{"paper_id":"1fdb53c6-5b63-4d6c-90b2-323ba6856468","body_text":"Page 1 of 1\nAn Overview of the Basic Knowledge of \nLevonorgestrel-Releasing Intrauterine System\nJunling Liu, Mengyue Chen, Zhiyong Dong, Shoufeng Zhang, Wendi Zhang, Zhenyue Qin and Chen Jiming* \nDepartment of Obstetrics and Gynecology, The Affiliated Changzhou NO. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, China\nAbstract\nLevonorgestrel-releasing Intrauterine system (LNG-IUS, Mirena) is a very safe, efficient, long-acting and reversible intrauterine device, which \nreleases high-efficiency at a daily dose of 20ug Progesterone mainly acts on the part of the endometrium, causing the endometrial glands to shrink. \nA large number of studies have fully proved that LNG-IUS is not only effective in contraception, but also widely used in non-contraceptive fields. \nLNG-IUS is effective in treating gynecological diseases such as menorrhagia and dysmenorrhea. In addition, LNG-IUS is also used in endometriosis, \nadenomyosis, endometrial polyps, endometrial hyperplasia, and early endometrial cancer. Reversal of cancer and endometrial protection in breast \ncancer patients. This article will briefly summarize the basic knowledge of LNG-IUS and the clinical application of LNG-IUS in gynecological diseases.\nKeywords: Levonorgestrel-releasing Intrauterine system; Mirena; High-efficiency progesterone; Long-acting reversible contraception\nThis work is licensed under Creative Commons Attribution 4.0 License   WJGWH.MS.ID.000602. \nISSN: 2641-6247                                                                                                                           DOI: 10.33552/WJGWH.2021.05.000602\nWorld Journal of \nGynecology & Women’s Health\nReview Article Copyright © All rights are reserved by Chen Jiming\nIntroduction\nLevonorgestrel-releasing Intrauterine system (LNG-IUS),its \ntrade name is Mirena. It was originally designed in the 1970s, \nwhen the main purpose was to provide safe, efficient, long-acting \nand reversible contraception (LARC) for women of childbearing \nage [1]. LNG-IUS is a T-shaped device with a white cylindrical \ndrug core rack on the longitudinal arm, which contains 52mg of \nlevonorgestrel (LNG). The independently designed slow-release \nsystem releases 20ug of LNG into the uterine cavity every day. \nThe validity period is 5 years [2]. Currently in China, the approved \nclinical indications for LNG-IUS mainly include contraception and \nidiopathic menorrhagia. However, with the continuous deepening \nof research in recent years, the clinical application of LNG-IUS has \nbecome increasingly widespread, and it has already surpassed the \nscope of approved clinical indications [3]. Based on this, this article \nwill mainly introduce the basic knowledge about LNG-IUS, and \nbriefly summarize the clinical application scope of LNG-IUS and the \ncommon confusions and countermeasures of using LNG-IUS.\n \nAn Overview of the Basic Knowledge of Levonorge-\nstrel-Releasing Intrauterine System\nLevonorgestrel-releasing Intrauterine system (LNG-IUS, \nMirena) releases a low blood concentration of levonorgestrel. The \nblood concentration is reported to be 0.1-0.2ng/ml in the literature \n[1]. Some key points of knowledge of the Levonorgestrel-releasing \nIntrauterine system are briefly summarized: ①Levonorgestrel-\nreleasing Intrauterine system contains 52mg of levonorgestrel \nand releases 20ug of levonorgestrel every 24 hours, the validity \nperiod is 5 years [2]. ②What is levonorgestrel (levonorgestrel, \nLNG)? LNG is a fully synthetic high-efficiency progesterone \n(sterane synthetic progesterone preparation) It is the optically \nactive form of racemic norgestrel. The progestin activity is twice as \nstrong as norgestrel, which is about 100 Times of norethindrone. \nTherefore, the dose can be halved compared with norgestrel, and \nadverse reactions will be reduced accordingly. Levonorgestrel \nmainly acts on the hypothalamus and pituitary gland, which \n*Corresponding author: Chen Jiming, Department of Obstetrics and Gynecology, \nThe Affiliated Changzhou NO. 2 People’s Hospital of Nanjing Medical University, \nChangzhou 213000, Jiangsu Province, China.\nReceived Date: May 24, 2021\nPublished Date: June 07, 2021\n\nCitation: Junling Liu, Mengyue Chen, Zhiyong Dong, Shoufeng Zhang, Wendi Zhang, Zhenyue Qin, Chen Jiming. An Overview of the \nBasic Knowledge of Levonorgestrel-Releasing Intrauterine System. W J Gynecol Women’s Health. 5(1): 2021. WJGWH.MS.ID.000602. \nDOI: 10.33552/WJGWH.2021.05.000602.