This project takes a novel, multidisciplinary approach to understanding endocrine factors and neurocircuitry underlying appetite and eating behavior in anorexia nervosa (AN). AN, characterized by self-induced starvation, is associated with medical complications, depression, and the highest mortality of any psychiatric disease. Treatment strategies have been ineffective. Hormones involved in eating behavior are abnormal in AN, and brain regions in these pathways can now be examined with dynamic paradigms using functional MRI (fMRI). AN is also associated with testosterone (T) deficiency, and preliminary data indicates that physiologic replacement leads to an increase in body mass index (BMI). Studies in animals and humans implicate T in feeding behavior. Moreover, pilot data demonstrate hypoactivation by fMRI in brain regions implicated in T deficiency in response to a food-related paradigm, suggesting that T may influence eating behavior through direct effects on the brain, and has therapeutic potential in AN. The goal of this application is to investigate the hypothesis that the AN phenotype is characterized by abnormalities in hormones and neurocircuitry involved in food motivation and reward, and that T administration improves outcomes by modulating these pathways. 60 women with AN and 20 controls aged 20-30 will be studied. During a single visit, subjects will undergo measurement of BMI;a fasting blood draw for hormone levels (eg, ghrelin, PYY);assessment of appetite, mood and disordered eating psychopathology;and fMRI with visual food and non-food stimuli. After consumption of a standardized mixed meal, appetite and mood will be reassessed, serial blood samples will be obtained for hormone levels, and fMRI will be repeated. Of the 60 AN who participate in the cross-sectional visit, 40 AN with relative T deficiency will be randomized in a double-blind design to receive low-dose transdermal T (300mcg qd), and will return to repeat the above procedures at 4 weeks and 6 months. Dr. Lawson is an Instructor in Medicine at Harvard Medical School (HMS) and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. Her expertise in studying hormonal abnormalities in AN and established collaboration investigating the neurocircuitry of appetite positions her to lead the proposed project. She completed her Masters of Medical Science through HMS and Massachusetts Institute of Technology (MIT) in June, and plans to expand her training to include advanced statistics, neuroanatomy and neuroimaging technology. She is well-supported by MGH and has full access to Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst resources. Her co-mentors, Drs. Anne Klibanski and Jill Goldstein, are well-funded and invested in the direction of Dr. Lawson's research. This project will support Dr. Lawson's training in clinical research, with the ultimate goal of becoming an independent investigator with an expertise in combining neuroendocrinology and neuroimaging technology to better understand pathophysiology of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH092560-03
Application #
8485681
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Wynne, Debra K
Project Start
2011-07-06
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$186,908
Indirect Cost
$13,845
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Singhal, Vibha; Lawson, Elizabeth A; Ackerman, Kathryn E et al. (2014) Irisin levels are lower in young amenorrheic athletes compared with eumenorrheic athletes and non-athletes and are associated with bone density and strength estimates. PLoS One 9:e100218
Lawson, Elizabeth A; Ackerman, Kathryn E; Slattery, Meghan et al. (2014) Oxytocin secretion is related to measures of energy homeostasis in young amenorrheic athletes. J Clin Endocrinol Metab 99:E881-5
Lawson, Elizabeth A; Holsen, Laura M; Santin, McKale et al. (2013) Postprandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa. J Clin Psychiatry 74:e451-7
Lawson, Elizabeth A; Holsen, Laura M; Desanti, Rebecca et al. (2013) Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa. Eur J Endocrinol 169:639-47
Lawson, Elizabeth A; Ackerman, Kathryn E; Estella, Nara Mendes et al. (2013) Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters. Eur J Endocrinol 168:457-64