During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.

GnRH is one of the paracrine/autocrine regulators of hCG secretion produced by the human trophoblast during pregnancy. We hypothesized that GnRH may play a role in the embryonic/endometrial dialogue during early implantation. To examine this hypothesis, we assessed GnRH and GnRH-receptor mRNA and protein expression in human endometrium throughout the menstrual cycle of premenopausal fertile patients. Quantitation of the mRNA was performed by reverse transcription (RT)-competitive polymerase chain reaction (PCR) in the presence of a competitive cDNA fragment. RT-PCR revealed that unfractioned endometrium and isolated endometrial stromal and epithelial cells express GnRH and GnRH-receptor mRNA throughout all phases of the menstrual cycle. Quantitative PCR showed a dynamic pattern in the GnRH mRNA expression throughout the cycle, with a significant increase (p < 0.05) in the secretory phase as compared to the proliferative phase. Furthermore, quantitative competitive PCR of isolated glandular and stromal cells showed higher mRNA levels (p < 0.05) in the luteal phase in both compartments. GnRH immunostaining was localized in all major compartments, with the most intense staining during the luteal phase. On the basis of these data, we suggest that during reproductive life, endometrial GnRH may play a paracrine/autocrine role in the early stages of implantation by modulating embryonic trophoblastic secretion of hCG.

Oral NAC was found to reduce the recurrence of preterm birth in patients with bacterial vaginosis.

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