Anne Klibanski

Publications of Anne Klibanski

• Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa.

  Authors: Pouneh K Fazeli, Miriam A Bredella, Lauren Freedman, Bijoy J Thomas, Anne Breggia, Erinne Meenaghan, Clifford J Rosen, Anne Klibanski

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 04/2012;

  Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat massWomen with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat with recovery from AN and the relationship between preadipocyte factor (Pref)-1-a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation - and fat depots and BMD in women who have recovered from AN (AN-R) compared to women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years (mean ± SEM)) and 15 normal-weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by (1) H-magnetic resonance spectroscopy, BMD of the spine, hip and total body by DXA and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R as compared to AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R as compared to AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = -0.71; p = 0.004). Therefore, we have demonstrated that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation as compared to nutritional sufficiency. © 2012 American Society for Bone and Mineral Research.

• Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa.

  Authors: Laura M Holsen, Elizabeth A Lawson, Justine Blum, Eunice Ko, Nikos Makris, Pouneh K Fazeli, Anne Klibanski, Jill M Goldstein

  Journal of psychiatry & neuroscience : JPN. 04/2012; 37(3):110156.

  Background: Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to theBackground: Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. Methods: We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. Results: We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. Limitations: Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. Conclusion: Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food's reward value and integration of these with interoceptive signalling of one's internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa.

• MEG3 noncoding RNA: a tumor suppressor.

  Authors: Yunli Zhou, Xun Zhang, Anne Klibanski

  Journal of molecular endocrinology. 03/2012; 48(3):R45-53.

  Maternally expressed gene 3 (MEG3) is an imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3 in humans. Its mouse ortholog, Meg3, also known as gene trap locus 2Maternally expressed gene 3 (MEG3) is an imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3 in humans. Its mouse ortholog, Meg3, also known as gene trap locus 2 (Gtl2), is located at distal chromosome 12. The MEG3 gene encodes a long noncoding RNA (lncRNA) and is expressed in many normal tissues. MEG3 gene expression is lost in an expanding list of primary human tumors and tumor cell lines. Multiple mechanisms contribute to the loss of MEG3 expression in tumors, including gene deletion, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region. Re-expression of MEG3 inhibits tumor cell proliferation in culture and colony formation in soft agar. This growth inhibition is partly the result of apoptosis induced by MEG3. MEG3 induces accumulation of p53 (TP53) protein, stimulates transcription from a p53-dependent promoter, and selectively regulates p53 target gene expression. Maternal deletion of the Meg3 gene in mice results in skeletal muscle defects and perinatal death. Inactivation of Meg3 leads to a significant increase in expression of angiogenesis-promoting genes and microvessel formation in the brain. These lines of evidence strongly suggest that MEG3 functions as a novel lncRNA tumor suppressor.

• Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: A preliminary study.

  Authors: Laura M Holsen, Jong-Hwan Lee, Sarah B Spaeth, Lauren A Ogden, Anne Klibanski, Susan Whitfield-Gabrieli, Richard P Sloan, Jill M Goldstein

  Neuroscience letters. 02/2012; 514(1):57-61.

  The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence ofThe comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence of these disorders will have major public health significance. MDD is associated with an abnormal stress response, manifested in brain circuitry deficits, gonadal dysfunction, and autonomic nervous system (ANS) dysregulation. Contribution of the relationships between these systems to the pathophysiology of MDD is not well understood. The objective of this preliminary study was to investigate, in parallel, relationships between HPG-axis functioning, stress response circuitry activation, and parasympathetic reactivity in healthy controls and women with MDD. Using fMRI with pulse oximetry [from which we calculated the high frequency (HF) component of R-R interval variability (HF-RRV), a measure of parasympathetic modulation] and hormone data, we studied eight women with recurrent MDD in remission and six controls during a stress response paradigm. We demonstrated that hypoactivations of hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subgenual ACC were associated with lower parasympathetic cardiac modulation in MDD women. Estradiol and progesterone attenuated group differences in the effect of HF-RRV on hypoactivation in the amygdala, hippocampus, ACC, and OFC in MDD women. Findings have implications for understanding the relationship between mood, arousal, heart regulation, and gonadal hormones, and may provide insights into MDD and CVD risk comorbidity.

