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Levonorgestrel IUD: is there a long-lasting effect on return to fertility?

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Abstract

Intrauterine devices (IUDs) are effective and safe long-acting reversible contraceptive methods for preventing unplanned pregnancies. While extensive studies were conducted to evaluate return to fertility after removal of IUDs, majority of them were focused on multiparous women using copper IUDs. Current trends indicate increased use of levonorgestrel (LNG) IUDs in nulliparous women for very long periods of time, with both nulliparity and long duration of LNG-IUD use being potentially associated with trends towards longer time to conception post removal. Understanding the effects that LNG-IUDs may have on endometrial morphology and gene expression has important implications to further understanding their mechanism of action. Studies examining endometrial gene expression show persistent changes in receptivity markers up to 1 year after removal of an inert IUD, and no similar studies have been performed after removal of LNG-IUDs. Given the current gap in the literature and trends in LNG-IUD use in nulliparous young women, studies are needed that specifically look at the interaction of nulliparity, long-term use of LNG-IUD, and return to normal fertility. Herein, we review the available literature on the mechanism of action of IUDs with a specific focus on the effect on endometrial gene expression profile changes associated with IUDs.

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References

  1. Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PGA. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online. 2004;9(6):692–715.

    Article  Google Scholar 

  2. Miravet-Valenciano JA, Rincon-Bertolin A, Vilella F, Simon C. Understanding and improving endometrial receptivity. Curr Opin Obstet Gynecol. 2015;27(3):187–92. https://doi.org/10.1097/GCO.0000000000000173.

    Article  PubMed  Google Scholar 

  3. Valbuena D, Valdes CT, Simon C. Introduction: endometrial function: facts, urban legends and an eye to the future. Fertil Steril. 2017;108(1):4–8. https://doi.org/10.1016/j.fertnstert.2017.05.030.

    Article  PubMed  Google Scholar 

  4. Aghajanova L, Hamilton AE, Giudice LC. Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics. Semin Cell Dev Biol. 2008;19(2):204–11. https://doi.org/10.1016/j.semcdb.2007.10.008.

    Article  CAS  PubMed  Google Scholar 

  5. Lawrenz B, Fatemi H. Effect of progesterone elevation in follicular phase of IVF-cycles on the endometrial receptivity. Reprod Biomed Online. 2017;34(4):422–8. https://doi.org/10.1016/j.rbmo.2017.01.011.

    Article  CAS  PubMed  Google Scholar 

  6. Bouchard P. Progesterone and the progesterone receptor. J Reprod Med. 1999;44(2 Suppl):153–7.

    CAS  PubMed  Google Scholar 

  7. Ing NH, Tornesi MB. Estradiol up-regulates estrogen receptor and progesterone receptor gene expression in specific ovine uterine cells. Biol Reprod. 1997;56(5):1205–15.

    Article  CAS  Google Scholar 

  8. Snijders MP, de Goeij AF, Debets-Te Baerts MJ, Rousch MJ, Koudstaal J, Bosman FT. Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause. J Reprod Fertil. 1992;94(2):363–71.

    Article  CAS  Google Scholar 

  9. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1(1):3–25. https://doi.org/10.1097/00006254-195008000-00044.

    Article  Google Scholar 

  10. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–34. https://doi.org/10.1016/j.fertnstert.2008.03.029.

    Article  CAS  PubMed  Google Scholar 

  11. Munro MG. Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity. Fertil Steril. 2019;111(4):629–40. https://doi.org/10.1016/j.fertnstert.2019.02.008.

    Article  PubMed  Google Scholar 

  12. Fernandez H, Al-Najjar F, Chauveaud-Lambling A, Frydman R, Gervaise A. Fertility after treatment of Asherman’s syndrome stage 3 and 4. J Minim Invasive Gynecol. 2006;13(5):398–402. https://doi.org/10.1016/j.jmig.2006.04.013.

    Article  PubMed  Google Scholar 

  13. Liu Y, Chen X, Huang J, et al. Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure. Fertil Steril. 2018;109(5):832–9. https://doi.org/10.1016/j.fertnstert.2018.01.022.

    Article  PubMed  Google Scholar 

  14. McQueen DB, Perfetto CO, Hazard FK, Lathi RB. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril. 2015;104(4):927–31. https://doi.org/10.1016/j.fertnstert.2015.06.044.

    Article  PubMed  Google Scholar 

  15. Aghajanova L, Giudice LC. Effect of bisphenol A on human endometrial stromal fibroblasts in vitro. Reprod Biomed Online. 2011;22(3):249–56. https://doi.org/10.1016/j.rbmo.2010.12.007.

