Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study.

CONTEXT: Anorexia nervosa (AN), a state of chronic nutritional deprivation, is characterized by GH resistance with elevated GH levels and decreased levels of IGF-I. The effects of supraphysiological recombinant human GH (rhGH) on GH resistance in AN are not currently known. OBJECTIVE: The aim was to investigate whether supraphysiological rhGH increases IGF-I levels in AN. DESIGN AND SETTING: We conducted a randomized, placebo-controlled study in a Clinical Research Center. PATIENTS: We studied 21 women with AN, 10 (mean age, 28 ± 2.1 yr) treated with rhGH and 11 (mean age, 29.2 ± 2.6 yr) treated with placebo. INTERVENTIONS: rhGH (mean maximum daily dose, 1.4 ± 0.12 mg/d) or placebo was administered to patients for 12 wk. MAIN OUTCOME MEASURES: IGF-I, N-terminal propeptide of type 1 procollagen, type I collagen C-telopeptide, glucose, and insulin levels were measured at wk 0, 1, 2, 3, 4, 8, and 12; C-terminal propeptide of type 1 procollagen, leptin, and free fatty acid levels were measured at wk 0 and 12. Body composition, including total fat and lean mass, was measured by dual-energy x-ray absorptiometry at wk 0 and 12. RESULTS: IGF-I levels did not differ between the groups at baseline or after treatment (median after 12 wk-rhGH, 124 ng/ml, interquartile range, 94.5, 170.3; vs. placebo, 85.5 ng/ml, interquartile range, 62, 139; P = 0.3). Similarly, changes in glucose, insulin, free fatty acids, and bone markers did not differ between the groups. Total fat mass and percentage fat mass (rhGH, -2.5 ± 0.6%, vs. placebo, 2.2 ± 1.1%; P = 0.004) decreased significantly in the rhGH group compared to placebo despite comparable weight. CONCLUSIONS: Supraphysiological rhGH administration decreases fat mass in AN without increasing IGF-I levels, supporting the role of GH as a mediator of lipolysis independent of IGF-I.

Determinants of height in adolescent girls with anorexia nervosa.

BACKGROUND: Anorexia nervosa, a condition characterized by marked caloric restriction and low insulin like growth factor-1 levels, would be expected to cause short stature. However, this disorder is also associated with hypogonadotropic hypogonadism and high growth hormone levels. Delays in growth-plate closure from associated hypogonadism may result in a longer period of time available for statural growth with protective effects on stature. In addition, growth hormone may have direct effects on the growth plate independent of insulin-like growth factor 1 to increase statural growth. OBJECTIVES AND METHODS: To determine the impact of undernutrition, hypogonadism, and acquired growth hormone resistance on height in adolescents with anorexia nervosa (aged 12-18 years), we examined 208 girls: 110 with anorexia nervosa and 98 controls of comparable chronological age. Sixty-three girls with anorexia nervosa and 79 controls were followed prospectively over 1 year. Mean duration of illness was 11.6 +/- 13.2 months. In a subset, overnight growth hormone sampling was performed every 30 minutes for 12 hours, and fasting insulin-like growth factor 1 levels were obtained. RESULTS: The difference between height and target height and between predicted adult height and target height did not differ between the groups, indicating preservation of height potential. The groups had comparable bone age, but bone age was lower than chronological age in girls with anorexia nervosa. Girls with anorexia nervosa had lower insulin-like growth factor 1 levels and higher nadir growth hormone levels than those of controls. Nadir growth hormone levels predicted height SD scores and predicted adult-height SD scores in controls but not in the girls with anorexia nervosa. In girls with anorexia nervosa, insulin-like growth factor 1 and duration of illness predicted height measures. Height SD scores of <0 were more likely after 32 months of illness and at insulin-like growth factor 1 levels of <134 ng/mL. Delayed baseline bone age predicted subsequent increases in height SD scores in immature girls with anorexia nervosa. CONCLUSIONS: Our data suggest that preservation of height potential in this cohort of girls with anorexia nervosa may be a consequence of delayed bone age. Hypogonadism may negate the deleterious effects of undernutrition on stature by allowing for a longer duration of growth.

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.

Prognostic indicators of changes in bone density measures in adolescent girls with anorexia nervosa-II.

INTRODUCTION: Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD). Baseline predictors of temporal BMD changes (DeltaBMD) in AN, including 1) gastrointestinal peptides regulating food intake and appetite that have been related to bone metabolism and 2) bone turnover markers, have not been well characterized. We hypothesized that baseline levels of nutritionally regulated hormones and of bone turnover markers would predict DeltaBMD overall. METHODS: In a prospective observational study, lumbar and whole-body BMD was measured at 0, 6, and 12 months in 34 AN girls aged 12-18 yr and 33 controls. Baseline body mass index, lean mass, nutritionally regulated hormones [IGF-I, cortisol, ghrelin, leptin, and peptide YY (PYY)], bone formation, and resorption markers were examined to determine nutritional and hormonal predictors of bone density changes. RESULTS: In a regression model, baseline ghrelin and PYY predicted changes in spine bone measures; and baseline ghrelin, cortisol, and PYY predicted changes in whole-body bone measures independent of baseline nutritional status. CONCLUSIONS: Neuroendocrine gastrointestinal-derived peptides regulating food intake are independent predictors of changes in bone mass in AN.