• Growth Hormone Replacement has a Greater Effect on Quality of Life in Growth Hormone-Deficient Women with a History of Acromegaly.

  Authors: Elena Valassi, Danielle J Brick, Jessica C Johnson, Beverly M K Biller, Anne Klibanski, Karen K Miller

  Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 02/2012;

  Objective: To compare the response in quality of life (QoL) to GH replacement in GH-deficient women with a history of acromegaly to that of women with GHD of other etiologies.Methods: Fifty-fiveObjective: To compare the response in quality of life (QoL) to GH replacement in GH-deficient women with a history of acromegaly to that of women with GHD of other etiologies.Methods: Fifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other etiologies of GHD. We compared two, six-month, randomized, placebo-controlled studies of GH therapy in women with hypopituitarism conducted using the same design - one in women with a history of acromegaly and one without. QoL was assessed with the following questionnaires: Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA); Symptom Questionnaire; Short-Form Health Survey (SF-36).Results: The two groups had comparable mean pretreatment age, BMI and QoL scores, and comparable mean GH dose at 6 months (0.61±0.30 vs. 0.67±0.27 mcg/d). After 6 months of GH replacement, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 subscales (Role Limitations due to Physical Health, Energy/Fatigue, Emotional Well-Being, Social Functioning), and the Somatic Symptom subscale of the Symptom Questionnaire, than women with GHD of other etiologies. Poorer pre-treatment QoL was associated with a greater improvement in QoL after GH administration.Conclusions: In this study, GH replacement therapy improved QoL in women with GHD and a previous history of acromegaly but not in women with GHD due to other hypothalamic / pituitary disorders. Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly.

• Transsphenoidal Surgery for Cushing's Disease after Non-diagnostic Inferior Petrosal Sinus Sampling.

  Authors: Sameer A Sheth, Matthew K Mian, Jonathan Neal, Nicholas A Tritos, Lisa Nachtigall, Anne Klibanski, Beverly M K Biller, Brooke Swearingen

  Neurosurgery. 02/2012;

  BACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of ACTH overproduction in Cushing's disease (CD). Uncertainty still remains regarding theBACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of ACTH overproduction in Cushing's disease (CD). Uncertainty still remains regarding the appropriate course of therapy when an ectopic tumor is predicted by IPSS but none can be found, and in circumstances when the procedure cannot be successfully completed due to technical or anatomical limitations. OBJECTIVE: To determine an appropriate course of action following non-diagnostic IPSS. METHODS: We reviewed 288 IPSS procedures in 283 patients between 1986 and 2010 at our Center. An IPS:peripheral (IPS:P) ACTH ratio ≥2 at baseline or ≥3 after corticotropin releasing hormone (CRH) was considered predictive of a pituitary source of ACTH. A procedure was considered "non-diagnostic" if 1) the procedure was successfully performed and the results predicted an ectopic source, but none could be found despite extensive imaging, or 2) the IPS could not be bilaterally cannulated because of technical difficulties or anatomic variants. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of IPSS for detecting a pituitary source in CD were 94%, 50%, 98%, and 29%, respectively. We identified 3 categories of non-diagnostic IPSS, comprising 44 of the total procedures. These patients underwent exploratory transsphenoidal surgery (TSS), and in 42 of these (95%), a pituitary source was surgically proven, with a remission rate of 83%. CONCLUSION: TSS should be considered in cases of ACTH-dependent Cushing's and non-centralized or technically unsuccessful IPSS without evidence of ectopic tumor.

