Liver receptor homolog-1 is essential for pregnancy

Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, the liver receptor homolog-1 (Lrh-1, NR5A2), is an orphan nuclear receptor that regulates metabolism and hormone synthesis(1). It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents(2) and humans. Germline ablation of the Lrh-1 gene in mice is embryo-lethal at gastrulation(3). Depletion of Lrh-1 in the ovarian follicle demonstrates that it regulates genes required for both steroid synthesis and ovulation(4). To study the effects of Lrh-1 on mouse gestation, we disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation, and fetal death. Lrh-1 is expressed in the mouse and human endometrium. In a human model of primary culture of endometrial stromal cells, depletion of Lrh-1 by siRNA abrogated decidualization. These findings demonstrate that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for placental formation. It therefore plays multiple, indispensible roles in establishing and sustaining pregnancy.