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Context Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis. Objective The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)−, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly. Design Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly. Main Outcome Measures Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids. Results Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone−binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass. Conclusions Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass.

Context Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA). Objective To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls. Design and subjects Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls). Outcome measures Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia. Results aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area (P P = 0.0038), cortical pore volume (P P = 0.0008), but lower trabecular bone density (P = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density (P = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD. Conclusions Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.

Background Altered bone microarchitecture and higher marrow adipose tissue (MAT) may reduce bone strength. High resolution pQCT (HRpQCT) allows assessment of volumetric BMD (vBMD), and size and microarchitecture parameters of bone, while 1H–magnetic resonance spectroscopy (1H–MRS) allows MAT evaluation. We have reported impaired microarchitecture at the non-weight bearing radius in adolescents with anorexia nervosa (AN) and that these changes may precede aBMD deficits. Data are lacking regarding effects of AN on microarchitecture and strength at the weight-bearing tibia in adolescents and young adults, and the impact of changes in microarchitecture and MAT on strength estimates. Objective To compare strength estimates at the distal tibia in adolescents/young adults with AN and controls in relation to vBMD, bone size and microarchitecture, and spine MAT. Design and methods This was a cross-sectional study of 47 adolescents/young adults with AN and 55 controls 14–24 years old that assessed aBMD and body composition using DXA, and distal tibia vBMD, size, microarchitecture and strength estimates using HRpQCT, extended cortical analysis, individual trabecular segmentation, and finite element analysis. Lumbar spine MAT (1H–MRS) was assessed in a subset of 19 AN and 22 controls. Results Areal BMD Z -scores were lower in AN than controls. At the tibia, AN had greater cortical porosity, lower total and cortical vBMD, cortical area and thickness, trabecular number, and strength estimates than controls. Within AN, strength estimates were positively associated with lean mass, aBMD, vBMD, bone size and microarchitectural parameters. MAT was higher in AN, and associated inversely with strength estimates. Conclusions Adolescents/young adults with AN have impaired microarchitecture at the weight-bearing tibia and higher spine MAT, associated with reduced bone strength.

Purpose Women with anorexia nervosa (AN) have increased marrow fat despite severe depletion of body fat. Recent studies have suggested that marrow fat composition may serve as a biomarker for bone quality. The purpose of our study was to investigate marrow fat composition of the femur using proton MR spectroscopy ( 1 H MRS), and the relationship between measures of marrow fat composition and BMD and body composition in women with AN and normal-weight controls. Materials and methods 14 women with AN (29.5 ± 1.9 years) and 12 age-matched normal-weight controls underwent 1 H MRS to determine total marrow fat content and marrow fat composition of the femoral diaphysis and soleus intramyocellular lipids und unsaturated muscle lipids. MRI was performed to quantify abdominal fat, thigh fat and muscle areas. Lumbar spine BMD, fat and lean mass were assessed by DXA. Results Subjects with AN had higher marrow fat content (p 0.05) compared to normal-weight controls. There was an inverse association between marrow methylene protons, an estimate of fatty acid (FA) saturated bonds, and lumbar spine BMD (r = − 0.52, p = 0.008) independent of %ideal body weight (%IBW). Olefinic protons at 5.3 ppm, an estimate of FA unsaturated bonds, were inversely associated with body fat depots, independent of %IBW, and positively associated with soleus unsaturation (p ≤ 0.05). Conclusion Women with AN have higher total femoral marrow fat but similar composition compared to normal-weight controls. The degree of marrow FA saturation correlates inversely with BMD, suggesting that saturated lipids may have negative effects on BMD. The degree of marrow FA unsaturation correlates positively with soleus unsaturation, suggesting that marrow fat composition may be influenced by the same factors as ectopic lipid composition in muscle.

Anorexia nervosa is a psychiatric illness of unknown etiology defined by aberrant eating behaviors, persistent low body weight, body image disturbance, and amenorrhea.1 Anorexia nervosa is associated with refractoriness to treatment, an often chronic course, and increased mortality risk. The DSM-5 defines 2 anorexia nervosa subtypes: restricting type, in which weight loss is achieved or maintained primarily through dietary restriction, and binge-eating/purging type, in which restriction is coupled with binge eating and/or purging behaviors. Approximately 50% of patients will experi ence diagnostic “crossover” from pure restriction to binge/purge behaviors during their illness course.2,3 Binge-eating/purging type anorexia nervosa is considered to be a more pernicious form of the illness, associated with increased medical morbidity, impulsivity, suicidality, and poor outcome, relative to restricting type anorexia nervosa. However, hormonal mechanisms underlying disordered eating behaviors that characterize anorexia nervosa and the subtypes or predict crossover are unknown, which challenges identification of those with anorexia nervosa who may be at greatest risk. Neuroendocrine dysfunction is a hallmark of anorexia nervosa, although it is not universally manifested by such patients,4 and appetite-regulating hormone patterns may be involved in the pathophysiology of the subtypes. Peptide YY (PYY), brain-derived neurotrophic factor (BDNF), and leptin are anorexigenic appetite-regulating hormones, and knock-out rodent models are characterized by hyperphagia, 5–7 suggesting a possible role for these hormones in the development or maintenance of binge/purge or restrictive behaviors. 8 Although these hormones have been found to be dysregulated in anorexia nervosa, whether between-subtype differences exist is not known. Peptide YY is a 36-amino acid polypeptide hormone released in the ileum and colon in response to food ingestion that modulates appetite by binding with receptors to signal satiety and cue appetite reduction. Peptide YY 3-36 is the main circulating form of the peptide released in both the fasting and postprandial states. Studies report that fasting and postprandial PYY and PYY 3-36 are increased in those with active anorexia nervosa relative to controls.9–11 Our group previously reported that PYY was positively associated with a drive for thinness and eating concerns in women with anorexia nervosa, lean and obese controls. 9 However, differences between the anorexia nervosa sub-types were not examined. 9 Most studies of PYY demonstrate higher levels in anorexia nervosa than controls, despite the fact that PYY is anorexigenic and therefore would be expected to be suppressed in anorexia nervosa (ie, if it were to function adaptively). However, the literature focuses mostly on restricting type anorexia nervosa. Only 1 study12 has examined differences in PYY between anorexia nervosa subtypes, finding that PYY was decreased in both anorexia nervosa subtypes, with no differences in PYY between restricting type and binge-eating/purging type. Studies ofPYY in normal-weight bulimia nervosa are inconsistent, with some studies reporting decreased levels12–14 and others reporting an increased response.15 Brain-derived neurotrophic factor is also an anorexigenic hormone. Brain-derived neurotrophic factor, a neurotrophic protein and member of the nerve growth factor family, is dist ributed throughout the central nervous system and is known to exert effects on neuronal growth, differentiation, plasticity (specifically memory and learning), and functions to modulate neurotransmitters. Researchers have postulated a role for BDNF in the regulation of eating behaviors.16–17 However, the specific nature of the relationship between BDNF and eating behaviors in humans is not understood. A recent meta-analysis18 found that BDNF levels were lower in active restricting type relative to healthy controls. Further, population genetic studies have raised the possibility that the BDNF gene could be an etiopathological factor in the development of restricting-type anorexia nervosa.19 Published studies in anorexia nervosa have not had sufficient power to examine this possibility. Saito et al20 demonstrated higher mean serum BDNF levels in a group of normal-weight women with bulimia nervosa compared with women with anorexia nervosa, but the differences between the groups may have been attributable to the differences in weight between the groups. Whether BDNF levels in women with eating disorders are related to restriction, binge eating, and purging behaviors rather than weight has not been previously explored. Leptin is a fat-derived hormone that signals satiety and is decreased in anorexia nervosa compared to healthy controls21,22 and increases with weight restoration.23,24 As it is a fat-derived hormone, it is not clear whether low leptin levels are related to eating disorder psychopathology independent of body weight. Yet, decreased leptin levels have also been found in some women with bulimia nervosa relative to healthy controls and are inversely related to duration of illness and binge/purge frequency.25 Leptin has not been examined between the anorexia nervosa subtypes. We chose to examine anorexigenic appetite-regulating hormones in individuals with anorexia nervosa to explore the role of these hormones in relation to the array of eating-related symptoms focusing expressly on anorexia nervosa subtypes; we investigated between-subtype differences in addition to differences between women with anorexia nervosa and healthy control females. We hypothesized that differences in secretion of these hormones in restricting versus binge-eating/purging anorexia nervosa subtypes would reflect the phenotypic differences in eating-related behaviors and possibly also comorbid psychopathology. On the basis of the limited extant literature, we hypothesized that PYY would not differ between the anorexia nervosa subtypes and would be increased in anorexia nervosa relative to controls; that BDNF would be lower in restricting type than in binge-eating/purging type, and lower in both groups relative to controls; and that leptin would be decreased in both anorexia nervosa subtypes relative to controls and explained by differences in body mass index (BMI).

Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity.In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21-45 y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1.GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, a 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. A six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. A six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP.GH replacement in abdominally obese premenopausal women for 6 months increased bone turnover and bone marrow fat. Reductions in abdominal fat, and inflammation, and increases in IGF-1, lean mass and vitamin D were associated with increased bone formation. The increase in bone marrow fat may reflect changes in energy demand from increased bone turnover.

Anorexia nervosa (AN), a prevalent psychiatric disorder predominantly affecting women, is characterized by self-induced starvation and low body weight. Increased clinical fractures are common, and most women have low bone mineral density (BMD). Previously investigated treatments have led to no or modest increases in BMD in AN.Our objective was to investigate the effect of teriparatide (TPT; human PTH[1-34]), an anabolic agent, on low bone mass in women with AN.This randomized, placebo-controlled trial at a clinical research center included 21 women with AN: 10 (mean age ± SEM, 47 ± 2.7 years) treated with TPT and 11 (47.1 ± 2.3 years) treated with placebo.TPT (20 μg s.c.) or placebo was administered for 6 months.Our primary outcome measure was change in BMD of the spine and hip by dual-energy x-ray absorptiometry. Secondary outcome measures included changes in serum N-terminal propeptide of type 1 procollagen (P1NP), C-terminal collagen cross-links, sclerostin, and IGF-1 levels.At 6 months, spine BMD increased significantly more with TPT (posteroanterior spine, 6.0% ± 1.4%; lateral spine, 10.5% ± 2.5%) compared with placebo (posteroanterior spine, 0.2% ± 0.7%, P.01; lateral spine, -0.6% ± 1.0%; P.01). The results remained significant after controlling for baseline body mass index, P1NP, and IGF-1. Changes in femoral neck (P = .4) and total hip (P = 0.8) BMD were comparable in both groups, as were changes in weight. Serum P1NP levels increased after 3 months of TPT treatment and remained at this higher level at 6 months, whereas P1NP levels were unchanged in the placebo group (P = .02). TPT was well-tolerated by all subjects.This study demonstrates that TPT administration increases spine BMD substantially after only 6 months of therapy in women with AN.

Anorexia nervosa (AN) is reported in 0.3% of young females 1. It is the third most common medical condition among adolescent girls based on one report, and the incidence of AN appears to be increasing in this population 2. Girls with AN are characterized by low weight and multiple hormonal abnormalities which impact bone metabolism. Some of these alterations include low levels of leptin, hypogonadism, relative IGF-1 deficiency, and hypercortisolism 3–6. Markers of bone turnover are suppressed in adolescent girls with AN 4,7,8, and bone mineral accrual is reduced 4,9,10. Girls with AN consequently have decreased areal bone mineral density (aBMD) compared to normal-weight individuals 11. Furthermore, cortical and trabecular microarchitecture is impaired in girls with AN, and finite element-derived estimates of stiffness and failure load are also lower than in controls 12,13. However, it is not known whether lower aBMD in adolescents with AN translates to an increased risk for fractures during childhood. The onset of AN occurs most commonly during adolescence 14. Adolescence is normally marked by rapid bone accumulation 15. Diseases, such as AN, which impair bone accrual during this period can adversely affect attainment of peak bone mass, and therefore BMD later in life. In patients with AN, disease onset prior to the attainment of peak bone mass results in more severe skeletal outcomes compared to disease onset in adulthood 16. Several studies have demonstrated an increased fracture risk in adults with AN. Fracture incidence increases soon after the diagnosis of AN and remains elevated many years later 17–19. However, no prior study has examined the prevalence of childhood and adolescent fracture before or after the diagnosis of AN in adolescents. In addition, although measurement of aBMD is a valuable tool to estimate fracture risk in postmenopausal women 20, data demonstrating its ability to predict fractures in children are limited 21. The relationship between aBMD and fracture prevalence has not been examined in adolescents with AN. We assessed fracture history and aBMD in a large group of adolescents females with AN and normal-weight controls. The study was conducted to determine whether the prevalence of childhood and adolescent fracture is increased in adolescent females with AN compared to normal-weight controls, and to examine whether reductions in aBMD predict fracture risk in females with AN. We hypothesized that the risk of fracture would be increased among adolescent females with AN compared to controls and that decreases in aBMD would be associated with a history of fracture.