• Young Women with Cold-Activated Brown Adipose Tissue Have Higher Bone Mineral Density and Lower Pref-1 than Women without Brown Adipose Tissue: A Study in Women with Anorexia Nervosa, Women Recovered from Anorexia Nervosa, and Normal-Weight Women.

  Authors: Miriam A Bredella, Pouneh K Fazeli, Lauren M Freedman, Genevieve Calder, Hang Lee, Clifford J Rosen, Anne Klibanski

  The Journal of clinical endocrinology and metabolism. 01/2012;

  Context:Anorexia nervosa (AN) is associated with depletion of body fat, loss of bone mineral density (BMD), and impaired thermogenesis. Brown adipose tissue (BAT) is lower in obese individuals andContext:Anorexia nervosa (AN) is associated with depletion of body fat, loss of bone mineral density (BMD), and impaired thermogenesis. Brown adipose tissue (BAT) is lower in obese individuals and decreases during aging. Recent studies have suggested a link between BAT and bone metabolism.Objective:Our objective was to investigate the presence and quantity of BAT in patients with AN, recovered AN (AN-R), and normal-weight controls and to study the relationship between BAT and BMD and body composition and investigate hormonal predictors of BAT.Design and Setting:This was a cross-sectional study at a clinical research center.Patients:Patients included 15 women: five with AN (mean age 30 ± 6.3 yr), five AN-R, and five healthy nonobese controls of comparable age.Main Outcome Measures:Cold-activated BAT was determined by fluorodeoxyglucose-positron emission tomography/computed tomography. BMD of total-body, spine, and hip, fat and lean mass was determined by dual-energy x-ray absorptiometry. Single-slice magnetic resonance imaging at L4 was done for abdominal fat compartments, and preadipocyte factor-1 (Pref-1), T(3), and T(4) were measured.Results:Within the AN group, one of five; in the AN-R group, two of five; and in the healthy nonobese control group, four of five subjects were BAT positive. Subjects were divided into groups based on the presence (n = 7) or absence (n = 8) of BAT. Both groups were of comparable age and body mass index. Women with BAT had higher total-body BMD, higher T(3), and lower Pref-1 compared with women without BAT. There was a positive correlation between BAT and BMD that remained significant after controlling for disease status and body mass index.Conclusion:Young women with AN have low cold-activated BAT, which may be due to impaired BAT thermogenesis. Young women with BAT have higher BMD and lower Pref-1 compared with women without BAT, suggesting that BAT may be involved in the regulation of stem cell differentiation into the bone lineage at the expense of adipogenesis.

• Effects of Recombinant Human Growth Hormone Therapy in Adults with Prader-Willi Syndrome: A Meta-Analysis.

  Authors: Ruth Sanchez-Ortiga, Anne Klibanski, Nicholas A Tritos

  Clinical endocrinology. 11/2011;

  Objective:  Prader-Willi syndrome (PWS) is associated with GH deficiency, deleterious changes in body composition and function. As the effects of recombinant human GH (rhGH) in PWS adults have notObjective:  Prader-Willi syndrome (PWS) is associated with GH deficiency, deleterious changes in body composition and function. As the effects of recombinant human GH (rhGH) in PWS adults have not been well-established, we sought to conduct a meta-analysis of pertinent studies. Design:  Meta-analysis of studies examining the effects of rhGH therapy in PWS adults. Patients:  134 PWS adults (75 men, 59 women). Measurements:  Literature searches, including publications (PubMed, EMBASE and the Cochrane Register), and abstracts presented at meetings through July 2011 describing studies of rhGH therapy in PWS adults. 8/1194 articles, describing unique cohorts, were included. Two authors independently extracted data and examined study quality. Results:  rhGH therapy for 12 months led to [weighted mean difference (95% CI)] decreased body fat [-2.91% (-3.90, -1.91)], visceral [-32.97 cm(2) (-55.67, -10.26)] and subcutaneous adiposity [-55.24 cm(2) (-89.05, -21.44)], and increased lean body mass [2.41 Kg (1.32, 3.49)]. Similar changes in body fat [-2.89% (-4.69, -1.07)] and lean body mass [2.82 Kg (1.31, 4.33)] were found in longer studies. There were no changes in body mass index (BMI) or lipids. There was a small increase in fasting glucose [0.27 mmol/L (0.05, 0.49)] and trends towards higher fasting insulin [20.24 pmol/L (-0.55, 41.02)] and insulin resistance [HOMA: 0.60 (-0.04, 1.24)] after rhGH therapy for 12 months. Conclusions:  In PWS adults, rhGH therapy led to decreased body adiposity and increased lean body mass without changes in BMI or lipids. There was a small increase in fasting glucose and trends towards higher insulin and insulin resistance.

