Administration of estradiol metabolites for the treatment or prevention of obesity, metabolic syndrome, diabetes and vascular and renal disorders

Abstract

Methods are provided for preventing or treating risk factors for cardiovascular disease in an individual, comprising administering a therapeutically effective amount of a composition comprising an estradiol metabolite to said individual. Such risk factors include obesity, the metabolic syndrome, diabetes mellitus, vascular disorders, and renal disorders. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol or prodrugs thereof. The compositions may also be in the form of a controlled release formulation. Methods are also provided for use of estradiol metabolites to treat or prevent insulin resistance, vascular endothelial dysfunction, hyperlipidemia, hypertension, diabetic nephropathy, proteinuria and reducing leptin levels. In addition, the methods provide a method of stabilizing glucose levels. These treatments may be used in either gender because of their lack of a feminizing estrogenic effect.

1 . A method for preventing or treating risk factors for cardiovascular disease in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         2 . The method of  claim 1 , wherein said risk factors for cardiovascular disease are selected from the group consisting of obesity, the metabolic syndrome, diabetes, vascular disorders and renal disorders. 
     
     
         3 . The method of  claim 1 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         4 . The method of  claim 1 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         5 . The method of  claim 1 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         6 . A method for the prevention or treatment of obesity in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         7 . The method of  claim 6 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         8 . The method of  claim 6 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         9 . The method of  claim 6 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         10 . A method for the prevention or treatment of the metabolic syndrome in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         11 . The method of  claim 10 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         12 . The method of  claim 10 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         13 . The method of  claim 10 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         14 . A method for the prevention or treatment of diabetes mellitus in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         15 . The method of  claim 14 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         16 . The method of  claim 14 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         17 . The method of  claim 14 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         18 . A method for the prevention or treatment of renal disease in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         19 . The method of  claim 18 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         20 . The method of  claim 18 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         21 . The method of  claim 18 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         22 . A method for the prevention or treatment of insulin resistance in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         23 . The method of  claim 22 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         24 . The method of  claim 22 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         25 . The method of  claim 22 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         26 . A method for the prevention or treatment of vascular endothelial dysfunction in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         27 . The method of  claim 26 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         28 . The method of  claim 26 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         29 . The method of  claim 26 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         30 . A method for the prevention or treatment of hyperlipidemia in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         31 . The method of  claim 30 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         32 . The method of  claim 30 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         33 . The method of  claim 30 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         34 . The method of  claim 30 , wherein said hyperlipidemia is hypercholesterolemia. 
     
     
         35 . A method for the prevention or treatment of hypertension in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         36 . The method of  claim 35 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         37 . The method of  claim 35 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         38 . The method of  claim 35 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         39 . A method for the prevention or treatment of diabetic nephropathy in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         40 . The method of  claim 39 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         41 . The method of  claim 39 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         42 . The method of  claim 39 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         43 . A method for the prevention or treatment of proteinuria in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         44 . The method of  claim 43 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         45 . The method of  claim 43 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         46 . The method of  claim 43 , wherein said composition comprises a prod rug of said estradiol metabolite. 
     
     
         47 . A method for the purpose of controlling glucose levels in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         48 . The method of  claim 47 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol and 4-hydroxyestradiol. 
     
     
         49 . The method of  claim 47 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         50 . The method of  claim 47 , wherein said composition comprises a prodrug of said estradiol metabolite. 
     
     
         51 . The method of  claim 47 , wherein said estradiol metabolite decreases polyuria in said individual. 
     
     
         52 . The method of  claim 47 , wherein said estradiol metabolite decreases polydipsia in said individual. 
     
     
         53 . The method of  claim 47 , wherein said estradiol metabolite decreases glycated hemoglobin levels in said individual. 
     
     
         54 . The method of  claim 47 , wherein said estradiol metabolite improves oral glucose tolerance in said individual. 
     
     
         55 . The method of  claim 47 , wherein said estradiol metabolite decreases glucosuria in said individual. 
     
     
         56 . A method for reducing leptin levels in an individual, comprising:
 administering to said individual a therapeutically effective amount of a composition comprising an estradiol metabolite.   
     
     
         57 . The method of  claim 56 , wherein said estradiol metabolite is selected from the group consisting of 2-methoxyestradiol, 4-methoxy estradiol, 2-hydroxyestradiol and 4-hydroxy estradiol. 
     
     
         58 . The method of  claim 56 , wherein said composition comprises a controlled release formulation of said composition. 
     
     
         59 . The method of  claim 56 , wherein said composition comprises a prodrug of said estradiol metabolite.