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Vol. 299, Issue 3, 973-977, December 2001
Center for Clinical Pharmacology (S.P.T., R.K.D., E.K.J.) and
Departments of Pharmacology (E.K.J.) and Medicine (S.P.T., R.K.D.,
E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania; and Department of Obstetrics and Gynecology (R.K.D.),
Clinic for Endocrinology, University Hospital, Zurich, Switzerland
A pandemic of obesity is contributing importantly to the prevalence of
the metabolic syndrome characterized by hypertension, insulin
resistance, and hyperlipidemia. In turn, the metabolic syndrome is
contributing to vascular disease and the accelerating epidemic of
chronic renal failure. Currently, pharmacological approaches to
attenuate obesity and its cardiovascular/renal sequelae are limited.
The purpose of this study was to determine the effects of
2-hydroxyestradiol, a metabolite of 17
-estradiol with minimal estrogenic activity, on the development of obesity, the metabolic syndrome, and heart, vascular, and renal dysfunction in obese ZSF1
rats, a well-characterized genetic model of obesity and the metabolic
syndrome with concomitant heart, vascular, and kidney disease. ZSF1
rats were treated, beginning at 12 weeks of age, for 26 weeks with
vehicle or 2-hydroxyestradiol (10 µg/kg/h). At baseline and after 24 weeks of treatment, animals were placed in metabolic cages, and food
intake, water intake, urine output, and urinary excretion of proteins
and glucose were determined. Next, in fasting animals, plasma
cholesterol was measured, an oral glucose tolerance test was conducted,
and total glycated hemoglobin levels were determined. At the end of the
study, animals were anesthetized and instrumented for assessment of
heart performance, renal hemodynamics, and mesenteric vascular
reactivity. 2-Hydroxyestradiol attenuated the development of obesity
and improved endothelial function, decreased nephropathy, decreased the
severity of diabetes, lowered arterial blood pressure, and reduced
plasma cholesterol. 2-Hydroxyestradiol may be an important lead for the
development of safe and effect drugs to attenuate obesity and its
metabolic, vascular, and renal sequelae.
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