To investigate the associations between ectopic and serum lipid levels and bone marrow fat, as a marker of stem cell differentiation, in young obese men and women, with the hypothesis that ectopic and serum lipid levels would be positively associated with bone marrow fat.The study was institutional review board approved and complied with HIPAA guidelines. Written informed consent was obtained. The study group comprised 106 healthy young men and women (mean age, 33.7 years ± 6.8 [standard deviation]; range, 19-45 years; mean body mass index (BMI), 33.1 kg/m(2) ± 7.1; range, 18.1-48.8 kg/m(2)) who underwent hydrogen 1((1)H) magnetic resonance (MR) spectroscopy by using a point-resolved spatially localized spectroscopy sequence at 3.0 T of L4 for bone marrow fat content, of soleus muscle for intramyocellular lipids (IMCL), and liver for intrahepatic lipids (IHL), serum cholesterol level, serum triglyceride level, and measures of insulin resistance (IR). Exercise status was assessed with the Paffenbarger activity questionnaire.There was a positive correlation between bone marrow fat and IHL (r = 0.21, P = .048), IMCL (r = 0.27, P = .02), and serum triglyceride level (r = 0.33, P = .001), independent of BMI, age, IR, and exercise status (P.05). High-density lipoprotein cholesterol levels were inversely associated with bone marrow fat content, independent of BMI, age, IR, and exercise status (r = -0.21, P = .019).Results of this study suggest that ectopic and serum lipid levels are positively associated with bone marrow fat in obese men and women.

Context: Temozolomide (TMZ) is an alkylating agent primarily used to treat tumors of the central nervous system. We describe 2 patients with apparent TMZ-induced central diabetes insipidus. Using our institution's Research Patient Database Registry, we identified 3 additional potential cases of TMZ-induced diabetes insipidus among a group of 1545 patients treated with TMZ. Case Presentations: A 53-year-old male with an oligoastrocytoma and a 38-year-old male with an oligodendroglioma each developed symptoms of polydipsia and polyuria approximately 2 months after the initiation of TMZ. Laboratory analyses demonstrated hypernatremia and urinary concentrating defects, consistent with the presence of diabetes insipidus, and the patients were successfully treated with desmopressin acetate. Desmopressin acetate was withdrawn after the discontinuation of TMZ, and diabetes insipidus did not recur. Magnetic resonance imaging of the pituitary and hypothalamus was unremarkable apart from the absence of a posterior pituitary bright spot in both of the cases. Anterior pituitary function tests were normal in both cases. Using the Research Patient Database Registry database, we identified the 2 index cases and 3 additional potential cases of diabetes insipidus for an estimated prevalence of 0.3% (5 cases of diabetes insipidus per 1545 patients prescribed TMZ). Conclusions: Central diabetes insipidus is a rare but reversible side effect of treatment with TMZ.

A key feature of anorexia nervosa, a disease primarily psychiatric in origin, is chronic starvation, which results in profound neuroendocrine dysregulation, including hypogonadism, relative growth hormone resistance, and hypercortisolemia. A recent area of investigation is appetite hormone dysregulation. Whether such dysregulation is compensatory or plays a role in the pathophysiology of anorexia nervosa is incompletely understood. The primary therapy for anorexia remains psychiatric, and endocrine abnormalities tend to improve with weight restoration, although residual endocrine dysfunction can occur. In addition, therapies directed at specific complications have been a particular focus of research.

Objective Anorexia nervosa is characterized by low weight, aberrant eating attitudes, body image distortion, and hypogonadism. Anxiety is a common comorbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in anorexia nervosa. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes without affecting body image in anorexia nervosa. Method Girls 13-18 years old with anorexia nervosa (DSM-IV) were randomized to transdermal estradiol (100 μg twice weekly) with cyclic progesterone or placebo patches and pills for 18-months, between 2002 and 2010. The State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory-2 (EDI-2), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these measures at baseline (n=38 [girls receiving estrogen] and n=34 [girls receiving placebo]) and 37 at 18 months (n=20 [girls receiving estrogen] and n=17 [girls receiving placebo]). The primary outcome measure was the change in these scores over 18 months. Results Estrogen replacement caused a decrease in STAIC-trait scores (-3.05 [1.22] vs. 2.07 [1.73], P=.02), without impacting STAIC-state scores (-1.11 [2.17] vs. 0.20 [1.42], P=.64). There was no effect of estrogen replacement on EDI-2 or BSQ-34 scores. Body mass index (BMI) changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (P=.03). Increases in serum estradiol were significantly associated with decreases in STAIC-trait scores (Spearman ρ = -0.45, P=.03). Conclusions Estrogen replacement improved trait anxiety (the tendency to experience anxiety) but did not impact eating attitudes or body shape perception. Trial registration ClinicalTrials.gov identifier: NCT00088153.

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.

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

We have reported lower hip bone mineral density (BMD) in adolescent boys with anorexia nervosa (AN) compared with controls. Although studies have described bone structure in girls with AN, these data are not available for boys. Hip structural analysis (HSA) using dual-energy x-ray absorptiometry is a validated technique to assess hip geometry and strength while avoiding radiation associated with quantitative computed tomography.We hypothesized that boys with AN would have impaired hip structure/strength (assessed by HSA) compared with controls.We conducted a cross-sectional study at a clinical research center.We used HSA techniques on hip dual-energy x-ray absorptiometry scans in 31 previously enrolled boys, 15 with AN and 16 normal-weight controls, 12 to 19 years old.AN boys had lower body mass index SD score (P.0001), testosterone (P = .0005), and estradiol (P = .006) than controls. A larger proportion of AN boys had BMD Z-scores-1 at the femoral neck (60% vs 12.5%, P = 0008). Using HSA, at the narrow neck and trochanter region, boys with AN had lower cross-sectional area (P = .03, 0.02) and cortical thickness (P = .02, 0.03). Buckling ratio at the trochanter region was higher in AN (P = .008). After controlling for age and height, subperiosteal width at the femoral shaft, cross-sectional moment of inertia (narrow neck and femoral shaft), and section modulus (all sites) were lower in AN. The strongest associations of HSA measures were observed with lean mass, testosterone, and estradiol. On multivariate analysis, lean mass remained associated with most HSA measures.Boys with AN have impaired hip geometric parameters, associated with lower lean mass.

Objective: To test a newly developed dual energy X-ray absorptiometry (DXA) method for abdominal fat depot quantification in subjects with anorexia nervosa (AN), normal weight, and obesity using CT as a gold standard. Design and Methods: 135 premenopausal women (overweight/obese: n = 89, normal-weight: n = 27, AN: n = 19); abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT) areas determined on CT and DXA. Results: There were strong correlations between DXA and CT measurements of abdominal fat compartments in all groups with the strongest correlation coefficients in the normal-weight and overweight/obese groups. Correlations of DXA and CT VAT measurements were strongest in the obese group and weakest in the AN group. DXA abdominal fat depots were higher in all groups compared to CT, with the largest % mean difference in the AN group and smallest in the obese group. Conclusion: A new DXA technique is able to assess abdominal fat compartments including VAT in premenopausal women across a large weight spectrum. However, DXA measurements of abdominal fat were higher than CT, and this percent bias was most pronounced in the AN subjects and decreased with increasing weight, suggesting that this technique may be more useful in obese individuals.

