Postcoital administration of asoprisnil inhibited embryo implantation and disturbed ultrastructure of endometrium in implantation window in mice

  • Xiao-li Wu (吴晓丽)
  • Zhi-hong Yu (余志红)
  • Jun Qiu (仇 君)
  • Yi-hong Yang (杨宜红)
  • Xiao-li Shen (沈小力)
  • Ping Su (苏 萍)
Article
First Online:
Received:
  • 142 Downloads

Summary

Asoprisnil, a member of the selective progesterone receptor modulators, exerts high progesterone receptor selectivity, endometrial targeted advantages and significant anti-implantation effect in rats. The purpose of this study was to confirm the anti-implantation effect of asoprisil, investigate the ultrastructural changes of the peri-implantation endometrium in mice and explore the effect of asoprisnil on endometrial receptivity and its targeted contraceptive proficiency. Post-coitus mice were administered with different dosages (0.2, 0.1, 0.05 mg·g−1·day−1) of asoprisnil from day 1 of pregnancy to day 3. Then 3 animals in each group were killed on day 5 of pregnancy, and uteri were collected to examine the ultrastructural changes of endometria under a transmission electron microscope (TEM). A total of 80 animals were sacrificed on day 8 of pregnancy, and the uterine horns were examined for the presence or absence of nidation sites and the number of implantation embryos. The results showed that the implantation rate and the average number of implantation embryos in asoprisnil groups were statistically significantly decreased as compared with the vehicle control group (P<0.05). The TEM results revealed that, in vehicle control group, the tight junction between the luminal epithelia cells was short and straight, the gap was wide; the luminal epithelia cells were covered with plenty of short, clavate and neatly arranged microvilli; the endometril stromal cells were large with plenty of cytoplasm, and showed significant decidual change; there was more than one nucleus in stromal cells, and the karyotheca was integrity. In low dosage and high dosage asoprisnil groups, the tight junction was longer and more curve than in the vehicle control group; microvilli were uneven and asymmetrically distributed in luminal epithelia; the stromal cells were small and the decidual change was not significant; there were karyopyknosis and karyolysis in stromal cells; there were abnormal thick-wall vessels in the endometrium. It was suggested that asoprisnil changed the ultrastructure of the endometrium in implantation window, disturbed the endometrial receptivity and finally resulted in embryo implantation failure.

