Systemic Morphine Treatment Derails Normal Uterine Receptivity, Leading to Embryo Implantation Failure in Mice1

Abstract The study investigated the effect of normal and supraphysiological (resulting from gonadotropin-dependent ovarian stimulation) levels of estradiol (E2) and progesterone (P4) on mouse uterine aquaporin gene/protein (Aqp/AQP) expression on Day 1 (D1) and D4 of pregnancy. The study also examined the effect of ovarian stimulation on uterine luminal closure and uterine receptivity on D4 of pregnancy and embryo implantation on D5 and D7 of pregnancy. These analyses revealed that the expression of Aqp3, Aqp4, Aqp5 and Aqp8 is induced by E2 while the expression of Aqp1 and Aqp11 is induced by P4. Additionally, P4 inhibits E2 induction of Aqp3 and Aqp4 expression while E2 inhibits Aqp1 and Aqp11 expression. Aqp9, however, is constitutively expressed. Ovarian stimulation disrupts Aqp3, Aqp5 and Aqp8 expression on D4 and AQP1, AQP3 and AQP5 spatial expression on both D1 and D4, strikingly so in the myometrium. Interestingly, while ovarian stimulation has no overt effect on luminal closure and uterine receptivity, it reduces implantation events, likely through a disruption in myometrial activity and embryo development. The wider implication of this study is that ovarian stimulation, which results in supraphysiological levels of E2 and P4 and changes (depending on the degree of stimulation) in the E2:P4 ratio, triggers abnormal expression of uterine AQP during pregnancy, and this is associated with implantation failure. These findings lead us to recognize that abnormal expression would also occur under any pathological state (such as endometriosis) that is associated with changes in the normal E2:P4 ratio. Thus, infertility among these patients might in part be linked to abnormal uterine AQP expression.

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Gram-Negative Bacterial LPS Induced Poor Uterine Receptivity and Implantation Failure in Mouse: Alterations in IL-1β Expression in the Preimplantation Embryo and Uterine Horns

Infectious Diseases in Obstetrics and Gynecology ◽

10.1080/10647440500147885 ◽

2005 ◽

Vol 13 (3) ◽

pp. 125-133 ◽

Cited By ~ 18

Author(s):

Kaushik Deb ◽

Madan Mohan Chaturvedi ◽

Yogesh Kumar Jaiswal

Keyword(s):

Cross Sections ◽

Pregnancy Loss ◽

Embryo Implantation ◽

Preimplantation Embryos ◽

Soluble Form ◽

Implantation Failure ◽

Perinatal Complications ◽

Uterine Receptivity ◽

Gram Negative ◽

Blastocyst Implantation

Genito-urinary tract or systemic infections of the gram-negative bacteria in pregnant women, causes abortions, preterm labor, and several other perinatal complications. LPS is the most potent antigenic component of the gram-negative bacterial cell wall and is known to modulate the expression of various proinflammatory cytokines. Here we investigate the role of the soluble form of IL-1 i.e., IL-1β in the ‘minimum dose’ of LPS induced pregnancy loss in mice. Uterine cross-sections on each day of the preimplantation period of pregnancy were examined histopathologically for finding out LPS induced changes in the uterine preparation for embryo implantation. The expression of IL-1β in the various stages of the preimplantation period of pregnancy was studied by RT-PCR in the embryos and the uterine horns of the LPS treated and normal pregnant mice. We found that LPS significantly alters the proliferation of the glandular epithelium, luminal epithelium and stroma during the preimplantation period. We also found large infiltration of macrophages into the uterine horns of the LPS treated animals. The level and pattern of IL-1β expression in the preimplantation embryos and uterine horns were also altered in LPS treated animals. These observations indicate that LPS can alter the uterine preparation for blastocyst implantation, which could be due to the change in the IL-1β expression in the uterine horns. However, a change in the expression pattern of IL-1β in the preimplantation embryos underlines the significance of this molecule in LPS induced pregnancy loss or implantation failure in mouse.