Objective Obesity has been associated with cognitive decline in longitudinal studies of older individuals. We hypothesized that the cognitive sequelae of obesity may be detectable in the reproductive years. In addition, we explored the hypothesis that these associations may be mediated by the hormonal milieu. Design and Methods Of 49 young healthy lean and overweight women aged 20-45, we investigated the association between performance on a battery of cognitive tests, body composition parameters [body mass index, total fat, abdominal (visceral, subcutaneous, and total) adipose tissue, and muscle], and hormone levels (insulin, adiponectin, leptin, insulin-like growth factor 1 (IGF-1), estrogen, testosterone, and vitamin D). Results We found a significant negative association between both visceral adiposity and muscle, and performance in the domain of verbal learning and memory, after controlling for age and education. Other body composition parameters showed similar trends (0.05 < P < 0.10). Additionally, the degree of insulin resistance was negatively associated with executive function domain. None of the associations between the other hormones examined (adipokines, IGF-1, gonadal hormones, and vitamin D) and cognitive function were significant. Conclusion These preliminary findings suggest a possible association between obesity and cognitive function in healthy young women of reproductive age. More research is warranted into the potential modulatory effect of insulin resistance on this association.

Adolescents with anorexia nervosa (AN) have low areal bone mineral density (aBMD) at both cortical and trabecular sites, and recent data show impaired trabecular microarchitecture independent of aBMD. However, data are lacking regarding both cortical microarchitecture and bone strength assessment by finite element analysis (FEA) in adolescents with AN. Because microarchitectural abnormalities and FEA may predict fracture risk independent of aBMD, these data are important to obtain.Our objective was to compare both cortical and trabecular bone microarchitecture and FEA estimates of bone strength in adolescent girls with AN vs normal-weight controls.We conducted a cross-sectional study at a clinical research center that included 44 adolescent girls (21 with AN and 23 normal-weight controls) 14 to 22 years old.We evaluated 1) aBMD (dual-energy x-ray absorptiometry) at the distal radius, lumbar spine, and hip, 2) cortical and trabecular microarchitecture at the ultradistal radius (high-resolution peripheral quantitative computed tomography), and 3) FEA-derived estimates of failure load at the ultradistal radius.aBMD was lower in girls with AN vs controls at the lumbar spine and hip but not at the distal radius. Girls with AN had lower total (P.0001) and trabecular volumetric BMD (P = .02) and higher cortical porosity (P = .03) and trabecular separation (P = .04). Despite comparable total cross-sectional area, trabecular area was higher in girls with AN (P = .04), and cortical area and thickness were lower (P = .002 and .02, respectively). FEA-estimated failure load was lower in girls with AN (P = .004), even after controlling for distal radius aBMD.Both cortical and trabecular microarchitecture are altered in adolescent girls with AN. FEA-estimated failure load is decreased, indicative of reduced bone strength. The finding of reduced cortical bone area in girls with AN is consistent with impaired cortical bone formation at the endosteum as a mechanism underlying these findings.

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson's disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

Areal bone mineral density (BMD) is lower, particularly at the spine, in low-weight women with anorexia nervosa (AN). However, little is known about vertebral integral volumetric BMD (Int.vBMD) or vertebral strength across the AN weight spectrum, including "atypical" AN [body mass index (BMI) ≥18.5 kg/m2].To investigate Int.vBMD and vertebral strength, and their determinants, across the AN weight spectrum.Cross-sectional observational study.Clinical research center.153 women (age 18 to 45): 64 with low-weight AN (BMI18.5 kg/m2; 58% amenorrheic), 44 with atypical AN (18.5≤BMI23 kg/m2; 30% amenorrheic), 45 eumenorrheic controls (19.2≤BMI25 kg/m2).Int.vBMD and cross-sectional area (CSA) by quantitative computed tomography of L4; estimated vertebral strength (derived from Int.vBMD and CSA).Int.vBMD and estimated vertebral strength were lowest in low-weight AN, intermediate in atypical AN, and highest in controls. CSA did not differ between groups; thus, vertebral strength (calculated using Int.vBMD and CSA) was driven by Int.vBMD. In AN, Int.vBMD and vertebral strength were associated positively with current BMI and nadir lifetime BMI (independent of current BMI). Int.vBMD and vertebral strength were lower in AN with current amenorrhea and longer lifetime amenorrhea duration. Among amenorrheic AN, Int.vBMD and vertebral strength were associated positively with testosterone.Int.vBMD and estimated vertebral strength (driven by Int.vBMD) are impaired across the AN weight spectrum and are associated with low BMI and endocrine dysfunction, both current and previous. Women with atypical AN experience diminished vertebral strength, partially due to prior low-weight and/or amenorrhea. Lack of current low-weight or amenorrhea in atypical AN does not preclude compromise of vertebral strength.

Long-acting somatostatin analogs are one of the main classes of medical therapy used for acromegaly and most patients require ongoing treatment. Few studies have evaluated the long-term efficacy and safety of lanreotide depot beyond 2 years. The goal of this study was to provide a long-term longitudinal assessment of efficacy and safety of lanreotide depot in lanreotide responders compared to a surgically cured control group. In this retrospective longitudinal case-control study, patients with acromegaly receiving lanreotide depot monotherapy continuously for at least 24 months (N = 24) and surgically cured patients (N = 39) were compared. Serum IGF-1, pituitary MRIs, lanreotide dose, co-morbidities and adverse effects were assessed longitudinally. In the lanreotide group, IGF-1 remained normal and unchanged over 6 years; comparable to the surgery only group. There was no difference in prevalence of normal IGF-1 between the lanreotide and surgery only groups at 6 months (100 vs. 97 %), 6 years (89 vs. 90 %) and at last follow-up (96 vs. 92 %). Tumor size remained stable (79 %) or decreased (21 %) in the lanreotide group. In the surgery only group, tumor size remained unchanged in all patients. Hemoglobin A1C did not differ between lanreotide and surgery only groups (baseline 5.8 vs. 6.1 %; last follow-up 6.0 vs. 5.7 %). Two (8 %) of the lanreotide and none of the surgery only group developed new diabetes mellitus. Lanreotide depot maintains normalization of IGF-1 in 89 % of responders after 6 years, comparable to surgically cured controls, and controlled tumor size in all without significant adverse effects.

