Recently, we generated transgenic mice in which ER alpha can be inducibly overexpressed in reproductive tissues (ER alpha overexpressors). These mice were used to test the hypothesis that prenatal and postnatal ER alpha overexpression reduces female fertility. To do so, litter sizes, ovulation, follicle numbers, uterine histology, implantation sites, and hormone levels were compared in ER alpha overexpressors and controls. The data indicate that ER alpha overexpressors have reduced fertility compared to controls and that the reduced fertility is not due to reduced ovulatory capacity, altered levels of estradiol, FSH, and LH, or impaired follicular growth, ER alpha overexpressors, however, had a higher number of apoptotic cells in the endometrial epithelium and a reduced number of implantation sites compared to controls. Thus, the increased number of apoptotic cells and reduced number of implantation sites observed in ER alpha overexpressing uteri compared to controls may, in part, account for the reduced litter size produced by ER alpha overexpressing females. (c) 2006 Elsevier Inc. All rights reserved.