Weight gain and restoration of menses as predictors of bone mineral density change in adolescent girls with anorexia nervosa-1.

CONTEXT: Adolescents with anorexia nervosa (AN) have low bone mineral density. However, the effect of disease recovery, first, on bone density measures assessed using the Molgaard approach, which differentiates between reported low bone density resulting from short bones (based on height Z-scores) and that resulting from thin bones [based on measures of bone area (BA) for height] or light bones [based on measures of bone mineral content (BMC) for BA]; and second, on height-adjusted bone density measures, has not been well characterized. We hypothesized that menstrual recovery and weight gain (> or =10% increase in body mass index) would predict an increase in these measures of bone density. METHODS: In a prospective observational study, lumbar and whole-body (WB) bone density was measured at 0, 6, and 12 months in 34 AN girls aged 12-18 yr and 33 controls. Using Ward's modification of the Molgaard approach, we determined measures of BMC for BA and BA for height at the lumbar spine and WB and also determined spine bone mineral apparent density and WB BMC adjusted for height. RESULTS: Girls with AN had lower spine BMC for BA Z-scores (P = 0.0009), and lower WB BA for height Z (P < 0.0001), compared with controls. Menstrual recovery and weight gain in AN (AN-recovered) (median 9 months) resulted in a stabilization of BMD measures, whereas BMD continued to decrease in AN who did not gain weight and recover menses (AN-not recovered). AN-recovered also predicted greater increases in spine BMC for BA and WB BA for height, compared with AN-not recovered (P < 0.05). CONCLUSIONS: Even short-term weight gain with menstrual recovery is associated with a stabilization of BMD measures.

Growth hormone suppression after an oral glucose load in children.

BACKGROUND: GH nonsuppression after oral glucose is diagnostic for GH excess, but normative data are lacking in children. Adult data cannot be extrapolated to children given the pubertal increase in GH concentration. In addition, because GH levels are higher in pubertal girls than boys, nadir GH may differ across gender. OBJECTIVE: Our objective was to determine whether nadir GH during an oral glucose tolerance test (OGTT) is gender and pubertal stage specific. We hypothesized that nadir GH would be higher in girls, and at the pubertal stage known to correspond with peak height velocity (Tanner 2-3 in girls and Tanner 3-4 in boys) and maximal GH concentrations. SUBJECTS/ METHODS: A 2-h OGTT using 2.35 g/kg oral glucose (maximum 100 g) was performed in 64 girls and 43 boys, 9-17 yr (10th-90th percentiles for body mass index). Girls were grouped as group 1 (Tanner 1), group 2 (Tanner 2-3), and group 3 (Tanner 4-5), and boys as group 1 (Tanner 1-2), group 2 (Tanner 3-4), and group 3 (Tanner 5). RESULTS: Nadir GH was higher in girls than boys, and in group 2 girls and boys than the other two groups. The upper limit for nadir GH was highest in group 2 girls (1.57 ng/ml), and lower for the other two groups of girls (0.64 ng/ml), and for boys (0.50 ng/ml). All but one girl, and all boys suppressed to less than 1.0 ng/ml. There were 16 girls and five boys who had a nadir GH of more than 0.3 ng/ml. CONCLUSION: GH suppression after oral glucose is gender and pubertal stage specific.

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.

Role of cortisol in menstrual recovery in adolescent girls with anorexia nervosa.

Neuroendocrine abnormalities in anorexia nervosa (AN) include hypercortisolemia, hypogonadism, and hypoleptinemia, and neuroendocrine predictors of menstrual recovery are unclear. Preliminary data suggest that increases in fat mass may better predict menstrual recovery than leptin. High doses of cortisol decrease luteinizing hormone (LH) pulse frequency, and cortisol predicts regional fat distribution. We hypothesized that an increase in fat mass and decrease in cortisol would predict menstrual recovery in adolescents with AN. Thirty-three AN girls 12-18 y old and 33 controls were studied prospectively for 1 y. Body composition [dual energy x-ray absorptiometry (DXA)], leptin, and urinary cortisol (UFC) were measured at 0, 6, and 12 mo. Serum cortisol was measured overnight (every 30 min) in 18 AN subjects and 17 controls. AN subjects had higher UFC/cr x m2 and cortisol area under curve (AUC), and lower leptin levels than controls. Leptin increased significantly with recovery. When menses-recovered AN subjects were compared with AN subjects not recovering menses and controls, menses-recovered AN subjects had higher baseline cortisol levels and greater increases in leptin than controls and greater increases in fat mass than AN subjects not recovering menses and controls (adjusted for multiple comparisons). In a logistic regression model, increasing fat mass, but not leptin, predicted menstrual recovery. Baseline cortisol level strongly predicted increases in the percentage of body fat. We demonstrate that 1) high baseline cortisol level predicts increases in body fat and 2) increases in body fat predict menses recovery in AN.