Key words

Asoprisnil anti-implantation tight junction 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chwalisz K, Perez MC, Demanno D, et al. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev, 2005,26(3):423–438PubMedCrossRefGoogle Scholar
  2. 2.
    Csapo A. Progesterone block. Am J Anat, 1956,98(2):273–291PubMedCrossRefGoogle Scholar
  3. 3.
    Philibert D, Deraedt R, Teutsch G. RU38486: an original multifaceted antihormone in vivo. Tokyo, Japan: 1981, in The VII International Congress of Pharmacology.Google Scholar
  4. 4.
    Benagiano G, Bastianelli C, Farris M. Selective progesterone receptor modulators 1: use during pregnancy. Expert Opin Pharmacother, 2008,9(14):2459–2472PubMedCrossRefGoogle Scholar
  5. 5.
    Chabbert-Buffet N, Meduri G, Bouchard P, et al. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update, 2005,11(3):293–307PubMedCrossRefGoogle Scholar
  6. 6.
    Olive DL. Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv, 2002,57(11 Suppl 4):S55–S63.PubMedCrossRefGoogle Scholar
  7. 7.
    Schubert G, Elger W, Kaufmann G, et al. Discovery, chemistry, and reproductive pharmacology of Asoprisnil and related 11beta-benzaldoxime substituted selective progesterone receptor modulators (SPRMs). Semin Reprod Med, 2005,23(1):58–73PubMedCrossRefGoogle Scholar
  8. 8.
    Elger W, Bartley J, Schneider B, et al. Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids, 2000,65(10–11):713–723PubMedCrossRefGoogle Scholar
  9. 9.
    Chwalisz K, Mattia-Goldberg C, Lee M, et al. Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) Asoprisnil. Fertility and Sterility, 2004,822:S83–S84.Google Scholar
  10. 10.
    Stovall DW, Mikdachi HE. Treatment of symptomatic uterine leiomyomas with selective progesterone receptor modulators. Gynecol, 2011,6(6):579–582Google Scholar
  11. 11.
    Williams AR, Critchley HO, Osei J, et al. The effects of the selective progesterone receptor modulator Asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata. Hum Reprod, 2007,22(6):1696–1704PubMedCrossRefGoogle Scholar
  12. 12.
    DeManno D, Elger W, Garg R, et al. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids, 2003,68(10–13):1019–1032PubMedCrossRefGoogle Scholar
  13. 13.
    Chwalisz K, Elger W, Stickler T, et al. The effects of 1-month administration of Asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women. Hum Reprod, 2005,20(4):1090–1099PubMedCrossRefGoogle Scholar
  14. 14.
    Brenner RM, Slayden OD, Garg RC, et al. Asoprisnil suppresses endometrial proliferation in cynomolgus macaques. J Soc Gynecol Invest, 2005,12S(2):208A–209AGoogle Scholar
  15. 15.
    Chwalisz K, Brenner RM, Fuhrmann UU, et al. Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium. Steroids, 2000,65(10–11):741–751PubMedCrossRefGoogle Scholar
  16. 16.
    Slayden OD, Chwalisz K, Brenner RM. Reversible suppression of menstruation in normal women irrespective of the effect on ovulation with the novel selective progesterone receptor. Human Reproduction, 2001,16(8):1562–1574PubMedCrossRefGoogle Scholar
  17. 17.
    Murphy CR, Shaw TJ. Plasma membrane transformation: a common response of uterine epithelial cells during the peri-implantation period. Cell Biol Int, 1994,18(12):1115–1128PubMedCrossRefGoogle Scholar
  18. 18.
    Psychoyos A. Uterine receptivity for nidation. Ann NY Acad Sci, 1986(476):36–42Google Scholar
  19. 19.
    Psychoyos A. Hormonal control of uterine receptivity for nidation. J Reprod Fertil Suppl. 1976(25):17–28Google Scholar
  20. 20.
    Psychoyos A. Hormonal control of ovoimplantation. Vitam Horm, 1973,31:201–256PubMedCrossRefGoogle Scholar
  21. 21.
    Murphy AA, Kettel LM, Morales AJ, et al. Endometrial effects of long-term low-dose administration of RU486. Fertil Steril, 1995,63(4):761–766PubMedGoogle Scholar
  22. 22.
    Nikas G. Endometrial receptivity: changes in cell-surface morphology. Semin Reprod Med, 2000,18(3):229–235PubMedCrossRefGoogle Scholar
  23. 23.
    Nikas G. Pinopodes as markers of endometrial receptivity in clinical practice. Hum Reprod, 1999,14 (Suppl 2):99–106CrossRefGoogle Scholar
  24. 24.
    Meseguer M, Aplin J D, Caballero-Campo P, et al. Human endometrial mucin MUC1 is up-regulated by progesterone and down-regulated in vitro by the human blastocyst. Biol Reprod, 2001,64(2):590–601PubMedCrossRefGoogle Scholar
  25. 25.
    Ghaemi SR, Salehnia M, Valojerdi MR. The effect of progesterone and exogenous gonadotropin on preimplantation mouse embryo development and implantation. Exp Anim, 2008,57(1):27–34PubMedCrossRefGoogle Scholar
  26. 26.
    Lessey BA. Two pathways of progesterone action in the human endometrium: implications for implantation and contraception. Steroids, 2003,68(10–13):809–815PubMedCrossRefGoogle Scholar
  27. 27.
    Murphy CR. Junctional barrier complexes undergo major alterations during the plasma membrane transformation of uterine epithelial cells. Hum Reprod, 2000,15(Suppl 3):182–188PubMedCrossRefGoogle Scholar
  28. 28.
    Denker HW, Thie M. The regulatory function of the uterine epithelium for trophoblast attachment: experimental approaches. Ital J Anat Embryol, 2001,106(2 Suppl 2):291–306PubMedGoogle Scholar
  29. 29.
    Buck VU, Windoffer R, Leube RE, et al. Redistribution of adhering junctions in human endometrial epithelial cells during the implantation window of the menstrual cycle. Histochem Cell Biol, 2012,137(6):777–790PubMedCrossRefGoogle Scholar
  30. 30.
    Enders AC, Hendrickx AG, Schlafke S. Implantation in the rhesus monkey: initial penetration of endometrium. Am J Anat, 1983,167(3):275–298PubMedCrossRefGoogle Scholar
  31. 31.
    Satterfield MC, Dunlap KA, Hayashi K, et al. Tight and adherens junctions in the ovine uterus: differential regulation by pregnancy and progesterone. Endocrinology, 2007,148(8):3922–3931PubMedCrossRefGoogle Scholar
  32. 32.
    Bell S. Decidualization: regional differentiation and associated function. Oxf Rev Biol, 1983(5):220–271Google Scholar
  33. 33.
    Turner HE, Wass JA. Are markers of proliferation valuable in the histological assessment of pituitary tumours? Pituitary, 1999,1(3–4):147–151PubMedCrossRefGoogle Scholar
  34. 34.
    Correia-Da-Silva G, Bell SC, Pringle JH, et al. Patterns of uterine cellular proliferation and apoptosis in the implantation site of the rat during pregnancy. Placenta, 2004,25(6):538–547PubMedCrossRefGoogle Scholar
  35. 35.
    Lydon JP, Demayo FJ, Funk CR, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev, 1995,9(18):2266–2278PubMedCrossRefGoogle Scholar
  36. 36.
    Huang DM, Huang GY, Lu FE. Effect of Bushenyiqihexue recipe on the expression of endometrial pinopodes in blastocyst implantation dysfunctional mice. Zhonghua Fu Chan Ke Za Zhi (Chinese), 2004,39(4): 230–233.Google Scholar

Copyright information

© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Xiao-li Wu (吴晓丽)
    • 1
  • Zhi-hong Yu (余志红)
    • 2
  • Jun Qiu (仇 君)
    • 3
  • Yi-hong Yang (杨宜红)
    • 1
  • Xiao-li Shen (沈小力)
    • 1
  • Ping Su (苏 萍)
    • 1
  1. 1.The Family Planning Research Institute, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of PharmacyWuhan Centre HospitalWuhanChina
  3. 3.Department of Maternal and Child Health, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations