PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor gene, mutated frequently in a variety of human tumors. PTEN regulates cell growth, apoptosis, and proliferation. Phosphorylation in PTEN tail causes its inactivation and decreases its degradation. There is little known about the regulation of PTEN by ovarian steroids. We hypothesized that PTEN expression in human endometrium is variable throughout the menstrual cycle and early pregnancy, and that ovarian steroids regulate PTEN expression because PTEN is critical in many steroid-sensitive tissues such as endometrium, prostate, and breast. In the present study, we have observed a direct regulation of PTEN by ovarian steroids. Estradiol increased PTEN phosphorylation at 5-15 min. After 24-h treatment, progesterone induced a significant increase in PTEN protein levels, assessed by Western blot. Furthermore, we evaluated for the first time a comparison between menstrual cycle and early pregnancy, immunohistochemically. Endometrial PTEN expression revealed temporal and spatial changes throughout the menstrual cycle and during early pregnancy. We conclude that estradiol may down-regulate PTEN activity by increasing its phosphorylation, but progesterone is likely to regulate the PTEN pool by decreasing its phosphorylation and increasing its protein level. Presented data, therefore, suggest that ovarian steroids regulate the endometrial PTEN pool. We propose that PTEN might be one of the signaling proteins that estrogen and progesterone are acting to affect endometrial cell proliferation and/or apoptosis.