DSM-5 revised the diagnostic criteria for anorexia nervosa (AN) by eliminating the amenorrhea requirement, liberalizing weight and psychological criteria, and adding the formal diagnosis of "atypical AN" for individuals with AN psychological symptoms without low weight. We sought to determine whether bone density (BMD) is impaired in women diagnosed with AN using the new, more liberal, DSM-5 criteria.Cross-sectional study of 168 women, 18 - 45y: (1) AN by DSM-IV (DSM-IV AN) (n = 37), (2) AN by DSM-5 but not DSM-IV criteria (DSM-5 AN) (n = 33), (3) atypical AN (ATYPICAL AN) (n = 77), (4) healthy comparison group (HC) (n = 21). Measurements included dual energy X-ray absorptiometry, Eating Disorder Examination-Questionnaire, Eating Disorder Inventory-2, Hamilton Depression and Anxiety Rating Scales.BMD Z-score-1.0 was present in 78% of DSM-IV, 82% of DSM-5, and 69% of ATYPICAL. Mean Z-scores were comparably low in DSM-IV and DSM-5, intermediate in ATYPICAL, and highest in HC. Lack of prior low weight or amenorrhea was, but history of overweight/obesity was not, protective against bone loss. Mean lean mass and percent fat mass were significantly lower in all AN groups than HC. DSM-IV, DSM-5, and ATYPICAL had comparable psychopathology.Despite liberalizing diagnostic criteria, many women diagnosed with AN and atypical AN using DSM-5 criteria have low BMD. Presence or history of low weight and/or amenorrhea remain important indications for DXA. Loss of lean mass, in addition to fat mass, is present in all AN groups, and may contribute to low BMD. The deleterious effect of eating disorders on BMD extends beyond those with current low weight and amenorrhea. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:343-351).

To determine body composition predictors of skeletal integrity in overweight/obese subjects using dual energy X-ray absorptiometry (DXA). We hypothesized that visceral adiposity would be negatively, and lean mass positively, associated with DXA measures of skeletal integrity in obesity. Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant and written informed consent was obtained. We studied 82 overweight or obese, but otherwise healthy premenopausal women and men of similar age who were part of a clinical trial (mean age: 37 ± 10 years, mean BMI: 34 ± 7 kg/m2). All subjects underwent DXA of the spine and hip for assessment of bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA), and of the whole body for the assessment of body composition, including estimated visceral adipose tissue (VAT). Sixty-three subjects (77 %) had normal BMD and 19 subjects (23 %) had osteopenia. There were strong age-, sex-, and BMD-independent positive associations between lean mass and HSA parameters (r = 0.50 to r = 0.81, p

OBJECTIVE This study aimed to assess short- and long-term reproducibility of intrahepatic lipid (IHL) quantification by proton magnetic resonance spectroscopy (H-MRS) and computed tomography (CT). METHODS Sixteen obese subjects underwent H-MRS using a single-voxel point-resolved single-voxel spectroscopy sequence at 3 T and noncontrast single-slice CT of the liver. Measurements were repeated after 6 weeks and 6 months. Clinical parameters (weight, activity, serum lipids) were collected. Short-term (baseline to 6 weeks) and long-term (baseline to 6 months) reproducibility of IHL was assessed by coefficient of variance (CV), SD, and intraclass correlation coefficient (ICC). RESULTS Short-term reproducibility and long-term reproducibility of H-MRS were as follows: CV, 5.9% to 18.8%; SD, 0.7 to 1.9; and ICC, 0.998 to 0.995 (95% confidence interval, 0.942-0.999). Short-term reproducibility and long-term reproducibility of CT were as follows: CV, 4.4% to 14.2%; SD, 2.4 to 8.7; and ICC, 0.766 to 0.982 (95% confidence interval, 0.271-0.994). There was no significant change in clinical parameters (P > 0.3). CONCLUSIONS Proton magnetic resonance spectroscopy and CT are reproducible methods for short- and long-term quantification of IHL content. Our results can guide sample size calculations for interventional and longitudinal studies.

Patients with thyrotropin-secreting pituitary adenomas may present with mass effect, hypopituitarism, and/or hyperthyroidism. The spectrum of pathologic and clinical features of patients whose tumors demonstrate β-thyrotropin immunoreactivity (β-TSH IR) has not been characterized. To characterize the phenotype of patients with pituitary adenomas with positive β-TSH IR, we conducted a retrospective analysis of patient records of all adult patients (n = 1,223) undergoing pituitary surgery in our institution over one decade (1999–2009). The search identified 166 adults with tumors which had β-TSH IR. These patients were individually matched to 166 patients whose tumors revealed no β-TSH IR. Clinical, pathological, imaging and biochemical data were extracted. 332 patients, aged 51.4 ± 15.1 years [150 women (45 %) and 182 men (55 %)], with pituitary adenomas (mean tumor diameter ± SD: 22.7 ± 9.0 mm) were studied. The degree of β-TSH IR was associated with the presence of central hyperthyroidism (p

Anorexia nervosa, a psychiatric disorder characterized by extreme, self-induced weight-loss and fear of gaining weight, affects 0.5–1% of college-aged women in the US (1, 2). Anorexia nervosa is a chronic disease with long-term relapse rates approaching 50% (3, 4) and has the highest mortality rate of any psychiatric illness, with the risk of death approaching five to ten times that expected for an age-matched population (5–8). Therefore, effective treatments for this disease are of critical importance. Potential treatment strategies for adult women with anorexia nervosa have included psychosocial treatments and psychopharmacologic therapies. The American Psychiatric Association guidelines currently recommend psychosocial therapies as first line treatment for adult women with anorexia nervosa, acknowledging that the data supporting specific therapeutic techniques are sparse (9). Psychopharmacologic therapies, particularly antidepressants and atypical antipsychotics, have been proposed for the treatment of anorexia nervosa, and randomized controlled trials have been conducted evaluating the efficacy of these medications in the treatment of anorexia nervosa and its co-morbidities. Anti-depressants, particularly selective serotonin reuptake inhibitors (SSRIs), have not been found to be beneficial in the treatment of anorexia nervosa or in the treatment of women with anorexia nervosa and co-morbid depression (10, 11). As many individuals with anorexia nervosa experience symptoms of depression, anti-depressants have been an attractive potential pharmacologic therapy. Trials with older anti-depressant agents, such as tricyclics and monoamine oxidase inhibitors have demonstrated modest, if any, benefits in decreasing anorexic symptoms and increasing weight and their use is severely limited by adverse side-effects including postural hypotension, tachycardia and psychotic symptoms (12–15). Randomized, placebo-controlled studies with fluoxetine have shown little benefit either to acutely ill or weight-recovered women (16, 17) and SSRIs have also been associated with serious side-effects, including bone loss (18, 19) and an increased risk of fracture (20–22). Antipsychotics have also been considered in the treatment of individuals with anorexia nervosa, as the distorted body image characteristic of anorexia nervosa can be considered a symptom of psychosis and weight-gain is a known side-effect of this class of medications. The use of first-generation, typical antipsychotics is complicated by potential serious adverse events, such as tardive dyskinesia. The newer, atypical antipsychotics are less likely to cause extrapyramidal side-effects but have other important side-effects including cardiovascular effects, hyperglycemia and hyperprolactinemia, which may be a mediator of bone loss in individuals using these medications (23, 24). Randomized, placebo-controlled trials investigating the use of atypical antipsychotics for the treatment of anorexia nervosa (25–27) have not demonstrated definitive benefit. The trials have been relatively short in duration and it is unknown whether any appreciated benefits will persist. Although studies of 8–10 weeks duration demonstrated a benefit with respect to weight-gain in olanzapine-treated patients (26, 27), a longer-term randomized trial investigating the use of olanzapine for three months in women with anorexia nervosa did not find a difference in weight-gain between the olanzapine and placebo groups (25). Therefore, current data do not support the use of atypical antipsychotics in the treatment of anorexia nervosa. We investigated the use of antidepressants, particularly SSRIs, and atypical antipsychotics from 1997–2009 in women with anorexia nervosa. We hypothesized that over the course of this 13-year period there would be a significant increase in both the use of these medications and in polypharmacy, despite the lack of evidence supporting psychopharmacologic treatment with antidepressants and atypical antipsychotics in patients with anorexia nervosa.

