Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Mitsunori Matsuo ◽  
Yasushi Hirota ◽  
Yamato Fukui ◽  
Hidetoshi Fujita ◽  
Tomoko Saito-Fujita ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Infertility Treatment ◽  
Vehicle Control ◽  
Inhibitory Factor ◽  
Wild Type ◽  
Attachment Sites ◽  
Attachment Inhibition ◽  
Evening Administration ◽  
Embryo Attachment

Abstract Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 μg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 μg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.

The role of the leukemia inhibitory factor receptor in embryo implantation and placentation

Placenta ◽  
2021 ◽  
Vol 114 ◽  
pp. 139
Author(s):  
Jumpei Terakawa ◽  
Kazuhiro Matsuo ◽  
Takafumi Namiki ◽  
Kana Ohtomo ◽  
Atsuko Kageyama ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor

scholarly journals miRNA-181 regulates embryo implantation in mice through targeting leukemia inhibitory factor

2015 ◽  
Vol 7 (1) ◽  
pp. 12-22 ◽  
Author(s):  
Bo Chu ◽  
Liangwen Zhong ◽  
Shuang Dou ◽  
Jun Wang ◽  
Jianmin Li ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Inhibitory Factor

scholarly journals Leukemia Inhibitory Factor: Roles in Embryo Implantation and in Nonhormonal Contraception

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Naguib Salleh ◽  
Nelli Giribabu
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Growth And Development ◽  
Immune Modulation ◽  
Embryo Implantation ◽  
Critical Role ◽  
Inhibitory Factor ◽  
Trophoblast Invasion ◽  
Leukaemia Inhibitory Factor ◽  
Multiple Processes

Leukaemia inhibitory factor (LIF) plays an indispensible role in embryo implantation. Aberrant LIF production is linked to implantation failure. LIF regulates multiple processes prior to and during implantation such as uterine transformation into a receptive state, decidualization, blastocyst growth and development, embryo-endometrial interaction, trophoblast invasion, and immune modulation. Due to its critical role, LIF has been a target for a nonhormonal contraception. In this review, we summarize up-to-date information on the role of LIF in implantation and its role in contraception.

Regulation of Notch Signaling by Leukemia Inhibitory Factor in the Murine Uterus During Embryo Implantation.

2010 ◽  
Vol 83 (Suppl_1) ◽  
pp. 81-81
Author(s):  
Gracy Xavier Rosario ◽  
Jianbo Hu Eiichi Hondo ◽  
Jae-Wook Jeong ◽  
Francesco J. DeMayo ◽  
Colin L. Stewart
Keyword(s):  
Notch Signaling ◽  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Inhibitory Factor

scholarly journals Implantation Failure in Female Kiss1−/− Mice Is Independent of Their Hypogonadic State and Can Be Partially Rescued by Leukemia Inhibitory Factor

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3065-3078 ◽  
Author(s):  
Michele Calder ◽  
Yee-Ming Chan ◽  
Renju Raj ◽  
Macarena Pampillo ◽  
Adrienne Elbert ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Hypogonadotropic Hypogonadism ◽  
Embryo Implantation ◽  
Critical Role ◽  
Inhibitory Factor ◽  
Implantation Failure ◽  
Mouse Uterus ◽  
Female Mice ◽  
Wild Type Female ◽  
Neuroendocrine Axis

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1−/− female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1+/− embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1−/− uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1−/− female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.

scholarly journals An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sean A. Hunter ◽  
Brianna J. McIntosh ◽  
Yu Shi ◽  
R. Andres Parra Sperberg ◽  
Chie Funatogawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Animal Models ◽  
Cancer Treatment ◽  
Leukemia Inhibitory Factor ◽  
Therapeutic Strategy ◽  
Inhibitory Factor ◽  
Wild Type ◽  
High Affinity ◽  
Mediated Effects ◽  
Pancreatic Cancer Cells

AbstractLeukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.

scholarly journals 227.An inhibitor of leukemia inhibitory factor signalling blocks embryo implantation in the mouse

2004 ◽  
Vol 16 (9) ◽  
pp. 227
Author(s):  
E. Dimitriadis ◽  
C. Stoikos ◽  
M. Baca ◽  
W. Fairlie ◽  
A. D. Uboldi ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Uterine Horn ◽  
Inhibitory Factor ◽  
Luminal Epithelium ◽  
Pregnant Uterus ◽  
Implantation Sites ◽  
Post Implantation

Embryo implantation is a critical step in the establishment of pregnancy. Endometrial leukemia inhibitory factor (LIF) is essential for embryo implantation in the mouse (1). Uterine LIF is expressed in the luminal epithelium on Day 3 of pregnancy (D3) (D0�=�day of plug detection) and signals via activation of signal transducer and activator of transcription (Stat) 3 (2). We examined the effect of a novel LIF signalling inhibitor on the phosphorylation (p) of Stat3 during early pregnancy and on embryo implantation in the mouse. We injected LIF inhibitor into one uterine horn and PBS into the other uterine horn of the mouse at D3 and examined the effect on pStat3 immunostaining in the luminal epithelium between 30 and 360�min later. We found no immunoreactive pStat3 in luminal epithelium following treatment with LIF inhibitor at 60 and 90�min but variable staining at other time points. The PBS-treated uterine horn showed intense immunostaining at all times. LIF inhibitor (1mg/kg body weight per day) or PBS was administered to mice (a) subcutaneously, (b) intraperitoneally, at 8-hourly intervals for 3�days from D2, or (c) continuously into the peritoneal cavity via Alzet pumps from D2. No effect was seen on implantation at D6. When LIF antagonist (3.5mg/kg/day) or PBS were administered by Alzet pumps from D2 together with ip injections, 4-hourly from D3 for 36�h, there were no implantation sites in the uteri of treated mice (n�=�5) while the control mice (n�=�4) had 3.6���0.5�sites (P�<�0.001). Histologically, the uteri of the treated mice resembled non-pregnant uterus, while the control uterus resembled post-implantation uterus. The results demonstrate that treatment of mice during early pregnancy with a novel LIF inhibitor blocks LIF action in vivo and embryo implantation. This knowledge is important for development of novel contraceptives. (1) Stewart, C. L., Kaspar, P., Brunet, L. J., Bhatt, H., Gadi, I., Kontgen, F., Abbondanzo, S. J. (1992) Nature 359, 76–79. (2) Cheng, J. G., Chen, J. R., Hernandez, L., Alvord, W. G., Stewart, C. L. (2001) Proc. Natl Acad. Sci. USA 98, 8680–8685.

scholarly journals Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 277 ◽  
Author(s):  
Stefan Kassumeh ◽  
Stephanie Leopold ◽  
Rudolf Fuchshofer ◽  
Carina N. Thomas ◽  
Siegfried G. Priglinger ◽  
...  
Keyword(s):  
Protective Factors ◽  
Mrna Expression ◽  
Retinal Ganglion Cells ◽  
Leukemia Inhibitory Factor ◽  
Ganglion Cells ◽  
Inhibitory Factor ◽  
Retinal Ganglion ◽  
Wild Type ◽  
Excitotoxic Damage ◽  
Deficient Mice

Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.

scholarly journals Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takehiro Hiraoka ◽  
Yasushi Hirota ◽  
Yamato Fukui ◽  
Mona Gebril ◽  
Tetsuaki Kaku ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Embryo Implantation ◽  
Uterine Receptivity ◽  
Uterine Lumen ◽  
Female Mice ◽  
Attachment Sites ◽  
Transcription 3 ◽  
Estrogenic Responses ◽  
Embryo Attachment

Abstract Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.

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