\nPage 2 of 4\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 5-Issue 1\nsignificantly reduces or disappears the peaks of FSH and LH \nlevels in the middle of menstruation. The ovaries do not ovulate \nand have obvious anti-estrogen activity. Its anti-estrogen activity \nis stronger than norethindrone 10 times(Note: Norethindrone \nis a synthetic progesterone preparation of estradiol, a synthetic \n19-desmethyltestosterone derivative, which has weak estrogenic \nand anti-estrogenic activity, and has mild androgen Activity and \nprotein assimilation, its androgenic activity is approximately \nequivalent to 1/6 of testosterone). LNG has almost no estrogenic \nactivity. It can thicken cervical mucus and hinder sperm penetration. \nIt shows strong progesterone activity for the transformation of the \nendometrium, which can make the endometrium thin, and the \nendometrial epithelial cells are low columnar, and the secretion \nfunction is poor, which is not conducive to the implantation of \npregnant eggs. LNG also has a certain androgenic activity and protein \nassimilation, which can inhibit ovulation by oral or subcutaneous \ninjection [3]. ③The levonorgestrel contained in the levonorgestrel \nintrauterine sustained-release system is an extremely effective \nprogesterone, which mainly acts locally [4-6]. ④ What is the \nactual blood concentration of levonorgestrel released by the \nintrauterine release system of levonorgestrel? It has been reported \nin the literature that about 10% of levonorgestrel is released in the \nsystemic circulation. Some patients may still have hormone-related \ncomplaints, such as breast tenderness, acne, mood changes, weight \ngain, hair loss, hirsutism or general swelling. Some patients will \nhave functional ovarian cysts. These phenomena are more obvious \nin the first few months of use and will gradually decrease with the \nextension of use time. This is actually related to the patients’ extreme \nsensitivity to levonorgestrel [7]. ⑤The concentration of LNG in the \nblood circulation of women using LNG-IUS is very low and stable. \nPharmacokinetic studies have shown that the plasma concentration \nreached by the LNG sustained-released by LNG-IUS in the uterine \ncavity is maintained at 0.4-0.6nmol/L (150-200pg/ml) through \nthe intimal basal capillary network to reach the blood circulation. \nThe blood concentration of commonly used oral contraceptives is \nlow, and the concentration in the fallopian tube is also very low [8]. \nAnother study reported that the median blood LNG concentration \nof women who used LNG-IUS within 7 years was 125-200ng/L [9]. \n⑥The Levonorgestrel-releasing Intrauterine system often causes \namenorrhea in patients. Isn’t menstruation after LNG-IUS a sign of \novarian function decline? Will the patient get older as a result? will \nnot. A large number of studies have confirmed [10-12] that LNG-\nIUS does not affect the patient’s ovarian function, ovarian cycle, and \nestrogen secretion. The amenorrhea caused by LNG-IUS is mainly \ncaused by the local inhibition of LNG on the endometrium. This \ninhibition is caused by the local high level of LNG on the endometrial \nestrogen receptor down-regulation, so that the endometrium is \nagainst the endogenous Sexual and exogenous estrogen are not \nsensitive, and inhibit the intimal hyperplasia reaction, resulting \nin oligomenorrhea and even amenorrhea after LNG-IUS use. And \nthis inhibition is reversible. After the birth control ring is removed, \nas long as the patient’s ovarian function is present, the normal \nmenstrual cycle can still be restored. After the LNG-IUS is taken out, \nmenstruation can be recovered, and the average recovery time is \n23 days. Therefore, the ovaries of patients with LNG-IUS can still \nsecrete E2 hormones normally, and will not cause the increase of \nFSH, and can have a normal ovulation cycle. ⑦So, what mechanism \ndoes the levonorgestrel intrauterine sustained-release system use \nto exert its high-efficiency contraceptive effect? It mainly includes \nthree aspects: a. Continuous inhibition of the endometrium, which \ninterferes with or is not conducive to the implantation of fertilized \neggs; b. Increases the consistency of cervical mucus and inhibits \nthe passage of sperm (the increase in the consistency of cervical \nmucus can effectively inhibit retrograde infection and reduce the \npelvic cavity The occurrence of inflammatory diseases); c. Anti-\nfertilization: inhibit the activity and function of sperm in the uterus \nand fallopian tubes, and prevent fertilization [5,9].\nClinical Application of Levonorgestrel-Releasing \nIntrauterine System\nWhat are the main clinical applications of Levonorgestrel-\nreleasing Intrauterine system? In summary, the main points are as \nfollows [13-24]: ①Long-acting reversible contraception (LARC), \nwhich has a contraceptive effect comparable to sterilization; \n②Functional uterine bleeding and menorrhagia; ③Resistance \nto menstruation caused by uterine fibroids More therapeutic \neffects; ④Therapeutic effect on adenomyosis; ⑤Maintenance \ntreatment after endometriosis; ⑥The effect of LNG-IUS in relieving \ndysmenorrhea; ⑦The protective effect of endometrium in HRT; \n⑧Tamoxifen treatment after breast cancer surgery Endometrial \nprotection; ⑨impact on endometrial hyperplasia and endometrial \ncancer.