Mice deficient for theAbdominal B (AbdB) HoxgeneHoxa-10exhibit reduced fertility due to defects in implantation. During the peri-implantation periodHoxa-10is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression ofHoxa-10and otherAbdB Hoxagenes. Here we show thatHoxa-10expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition,Hoxa-10expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacentAbdB Hoxagenes reveals thatHoxa-9anda-11are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation ofAbdB Hoxgene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression ofHoxa10is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those inHoxa-10knockout mice, suggesting thatHoxa-10gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, eitherin vivoor in organ culture, represses the expression ofHoxa-10in the Müllerian duct. Thus, these data not only establish a direct link between ovarian steroids andAbdB Hoxagene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.