Karen K. Miller

Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa.

Anorexia nervosa is highly prevalent among U.S. women (1, 2) and is associated with substantial bone loss (3-6). Bone loss in women with this disorder is multifactorial; is related in part to estrogen deficiency and to direct effects of undernutrition (3, 4, 7); and is rapid, often occurring within 6 months of disease onset (4) and persisting to some degree after weight recovery (8). It is important to determine the prevalence of regional bone loss at different skeletal sites because it may predict site-specific fracture rates (9). We therefore measured bone mineral density (BMD) at several skeletal sites to determine the prevalence rates and predictive factors of regional osteopenia and osteoporosis in a large community-based sample of women with anorexia nervosa. Methods We studied 130 women with anorexia nervosa recruited through community advertisements and community physician referral. Telephone screening interviews were used to exclude patients who reported normal weight and menses; use of bisphosphonates, calcitonin, or glucocorticoids; or medical conditions other than anorexia nervosa that are known to affect BMD. Women who had regular uterine withdrawal bleeding while receiving estrogen therapy and women with concomitant bulimia nervosa were permitted to participate. Eligible patients underwent a 3-hour outpatient visit at the General Clinical Research Center of the Massachusetts General Hospital in Boston. Height, weight, age at menarche, time since last menstrual period, previous and current estrogen use, fracture history, and frame size were determined. Calcium and vitamin D intake were determined by diet history in a subset of 60 patients. The diagnosis of anorexia nervosa, according to criteria specified in Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was confirmed in all patients (10). All patients gave written consent, as required by the Subcommittee on Human Studies. Bone mineral density at the anteriorposterior lumbar spine (L1L4), lateral spine, left total hip, femoral neck, and greater trochanter was determined with dual-energy x-ray absorptiometry using a Hologic 4500 densitometer (Hologic, Inc., Waltham, Massachusetts) (lumbar spine SD, 0.01 g/cm2) (11). At each skeletal site, patients were categorized as having normal BMD (T-score>1.0 SD), osteopenia (1.0 SD T-score>2.5 SD), or osteoporosis (T-score 2.5 SD), according to World Health Organization criteria. Data on BMD in a subset of 30 patients were published previously (7). Wrist and frame size were determined (12, 13), and body mass index and percentage of ideal body weight were calculated (14). Age at menarche and time since last menstrual period were assessed for all patients. Whenever possible, total duration of amenorrhea since menarche was determined (n =78). Current and previous lifetime estrogen use, including type of estrogen, was quantified and categorized for each patient. We used the MantelHaenszel test to compare BMD at the anteriorposterior and lateral spine, stratifying on patients. Standard least-squares multivariate regression models were constructed for each skeletal site by using age, age at menarche, time since last menstrual period, weight, height, wrist size, and fracture history as covariates. Covariates were chosen in advance as important clinical variables affecting BMD. Adjusted regression coefficients and confidence intervals were determined for each covariate. Data are expressed as the mean SE. The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Clinical data and data on BMD are shown in Table 1. Ninety-eight percent of patients were white and 2% were Asian. Mean T-scores were 1.4 0.1 SD for the anteriorposterior spine, 1.8 0.1 SD for the lateral spine, and 1.4 0.1 SD for the total hip. Twenty-six percent of patients (n =34) reported a history of fracture (foot or ankle [n =6], hand or wrist [n =7], leg [n =1], arm or elbow [n =4], stress fracture [n =5], and other fracture [n =11]). Table 1. Clinical Characteristics of Study Patients and Comparison by Estrogen Use and Menstrual History Osteopenia and osteoporosis, respectively, were seen at the anteriorposterior spine in 50% and 13% of patients, at the lateral spine in 57% and 24% of patients, and at the total hip in 47% and 16% of patients. Normal BMD was seen at the anteriorposterior spine in only 37% of patients, at the lateral spine in 19% of patients, and at the total hip in 37% of patients. Results of lateral and anteriorposterior spinal tests of BMD were discordant in 36 patients, of whom 31 had normal BMD at the anteriorposterior spine (T-score>1.0) but low BMD at the lateral spine (T-score 1.0) (P<0.001). Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 92% of patients and by at least 2.5 SD in 38% of patients. No differences in BMD were observed between patients with anorexia nervosa alone and patients with anorexia nervosa and concomitant bulimia nervosa (P>0.05 at all sites; data not shown). Twenty-three percent of patients were current estrogen users (mean duration, 25.3 5.4 months) and 58% were previous estrogen users (mean duration, 23.9 3.1 months). Bone mineral density did not differ at any site according to current or previous estrogen use (Table 1). Age, body mass index, and age at menarche were similar in the subgroup comparisons according to estrogen status. Oral contraceptives were used in all but 3 of the current estrogen users (10%) and all but 7 of the ever-estrogen users (10%); these 10 women received conjugated estrogen. Similar results were obtained in a subanalysis limited to the patients receiving oral contraceptives (data not shown). Total duration of estrogen use was not correlated with BMD at the anteriorposterior spine, lateral spine, femoral neck, total hip, trochanter, or total body (P>0.10 for all comparisons). Patients with primary amenorrhea (n =7) weighed less and had lower BMD at all sites than patients with secondary amenorrhea (n =123) (Table 1), although sample size was small in the primary amenorrhea group. Total calcium intake was not correlated with BMD at any site (P>0.1 for all sites). Fifty-seven percent of patients were receiving calcium supplements, 53% were receiving a multivitamin containing 400 IU of vitamin D, and 43% were receiving both. Bone mineral density did not differ in patients receiving nutritional supplements (data not shown). Weight was a significant independent predictor of BMD at all skeletal sites (Table 2). Patients with normal BMD, osteopenia, and osteoporosis at the total hip weighed 48.7 0.8 kg, 45.9 0.8 kg, and 39.0 0.7 kg, respectively. Similar trends were seen at other skeletal sites (data not shown). Age at menarche was a significant independent predictor of BMD measured by anteriorposterior spinal densitometry. Time since last menstrual period was a significant predictor of BMD at the anteriorposterior and lateral spine. Our results were similar when we used multivariate regression models with total duration of amenorrhea instead of last menstrual period in patients for whom this information was available (n =78) (data not shown). Table 2. Univariate and Multivariate Regression Analyses Discussion Our data demonstrate the high prevalence and profound degree of site-specific bone loss in women with anorexia nervosa. Our study design had advantages: Patients were recruited from the community and were not preselected for bone loss, and we evaluated bone loss at several skeletal sites. Although weight was highly significant as a predictor of bone loss at all sites, time since last menstrual period and age at menarche were significant predictive factors for BMD at the anteriorposterior spine, suggesting a greater relative influence of estrogen deficiency at this site. Other mechanisms may also contribute to reduced BMD in patients with anorexia nervosa, such as failure to achieve peak BMD, hypercortisolemia, and reduced vitamin D intake (4). However, we did not see any association between calcium or vitamin D intake and BMD. Increased risk for fracture is the major clinical implication of bone loss in women with anorexia nervosa. Fracture risk doubles with each decrease of 1 SD in BMD (9). Our data therefore suggest that patients with anorexia are at a markedly increased risk for fracture at many skeletal sites. A relatively high percentage of patients reported a previous history of fracture, but because radiologic confirmation was not obtained, relative risk for fracture was not determined. Bone mineral density was reduced by at least 1.0 SD at one or more skeletal sites in 97% of women with fractures, but fracture site was not correlated with the location of osteopenia. Although our study was not designed to prospectively investigate the efficacy of estrogen use in women with anorexia nervosa, no effect of previous or current estrogen use on BMD was demonstrated at any skeletal sites. These retrospective data stand in partial contrast to cross-sectional data from a previous study, which suggested an effect of estrogen exposure at the lumbar spine but not at other sites (15). The minimal effect of estrogen exposure on BMD in our study is consistent with that seen in a previous randomized study, which showed no effect of estrogenprogestin replacement therapy on BMD in patients with anorexia nervosa (16). The effectiveness of estrogen in increasing or preserving BMD in women with anorexia nervosa may be mitigated by continued undernutrition, which may act to uncouple bone formation and resorption. We have previously shown that women with anorexia nervosa exhibit low bone formation rates and increased resorption rates (3). Hotta and colleagues (17) have shown that low rates of bone formation in patients with anorexia nervosa increase with feeding, suggesting a mechanism whereby bone formation is reduced by undernutrition and

