) and percent trunk lean mass and T/E lean in AN. Trunk fat was lowest in girls with AN who had high GH but low cortisol levels (based on median values), whereas some preservation of trunk fat was observed in girls with low GH and high cortisol levels. Weight recovery occurred in seven of 11 girls with low GH and high cortisol values; however, only two of the nine girls with high GH and low cortisol recovered weight. High GH with lower cortisol levels may thus be a marker of greater severity of AN. Our results suggest that in healthy controls, GH concentration predicts regional body composition and favors a redistribution of body fat such that T/E fat ratio decreases. In AN, however, high levels of GH and cortisol have contrasting associations with fat mass. High cortisol levels in AN predict a redistribution of lean body mass such that extremity lean mass decreases. Further studies are necessary to better understand the implications of these data.

Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls.

OBJECTIVE: Anorexia nervosa (AN) is an eating disorder that leads to a number of medical sequelae in adult women and has a mortality rate of 5.6% per decade; known complications include effects on hematologic, biochemical, bone density, and body composition parameters. Few data regarding medical and developmental consequences of AN are available for adolescents, in particular for an outpatient community-dwelling population of girls who have this disorder. The prevalence of AN is increasing in adolescents, and it is the third most common chronic disease in adolescent girls. Therefore, it is important to determine the medical effects of this disorder in this young population. METHODS: We examined clinical characteristics and performed hematologic, biochemical, hormonal, and bone density evaluations in 60 adolescent girls with AN (mean age: 15.8 +/- 1.6 years) and 58 healthy adolescent girls (mean age: 15.2 +/- 1.8 years) of comparable maturity. Nutritional and pubertal status; vital signs; a complete blood count; potassium levels; hormonal profiles; bone density at the lumbar and lateral spine; total body, hip, and femoral neck (by dual-energy x-ray absorptiometry) and body composition (by dual-energy x-ray absorptiometry) were determined. RESULTS: All measures of nutritional status such as weight, percentage of ideal body weight, body mass index, lean body mass, fat mass, and percentage of fat mass were significantly lower in girls with AN than in control subjects. Girls with AN had significantly lower heart rates, lower systolic blood pressure, and lower body temperature compared with control subjects. Total red cell and white cell counts were lower in AN than in control subjects. Among girls with AN, 22% were anemic and 22% were leukopenic. None were hypokalemic. Mean age at menarche did not differ between the groups. However, the proportion of girls who had AN and were premenarchal was significantly higher compared with healthy control subjects who were premenarchal, despite comparable maturity as determined by bone age. Ninety-four percent of premenarchal girls with AN versus 28% of premenarchal control subjects were above the mean age at menarche for white girls, and 35% of premenarchal AN girls versus 0% of healthy adolescents were delayed >2 SD above the mean. The ratio of bone age to chronological age, a measure of delayed maturity, was significantly lower in girls with AN versus control subjects and correlated positively with duration of illness and markers of nutritional status. Serum estradiol values were lower in girls with AN than in control subjects, and luteinizing hormone values trended lower in AN. Levels of insulin-like growth factor-I were also significantly lower in girls with AN. Estradiol values correlated positively with insulin-like growth factor-I, a measure of nutritional status essential for growth (r = 0.28). All measures of bone mineral density (z scores) were lower in girls with AN than in control subjects, with lean body mass, body mass index, and age at menarche emerging as the most important predictors of bone density. Bone density z scores of <-1 at any one site were noted in 41% of girls with AN, and an additional 11% had bone density z scores of <-2. CONCLUSIONS: A high prevalence of hemodynamic, hematologic, endocrine, and bone density abnormalities are reported in this large group of community-dwelling adolescent girls with AN. Although a number of these consequences of AN are known to occur in hospitalized adolescents, the occurrence of these findings, including significant bradycardia, low blood pressure, and pubertal delay, in girls who are treated for AN on an outpatient basis is of concern and suggests the need for vigilant clinical monitoring, including that of endocrine and bone density parameters.

Effects of estrogen and recombinant human insulin-like growth factor-I on ghrelin secretion in severe undernutrition.

