Implantation in the baboon: Endometrial responses

Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and im mediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is t he further modulation of these steroid induced changes in both epithelial a nd stromal cells by embryonic signals. The final phase is associated with t rophoblast invasion and the remodeling of the endometrial stromal compartme nt. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (EA) and the progesterone receptor (PX), while progestero ne down-regulates this expression pattern. However, the pattern of progeste rone-induced down-regulation of EX and PX is confined to the epithelial cel ls and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PA is closely corre lated with the establishment of uterine receptivity. Coincident with the ch anges in EX and PX expression, epithelial cells undergo alterations in thei r cytoskeletal architecture and secretory profile. These changes can be cou nteracted by PX antagonist treatment during the luteal phase. Although estr ogen and progesterone play a critical role in establishing the initial phas e of uterine receptivity, it is becoming increasingly evident that the embr yo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium u ndergoes endoreplication and distinct epithelial plaques are evident. The g landular epithelium responds by inducing transcriptional and post-translati onal modifications in the major secretory product, glycodelin. The stromal fibroblasts initiate their differentiation process into a decidual phenotyp e and ave characterized by the expression of actin filaments. In phase thre e, blastocyst attachment to the surface epithelium and subsequent implantat ion is associated with local remodeling of the maternal stroma, smooth musc le, and endothelium of the blood vessels by the trophoblast. In addition, t here is a gradual diminution of the epithelial plaques on the luminal surfa ce although the glandular epithelium remains highly secretory. The most dra matic effect is on the stromal fibroblasts, which in response to embryonic stimuli, differentiate into decidual cells, the major cell type of the gest ational endometrium. This differentiation is characterized by the expressio n of insulin-like growth factor binding protein-1 (IGFBP-1) in these cells. The cytokine IL-1 beta is one possible embryonic signal. COX-2 is the rate -limiting enzyme for prostaglandin biosynthesis and transcription of this e nzyme in response to the embryonic stimulus (IL-1 beta) results in an incre ase in, prostaglandin biosynthesis in stromal fibroblasts at the site of im plantation. Prostaglandins and PGE2 in particular, binds to its specific re ceptor (EP2 or EP4) and activates adenyl cyclase. The resulting increase in intracellular levels of cAMP can now activate IGFBP-1 gene transcription a t the site of implantation. In summary, our studies have demonstrated that chorionic gonadotrophin, whe n infused into non-pregnant baboons during the window of uterine receptivit y can induce epithelial responses that are similar to those observed in a f ertile cycle, Stromal differentiation is initiated; however, decidualizatio n requires a signal from the conceptus.