Conflict of interest:The authors have declared that no conflict of interest exists.Nonstandard abbreviations used: SGK1, serum-and glucocorticoid-inducible kinase 1; RPL, recurrent pregnancy loss; ENaC, epithelial sodium channel; HESC, human endometrial stromal cells; ROS, reactive oxygen species; IVF, in vitro fertilization; dpc, days post coitus.
2Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations 1,2 .Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling, and abolished embryo implantation.By contrast, implantation was unhindered in Sgk1 -/-mice but pregnancy was often complicated by bleeding at the decidual-placental interface, fetal growth retardation and subsequent demise. Compared to WT animals, pregnancy-dependent induction of genes involved in oxidative stress defenses was grossly impaired in Sgk1 -/-mice. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from RPL subjects and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.The sustained rise in postovulatory circulating progesterone levels renders the endometrium transiently receptive to embryo implantation. This 'window of implantation', confined to 2 to 4 days during the mid-secretory phase of the cycle, enables the embryo to contact and stably adhere to the endometrial luminal epithelium before invading the decidualizing stroma 7-9 . Decidualization, which denotes the transformation of stromal fibroblasts into specialized secretory decidual cells, is indispensable for pregnancy as it governs local immune responses, controls trophoblast invasion, and protects the conceptus against a variety of physiological stressors associated with pregnancy [10][11][12] . Failure of the endometrium to express a receptive phenotype is a major cause of conception delay and IVF 3 treatment failure. On the other hand, perturbations in the maternal decidual response inevitably lead to pregnancy complications, most prevalent of which is miscarriage 2 . SGK1, a serine/threonine protein kinase homologous to AKT, is rapidly induced in response to a rise in progesterone levels in both human and mouse endometrium, first in epithelial cells and then in the decidualizing st...