• Adipokines and Cardiovascular Risk in Cushing's Syndrome.

  Authors: Elena Valassi, Beverly M K Biller, Anne Klibanski, Madhusmita Misra

  Neuroendocrinology. 11/2011;

  Cushing's syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Recent evidence also suggests that increased cardiovascular risk may persist even after long-termCushing's syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Recent evidence also suggests that increased cardiovascular risk may persist even after long-term remission of CS. Increased central obesity, a typical feature of CS, is associated with altered production of adipokines, which contributes to the pathogenesis of several metabolic and cardiovascular complications observed in this condition. In vitro and in vivo studies have shown a relationship between cortisol and adipokines in several experimental settings. In patients with either active or 'cured' CS, an increase in leptin and resistin levels as well as the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, may be associated with increased cardiovascular risk. For other adipokines, including adiponectin, results are inconclusive. Studies are needed to further elucidate the interactions between clinical and subclinical increases in cortisol production and altered adipokine release in CS.

• Bone health in anorexia nervosa.

  Authors: Madhusmita Misra, Anne Klibanski

  Current opinion in endocrinology, diabetes, and obesity. 09/2011; 18(6):376-82.

  Anorexia nervosa is associated with low bone mineral density (BMD), concerning for an increased risk of fractures, and decreased bone accrual in adolescents, concerning for suboptimal peak bone mass.Anorexia nervosa is associated with low bone mineral density (BMD), concerning for an increased risk of fractures, and decreased bone accrual in adolescents, concerning for suboptimal peak bone mass. This review discusses causes of impaired bone health in anorexia nervosa and potential therapeutic strategies. Low BMD in anorexia nervosa is consequent to decreased lean mass, hypogonadism, low insulin-like growth factor-1 (IGF-1), relative hypercortisolemia and alterations in hormones impacted by energy availability. Weight gain causes some improvement in bone accrual, but not to the extent observed in controls, and vitamin D supplementation does not increase BMD. Oral estrogen is not effective in increasing BMD, likely from IGF-1 suppressive effects. In contrast, transdermal estrogen replacement is effective in increasing bone accrual in adolescents with anorexia nervosa, although not to the extent seen in controls. Recombinant human IGF-1 increases bone formation in adolescents, and with oral estrogen increases BMD in adults with anorexia nervosa. Bisphosphonates increase BMD in adults, but not in adolescents, and should be used cautiously given their long half-life. Further investigation is necessary to explore therapies for low BMD in anorexia nervosa. Weight gain is to be encouraged. Transdermal estrogen in adolescents, and bisphosphonates in adults, have a potential therapeutic role.

• Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas.

  Authors: Pornsuk Cheunsuchon, Yunli Zhou, Xun Zhang, Hang Lee, Wendy Chen, Yuki Nakayama, Kimberley A Rice, E Tessa Hedley-Whyte, Brooke Swearingen, Anne Klibanski

  The American journal of pathology. 08/2011; 179(4):2120-30.

  DLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) isDLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly down-regulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.

• Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass.