ObjectiveAbdominal adiposity is associated with increased cardiovascular risk and decreased GH secretion. The objective of our study was to determine the effects of GH on body composition and cardiovascular risk markers in abdominally obese women.Materials and methodsIn this randomized, double-blind, placebo-controlled study, 79 obese premenopausal women received GH vs placebo for 6 months. Primary endpoints were i) total abdominal (total abdominal adipose tissue, TAT) fat by computed tomography (CT) (body composition) and ii) high-sensitivity C-reactive protein (hsCRP) (cardiovascular risk marker). Body composition was assessed by CT, dual-energy X-ray absorptiometry, and proton MR spectroscopy. Serum cardiovascular risk markers, carotid intima-media thickness, and endothelial function were measured.ResultsMean 6-month GH dose was 1.7±0.1 mg/day, resulting in a mean IGF1 SDS increase from −1.7±0.08 to −0.1±0.3 in the GH group. GH administration decreased TAT and hsCRP compared with placebo. In addition, it increased thigh muscle mass and lean body mass and decreased subcutaneous abdominal and trunk fat, tissue plasminogen activator, apoB, and apoB/low-density lipoprotein compared with placebo. Visceral adipose tissue (VAT) decreased and intramyocellular lipid increased within the GH group. Six-month change in IGF1 levels was negatively associated with 6-month decrease in TAT and VAT. One subject had a 2 h glucose >200 mg/ml at 3 months; four subjects, three of whom were randomized to GH, had 2 h glucose levels >200 mg/ml at the end of the study.ConclusionGH administration in abdominally obese premenopausal women exerts beneficial effects on body composition and cardiovascular risk markers but is associated with a decrease in glucose tolerance in a minority of women.

Objective Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in obesity. Ghrelin opposes leptin effects on appetite and is negatively associated with body mass index. These appetite regulating hormones may have opposing effects on mood and stress pathways. Women with anorexia nervosa (AN), hypothalamic amenorrhea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contribute to the development of depression and/or anxiety in these disorders. We investigated the relationship between leptin and ghrelin levels and symptoms of depression, anxiety and perceived stress in women across the weight spectrum.

Breast cancer remained a hidden disease among women in the United States until the 20th century. It was initially brought into the open with public revelations from individual women, which was followed by the development of support groups and ultimately the formation of political activist groups with various priorities. Those concerned with toxic environmental exposures as a potential cause of breast cancer organized, demonstrated, and lobbied for research funding and eventually became partners in the research that arose from their efforts. One representative example was the Breast Cancer and Environment Research Centers (BCERC) Project (2003–2010), supported by the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI). The BCERC embedded a Community Outreach and Translational Core into its formal organizational infrastructure to ensure advocate involvement in the standing scientific subcommittees of BCERC, the first project funded by NIEHS and NCI to do so. The formal integration of advocates as partners in scientific studies focused on breast cancer is embedded in a rich history of action on the part of many courageous women. This article describes the historical evolution of breast cancer activism in the United States, which provided a critical foundation for the formation of BCERC. This description is followed by a discussion of BCERC as an example of the transdisciplinary research model, a paradigm that strives for inclusion of multiple stakeholders and increased interaction between scientists from a wide spectrum of disciplines, advocates, and lay audiences in order to more effectively conduct critical research and to translate and disseminate its findings.

Summary Objective Strenuous training commonly results in amenorrhoea, which contributes to bone loss in some female collegiate athletes. However, the impact of athletic training on endocrine function and bone mineral density (BMD) in male collegiate athletes is less well understood. The objective of the study was to investigate the specific endocrine determinants of BMD in male collegiate runners and wrestlers, including the potential impact of gonadal steroid levels. Design Cross-sectional study. Patients Twenty-six division I collegiate male athletes (wrestlers, runners and golfers). Measurements Main outcome measures included (i) BMD endpoints measured by dual energy x-ray absorptiometry (DXA); (ii) endocrine end-points: total and free oestradiol, total and free testosterone; (iii) body composition end-points: lean and fat mass, measured by DXA; and (iv) exercise end-points: maximal oxygen uptake (VO2 max), number of miles run weekly and grip strength. Results Free and total oestradiol levels were important positive determinants of BMD. In contrast, total and free testosterone levels were not significant predictors of BMD at any skeletal site (except for free testosterone at the radius). In addition, lean body mass, % ideal body weight, total body weight, body mass index (BMI) and hours per week of resistance training were positive predictors of BMD. VO2 max was a negative predictor of BMD. Mean BMD was higher at all skeletal sites in the wrestlers compared with the runners and a comparison group (golfers). Conclusions Our data suggest that oestradiol levels, BMI, and resistance training are more important determinants of BMD in male collegiate athletes than testosterone.

Objective To investigate whether testosterone administration alters natriuretic peptide levels in women. Design Three-month, double-blind, randomized, placebo-controlled study. Setting Clinical research center. Patient(s) Fifty-one women with hypoandrogenemia due to hypopituitarism. Intervention(s) Transdermal testosterone (300 μg daily) or placebo patch. Main Outcome Measure(s) N-Terminal pro–B-type natriuretic peptide (NT-proBNP) levels. Result(s) NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months. The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model assessment of insulin resistance. Change in NT-proBNP over 3 months was inversely associated with change in free testosterone levels. Conclusion(s) Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. Clinical Trials Registration Number NCT00027430.

Background Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps. Methods We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC). Results Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations. Conclusions Our data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation.

