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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Chavez, Mark
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Massachusetts General Hospital
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Schmelkin, Cindy; Plessow, Franziska; Thomas, Jennifer J et al. (2017) Low oxytocin levels are related to alexithymia in anorexia nervosa. Int J Eat Disord 50:1332-1338
Schorr, Melanie; Marengi, Dean A; Pulumo, Reitumetse L et al. (2017) Oxytocin and Its Relationship to Body Composition, Bone Mineral Density, and Hip Geometry Across the Weight Spectrum. J Clin Endocrinol Metab 102:2814-2824
Baskaran, Charumathi; Plessow, Franziska; Silva, Lisseth et al. (2017) Oxytocin secretion is pulsatile in men and is related to social-emotional functioning. Psychoneuroendocrinology 85:28-34
Baskaran, Charumathi; Eddy, Kamryn T; Miller, Karen K et al. (2016) Leptin secretory dynamics and associated disordered eating psychopathology across the weight spectrum. Eur J Endocrinol 174:503-12
Afinogenova, Yuliya; Schmelkin, Cindy; Plessow, Franziska et al. (2016) Low Fasting Oxytocin Levels Are Associated With Psychopathology in Anorexia Nervosa in Partial Recovery. J Clin Psychiatry 77:e1483-e1490
Neumeyer, Ann M; O'Rourke, Julia A; Massa, Alexandra et al. (2015) Brief report: bone fractures in children and adults with autism spectrum disorders. J Autism Dev Disord 45:881-7
Lawson, Elizabeth A; Marengi, Dean A; DeSanti, Rebecca L et al. (2015) Oxytocin reduces caloric intake in men. Obesity (Silver Spring) 23:950-6
Holsen, Laura M; Lawson, Elizabeth A; Christensen, Kara et al. (2014) Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa. Psychiatry Res 223:94-103
Bachmann, Katherine Neubecker; Fazeli, Pouneh K; Lawson, Elizabeth A et al. (2014) Comparison of hip geometry, strength, and estimated fracture risk in women with anorexia nervosa and overweight/obese women. J Clin Endocrinol Metab 99:4664-73
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

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