Role of the levonorgestrel intrauterine system in effective contraception

Abdelhamid M Attia, Magdy M Ibrahim, Ahmed M Abou-Setta, Abdelhamid M Attia, Magdy M Ibrahim, Ahmed M Abou-Setta

Abstract

Norgestrel, a synthetic progestin chemically derived from 19-nortestosterone, is six times more potent than progesterone, with variable binding affinity to various steroid receptors. The levonorgestrel-releasing intrauterine system (LNG IUS) provides a long-acting, highly effective, and reversible form of contraception, with a pearl index of 0.18 per 100 women-years. The locally released hormone leads to endometrial concentrations that are 200-800 times those found after daily oral use and a plasma level that is lower than that with other forms of levonorgestrel-containing contraception. The contraceptive effect of the LNG IUS is achieved mainly through its local suppressive effect on the endometrium, leading to endometrial thinning, glandular atrophy, and stromal decidualization without affecting ovulation. The LNG IUS is generally well tolerated. The main side effects are related to its androgenic activity, which is usually mild and transient, resolving after the first few months. Menstrual abnormalities are also common but well tolerated, and even become desirable (eg, amenorrhea, hypomenorrhea, and oligomenorrhea) with proper counseling of the patient during the choice of the method of contraception. The satisfaction rates after 3 years of insertion are high, reaching between 77% and 94%. The local effect of the LNG IUS on the endometrium and low rates of systemic adverse effects have led to its use in other conditions rather than contraception, as for the treatment of endometrial hyperplasia, benign menorrhagia, endometriosis, adenomyosis, and uterine fibroids.

Keywords: Mirena; Skyla; contraception; family planning; intrauterine device; levonorgestrel.

References

    1. Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet. 2000;356(9234):1013–1019.
    1. Sondheimer SJ. Oral contraceptives: mechanism of action, dosing, safety, and efficacy. Cutis. 2008;81(Suppl 1):19–22.
    1. World Health Organization . Medical Eligibility Criteria for Contraceptive Use. 4th ed. Geneva: WHO; 2010.
    1. Trussell J, Vaughan B. Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth. Fam Plann Perspect. 1999;31(2):64–72.
    1. Stanczyk FZ, Henzl MR. Use of the name “Progestin”. Contraception. 2001;64(1):1–2.
    1. Rose S, Chaudhari A, Peterson CM. Mirena (levonorgestrel intrauterine system): a successful novel drug delivery option in contraception. Adv Drug Deliv Rev. 2009;61(10):808–812.
    1. Samra-Latif OM.Contraception 2013Available from: Accessed July 17, 2013
    1. Luukkainen T, Lahteenmaki P, Toivonen J. Levonorgestrel-releasing intrauterine device. Ann Med. 1990;22(2):85–90.
    1. Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids. 2000;65(10–11):693–697.
    1. Dean G, Goldberg AB.Overview of intrauterine contraception 2013Available from: Accessed July 19, 2013
    1. Benagiano G, Primiero FM, Farris M. Clinical profile of contraceptive progestins. Eur J Contracept Reprod Health Care. 2004;9(3):182–193.
    1. Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update. 2006;12(2):169–178.
    1. Benagiano G, Carrara S, Filippi V. Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives. Patient Prefer Adherence. 2009;3:131–143.
    1. Rowlands S. Newer progestogens. J Fam Plann Reprod Health Care. 2003;29(1):13–16.
    1. Sitruk-Ware R. New progestogens: a review of their effects in perimenopausal and postmenopausal women. Drugs Aging. 2004;21(13):865–883.
    1. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003;46( Suppl 1):S7–S16.
    1. Stanczyk FZ, Roy S. Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception. 1990;42(1):67–96.
    1. Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril. 1986;45(6):805–807.
    1. Klaisle CM, Wysocki S. Innovations in contraception: the Norplant system. NAACOGS Clin Issu Perinat Womens Health Nurs. 1992;3(2):267–279.
    1. 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):235–241.
    1. Critchley HO, Wang H, Kelly RW, Gebbie AE, Glasier AF. Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system. Hum Reprod. 1998;13(5):1210–1217.
    1. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception. 1994;49(1):56–72.
    1. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception. 2007;75(Suppl 6):S16–S30.
    1. Guillebaud J. The levonorgestrel intrauterine system: a clinical perspective from the UK. Ann N Y Acad Sci. 2003;997:185–193.
    1. Sivin I, Stern J, Coutinho E, et al. Prolonged intrauterine contraception: a seven-year randomized study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS. Contraception. 1991;44(5):473–480.
    1. Cox M, Tripp J, Blacksell S. Clinical performance of the levonorgestrel intrauterine system in routine use by the UK Family Planning and Reproductive Health Research Network: 5-year report. J Fam Plann Reprod Health Care. 2002;28(2):73–77.
    1. French R, Van Vliet H, Cowan F, et al. Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy. Cochrane Database Syst Rev. 2004;3:CD001776.
    1. Chiou CF, Trussell J, Reyes E, et al. Economic analysis of contraceptives for women. Contraception. 2003;68(1):3–10.
    1. Carusi DA, Goldberg AB.Insertion and removal of an intrauterine contraceptive device 2013Available from: Accessed July 19, 2013
    1. Chen BA, Reeves MF, Hayes JL, Hohmann HL, Perriera LK, Creinin MD. Postplacental or delayed insertion of the levonorgestrel intrauterine device after vaginal delivery: a randomized controlled trial. Obstet Gynecol. 2010;116(5):1079–1087.
    1. Hayes JL, Cwiak C, Goedken P, Zieman M. A pilot clinical trial of ultrasound-guided postplacental insertion of a levonorgestrel intrauterine device. Contraception. 2007;76(4):292–296.
    1. Allen RH, Bartz D, Grimes DA, Hubacher D, O’Brien P. Interventions for pain with intrauterine device insertion. Cochrane Database Syst Rev. 2009;3:CD007373.
    1. Maguire K, Davis A, Rosario Tejeda L, Westhoff C. Intracervical lidocaine gel for intrauterine device insertion: a randomized controlled trial. Contraception. 2012;86(3):214–219.
    1. McNicholas CP, Madden T, Zhao Q, Secura G, Allsworth JE, Peipert JF. Cervical lidocaine for IUD insertional pain: a randomized controlled trial. Am J Obstet Gynecol. 2012;207(5):384 .e1–e6.
    1. Oloto EJ, Bromham DR, Murty JA. Pain and discomfort perception at IUD insertion – effect of short-duration, low-volume, intracervical application of two percent lignocaine gel (Instillagel) – a preliminary study. Br J Fam Plann. 1997;22(4):177–180.
    1. Bednarek PH, Micks EA, Edelman AB, Li H, Jensen JT. The effect of nitroprusside on IUD insertion experience in nulliparous women: a pilot study. Contraception. 2013;87(4):421–425.
    1. Dijkhuizen K, Dekkers OM, Holleboom CA, et al. Vaginal misoprostol prior to insertion of an intrauterine device: an RCT. Hum Reprod. 2011;26(2):323–329.
    1. Edelman AB, Schaefer E, Olson A, et al. Effects of prophylactic misoprostol administration prior to intrauterine device insertion in nulliparous women. Contraception. 2011;84(3):234–239.