Growth hormone (GH) administration reduces abdominal, but not lower body, fat mass. To gain insight into the underlying mechanisms, this study examined the expression of the GH receptor (GHR) and some of its targets in abdominal and gluteal adipose tissue.GHR and GH targets in the lipolytic pathway were assessed (quantitative PCR/Western blotting) in adipose aspirates from premenopausal women [n = 15, age 26.9 ± 6.1 years, body mass index (BMI) 28.0 ± 6.8 kg/m(2) ] and men (n = 28, age 29.2 ± 7.0 years, BMI 26.9 ± 3.7 kg/m(2) ).GHR mRNA expression was lower in the gluteal depot when compared with the abdominal depot (P = 0.01). Abdominal GHR correlated negatively with age and BMI, whereas gluteal GHR was associated with lower waist-to-hip ratio (WHR), that is, pear shape. In both sites, GHR mRNA correlated strongly with genes important for the regulation of lipolysis: adipose tissue triglyceride lipase (ATGL), hormone-sensitive lipase, perilipin, and CIDEA (all P 0.001), independently of BMI, WHR, age, and sex. GHR protein was lower in the gluteal fat when compared with the abdominal fat (P = 0.03) and correlated with ATGL protein in the gluteal depot (P 0.001).GHR levels correlate with levels of lipases and lipid droplet-associated proteins crucial for lipolysis. Thus, higher GHR expression in the abdominal depot when compared with the gluteal depot may underlie the in vivo effect of GH to specifically reduce abdominal adipose tissue mass.

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.

Anorexia nervosa is complicated by severe bone loss and clinical fractures. Mechanisms underlying bone loss in adults with anorexia nervosa include increased bone resorption and decreased formation. Estrogen administration has not been shown to prevent bone loss in this population, and to date, there are no approved, effective therapies for this comorbidity.To determine whether antiresorptive therapy with a bisphosphonate alone or in combination with low-dose transdermal testosterone replacement would increase bone mineral density (BMD) in women with anorexia nervosa.We conducted a12-month, randomized, placebo-controlled study at a clinical research center.Participants included 77 ambulatory women with anorexia nervosa.Subjects were randomized to risedronate 35 mg weekly, low-dose transdermal testosterone replacement therapy, combination therapy or double placebo.BMD at the spine (primary endpoint), hip, and radius and body composition were measured by dual-energy x-ray absorptiometry.Risedronate increased posteroanterior spine BMD 3%, lateral spine BMD 4%, and hip BMD 2% in women with anorexia nervosa compared with placebo in a 12-month clinical trial. Testosterone administration did not improve BMD but increased lean body mass. There were few side effects associated with either therapy.Risedronate administration for 1 yr increased spinal BMD, the primary site of bone loss in women with anorexia nervosa. Low-dose testosterone did not change BMD but increased lean body mass.

Despite being a risk factor for cardiovascular disease and diabetes mellitus, obesity has been thought to protect against osteoporosis. However, recent studies have demonstrated a differential impact of specific fat compartments on bone mineral density (BMD) with visceral adipose tissue (VAT) having potential detrimental effects on BMD. Visceral obesity is also associated with dysregulation of the GH/IGF-1 axis, an important regulator of bone homeostasis. The purpose of our study was to evaluate the differential effects of abdominal fat depots and muscle, vitamin D, and hormonal determinants, including insulin-like growth factor-1 (IGF-1), testosterone, and estradiol, on trabecular BMD of the lumbar spine. We studied 68 healthy obese premenopausal women (mean BMI: 36.7 ± 4.2 kg/m2). Quantitative computed tomography (QCT) was used to assess body composition and lumbar trabecular BMD. There was an inverse association between BMD and VAT, independent of age and BMI (p= 0.003). IGF-1 correlated positively with BMD and negatively with VAT and, in stepwise multivariate regression modeling, was the strongest predictor of BMD and procollagen type 1 amino-terminal propeptide (P1NP). Thigh muscle cross sectional area (CSA), and thigh muscle density were also associated with BMD (p

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.The aim was to investigate whether supraphysiological rhGH increases IGF-I levels in AN.We conducted a randomized, placebo-controlled study in a Clinical Research Center.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.rhGH (mean maximum daily dose, 1.4 ± 0.12 mg/d) or placebo was administered to patients for 12 wk.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.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.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.

Growth hormone excess and growth hormone deficiency (GHD) are both associated with increased cardiovascular morbidity. A specific acromegaly-related cardiomyopathy has been described, characterized in part by increased left ventricular mass (LVM). Growth hormone deficiency is associated with reduced LVM. Following cure of acromegaly with surgery or radiation therapy, GHD may develop; however, its effects on cardiac morphology and function in this population are not established.We hypothesized that the development of GHD in patients with prior acromegaly would be associated with cardiac morphologic and functional changes that differ from those in patients who are GH sufficient following cure of acromegaly.A cross-sectional study was conducted in a Clinical Research Center. Study participants consisted of three groups of subjects (n=34): I. Cured acromegaly with GHD (n=15), II. Cured acromegaly with GH sufficiency (n=8), and III. Active acromegaly (n=11). Main outcome measures included cardiac morphology and function, using echocardiography parameters.Mean age and BMI, 44.6 ± 2.3 years (SEM) and 30.7 ± 1.3 kg/m², respectively, were not different among the three groups. Mean peak GH values were: I. 2.8 ± 0.4 ng/ml; II. 30.1 ± 9.1 ng/ml (p=0.0002.) In group I, left ventricular mass, indexed to body surface area (LVMi), was within the normal range in all patients; moreover, left ventricular (LV) geometry was normal. At least 50% of patients in groups II and III had elevated LVMi, and in 50% of patients, LV geometry was abnormal, indicating pathologic hypertrophy. Ejection fraction was similar between all three groups. There were no significant differences in diastolic function.Patients who develop GHD following cure of acromegaly do not demonstrate elevated LV mass, in contrast to patients with a history of acromegaly but normal GH levels or to patients with active acromegaly. This suggests that GH status after treatment of acromegaly correlates with LV mass, and that, in GH sufficient patients, reversal of remodeling may be slower than previously thought. These data suggest that it will be important to determine whether GH replacement alters left ventricular morphology over time.

We describe a 34-year-old female treated with IFN-β for 8 years with a biochemical profile suggestive of acromegaly. The patient presented with elevated serum insulin-like growth factor-I (IGF-I) and insufficient suppression of growth hormone (GH) during oral glucose tolerance test (OGTT). There were no clinical features of acromegaly. A 5-day profile showed higher GH levels on the 3 days following IFN-β injections. Total and bioactive IGF-I were also elevated but did not fluctuate. Four weeks off IFN-β normalized suppression of GH during OGTT but did not reduce serum IGF-I or bioactive IGF-I. In conclusion, IFN-β treatment mimicked acromegaly biochemically. The changes were partially reversible.