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.

Abnormal Bone Mineral Accrual in Adolescent Girls with Anorexia Nervosa

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN.

Increased Bone Marrow Fat in Anorexia Nervosa

CONTEXT Although women with anorexia nervosa (AN) have severe depletion of body fat, a paradoxical increase in bone marrow fat has been described. Recent data suggest that marrow fat measured by 1H-magnetic resonance spectroscopy (MRS) in combination with bone mineral density (BMD) may be more valuable than either parameter alone in detecting bone weakness. OBJECTIVE The objective of the study was to investigate the effect of AN on accumulation of marrow fat in spine and femur using 1H-MRS and the relationship between marrow fat, BMD, and body composition in subjects with AN and normal-weight controls. DESIGN This was a cross-sectional study. SETTING The study was conducted at a referral center. PATIENTS Patients included 10 women with AN (29.8 +/- 7.6 yr) and 10 normal-weight age-matched women (29.2 +/- 5.2 yr). INTERVENTIONS There were no interventions. MAIN OUTCOMES MEASURE Marrow fat content of the fourth lumbar vertebra and femur measured by 1H-MRS. BMD of spine and hip measured by dual-energy x-ray absorptiometry. RESULTS Subjects with AN had higher marrow fat at the fourth lumbar vertebra and femur compared with controls (P = 0.004-0.01). There was an inverse correlation between marrow fat of L4 and femur and BMD of the spine and hip (r = -0.56 to -0.71, P = 0.01-0.0002) and body mass index and sc adipose tissue of the thigh (r = -0.49 to -0.71, P = 0.03-0.0007). There was an inverse correlation between femur marrow fat and sc and total abdominal adipose tissue (r = -0.53 to -0.67, P = 0.003-0.03). CONCLUSION Women with AN have greater lumbar and femoral marrow fat than controls, and marrow fat correlates inversely with BMD. This paradoxical increase in marrow fat at a time when sc and visceral fat are markedly reduced raises important questions about functional consequences of this process.

Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women.

Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin‐like growth factor 1 (IGF‐1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF‐1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18–41 kg/m2, mean 30 ± 7 kg/m2) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H‐MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF‐1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF‐1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF‐1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF‐1 as an important regulator of the fat and bone lineage.

Pseudo-Cushing's Syndrome in Human Immunodeficiency Virus—Infected Patients

To our knowledge, an association between human immunodeficiency virus infection and pseudo-Cushings syndrome has not previously been described. We describe four HIV-infected patients with pseudo-Cushings syndrome, characterized by striking dorsocervical and submandibular fat accumulation and central obesity. In each case, cortisol levels were either normal or suppressed adequately with administration of dexamethasone, excluding the diagnosis of true Cushings syndrome. Immune function and weight improved significantly preceding the development of pseudo-Cushings syndrome. Three of the four patients were taking a common protease inhibitor at the onset of symptoms, and the fourth reported the exacerbation of his symptoms with the addition of a protease inhibitor. The observed characteristic pattern of fat deposition may be attributable to a specific effect of new antiretroviral therapies or may relate to recovery independent of medication usage. Distinguishing between pseudo-Cushings syndrome and true Cushings syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. Further research into the mechanisms of this novel phenomenon is needed.

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 17β‐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.

Assessment of macronutrient and micronutrient intake in women with anorexia nervosa

OBJECTIVE The purpose of this study is to evaluate the accuracy of diet history compared to observed food intake in the nutritional assessment of women with anorexia nervosa (AN) and healthy age-matched controls. METHOD One-month diet history was compared to 1-day observed food intake in 30 women with AN and 28 control subjects. RESULTS Reported intake by diet history was similar to observed intake for macronutrient composition and fat intake for patients with AN. Reported energy intake was higher than observed intake (1,602 +/- 200 kcal vs. 1,289 +/- 150 kcal, p <.05), but was in agreement with predicted energy expenditure by the Harris-Benedict equation (1,594 +/- 18 kcal, p =.97) in patients with AN. Micronutrient intake by diet history was highly correlated with observed intake in patients with AN. More than one half of the patients with AN failed to meet the recommended dietary allowance (RDA) for vitamin D, calcium, folate, vitamin B12, zinc, magnesium, and copper when assessed by diet history. In contrast to patients with AN, diet history did not correlate with observed intake of energy, macronutrients, or most micronutrients among the controls. DISCUSSION Diet history is an accurate tool to assess fat intake and macronutrient composition in patients with AN and demonstrates significant micronutrient deficiencies in this population. The agreement between total energy intake and predicted energy expenditure supports the overall utility of the diet history in the nutritional assessment of patients with AN.

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.

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.