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      GnRH agonist improves pregnancy outcome in mice with induced adenomyosis by restoring endometrial receptivity

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          Abstract

          Purpose

          Adenomyosis has a negative impact on female fertility. GnRH agonist treatment can improve pregnancy outcomes in women with adenomyosis. However, the impact of GnRH agonist upon endometrium receptivity of patients with adenomyosis remains unclear. In this study, endometrial receptivity and pregnancy outcome were investigated using a mouse model of adenomyosis.

          Materials and methods

          Adenomyosis was induced in 12 female ICR mice, neonatally treated with tamoxifen, while another six female mice (control group) received solvent only. At 75 days, the induced adenomyosis group was randomly divided into two groups: an untreated group and a group treated with GnRH agonist (n = 6 each). Sixty days later, the mice were mated and pregnancy outcomes were observed and compared among the three groups (n = 6 each). In a parallel experiment using the same treatment regimes, uterus samples were collected on day 4 of pregnancy for immunohistochemistry, gene (quantitative polymerase chain reaction) and protein expression (Western blot), and scanning electron microscopy analyses.

          Results

          We found that the average live litter size was reduced in the adenomyosis compared with control group (8 ± 0.56 versus 13 ± 0.71; P = 0.03). However, the litter size was significantly increased in the treated with GnRH agonist group compared with the untreated group (12 ± 0.35 versus 8 ± 0.56; P = 0.04). The uterine expression levels of Hoxa10, Hoxa11, Lif and integrin b3 mRNA and protein were decreased in the adenomyosis group, and were significantly increased after GnRH agonist treatment. Additionally, pinopodes were reduced in number and poorly developed in mice with induced adenomyosis. However, pinopodes were abundant and well-developed in the GnRH agonist treatment group.

          Conclusion

          Adenomyosis may have an adverse impact on endometrial receptivity and reduce pregnancy outcomes in mice. However, GnRH agonist may improve the pregnancy outcome by partially restoring endometrial receptivity.

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          Most cited references 42

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          Time of implantation of the conceptus and loss of pregnancy.

          Implantation of the conceptus is a key step in pregnancy, but little is known about the time of implantation or the relation between the time of implantation and the outcome of pregnancy. We collected daily urine samples for up to six months from 221 women attempting to conceive after ceasing to use contraception. Ovulation was identified on the basis of the ratio of urinary estrogen metabolites to progesterone metabolites, which changes rapidly with luteinization of the ovarian follicle. The time of implantation was defined by the appearance of chorionic gonadotropin in maternal urine. There were 199 conceptions, for 95 percent of which (189) we had sufficient data for analysis. Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss. Among the pregnancies that lasted six weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10. The risk of early pregnancy loss increased with later implantation (P<0.001). Among the 102 conceptuses that implanted by the ninth day, 13 percent ended in early loss. This proportion rose to 26 percent with implantation on day 10, to 52 percent on day 11, and to 82 percent after day 11. In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.
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            Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.

            The Abdominal B (AbdB) genes constitute a distinct subfamily of homeobox genes that exhibit posterior domains of expression, including the genital imaginal disc in Drosophila and the developing urogenital system in vertebrates. We have mutated the AbdB gene Hoxa10 in mice. We report here that homozygotes are fully viable and show an anterior homeotic transformation of lumbar vertebrae. All male homozygotes manifest bilateral cryptorchidism resulting in severe defects in spermatogenesis and increasing sterility with age. Female homozygotes ovulate normally, but about 80% are sterile because of death of embryos between days 2.5 and 3.5 post coitum. This coincides spatially and temporally with expression of maternal Hoxa10 in distal oviductal and uterine epithelium. These results indicate a role for AbdB Hox genes in male and female fertility and suggest that maternal Hoxa10 is required to regulate the expression of a factor that affects the viability of preimplantation embryos.
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              Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis.

              A stage critical in mammalian development is embryo implantation. At this point, the blastocyst establishes a close interaction with the uterine tissues, a step necessary for its continued embryonic development. In many mammalian species, including man, uterine expression of the cytokine, leukemia inhibitory factor (LIF) is coincident with the onset of implantation and in mice LIF is essential to this process. The reasons for implantation failure have not been established. Here we show in LIF-deficient mice that up to the onset of implantation, changes in uterine cell proliferation, hormone levels, blastocyst localization, as well as expression of lactoferrin and Muc-1, do not differ from wild-types. However, the uterus fails to respond to the presence of embryos or to artificial stimuli by decidualizing. In mice, implantation and decidualization are induced by nidatory estrogen. We show that uterine expression of LIF is up-regulated by estrogen and LIF can replace nidatory estrogen at inducing both implantation and decidualization in ovariectomized mice. Implantation of LIF-deficient embryos in the LIF-deficient females, with normal development to term is rescued by i.p. injection of LIF. Transient expression of LIF on D4 of pregnancy is therefore only required to induce a state of receptivity in the uterus permitting embryo implantation and decidualization. LIF is neither required by the embryo for development nor for the maintenance of pregnancy.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                07 June 2018
                : 12
                : 1621-1631
                Affiliations
                [1 ]Department of Gynaecology and Obstetrics, Qianfoshan Hospital, Shandong University, Jinan, China
                [2 ]Gynecology, Shanghai Ji Ai Genetics & In Vitro Fertilization Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
                [3 ]Reproductive Medicine Center, Department of Obstetrics and Gynecology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
                Author notes
                Correspondence: Li Yan, Department of Gynaecology and Obstetrics, Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan 250014, Shandong, China, Tel +86 531 8926 8217, Fax +86 531 8296 3647, Email yanliqy@ 123456163.com
                Yijuan Sun, Gynecology, Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, 588 Fangxie Road, Shanghai 200011, China, Tel +86 21 6345 5468, Fax +86 21 3318 0478, Email yijuansss@ 123456163.com
                Article
                dddt-12-1621
                10.2147/DDDT.S162541
                5995291
                © 2018 Guo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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