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
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.
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.
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.
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.
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.
Bouchard P. Progesterone and the progesterone receptor. J Reprod Med. 1999;44(2 Suppl):153–7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Jones RL, Critchley HO. Morphological and functional changes in human endometrium following intrauterine levonorgestrel delivery. Hum Reprod. 2000;15(Suppl 3):162–72.
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.
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.
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.
Elaine C. Esber. ParaGard Copper T Model TCU 380A Intrauterine Contraceptive.; 1984.
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.
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.
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.
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.
Sheppard BL. Endometrial morphological changes in IUD users: a review. Contraception. 1987;36(1):1–10.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Randic L, Vlasic S, Matrljan I, Waszak CS. Return to fertility after IUD removal for planned pregnancy. Contraception. 1985;32(3):253–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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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DOI: https://doi.org/10.1007/s10815-019-01624-5