The adipoeyte-secreted hormone leptin signals the amount of energy stored in adipose tissue to the central nervous system. We have shown, in the context of this grant, that leptin administration to normalize the relative leptin deficiency induced by short term energy deficiency results in normalization of reproductive and other neuroendocrine defects. We have also shown that altering leptin levels within the normal physiological range, or into supraphysiological levels, has no effect on the same outcomes. Thus, in humans, leptin serves as a critical link between the sufficiency of energy stores and the integrity of the hypothalamic-pituitary- peripheral axes in states of leptin deficiency only. We have subsequently hypothesized that the abnormalities in the reproductive and other neuroendocrine axes in women with hypothalamic amenorrhea (HA), a condition associated with low leptin levels, may also be related to the chronic hypoleptinemia induced by negative energy balance. In a recently completed, open-label, small pilot study using historical controls, we found that leptin replacement to correct the relative leptin deficiency in women with HA resulted in follicular growth and ovulation and significantly improved hormone levels, providing preliminary evidence that leptin may contribute to the etiology of the amenorrhea and that leptin replacement may be a potential treatment for disease states associated with relative leptin deficiency. The goal of this proposal is to confirm and extend these preliminary findings by performing a randomized, double-blinded, placebo-controlled trial of leptin treatment in women with HA and leptin deficiency which would eliminate potential bias and confounding and would verify safety and efficacy of leptin as a new treatment for HA. Since HA accounts for over 30% of amenorrhea in reproductive-aged women and can have significant deleterious effects on fertility, bone health, and overall well-being, this study would have considerable clinical impact if leptin becomes a new, more physiologic, therapeutic option for HA. This is particularly relevant since currently available treatment options for HA have side effects, are not well accepted by some patients, and have suboptimal effectiveness for complications such as osteoporosis. Results of this study will not only help elucidate the pathophysiology of HA but will also provide important new information on leptin physiology in neuroendocrine regulation, bone metabolism and immune function at large, using HA as a model of chronic leptin deficiency. Thus, findings of this study to elucidate leptin physiology may also have applications in the pathophysiology (and possibly therapeutics) of other leptin related diseases, including obesity, a major public health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058785-09
Application #
7999261
Study Section
Special Emphasis Panel (ZRG1-CIDO-K (01))
Program Officer
Malozowski, Saul N
Project Start
2000-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2011
Total Cost
$359,227
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Zong, Geng; Valvi, Damaskini; Coull, Brent et al. (2018) Persistent organic pollutants and risk of type 2 diabetes: A prospective investigation among middle-aged women in Nurses' Health Study II. Environ Int 114:334-342
Sun, Qi; Zong, Geng; Valvi, Damaskini et al. (2018) Plasma Concentrations of Perfluoroalkyl Substances and Risk of Type 2 Diabetes: A Prospective Investigation among U.S. Women. Environ Health Perspect 126:037001
Ding, M; Pan, A; Manson, J E et al. (2016) Consumption of soy foods and isoflavones and risk of type 2 diabetes: a pooled analysis of three US cohorts. Eur J Clin Nutr 70:1381-1387
Ding, Ming; Franke, Adrian A; Rosner, Bernard A et al. (2015) Urinary isoflavonoids and risk of type 2 diabetes: a prospective investigation in US women. Br J Nutr 114:1694-701
Sun, Qi; Wedick, Nicole M; Tworoger, Shelley S et al. (2015) Urinary Excretion of Select Dietary Polyphenol Metabolites Is Associated with a Lower Risk of Type 2 Diabetes in Proximate but Not Remote Follow-Up in a Prospective Investigation in 2 Cohorts of US Women. J Nutr 145:1280-8
Hamnvik, Ole-Petter Riksfjord; Thakkar, Bindiya; Chamberland, John et al. (2015) Omentin-1 levels are reduced by pharmacologic doses of leptin, but remain unaffected by energy deprivation and display no day-night variation. Int J Obes (Lond) 39:260-264
Hu, Yang; Song, Yan; Franke, Adrian A et al. (2015) A Prospective Investigation of the Association Between Urinary Excretion of Dietary Lignan Metabolites and Weight Change in US Women. Am J Epidemiol 182:503-11
Ley, Sylvia H; Sun, Qi; Jimenez, Monik C et al. (2014) Association between alcohol consumption and plasma fetuin-A and its contribution to incident type 2 diabetes in women. Diabetologia 57:93-101
Sun, Qi; Wedick, Nicole M; Pan, An et al. (2014) Gut microbiota metabolites of dietary lignans and risk of type 2 diabetes: a prospective investigation in two cohorts of U.S. women. Diabetes Care 37:1287-95
Song, Y; Hauser, R; Hu, F B et al. (2014) Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women. Int J Obes (Lond) 38:1532-7

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