Serum estradiol levels in controlled ovarian stimulation directly affect the endometrium

Abstract

Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10−9 M or 10−7 M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10−7 M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC–MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10−7 M estradiol. Differential expression of C3, plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C3, plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation.

Asynchronous Embryo Transfer Followed by Comparative Transcriptomic Analysis of Conceptus Membranes and Endometrium Identifies Processes Important to the Establishment of Equine Pregnancy

“…Furthermore, the kininogen protein has been detected in equine uterine luminal fluids on day 13 after ovulation, although it was not present in yolk sac fluid [22], and ULF kininogen concentration increases as pregnancy progresses in the pig [57]. These results suggest that the kininkallikrein system is active during early pregnancy and could be involved in the establishment of pregnancy by stimulating an inflammatory response, angiogenesis and prostaglandin production in the endometrium and/or the conceptus [54,[57][58][59][60]. The horse embryo is known to secrete large amounts of prostaglandins, including PGE2, PGF2α and PGI2, which are thought to play a role in stimulating a local increase in vascularity and in conceptus mobility [61].…”

Asynchronous Embryo Transfer Followed by Comparative Transcriptomic Analysis of Conceptus Membranes and Endometrium Identifies Processes Important to the Establishment of Equine Pregnancy

“…Furthermore, the kininogen protein has been detected in equine uterine luminal fluids on day 13 after ovulation, although it was not present in yolk sac fluid [22], and ULF kininogen concentration increases as pregnancy progresses in the pig [54]. These results suggest that the kinin-kallikrein system is active during early pregnancy and could be involved in the establishment of pregnancy by stimulating an inflammatory response, angiogenesis and prostaglandin production in the endometrium and/or the conceptus [51,[54][55][56][57]. The horse embryo is known to secrete large amounts of prostaglandins, including PGE 2 , PGF 2α and PGI 2 , which are thought to play a role in stimulating a local increase in vascularity and in conceptus mobility [58].…”

Dysregulation of collagen expression in peri‐implantation endometrium of women with high ovarian response

“…The appropriate estrogen/progesterone ratio is the major factor in establishing the receptive status of the pre‐implantation endometrium. In routine IVF‐ET process, supraphysiological concentration of estrogen and progesterone resulted in controlled ovarian hyperstimulation (COH) could alter endometrial development and lead to a nonreceptive status . Clinically, the pregnancy rate of fresh embryo transfer is lower than that in frozen embryo transfer, especially for patients with high ovarian response, suggesting that low pregnancy rate was due to impaired ER rather than embryo quality .…”

“…In routine IVF-ET process, supraphysiological concentration of estrogen and progesterone resulted in controlled ovarian hyperstimulation (COH) could alter endometrial development and lead to a nonreceptive status. 4,5 Clinically, the pregnancy rate of fresh embryo transfer is lower than that in frozen embryo transfer, especially for patients with high ovarian response, suggesting that low pregnancy rate was due to impaired ER rather than embryo quality. 6,7 The essential step in embryo implantation is well regulated degradation of the local ECM, accompanied by tissue remodeling.…”