  Authors: Elizabeth A Lawson, Daniel A Donoho, Justine I Blum, Erinne M Meenaghan, Madhusmita Misra, David B Herzog, Patrick M Sluss, Karen K Miller, Anne Klibanski

  The Journal of clinical psychiatry. 08/2011; 72(11):1546-51.

  Anorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data showAnorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data show that oxytocin has an anabolic effect on bone and stimulates osteoblast function. There is limited information about oxytocin levels or their relationship to decreased bone mineral density in anorexia nervosa. Our objective was to investigate the relationship between oxytocin levels, bone mineral density, and body composition in women with anorexia nervosa. We studied 36 women, mean ± SEM age 27.6 ± 1.3 years: 17 with DSM-IV anorexia nervosa and 19 healthy controls in a cross-sectional study. Oxytocin levels were determined from pooled serum samples obtained every 20 minutes from 8 pm to 8 am during an inpatient overnight visit. Fasting leptin levels were measured. Bone mineral density at the anterior-posterior and lateral spine and hip and body composition were assessed by dual energy x-ray absorptiometry. The study was conducted from September 2004 to June 2008. Subjects with anorexia nervosa versus healthy controls had lower mean ± SEM oxytocin levels (14.3 ± 1.5 vs 31.8 ± 5.1 pg/mL, P = .003), leptin levels (2.7 ± 0.5 vs 11.4 ± 1.1 ng/mL, P < .0001), bone mineral density (anterior-posterior spine: 0.83 ± 0.02 vs 1.04 ± 0.03; lateral spine: 0.63 ± 0.02 vs 0.81 ± 0.02; total hip: 0.79 ± 0.03 vs 0.97 ± 0.03 g/cm², P < .0001), and fat mass (8.8 ± 0.6 vs 19.7 ± 0.9 kg, P < .0001). Oxytocin levels were associated with bone mineral density at the anterior-posterior (r = 0.40, P = .02) and lateral (r = 0.36, P = .04) spine, fat mass (r = 0.42, P = .01), and leptin levels (r = 0.55, P = .001). Overnight secretion of oxytocin in women with anorexia nervosa is decreased compared with healthy women. Low oxytocin levels are associated with decreased bone mineral density and body fat and may contribute to anorexia nervosa-induced bone loss.

• Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat.

  Authors: Elizabeth A Lawson, Karen K Miller, Justine I Blum, Erinne Meenaghan, Madhusmita Misra, Kamryn T Eddy, David B Herzog, Anne Klibanski

  Clinical endocrinology. 07/2011; 76(4):520-5.

  Objective  Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negativelyObjective  Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with 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 amenorrhoea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contributes 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. Design  Cross-sectional. Patients  64 women: 15 with AN, 12 normal-weight with HA, 17 overweight or obese (OB) and 20 normal-weight in good health (HC). Measurements  Fasting serum leptin and plasma ghrelin levels were measured. Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Perceived Stress Scale were administered. Results  Leptin levels were inversely associated with HAM-D, HAM-A and Perceived Stress scores. The negative relationships between leptin and severity of symptoms of both depression and anxiety remained significant after controlling for body fat or weight. There was no relationship between ghrelin and symptoms of depression or anxiety. Although ghrelin levels were positively associated with the degree of perceived stress, this relationship was not significant after controlling for body fat or weight. Conclusions  Leptin may mediate depressive symptoms across the weight spectrum. Further investigation of the role of leptin in modulating mood will be important.

• Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats.

  Authors: Mohamed A Zeidan, Sarah A Igoe, Clas Linnman, Antonia Vitalo, John B Levine, Anne Klibanski, Jill M Goldstein, Mohammed R Milad

  Biological psychiatry. 07/2011; 70(10):920-7.

  Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiolMen and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction? All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment. In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall. We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women's endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.

• Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.