\nThe 2016 British Endometrial Hyperplasia Management \nGuidelines pointed out that for the hormone treatment of \nendometrial hyperplasia, the Levonorgestrel-releasing Intrauterine \nsystem is listed as the first choice. Progesterone therapy is prioritized \nto recommend the Levonorgestrel-releasing Intrauterine system, \nthat is, Mirena (LNG-IUS× at least 6 months, preferably × 5 years \nfor those without a childbirth plan), which can obtain a higher \nremission rate. According to the 2016 UK Endometrial Hyperplasia \nManagement Guidelines and the 2017 China Endometrial \nHyperplasia Diagnosis and Treatment Consensus [25-26], for the \ntreatment of endometrial hyperplasia, whether it is the treatment \nof no dysplasia or atypical hyperplasia, LNG-IUS seems to have \nbeen Placed in a very important position, this is slightly different \nfrom the previous view (the dysplasia should be converted with \nhigh-efficiency progesterone before considering the placement of \nLNG-IUS maintenance therapy [27-29]). However, whether these \nnew ideas can be widely and consistently adopted remains to be \nconfirmed by the test of time and further research.\n\nCitation: Junling Liu, Mengyue Chen, Zhiyong Dong, Shoufeng Zhang, Wendi Zhang, Zhenyue Qin, Chen Jiming. An Overview of the \nBasic Knowledge of Levonorgestrel-Releasing Intrauterine System. W J Gynecol Women’s Health. 5(1): 2021. WJGWH.MS.ID.000602. \nDOI: 10.33552/WJGWH.2021.05.000602.\nPage 3 of 4\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 5-Issue 1\nCommon Confusion and Countermeasures in \nthe Clinical Use of Levonorgestrel-Releasing \nIntrauterine System\nWhat are the main problems and confusions in the clinical \nuse of Levonorgestrel-releasing Intrauterine system? In summary, \nthe main points are as follows: ①Irregular vaginal bleeding often \noccurs during the first half of the year after using LNG-IUS. If the \namount of vaginal bleeding is small, it can be observed without \nspecial treatment; if the patient is worried and urgently requires \ntreatment, you can try estrogen therapy according to the following \nplan: low-dose compound oral contraceptives- compound LNG \ntablets (ethinyl estradiol 30µg / LNG150µg), one tablet a day for \n22 days; ethinyl estradiol 50µg once a day for 20 days; estradiol \nvalerate 2mg, continuous use for two months [22]; ② Patients \nwith adenomyosis have a large uterine cavity and should not be \nplaced directly. Consider three injections of GnRH-a and wait for \nthe uterus to shrink before placing it (uterus <8 weeks of gestation, \ncan be placed directly ; uterus> 8 weeks of gestation, placed \nafter GnRH-a is used, it is recommended to place a birth control \nring when menstruation is not regained) [23]. ③The problem of \nthe birth control ring moving down or falling off [30]. Lowering \nthe birth control ring often causes increased vaginal bleeding. \nTherefore, for patients with significantly increased vaginal bleeding \nafter LNG-IUS placement, it is necessary to consider the possibility \nof the contraceptive ring moving down or completely falling off. \nFor such patients, if the contraceptive ring does not protrude \nout of the uterine cavity, consider pushing the contraceptive ring \nup after disinfection to maintain the handle of the contraceptive \nring above the internal cervix. It does not necessarily require the \nposition of the contraceptive ring to be in the middle of the uterine \ncavity (the uterine cavity is often very Difficult to do). If the birth \ncontrol ring completely protrudes out of the uterine cavity, it is not \nrecommended to re-enter the original ring into the uterine cavity \n[13,22]. ④For patients with large uterine cavity, can a T-ring be \nplaced at the same time as LNG-IUS to prevent the contraceptive \nring from moving down or falling off? First of all, the efficacy of \nthis approach is not clear; secondly, it does not meet the criteria for \ndiagnosis and treatment. Therefore, it should be used with caution.\nSummary and Outlook\nIn summary, the Levonorgestrel-releasing Intrauterine system \nnot only has a long-term and reversible effect in contraception, but \nalso has a wide range of non-contraceptive clinical applications \nand good results. However, there are also many problems in the \nclinical application of Levonorgestrel-releasing Intrauterine \nsystem, which confuses clinicians. In order to facilitate memory, \nthe author compiled the essentials of the Levonorgestrel-releasing \nIntrauterine system (Mirena) for your reference:\n• Mirena ring is very different and contains levonorgestrel;\n• In fact, high-efficiency progesterone, the local effect is \nvery sufficient;\n• The concentration of hormones in the blood is low, and \nthe blood drug level is stable;\n• Complications take place in the initial use;\n• Often cause amenorrhea, and ovarian function does not \ndecline;\n• The inhibitory effect is often reversible, and ovarian \nhormones are still secreted;\n• The contraceptive effect can be assured;\n• Mirena has many effects, such as stopping bleeding, \nrelieving pain and protecting the endometrium;\nAcknowledgement\nThis work was supported by grants from the Scientific Research \nSupport Program for Postdoctoral of Jiangsu Province(2019K064) \n, the Major Science and Technology Program of Changzhou Health \nand Family Planning Commission (ZD201812), and the Scientific \nResearch Support Program for “333 Project” of Jiangsu Province \n(BRA2019161)\nConflict of Interest\nAuthors declare no conflict of interest.\nReferences\n1. 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