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Endometrial inflammation and effect on implantation improvement and pregnancy outcome

Reproduction ◽

10.1530/rep-12-0217 ◽

2012 ◽

Vol 144 (6) ◽

pp. 661-668 ◽

Cited By ~ 80

Author(s):

I Granot ◽

Y Gnainsky ◽

N Dekel

Keyword(s):

Inflammatory Response ◽

Pregnancy Outcome ◽

Immune Cells ◽

Embryo Implantation ◽

Substantial Improvement ◽

Subsequent Pregnancy ◽

Endometrial Biopsy ◽

Implantation Failure ◽

Uterine Receptivity ◽

Major Barrier

Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal–fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.

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Embryo implantation failure as a prognostic factor of ART outcomes: An evaluation of 3315 ART cycles

10.26226/morressier.5af300b0738ab10027aa9640 ◽

2018 ◽

Author(s):

Felipe Dieamant

Keyword(s):

Prognostic Factor ◽

Embryo Implantation ◽

Implantation Failure

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Effect of Growth Hormone on Uterine Receptivity in Women With Repeated Implantation Failure in an Oocyte Donation Program: A Randomized Controlled Trial

Journal of the Endocrine Society ◽

10.1210/js.2017-00359 ◽

2017 ◽

Vol 2 (1) ◽

pp. 96-105 ◽

Cited By ~ 17

Author(s):

Signe Altmäe ◽

Raquel Mendoza-Tesarik ◽

Carmen Mendoza ◽

Nicolas Mendoza ◽

Francesco Cucinelli ◽

...

Keyword(s):

Growth Hormone ◽

Randomized Controlled Trial ◽

Controlled Trial ◽

Oocyte Donation ◽

Implantation Failure ◽

Uterine Receptivity ◽

Repeated Implantation Failure ◽

Randomized Controlled

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Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation

Endocrinology ◽

10.1210/en.2018-00105 ◽

2018 ◽

Vol 159 (6) ◽

pp. 2459-2472 ◽

Cited By ~ 2

Author(s):

Yan Yin ◽

Adam Wang ◽

Li Feng ◽

Yu Wang ◽

Hong Zhang ◽

...

Keyword(s):

Signal Transduction ◽

Heparan Sulfate ◽

Signaling Pathways ◽

Reproductive Tract ◽

Ovarian Function ◽

Embryo Implantation ◽

Uterine Epithelium ◽

Female Reproductive Tract ◽

Uterine Receptivity ◽

Mouse Uterus

Abstract To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

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Uterine Insulin Sensitivity Defects Induced Embryo Implantation Loss Associated with Mitochondrial Dysfunction-Triggered Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6655685 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Meixia Chen ◽

Jie Li ◽

Bo Zhang ◽

Xiangfang Zeng ◽

Xiangzhou Zeng ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Sensitivity ◽

Mitochondrial Dysfunction ◽

Insulin Signaling ◽

Embryo Implantation ◽

Fetal Loss ◽

Enrichment Analysis ◽

Uterine Receptivity ◽

Resistant Mouse

Scope. Implantation loss is a considerable cause of early pregnancy loss in humans and mammalian animals. It is not addressed how proliferative uterine defects implicate in implantation loss. Methods and Results. Herein, a comprehensive proteomic analysis was conducted on proliferative endometria from sows with low and normal reproductive performance (LRP and NRP, respectively). Enrichment analysis of differentially expressed proteins revealed alterations in endometrial remodeling, substance metabolism (mainly lipid, nitrogen, and retinol metabolism), immunological modulation, and insulin signaling in LRP sows. Importantly, aberrant lipid metabolite accumulation and dysregulation of insulin signaling were coincidently confirmed in endometria of LPR sows, proving an impaired insulin sensitivity. Furthermore, established high-fat diet- (HFD-) induced insulin-resistant mouse models revealed that uterine insulin resistance beginning before pregnancy deteriorated uterine receptivity and decreased implantation sites and fetal numbers. Mitochondrial biogenesis and fusion were decreased, and reactive oxygen species was overproduced in uteri from the HFD group during the implantation period. Ishikawa and JAR cells directly demonstrated that oxidative stress compromised implantation in vitro. Conclusions. This study demonstrated that uterine insulin sensitivity impairment beginning before pregnancy resulted in implantation and fetal loss associated with oxidative stress induced by mitochondrial dysfunction.

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