  Authors: Madhusmita Misra, Debra Katzman, Karen K Miller, Nara Mendes, Deirdre Snelgrove, Melissa Russell, Mark A Goldstein, Seda Ebrahimi, Laura Clauss, Thomas Weigel, Diane Mickley, David A Schoenfeld, David B Herzog, Anne Klibanski

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 06/2011; 26(10):2430-8.

  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 andAnorexia 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.

• Growth hormone is positively associated with surrogate markers of bone turnover during puberty.

  Authors: Melissa Russell, Anne Breggia, Nara Mendes, Anne Klibanski, Madhusmita Misra

  Clinical endocrinology. 04/2011; 75(4):482-8.

  Puberty is characterized by increases in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent withPuberty is characterized by increases in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent with increased bone metabolism. To determine the relationship between pubertal bone metabolism, GH and IGF-1. We hypothesized that bone turnover peaks at the time of greatest pubertal GH secretion. Design and Subjects included 86 girls and boys, 9-17 years-old (BMI 10th-90th percentiles). Because higher endogenous GH secretion is associated with a higher nadir following oral glucose, we used the GH nadir following a 2-h OGTT as indicative of GH status. Fasting serum IGF-1, aminoterminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal collagen crosslinks (CTX) were obtained. Subjects were grouped per expected timing of peak growth. Group 1: Tanner 1 girls and Tanner 1-2 boys (period preceding peak growth), Group 2: Tanner 2-3 girls and Tanner 3-4 boys (period of peak growth) and Group 3: Tanner 4-5 girls and Tanner 5 boys (period following peak growth). GH peaked at mid-puberty (Group 2) and IGF-1 in late puberty (Group 3). P1NP and CTX were highest in mid-puberty compared with early and late puberty (P = 0·0009 and 0·006 in girls and P = 0·005 and 0·04 in boys). GH, but not IGF-1, correlated with P1NP (r = 0·46 in both genders, P ≤ 0·008) and CTX (r = 0·37 and 0·38, P = 0·04 and 0·02 in girls and boys, respectively). Similarly, on regression modelling, GH (but not IGF-1) predicted both bone turnover markers in both genders. GH is strongly associated with pubertal bone metabolism, independent of systemic IGF-1 in girls and boys.

• Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study.

  Authors: Karen K Miller, Erinne Meenaghan, Elizabeth A Lawson, Madhusmita Misra, Suzanne Gleysteen, David Schoenfeld, David Herzog, Anne Klibanski

  The Journal of clinical endocrinology and metabolism. 04/2011; 96(7):2081-8.

  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.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.

• Appetite-regulating hormones cortisol and peptide YY are associated with disordered eating psychopathology, independent of body mass index.

  Authors: Elizabeth A Lawson, Kamryn T Eddy, Daniel Donoho, Madhusmita Misra, Karen K Miller, Erinne Meenaghan, Janet Lydecker, David Herzog, Anne Klibanski

  European journal of endocrinology / European Federation of Endocrine Societies. 02/2011; 164(2):253-61.

  Disordered eating occurs in women at both weight extremes of anorexia nervosa (AN) and obesity. Cortisol, peptide YY (PYY), leptin, and ghrelin are hormones involved in appetite and feeding behaviorDisordered eating occurs in women at both weight extremes of anorexia nervosa (AN) and obesity. Cortisol, peptide YY (PYY), leptin, and ghrelin are hormones involved in appetite and feeding behavior that vary with weight and body fat. Abnormal levels of these hormones have been reported in women with AN, functional hypothalamic amenorrhea (HA), and obesity. The relationship between appetite-regulating hormones and disordered eating psychopathology is unknown. We therefore studied the relationship between orexigenic and anorexigenic hormones and disordered eating psychopathology in women across a range of weights. A cross-sectional study of 65 women, 18-45 years: 16 with AN, 12 normal-weight with HA, 17 overweight or obese, and 20 normal-weight in good health. Two validated measures of disordered eating psychopathology, the Eating Disorders Examination-Questionnaire (EDE-Q) and Eating Disorders Inventory-2 (EDI-2), were administered. Fasting PYY, leptin, and ghrelin levels were measured; cortisol levels were pooled from serum samples obtained every 20 min from 2000 to 0800 h. Cortisol and PYY levels were positively associated with disordered eating psychopathology including restraint, eating concerns, and body image disturbance, independent of body mass index (BMI). Although leptin levels were negatively associated with disordered eating psychopathology, these relationships were not significant after controlling for BMI. Ghrelin levels were generally not associated with EDE-Q or EDI-2 scores. Higher levels of cortisol and PYY are associated with disordered eating psychopathology independent of BMI in women across the weight spectrum, suggesting that abnormalities in appetite regulation may be associated with specific eating disorder pathologies.