    Article  CAS  PubMed  Google Scholar 

  16. Yuan M, Hu M, Lou Y, et al. Environmentally relevant levels of bisphenol A affect uterine decidualization and embryo implantation through the estrogen receptor/serum and glucocorticoid-regulated kinase 1/epithelial sodium ion channel α-subunit pathway in a mouse model. Fertil Steril. 2018;109(4):735–44.e1. https://doi.org/10.1016/j.fertnstert.2017.12.003.

    Article  CAS  PubMed  Google Scholar 

  17. Abdalla HI, Brooks AA, Johnson MR, Kirkland A, Thomas A, Studd JW. Endometrial thickness: a predictor of implantation in ovum recipients? Hum Reprod. 1994;9(2):363–5.

    Article  CAS  Google Scholar 

  18. Kasius A, Smit JG, Torrance HL, Eijkemans MJ, Mol BW, Opmeer BC, et al. Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(4):530–41. https://doi.org/10.1093/humupd/dmu011.

    Article  PubMed  Google Scholar 

  19. Goldfien GA, Barragan F, Chen J, et al. Progestin-containing contraceptives alter expression of host defense-related genes of the endometrium and cervix. Reprod Sci. 2015;22(7):814–28. https://doi.org/10.1177/1933719114565035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jones RL, Critchley HO. Morphological and functional changes in human endometrium following intrauterine levonorgestrel delivery. Hum Reprod. 2000;15(Suppl 3):162–72.

    Article  CAS  Google Scholar 

  21. Rutanen EM. Insulin-like growth factors and insulin-like growth factor binding proteins in the endometrium. Effect of intrauterine levonorgestrel delivery. Hum Reprod, 2000. 15(Suppl 3):173–81.

    Article  CAS  Google Scholar 

  22. Pakarinen PI, Lähteenmäki P, Lehtonen E, Reima I. The ultrastructure of human endometrium is altered by administration of intrauterine levonorgestrel. Hum Reprod. 1998;13(7):1846–53.

    Article  CAS  Google Scholar 

  23. Critchley HO, Wang H, Jones RL, Kelly RW, Drudy TA, Gebbie AE, et al. Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery. Hum Reprod. 1998;13(5):1218–24.

    Article  CAS  Google Scholar 

  24. Elaine C. Esber. ParaGard Copper T Model TCU 380A Intrauterine Contraceptive.; 1984.

    Google Scholar 

  25. Gemzell-Danielsson K, Berger C. P.G.L. L. Emergency contraception—mechanisms of action. Contraception. 2013;87(3):300–8. https://doi.org/10.1016/j.contraception.2012.08.021.

    Article  CAS  PubMed  Google Scholar 

  26. Carrascosa JP, Cotán D, Jurado I, Oropesa-Ávila M, Sánchez-Martín P, Savaris RF, et al. The effect of copper on endometrial receptivity and induction of apoptosis on decidualized human endometrial stromal cells. Reprod Sci. 2018;25(7):985–99. https://doi.org/10.1177/1933719117732165.

    Article  CAS  PubMed  Google Scholar 

  27. Apter D, Gemzell-Danielsson K, Hauck B, Rosen K, Zurth C. Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies. Fertil Steril. 2014;101(6):1656–62.e4. https://doi.org/10.1016/j.fertnstert.2014.03.004.

    Article  CAS  PubMed  Google Scholar 

  28. Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol. 1986;5(3):235–41.

    Article  CAS  Google Scholar 

  29. Sheppard BL. Endometrial morphological changes in IUD users: a review. Contraception. 1987;36(1):1–10.

    Article  CAS  Google Scholar 

  30. Philip S, Taylor AH, Konje JC, Habiba M. The levonorgestrel-releasing intrauterine device induces endometrial decidualisation in women on tamoxifen. J Obstet Gynaecol. 2019:1–6. https://doi.org/10.1080/01443615.2019.1587600.

    Article  CAS  Google Scholar 

  31. Engemise SL, Willets JM, Taylor AH, Emembolu JO, Konje JC. Changes in glandular and stromal estrogen and progesterone receptor isoform expression in eutopic and ectopic endometrium following treatment with the levonorgestrel-releasing intrauterine system. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):101–6. https://doi.org/10.1016/j.ejogrb.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  32. Meng C-X, Marions L, Bystrom B, Gemzell-Danielsson K. Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity. Hum Reprod. 2010;25(4):874–83. https://doi.org/10.1093/humrep/deq007.

    Article  CAS  PubMed  Google Scholar 

  33. Vargas MF. Tapia–Pizarro AA, Henríquez SP, et al. Effect of single post-ovulatory administration of levonorgestrel on gene expression profile during the receptive period of the human endometrium. J Mol Endocrinol. 2012;48(1):25–36. https://doi.org/10.1530/JME-11-0094.

    Article  CAS  PubMed  Google Scholar 

  34. Horcajadas JA, Sharkey AM, Catalano RD, Sherwin JR, Domínguez F, Burgos LA, et al. Effect of an intrauterine device on the gene expression profile of the endometrium. J Clin Endocrinol Metab. 2006;91(8):3199–207. https://doi.org/10.1210/jc.2006-0430.

