Estrogen receptor alpha (ER alpha) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a foxed ER alpha mouse line that can be used to knock out ER alpha in selected tissues by using the Cre/LoxP system. In this study, we established a new ER alpha knockout mouse line by crossing the foxed ER alpha mice with Cre deleter mice. Here we show that genetic disruption of the ERa gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ER alpha is necessary for reproductive tract development and has important functions as a regulator of metabolism in females. (c) 2012 Elsevier Inc. All rights reserved.