    1. Heikinheimo O, Inki P, Kunz M, et al. Double-blind, randomized, placebo-controlled study on the effect of misoprostol on ease of consecutive insertion of the levonorgestrel-releasing intrauterine system. Contraception. 2010;81(6):481–486.
    1. Li YT, Kuo TC, Kuan LC, Chu YC. Cervical softening with vaginal misoprostol before intrauterine device insertion. Int J Gynaecol Obstet. 2005;89(1):67–68.
    1. Saav I, Aronsson A, Marions L, Stephansson O, Gemzell-Danielsson K. Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: a randomized controlled trial. Hum Reprod. 2007;22(10):2647–2652.
    1. Swenson C, Turok DK, Ward K, Jacobson JC, Dermish A. Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. Obstet Gynecol. 2012;120(2 Pt 1):341–347.
    1. Scavuzzi A, Souza AS, Costa AA, Amorim MM. Misoprostol prior to inserting an intrauterine device in nulligravidas: a randomized clinical trial. Hum Reprod. 2013;28(8):2118–2125.
    1. Sufrin CB, Postlethwaite D, Armstrong MA, Merchant M, Wendt JM, Steinauer JE. Neisseria gonorrhea and Chlamydia trachomatis screening at intrauterine device insertion and pelvic inflammatory disease. Obstet Gynecol. 2012;120(6):1314–1321.
    1. American College of Obstetricians and Gynecologists ACOG Practice Bulletin No 121: Long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2011;118(1):184–196.
    1. Grimes DA, Schulz KF. Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Syst Rev. 2001;2:CD001327.
    1. Nishimura RA, Carabello BA, Faxon DP, et al. ACC/AHA 2008 guideline update on valvular heart disease: focused update on infective endocarditis: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118(8):887–896.
    1. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116(15):1736–1754.
    1. Suhonen S, Haukkamaa M, Jakobsson T, Rauramo I. Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study. Contraception. 2004;69(5):407–412.
    1. Luukkainen T, Toivonen J. Levonorgestrel-releasing IUD as a method of contraception with therapeutic properties. Contraception. 1995;52(5):269–276.
    1. Sitruk-Ware R. The levonorgestrel intrauterine system for use in peri- and postmenopausal women. Contraception. 2007;75(Suppl 6):S155–S160.
    1. Mansour D. The benefits and risks of using a levonorgestrel-releasing intrauterine system for contraception. Contraception. 2012;85(3):224–234.
    1. Dubuisson JB, Mugnier E. Acceptability of the levonorgestrel-releasing intrauterine system after discontinuation of previous contraception: results of a French clinical study in women aged 35 to 45 years. Contraception. 2002;66(2):121–128.
    1. McGavigan CJ, Dockery P, Metaxa-Mariatou V, et al. Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel. Hum Reprod. 2003;18(1):77–84.
    1. Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data. 2004;(350):1–36.
    1. Tewari R, Kay VJ. Compliance and user satisfaction with the intrauterine contraceptive device in Family Planning Service: the results of a survey in Fife, Scotland, August 2004. Eur J Contracept Reprod Health Care. 2006;11(1):28–37.
    1. Xiao B, Wu SC, Chong J, Zeng T, Han LH, Luukkainen T. Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia. Fertil Steril. 2003;79(4):963–969.
    1. Hidalgo M, Bahamondes L, Perrotti M, Diaz J, Dantas-Monteiro C, Petta C. Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years. Contraception. 2002;65(2):129–132.
    1. Ronnerdag M, Odlind V. Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use. Acta Obstet Gynecol Scand. 1999;78(8):716–721.
    1. Heliovaara-Peippo S, Oksjoki R, Halmesmaki K, et al. The effect of hysterectomy or levonorgestrel-releasing intrauterine system on cardiovascular disease risk factors in menorrhagia patients: a 10-year follow-up of a randomised trial. Maturitas. 2011;69(4):354–358.
    1. Rogovskaya S, Rivera R, Grimes DA, et al. Effect of a levonorgestrel intrauterine system on women with type 1 diabetes: a randomized trial. Obstet Gynecol. 2005;105(4):811–815.
    1. Graff-Iversen S, Tonstad S. Use of progestogen-only contraceptives/medications and lipid parameters in women age 40 to 42 years: results of a population-based cross-sectional Norwegian Survey. Contraception. 2002;66(1):7–13.
    1. Bahamondes L, Espejo-Arce X, Hidalgo MM, Hidalgo-Regina C, Teatin-Juliato C, Petta CA. A cross-sectional study of the forearm bone density of long-term users of levonorgestrel-releasing intrauterine system. Hum Reprod. 2006;21(5):1316–1319.
    1. Bahamondes MV, Monteiro I, Castro S, Espejo-Arce X, Bahamondes L. Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system. Hum Reprod. 2010;25(5):1158–1164.
    1. Morin-Papunen L, Martikainen H, McCarthy MI, et al. Comparison of metabolic and inflammatory outcomes in women who used oral contraceptives and the levonorgestrel-releasing intrauterine device in a general population. Am J Obstet Gynecol. 2008;199(5):529. e1–e529. e10.
    1. van Vliet HA, Tchaikovski SN, Rosendaal FR, Rosing J, Helmerhorst FM. The effect of the levonorgestrel-releasing intrauterine system on the resistance to activated protein C (APC) Thromb Haemost. 2009;101(4):691–695.
    1. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24):2257–2266.