Background Prolactinomas are the most common pituitary tumors; they are treated with dopamine agonists, which may cause psychotic symptoms as a side effect. Psychosis is treated with dopaminereceptor blockers that may result in elevated serum prolactin and symptomatic hyperprolactinemia. Objective The authors will review a case of a patient with a prolactinoma as well as schizophrenia and illustrate the management of psychosis in this case. Method The review describes the management of prolactinoma, symptoms of hyperprolactinemia, and long-term effects of hyperprolactinemia. Results In the case presentation reviewed, the patient was finally discharged on risperidone longacting injection and testosterone supplementation, with no growth of the adenoma after 3 years. Discussion This review provides recommendations and treatment strategy for management of prolactinoma in a patient with schizophrenia.

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

ContextChronic 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.ObjectiveTo investigate the determinants of IGF1 and GH across the weight spectrum in women.DesignCross-sectional study.SettingClinical research center.Study participantsIn 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.InterventionNone.Main outcome measuresPooled hourly overnight serum samples assayed for IGF1, GH, estradiol (E2), testosterone, SHBG, insulin, free fatty acids, and trunk fat.ResultsFree 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 (P2 (P=0.042) in the group as a whole, but was not a significant determinant of GH secretion when obese women were excluded.ConclusionsFree 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.

To compare correlations of intramyocellular lipids (IMCL) measured by short and long echo-time proton magnetic resonance spectroscopy (1H-MRS) with indices of body composition and insulin resistance in obese and normal-weight women.We quantified IMCL of tibialis anterior (TA) and soleus (SOL) muscles in 52 premenopausal women (37 obese and 15 normal weight) using single-voxel 1H-MRS PRESS at 3.0 T with short (30 msec) and long (144 msec) echo times. Statistical analyses were performed to determine correlations of IMCL with body composition as determined by computed tomography (CT) and insulin resistance indices and to compare correlation coefficients from short and long echo-time data. Signal-to-noise ratio (SNR), linewidth, and coefficients of variation (CV) of short and long echo-time spectra were calculated.Short and long echo-time IMCL from TA and SOL significantly correlated with body mass index (BMI) and abdominal fat depots (r = 0.32 to 0.70, P =0.05), liver density (r = -0.39 to -0.50, P0.05), and glucose area under the curve as a measure of insulin resistance (r = 0.47 to 0.49, P0.05). There was no significant difference between correlation coefficients of short and long echo-time spectra (P0.5). Short echo-time IMCL in both muscles showed significantly higher SNR (P0.0001) and lower CVs when compared to long echo-time acquisitions. Linewidth measures were not significantly different between groups.IMCL quantification using short and long echo-time 1H-MRS at 3.0 T is useful to detect differences in muscle lipid content in obese and normal-weight subjects. In addition, IMCL correlates with body composition and markers of insulin resistance in this population with no significant difference in correlations between short and long echo-times. Short echo-time IMCL quantification of TA and SOL muscles at 3.0 T was superior to long echo-time due to better SNR and better reproducibility.

Anorexia nervosa, characterized by extreme low body weight due to reduced nutrient intake, is associated with severe bone loss. Peptide hormones, including amylin, GIP, and GLP2, are released immediately after nutrient intake and may be involved in the regulation of bone turnover.To investigate fasting levels of amylin, GIP, and GLP2 and their relationships with bone mineral density (BMD) in women with anorexia nervosa compared to healthy controls.Cross-sectional.Clinical Research Center.15 women with anorexia nervosa and 16 healthy controls.None.Fasting serum amylin, GIP, and GLP2, and BMD.Women with anorexia nervosa had significantly lower fasting serum amylin and GIP levels than healthy controls. Fasting serum GLP2 levels were not significantly different between groups. Fasting amylin levels were positively associated with BMD and Z-score at the PA spine, total hip, and femoral neck. Fasting amylin levels were also positively associated with weight and percent fat; after controlling for these variables, amylin was still a significant predictor of BMD and Z-score at the femoral neck and of Z-score at the total hip. In the anorexia nervosa group, there was a trend toward an inverse association between amylin and C-terminal telopeptide (CTX) levels (R=-0.47, p=0.08). GIP and GLP2 levels did not predict BMD at any site.Decreased secretion of amylin may be a mechanism through which reduced nutrient intake adversely affects BMD in anorexia nervosa.

The accumulation of adipose tissue in 2 regional fat depots, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), have a differential impact on bone mineral density (BMD). In most studies, a positive association of SAT with bone density has been reported. There are conflicting data on the effect of VAT on bone. One recent study suggested that VAT was a negative and SAT a positive predictor of bone structural parameters in young adults. Various chemicals secreted from VAT and SAT appear to mediate these associations with bone but there is a limited knowledge of their role. Potential mediators include inflammatory cytokines such as IL-6, soluble intercellular adhesion molecules such as E-selectin, and adipokine hormones such as adiponectin and leptin. IL-6 and adiponectin can increase osteoclast activity and appear to have deleterious effects on BMD. In a previous report, VAT was an independent predictor of E-selectin and soluble intercellular adhesion molecule I (sICAM1), whereas SAT was a predictor of IL-6, and both SAT and VAT predicted adiponectin levels. Other studies have shown that VAT is an important determinant of levels of sICAM1 and E-selectin in obese and normal-weight girls. This cross-sectional study investigated associations of VAT and SAT and potential chemical mediators with BMD in adolescent obese and normal-weight girls. The investigators tested the hypothesis that adolescent girls with a greater VAT to SAT ratio would have lower bone density measures mediated by inflammatory cytokines, adiponectin, and leptin. Fifteen obese girls 12 to 18 years old were matched to 15 normal-weight controls for race, ethnicity, and bone age (within 2 year). Magnetic resonance imaging was used to measure SAT and VAT at the lumbar level. Dual-energy x-ray absorptiometry assessed bone density at the spine, hip, and whole body. Fasting serum levels of leptin, adiponectin, E-selectin, sICAM, and IL-6 were determined. The mean body mass index SD score was higher in obese subjects than in controls (3.7 ± 1.5 versus 0.1 ± 0.4 kg/m 2 ). After controlling for SAT, VAT was a negative predictor of whole-body BMD and bone mineral content/height in the whole group, and of BMD, bone mineral apparent density, whole-body BMD, and bone mineral content/height in obese girls. As hypothesized, obese girls with the highest VAT to SAT ratio had the lowest bone density measures. E-selectin and adiponectin were negative predictors for BMD, and leptin was a positive predictor in a regression model including VAT/SAT, adipokines, and cytokines. These findings indicate that VAT is a negative predictor of bone density in obese girls. Pro-inflammatory adhesion molecules such as E-selectin and adipokines such as adiponectin and leptin appear to mediate the association between VAT and bone density.