• Bone metabolism in adolescents with anorexia nervosa.

  Authors: M Misra, A Klibanski

  Journal of endocrinological investigation. 02/2011; 34(4):324-32.

  Adolescents with anorexia nervosa (AN) are at risk for low bone mass at multiple sites, associated with decreased bone turnover. Bone microarchitecture is also affected, with a decrease in boneAdolescents with anorexia nervosa (AN) are at risk for low bone mass at multiple sites, associated with decreased bone turnover. Bone microarchitecture is also affected, with a decrease in bone trabecular volume and trabecular thickness, and an increase in trabecular separation. The adolescent years are typically the time when marked increases occur in bone mass accrual towards the attainment of peak bone mass, an important determinant of bone health and fracture risk in later life. AN often begins in the adolescent years, and decreased rates of bone mass accrual at this critical time are therefore also concerning for deficits in peak bone mass. Factors contributing to low bone density and decreased rates of bone accrual include alterations in body composition such as low body mass index and lean body mass, and hormonal alterations such as hypogonadism, a nutritionally acquired resistance to GH and low levels of IGF-I, relative hypercortisolemia, low levels of leptin, and increased adiponectin (for fat mass) and peptide YY. Therapeutic strategies include optimizing weight and menstrual recovery, and adequate calcium and vitamin D replacement. Oral estrogen-progesterone combination pills are not effective in increasing bone density in adolescents with AN. Recombinant human IGF-I increases levels of bone formation markers in the short term, while long-term effects remain to be determined. Bisphosphonates act by decreasing bone resorption, and are not optimal for use in adolescents with AN, in whom the primary defect is low bone formation.

• A patient with diabetes insipidus, anterior hypopituitarism and pituitary stalk thickening.

  Authors: Nicholas A Tritos, Thomas N Byrne, Chin-Lee Wu, Anne Klibanski

  Nature reviews. Endocrinology. 01/2011; 7(1):54-9.

  A 42-year-old woman presented to the neuroendocrine unit of a hospital with recent-onset polydipsia, polyuria and oligomenorrhea. She had no visual symptoms, head injury or history ofA 42-year-old woman presented to the neuroendocrine unit of a hospital with recent-onset polydipsia, polyuria and oligomenorrhea. She had no visual symptoms, head injury or history of malignancy. Measurement of serum sodium and osmolality (as well as urine osmolality) after water deprivation, both before and after desmopressin administration. Measurement of basal serum concentrations of pituitary hormones, insulin-like growth factor 1 and thyroid hormone, cosyntropin stimulation testing of adrenal function, and growth-hormone-releasing hormone-arginine stimulation testing. MRI of the pituitary, CT of the chest and abdomen, skeletal surveys, analyses of cerebrospinal fluid, serology and histologic examination of an excised, painful submandibular salivary gland. Central diabetes insipidus and anterior hypopituitarism secondary to Langerhans cell histiocytosis. Replacement therapies, including desmopressin, levothyroxine, cyclic estrogen with medroxyprogesterone, and growth hormone. The stalk lesion remained stable after 7 years without specific therapy.