    1. Jarvela I, Tekay A, Jouppila P. The effect of a levonorgestrel-releasing intrauterine system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women. Hum Reprod. 1998;13(12):3379–3383.
    1. Baldaszti E, Wimmer-Puchinger B, Loschke K. Acceptability of the long-term contraceptive levonorgestrel-releasing intrauterine system (Mirena): a 3-year follow-up study. Contraception. 2003;67(2):87–91.
    1. Inki P, Hurskainen R, Palo P, et al. Comparison of ovarian cyst formation in women using the levonorgestrel-releasing intrauterine system vs hysterectomy. Ultrasound Obstet Gynecol. 2002;20(4):381–385.
    1. Berlex Laboratories Mirena [prescribing information] 2013Available from: Accessed July 19, 2013
    1. Backman T, Rauramo I, Jaakkola K, et al. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol. 2005;106(4):813–817.
    1. Dinger J, Bardenheuer K, Minh TD. Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. Contraception. 2011;83(3):211–217.
    1. Trinh XB, Tjalma WA, Makar AP, Buytaert G, Weyler J, van Dam PA. Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril. 2008;90(1):17–22.
    1. Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet. 1992;339(8796):785–788.
    1. Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. International Committee for Contraception Research (ICCR) Fertil Steril. 1994;61(1):70–77.
    1. Toivonen J, Luukkainen T, Allonen H. Protective effect of intrauterine release of levonorgestrel on pelvic infection: three years’ comparative experience of levonorgestrel- and copper-releasing intrauterine devices. Obstet Gynecol. 1991;77(2):261–264.
    1. Heinemann K, Barnett C, Dinger J.Risk factors for uterine perforations during IUD insertion: interim results from the EURAS-IUD study 2011Available from: Accessed July 19, 2013
    1. Caliskan E, Ozturk N, Dilbaz BO, Dilbaz S. Analysis of risk factors associated with uterine perforation by intrauterine devices. Eur J Contracept Reprod Health Care. 2003;8(3):150–155.
    1. Heartwell SF, Schlesselman S. Risk of uterine perforation among users of intrauterine devices. Obstet Gynecol. 1983;61(1):31–36.
    1. French RS, Cowan FM, Mansour D, et al. Levonorgestrel-releasing (20 microgram/day) intrauterine systems (Mirena) compared with other methods of reversible contraceptives. BJOG. 2000;107(10):1218–1225.
    1. Eroglu K, Akkuzu G, Vural G, et al. Comparison of efficacy and complications of IUD insertion in immediate postplacental/early postpartum period with interval period: 1 year follow-up. Contraception. 2006;74(5):376–381.
    1. Grimes D, Schulz K, Stanwood N. Immediate postabortal insertion of intrauterine devices. Cochrane Database Syst Rev. 2004;4:CD001777.
    1. Gemzell-Danielsson K, Schellschmidt I, Apter D. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine contraceptive systems and Mirena. Fertil Steril. 2012;97(3):616–622. e1–e3.
    1. Jensen JT. Contraceptive and therapeutic effects of the levonorgestrel intrauterine system: an overview. Obstet Gynecol Surv. 2005;60(9):604–612.
    1. Davie JE, Walling MR, Mansour DJ, Bromham D, Kishen M, Fowler P. Impact of patient counseling on acceptance of the levonorgestrel implant contraceptive in the United Kingdom. Clin Ther. 1996;18(1):150–159.
    1. Backman T, Huhtala S, Luoto R, Tuominen J, Rauramo I, Koskenvuo M. Advance information improves user satisfaction with the levonorgestrel intrauterine system. Obstet Gynecol. 2002;99(4):608–613.
    1. Inki P. Long-term use of the levonorgestrel-releasing intrauterine system. Contraception. 2007;75(Suppl 6):S161–S166.
    1. Sivin I, Alvarez F, Diaz J, et al. Intrauterine contraception with copper and with levonorgestrel: a randomized study of the TCu 380Ag and levonorgestrel 20 mcg/day devices. Contraception. 1984;30(5):443–456.
    1. Cibula D. Women’s contraceptive practices and sexual behaviour in Europe. Eur J Contracept Reprod Health Care. 2008;13(4):362–375.
    1. García IC, García EV, Rubio MT, et al. Estudio de satisfacción en usuarias españolas del DIU-LNG (Mirena) Rev Iberoam Fertil Reprod Hum. 2009;26(4):335–342.
    1. Luo L, Luo B, Zheng Y, Zhang H, Li J, Sidell N. Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia. Cochrane Database Syst Rev. 2013;6:CD009458.
    1. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;4:CD002126.
    1. Abou-Setta AM, Houston B, Al-Inany HG, Farquhar C. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2013;1:CD005072.
    1. Sangkomkamhang US, Lumbiganon P, Laopaiboon M, Mol BW. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev. 2013;2:CD008994.
    1. Dolapcioglu K, Boz A, Baloglu A. The efficacy of intrauterine versus oral progestin for the treatment of endometrial hyperplasia. A prospective randomized comparative study. Clin Exp Obstet Gynecol. 2013;40(1):122–126.
    1. Abu Hashim H, Zayed A, Ghayaty E, El Rakhawy M. LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial. J Gynecol Oncol. 2013;24(2):128–134.
    1. Ismail MT, Fahmy DM, Elshmaa NS. Efficacy of levonorgestrel-releasing intrauterine system versus oral progestins in treatment of simple endometrial hyperplasia without atypia. Reprod Sci. 2013;20(1):45–50.
    1. Wong AW, Chan SS, Yeo W, Yu MY, Tam WH. Prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen: a randomized controlled trial. Obstet Gynecol. 2013;121(5):943–950.

Source: PubMed

3
Abonnieren