    Article  CAS  PubMed  Google Scholar 

  35. Murray MJ, et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril. 2004;81(1):19–25. https://doi.org/10.1016/j.fertnstert.2003.

    Article  Google Scholar 

  36. Young SL, Savaris RF, Lessey BA, Sharkey AM, Balthazar U, Zaino RJ, et al. Effect of randomized serum progesterone concentration on secretory endometrial histologic development and gene expression. Hum Reprod. 2017;32(9):1903–14. https://doi.org/10.1093/humrep/dex252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Skjeldestad FE. The impact of intrauterine devices on subsequent fertility. Curr Opin Obstet Gynecol. 2008;20(3):275–80. https://doi.org/10.1097/GCO.0b013e3282fe7427.

    Article  PubMed  Google Scholar 

  38. Lohr PA, Lyus R, Prager S. Use of intrauterine devices in nulliparous women. Contraception. 2017;95(6):529–37. https://doi.org/10.1016/j.contraception.2016.08.011.

    Article  PubMed  Google Scholar 

  39. Andolsek L, Teeter RA, Kozuh-Novak M, Wheeler R, Fortney JA, Rosenberg MJ. Time to conception after IUD removal: importance of duration of use, IUD type, pelvic inflammatory disease and age. Int J Gynaecol Obstet. 1986;24(3):217–23.

    Article  CAS  Google Scholar 

  40. Eisenberg DL, Schreiber CA, Turok DK, Teal SB, Westhoff CL, Creinin MD. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception. 2015;92(1):10–6. https://doi.org/10.1016/j.contraception.2015.04.006.

    Article  CAS  PubMed  Google Scholar 

  41. Randic L, Vlasic S, Matrljan I, Waszak CS. Return to fertility after IUD removal for planned pregnancy. Contraception. 1985;32(3):253–9.

    Article  CAS  Google Scholar 

  42. Gemzell-Danielsson K, Apter D, Dermout S, et al. Evaluation of a new, low-dose levonorgestrel intrauterine contraceptive system over 5 years of use. Eur J Obstet Gynecol Reprod Biol. 2017;210:22–8. https://doi.org/10.1016/j.ejogrb.2016.11.022.

    Article  CAS  PubMed  Google Scholar 

  43. Andersson K, Batar I, Rybo G. Return to fertility after removal of a levonorgestrel-releasing intrauterine device and Nova-T. Contraception. 1992;46(6):575–84.

    Article  CAS  Google Scholar 

  44. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65(3):503–9.

    Article  CAS  Google Scholar 

  45. Gnoth C, Godehardt D, Godehardt E, Frank-Herrmann P, Freundl G. Time to pregnancy: results of the German prospective study and impact on the management of infertility. Hum Reprod. 2003;18(9):1959–66.

    Article  CAS  Google Scholar 

  46. Zhu H, Lei H, Huang W, et al. Fertility in older women following removal of long-term intrauterine devices in the wake of a natural disaster. Contraception. 2013;87(4):416–20. https://doi.org/10.1016/j.contraception.2012.11.002.

    Article  PubMed  Google Scholar 

  47. Doll H, Vessey M, Painter R. Return of fertility in nulliparous women after discontinuation of the intrauterine device: comparison with women discontinuing other methods of contraception. BJOG. 2001;108(3):304–14.

    CAS  PubMed  Google Scholar 

  48. Kavanaugh ML, Jerman J, Finer LB. Changes in use of long-acting reversible contraceptive methods among U.S. women, 2009–2012. Obstet Gynecol. 2015;126(5):917–27. https://doi.org/10.1097/AOG.0000000000001094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ashlyn H. Savage, MD and Sarah F. Lindsay M. ACOG Committee Opinion No. 735: Adolescents and long-acting reversible contraception implants and intrauterine devices. Obstet Gynecol. 2018;131(5):e130–9. https://doi.org/10.1097/AOG.0000000000002632.

    Article  Google Scholar 

  50. Steiner RJ, Liddon N, Swartzendruber AL, Rasberry CN, Sales JM. Long-acting reversible contraception and condom use among female US high school students. JAMA Pediatr. 2016;170(5):428–34. https://doi.org/10.1001/jamapediatrics.2016.0007.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, George Washington University, Washington, DC, USA

    Erin Dinehart

  2. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA

    Ruth B. Lathi & Lusine Aghajanova

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  1. Erin Dinehart
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  2. Ruth B. Lathi
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Dinehart, E., Lathi, R.B. & Aghajanova, L. Levonorgestrel IUD: is there a long-lasting effect on return to fertility?. J Assist Reprod Genet 37, 45–52 (2020). https://doi.org/10.1007/s10815-019-01624-5

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