Ghrelin is a nutritionally regulated gut peptide that increases with fasting and chronic undernutrition and decreases with food intake. Sex steroid levels change in chronic undernutrition and might signal changes in ghrelin. At the same time, chronic undernutrition is characterized by low IGF-I that might also influence ghrelin, either directly or through changes in the GH axis. Little is known regarding sex steroid regulation of ghrelin and the effects of IGF-I on ghrelin in severe undernutrition. We investigated the effects of sex steroids and IGF-I on ghrelin in 78 female subjects with anorexia nervosa simultaneously randomized to receive estrogen (Ovcon 35, 35 microg ethinyl estradiol, and 0.4 mg norethindrone) as well as recombinant human (rh)IGF-I (30 microg/kg sc twice a day) in a two-by-two factorial model, in which the individual effects of estrogen (E) and rhIGF-I on ghrelin could be determined. Subjects were 24.9 +/- 0.7 (mean +/- sem) yr of age and had low weight (body mass index, 16.7 +/- 0.2 kg/m(2)). At baseline, ghrelin was inversely correlated with body mass index (r = -0.39, P = 0.0005) and IGF-I (r = -0.30, P = 0.01). IGF-I increased significantly more in subjects receiving rhIGF-I alone (Delta 23.0 +/- 5.8 nmol/liter) and rhIGF-I and E (Delta 34.9 +/- 6.3 nmol/liter) compared with subjects receiving E alone (Delta -3.2 +/- 1.9 nmol/liter) or control (C; rhIGF-I placebo and no E) (Delta 0.4 +/- 2.0 nmol/liter) (overall P < 0.0001 by multivariate analysis of variance, P < 0.0001 for rhIGF-I vs. C, P < 0.0001 for rhIGF-I and E vs. C). Ghrelin increased significantly more over 6 months in response to E alone (Delta 150 +/- 86 pg/ml), rhIGF-I alone (Delta 198 +/- 116 pg/ml), and the combination (E and rhIGF-I) (Delta 441 +/- 214 pg/ml) compared with C (Delta -39 +/- 48 pg/ml) (overall P = 0.02 by multivariate analysis of variance, P = 0.01 for E vs. C, P = 0.04 for rhIGF-I vs. C, and P = 0.001 for rhIGF-I and E vs. C). Weight, caloric intake, and morning GH levels did not change significantly between the groups, but the change in ghrelin was inversely related to the change in GH among all subjects (r = -0.27, P = 0.03).Our data demonstrate that, in a model of severe undernutrition, rhIGF-I and E individually increase ghrelin levels. The mechanisms of these effects are unknown and may relate to direct effects on ghrelin or changes in GH. Further studies are needed to determine the mechanisms by which rhIGF-I and E increase ghrelin in human physiology.

Secondary prevention for eating disorders: the impact of education, screening, and referral in a college-based screening program.

OBJECTIVE: The first National Eating Disorders Screening Program (NEDSP), conducted on more than 400 college campuses in 1996, was an educational and two-stage screening program designed to detect potentially clinically significant disordered eating attitudes and behaviors and offer referrals for further evaluation when warranted. The current study assessed the impact of the NEDSP on participants. METHOD: A randomly selected subset of this sample (n = 289) was contacted approximately 2 years after the NEDSP to assess the impact of the program on knowledge and treatment-seeking behaviors for eating disorders. RESULTS: For greater than 80% of the participants, the program made participants aware of the danger of eating disorders and the availability of treatment. Of those who received a recommendation for further clinical evaluation of disordered eating (n = 109), nearly one half (47.7%) followed up on this recommendation and kept at least a first appointment and 39.4% actually sought treatment subsequent to the NEDSP. DISCUSSION: The results of the current study suggest that educational and screening programs may be a promising strategy for secondary prevention of eating disorders. They also suggest that awareness of the risks of disordered eating and available treatment may not be sufficient to motivate individuals to adhere to recommendations to seek treatment. Clinicians should, therefore, be vigilant for nonadherence to treatment recommendations and proactive in facilitating treatment.

Growth hormone and ghrelin responses to an oral glucose load in adolescent girls with anorexia nervosa and controls.

Anorexia nervosa (AN) is associated with high levels of GH and low levels of IGF-I suggestive of a nutritionally acquired lack of GH action or GH resistance. The suppression of GH levels after administration of inhibitors of GH secretion such as oral glucose is the definitive test to distinguish normal from pathological states of GH excess, such as acromegaly. However, suppression of GH by glucose has not been well characterized in states of adaptive GH excess, such as AN, especially in a younger adolescent population with relatively higher GH levels, compared with adults. In this study, we investigated GH suppression after a 100-g oral glucose load over a 1-h period in 19 adolescent girls with AN and 20 healthy controls of similar chronologic and bone age. We also compared nocturnal GH secretion characteristics by deconvolutional analysis in both groups to determine differences in secretory patterns between adolescents whose GH values suppressed vs. those whose values did not after oral glucose. Fasting levels of ghrelin, a GH secretagogue, and suppression of ghrelin with oral glucose were also determined to assess whether GH suppression or nonsuppression could be related to ghrelin values at respective time points. At 0 min (0') of the oral glucose tolerance test, girls with AN had significantly lower levels of glucose (P = 0.009) and higher levels of GH (P = 0.04) than controls. Nadir GH values were higher in AN than in controls (2.0 +/- 1.8 vs. 0.5 +/- 0.5 ng/ml, P = 0.001). Only 31.6% of girls with AN suppressed their GH values to 1 ng/ml or less vs. 85.0% of healthy adolescents (P = 0.0005). All healthy controls had nadir postglucose GH values of 2 ng/ml or less. Nadir GH concentrations during the oral glucose tolerance test correlated directly with all measures of GH secretion [basal (r = 0.37, P = 0.02), pulsatile (r = 0.56, P = 0.0002), and total (r = 0.57, P = 0.0002)]. Adolescent girls who did not suppress their GH values to 1 ng/ml or less had significantly higher levels of ghrelin at 0', 30', and 60' (P = 0.02, 0.004, and 0.008), significantly higher GH at 0' (P = 0.001), and higher nocturnal basal (P = 0.002), pulsatile (P = 0.05), and total GH secretion (P = 0.03) than those who did suppress below this level. Ghrelin values were higher in AN than in controls at each time point (P = 0.02, 0.0002, and 0.01 at 0', 30', and 60') but did not predict GH values at these time points. Adolescent girls with AN fail to adequately suppress their GH values after a 100-g oral glucose load. This lack of suppression may be related to the higher GH secretion seen in adolescents with this disorder. In contrast, all healthy adolescents suppress their GH values to 2 ng/ml or less but not 1 ng/ml or less after a glucose load. Although ghrelin values are higher in AN than in controls, we could not demonstrate a relationship between ghrelin and GH values. The inability of healthy girls to uniformly suppress GH levels to 1 ng/ml or less, a normal level defined for adults, may be related to higher GH secretion in the pubertal years, compared with adult life. Further studies are needed to define GH suppression in an adolescent population.

Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism.

Anorexia nervosa (AN) is a disorder that is increasing in frequency in adolescents, and the age of onset is often in the prepubertal years, potentially affecting the development of peak bone mass and linear growth. The GH-IGF-I axis plays an important role in bone formation, and alterations in GH secretory patterns have been described in adult women with AN. However, GH secretory dynamics in adolescents with AN have not been described, and the effects of alterations in GH secretory patterns and GH concentration on bone metabolism in AN are not known. We examined patterns of GH secretion by deconvolutional analysis, and GH concentration by Cluster analysis, in adolescent girls with AN (n = 22) and controls (n = 20) of comparable bone age and pubertal stage. We also examined the roles of cortisol, leptin, and estradiol in the regulation of GH secretion and concentration, and the relationship of GH secretory patterns and concentration to bone metabolism. Basal GH secretion and secretory pulse number in adolescent girls with AN were increased compared with control values (P = 0.03 and 0.007, respectively), and increased disorderliness of GH secretion (approximate entropy) was found in AN (P = 0.004). Mean and nadir GH concentrations and total area under the concentration curve were increased (P = 0.03, 0.002, and 0.03, respectively), and IGF-I levels were decreased (P = 0.0002) in girls with AN compared with healthy adolescent girls. IGF-I levels correlated negatively with nadir GH concentrations (r = -0.35; P = 0.02). Serum cortisol levels were higher in girls with AN than in controls (P < 0.0001) and correlated inversely with IGF-I (r = -0.58; P = 0.0001) and weakly with GH concentration (area under the concentration curve; r = -0.43; P = 0.05). A strong inverse relationship between markers of nutritional status (body mass index, fat mass, and leptin) and basal and pulsatile GH secretion, and mean and nadir GH concentrations was observed. GH concentration predicted levels of all markers of bone formation and a marker of bone resorption (N-telopeptide) in healthy controls, but not in AN. We demonstrate increases in basal GH secretion, number of secretory bursts, and GH concentration in adolescents with AN compared with controls, accompanied by low IGF-I levels. These data are consistent with the hypothesis that an acquired GH resistance occurs in this undernourished group. We also demonstrate that GH secretion and concentration are nutritionally regulated, and that the effects of nutrition exceed the effects of cortisol on GH concentration. Acquired GH resistance may play a role in the osteopenia and decreased peak bone mass frequently associated with AN.

Serum osteoprotegerin in adolescent girls with anorexia nervosa.

Low bone mineral density (BMD) in adolescents with anorexia nervosa (AN) is associated with a low bone turnover state. Osteoprotegerin (OPG), a cytokine that acts as a decoy receptor for receptor activator of nuclear factor-kappaB ligand, decreases bone resorption by inhibiting differentiation of osteoclast precursors and activation of mature osteoclasts, and by stimulating osteoclast apoptosis. We compared OPG levels in 43 adolescent girls with AN with 38 controls and examined bone density, bone turnover, and hormonal parameters. Girls with AN had lower fat mass, lean body mass, lumbar BMD z-scores, and lumbar bone mineral apparent density than controls. OPG levels were higher in girls with AN than in controls (44.5 +/- 22.5 pg/ml vs. 34.5 +/- 12.7 pg/ml, P = 0.02). Osteocalcin, deoxypyridinoline, estradiol, free testosterone, IGF-I, and leptin were lower in AN than in healthy adolescents. OPG values correlated negatively with body mass index (r = -0.27, P = 0.02), percent fat mass (r = -0.35, P = 0.0002), leptin (r = -0.28, P = 0.02), lumbar BMD z-scores (r = -0.25, P = 0.03), and lumbar bone mineral apparent density (r = -0.26, P = 0.03). In conclusion, adolescent girls with AN have higher serum OPG values than controls. OPG values correlate negatively with markers of nutritional status and lumbar bone density z-scores and may be a compensatory response to the bone loss seen in this population.