Bone marrow adipose tissue is associated with fracture history in anorexia nervosa.

Although bone mineral density (BMD) is decreased and fracture risk increased in anorexia nervosa, BMD does not predict fracture history in this disorder. We assessed BMD, bone microarchitecture, and bone marrow adipose tissue (BMAT) in women with anorexia nervosa and found that only BMAT was associated with fracture history. INTRODUCTION: Anorexia nervosa (AN) is a psychiatric disorder characterized by low body weight, low BMD, and increased risk of fracture. Although BMD is reduced and fracture risk elevated, BMD as assessed by DXA does not distinguish between individuals with versus those without prior history of fracture in AN. Despite having decreased peripheral adipose tissue stores, individuals with AN have enhanced bone marrow adipose tissue (BMAT), which is inversely associated with BMD. Whether increased BMAT is associated with fracture in AN is not known. METHODS: We conducted a cross-sectional study in 62 premenopausal women, including 34 with AN and 28 normal-weight women of similar age. Fracture history was collected during patient interviews and BMD measured by DXA, BMAT by 1H-MRS, and parameters of bone microarchitecture by HR-pQCT. RESULTS: Sixteen women (47.1%) with AN reported prior history of fracture compared to 11 normal-weight women (39.3%, p = 0.54). In the entire group and also the subset of women with AN, there were no significant differences in BMD or parameters of bone microarchitecture in women with prior fracture versus those without. In contrast, women with AN with prior fracture had greater BMAT at the spine and femur compared to those without (p = 0.01 for both). CONCLUSION: In contrast to BMD and parameters of bone microarchitecture, BMAT is able to distinguish between women with AN with prior fracture compared to those without. Prospective studies will be necessary to understand BMAT's potential pathophysiologic role in the increased fracture risk in AN.

IGF-1 is associated with estimated bone strength in anorexia nervosa.

IGF-1 and leptin are two nutritionally dependent hormones associated with low bone mass in women with anorexia nervosa. Using finite element analysis, we estimated bone strength in women with anorexia nervosa and found that IGF-1 but not leptin correlated significantly with estimated bone strength in both the radius and tibia. PURPOSE: Women with anorexia nervosa, a psychiatric disorder characterized by self-induced starvation and low body weight, have impaired bone formation, low bone mass, and an increased risk of fracture. IGF-1 and leptin are two nutritionally dependent hormones that have been associated with low bone mass in women with anorexia nervosa. We hypothesized that IGF-1 and leptin would also be positively associated with estimated bone strength in women with anorexia nervosa. METHODS: In this cross-sectional study of 38 women (19 with anorexia nervosa and 19 normal-weight controls), we measured serum IGF-1 and leptin and performed finite element analysis of high-resolution peripheral quantitative CT images to measure stiffness and failure load of the distal radius and tibia. RESULTS: IGF-1 was strongly correlated with estimated bone strength in the radius (R = 0.52, p = 0.02 for both stiffness and failure load) and tibia (R = 0.55, p = 0.01 for stiffness and R = 0.58, p = 0.01 for failure load) in the women with anorexia nervosa but not in normal-weight controls. In contrast, leptin was not associated with estimated bone strength in the group of women with anorexia nervosa or normal-weight controls. CONCLUSIONS: IGF-1 is strongly associated with estimated bone strength in the radius and tibia in women with anorexia nervosa. Further studies are needed to assess whether treatment with recombinant human IGF-1 will further improve bone strength and reduce fracture risk in this population.

Determinants of IGF1 and GH across the weight spectrum: from anorexia nervosa to obesity.

CONTEXT: Chronic starvation is characterized by GH resistance, and obesity is characterized by decreased GH secretion. In both extremes, IGF1 levels may be low and androgen levels may be abnormal. OBJECTIVE: To investigate the determinants of IGF1 and GH across the weight spectrum in women. DESIGN: Cross-sectional study. SETTING: Clinical research center. STUDY PARTICIPANTS: In total, 32 women had participated in the study: 11 women with anorexia nervosa (AN), 11 normal-weight women, and 10 obese women of comparable mean age. INTERVENTION: None. MAIN OUTCOME MEASURES: Pooled hourly overnight serum samples assayed for IGF1, GH, estradiol (E(2)), testosterone, SHBG, insulin, free fatty acids, and trunk fat. RESULTS: Free testosterone was higher in obese women and lower in women with AN than in normal-weight women, and was the only independent (and positive) predictor of IGF1 levels, accounting for 14% of the variability (P=0.032) in the group as a whole. This relationship was stronger when obese women were excluded, with free testosterone accounting for 36% of the variability (P=0.003). Trunk fat accounted for 49% of the variability (P<0.0001) of GH, with an additional 7% of the variability attributable to E(2) (P=0.042) in the group as a whole, but was not a significant determinant of GH secretion when obese women were excluded. CONCLUSIONS: Free testosterone is a significant determinant of IGF1 levels in women across the body weight spectrum. In contrast, GH secretion is differentially regulated at the extremes of the weight spectrum.

Adrenal glucocorticoid and androgen precursor dissociation in anorexia nervosa.

CONTEXT: Anorexia nervosa is characterized by hypogonadism and relative hypercortisolemia. We have demonstrated that free testosterone levels are low in women with anorexia nervosa, with the lowest levels in those receiving oral contraceptives (OCPs), and that dehydroepiandrosterone (DHEA) sulfate is reduced only in those receiving OCPs. OBJECTIVE: The aim of the study was to determine whether adrenal steroidogenesis dysregulation contributes to decreased androgen levels in anorexia nervosa. DESIGN AND SETTING: We conducted a cross-sectional study in a General Clinical Research Center. STUDY PARTICIPANTS: We studied 20 women with anorexia nervosa [10 women with anorexia nervosa receiving OCPs (AN+E) and 10 not receiving OCPs (AN-E)] and 20 healthy controls [10 healthy controls receiving OCPs (HC+E) and 10 not receiving OCPs (HC-E)]. MAIN OUTCOME MEASURES: We measured DHEA and cortisol levels in response to 250-microg cosyntropin stimulation after 1-mg overnight dexamethasone suppression. RESULTS: Mean basal and stimulated, peak stimulated, and area under the curve (AUC) cortisol levels were higher in AN-E than HC-E, but mean basal and stimulated, peak and AUC DHEA were comparable. Mean AUC and peak cortisol were higher and DHEA AUC was lower in AN+E than AN-E. However, after controlling for cortisol binding globulin levels, peak and AUC cortisol were comparable between AN+E and AN-E. After controlling for albumin levels, AUC DHEA was comparable between AN+E and AN-E. CONCLUSIONS: Adrenal glucocorticoid and androgen precursor secretion are dissociated in anorexia nervosa, with relative hypercortisolemia and a preservation of DHEA secretion. Reduced DHEA response to cosyntropin in women receiving OCPs is attributable to decreased albumin levels. In the setting of relative hypercortisolemia, reduced adrenal androgen precursor secretion is not a mechanism underlying low testosterone levels in anorexia nervosa.

Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea.

CONTEXT: Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population. OBJECTIVE: Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women. DESIGN AND SETTING: We conducted a cross-sectional study at a general clinical research center. STUDY PARTICIPANTS: A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls. MAIN OUTCOME MEASURES: Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed. RESULTS: Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass. CONCLUSIONS: Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether oral contraceptive use, mediated by reductions in endogenous androgen levels, is deleterious to skeletal health in such women.