Editing Levonorgestrel (section)

==Medical uses==

===Birth control===
{{See also|Ethinylestradiol/levonorgestrel}}

At low doses, levonorgestrel is used in [[oral contraceptive formulations|monophasic]] and [[oral contraceptive formulations|triphasic]] formulations of [[combined oral contraceptive pill]]s, with available monophasic doses ranging from 100 to 250&nbsp;μg, and triphasic doses of 50&nbsp;μg, 75&nbsp;μg, and 125&nbsp;μg.<ref name="Drugs.com" /> It is combined with the estrogen [[ethinylestradiol]] in these formulations.<ref name="Drugs.com" />

At very low daily dose of 30&nbsp;μg, levonorgestrel is used in some [[progestogen-only pill]] [[oral contraceptive formulations#Progestogen-only pills|formulations]].<ref name="Drugs.com" />

Levonorgestrel is the active ingredient in a number of [[intrauterine devices]] including Mirena and Skyla.<ref name="Drugs.com" /><ref name="pmid26732558" /> It is also the active ingredient in the [[birth control implant]]s [[Norplant]] and [[Norplant|Jadelle]].<ref name="Drugs.com" /><ref name="pmid26732558" />

One of the more common forms of contraception that contains only levonorgestrel is an IUD. One IUD, the Mirena, is a small hollow cylinder containing levonorgestrel and polydimethylsiloxane and covered with a release rate-controlling membrane.<ref name="Bao Q 2018">{{cite journal | vauthors = Bao Q, Gu B, Price CF, Zou Y, Wang Y, Kozak D, Choi S, Burgess DJ | title = Manufacturing and characterization of long-acting levonorgestrel intrauterine systems | journal = International Journal of Pharmaceutics | volume = 550 | issue = 1–2 | pages = 447–454 | date = October 2018 | pmid = 30195080 | doi = 10.1016/j.ijpharm.2018.09.004 | pmc = 6622171 }}</ref>

===Emergency birth control===
Levonorgestrel is used in [[Emergency contraceptive pill#Emergency contraceptive pills|emergency contraceptive pills]] (ECPs), both in a combined [[Yuzpe regimen]] which includes estrogen, and as a levonorgestrel-only method. The levonorgestrel-only method uses levonorgestrel 1.5&nbsp;mg (as a single dose or as two 0.75&nbsp;mg doses 12 hours apart) taken within three days of unprotected sex. One study indicated that beginning as late as 120 hours (5 days) after intercourse could be effective.{{medical citation needed|date=January 2020}} However, taking more than one dose of emergency contraception does not increase the chance of pregnancy not happening. Planned Parenthood asserts "Taking the morning-after pill (also known as emergency contraception) multiple times doesn't change its effectiveness, and won't cause any long-term side effects."<ref>{{Cite web |title=How often can you take the morning-after pill? |url=https://www.plannedparenthood.org/learn/ask-experts/how-often-can-you-take-the-morning-after-pill |access-date=18 June 2022 |website=www.plannedparenthood.org |language=en |archive-date=24 June 2022 |archive-url=https://web.archive.org/web/20220624164100/https://www.plannedparenthood.org/learn/ask-experts/how-often-can-you-take-the-morning-after-pill |url-status=live }}</ref>

The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is, according to [[International Federation of Gynecology and Obstetrics]] (FIGO), to prevent fertilization by inhibition of [[ovulation]] and thickening of cervical mucus.<ref name="Trussell 2011">{{cite book| vauthors = Trussell J, Schwarz EB | name-list-style = vanc |year=2011|chapter=Emergency contraception| veditors =  Hatcher RA, Trussell J, Nelson AL, Cates Jr W, Kowal D, Policar MS |title=Contraceptive technology|edition=20th revised|location=New York|publisher=Ardent Media|isbn=978-1-59708-004-0|issn=0091-9721|oclc=781956734|pages=113–145 }} p. 121:<blockquote>Mechanism of action<br />Copper-releasing IUCs<br />When used as a regular or emergency method of contraception, copper-releasing IUCs act primarily to prevent fertilization. Emergency insertion of a copper IUC is significantly more effective than the use of ECPs, reducing the risk of pregnancy following unprotected intercourse by more than 99%.<sup>2,3</sup> This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization.<br />Emergency contraceptive pills<br />To make an informed choice, women must know that ECPs—like the birth control pill, patch, ring, shot, and implant,<sup>76</sup> and even like breastfeeding<sup>77</sup>—prevent pregnancy primarily by delaying or inhibiting ovulation and inhibiting fertilization, but may at times inhibit implantation of a fertilized egg in the endometrium. However, women should also be informed that the best available evidence indicates that ECPs prevent pregnancy by mechanisms that do not involve interference with post-fertilization events.<br />ECPs do not cause abortion<sup>78</sup> or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health<sup>79</sup> and the American College of Obstetricians and Gynecologists (ACOG).<sup>80</sup><br />''Ulipristal acetate (UPA).'' One study has demonstrated that UP can delay ovulation.<sup>81</sup>... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown.<sup>82</sup><br />p. 122:<br />''Progestin-only emergency contraceptive pills.'' Early treatment with ECPs containing only the progestin levonorgestrel has been shown to impair the ovulatory process and luteal function.<sup>83–87</sup><br />p. 123:<br />''Combined emergency contraceptive pills.'' Several clinical studies have shown that combined ECPs containing ethinyl estradiol and levonorgestrel can inhibit or delay ovulation.<sup>107–110</sup></blockquote></ref><ref name="FSRH EC 2012">{{cite journal|author1=RCOG Faculty of Sexual|author2=Reproductive Healthcare|author3=Clinical Effectiveness Unit|date=January 2012|title=Clinical guidance: emergency contraception|journal=Clinical Guidance|location=London|publisher=Royal College of Obstetricians and Gynaecologists|issn=1755-103X|url=http://www.fsrh.org/pdfs/CEUguidanceEmergencyContraception11.pdf|access-date=30 April 2012|url-status=dead|archive-url=https://web.archive.org/web/20120526135043/http://www.fsrh.org/pdfs/CEUguidanceEmergencyContraception11.pdf|archive-date=26 May 2012}} p.3:<blockquote>How does EC work?<br />In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation.<sup>8</sup> The possible mechanisms of action should be explained to the patient as some methods may not be acceptable, depending on individual beliefs about the onset of pregnancy and abortion.<br />Copper-bearing intrauterine device (Cu-IUD). Copper is toxic to the ovum and sperm and thus the copper-bearing intrauterine device (Cu-IUD) is effective immediately after insertion and works primarily by inhibiting fertilisation.<sup>9–11</sup> A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy.<sup>11</sup> If fertilisation has already occurred, it is accepted that there is an anti-implantation effect,<sup>12,13</sup><br />Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation.<sup>16,17</sup><br />Ulipristal acetate (UPA). UPA's primary mechanism of action is thought to be inhibition or delay of ovulation.<sup>2</sup></blockquote></ref><ref name="WHO 2010">{{cite web|author=UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP)|date=25 March 2010|title=Fact sheet on the safety of levonorgestrel-alone emergency contraceptive pills (LNG ECPs)|location=Geneva|publisher=World Health Organization|url=http://whqlibdoc.who.int/hq/2010/WHO_RHR_HRP_10.06_eng.pdf|url-status=live|archive-url=https://web.archive.org/web/20120316134151/http://whqlibdoc.who.int/hq/2010/WHO_RHR_HRP_10.06_eng.pdf|archive-date=16 March 2012}}<blockquote>Can LNG ECPs cause an abortion?<br />LNG ECPs do not interrupt an established pregnancy or harm a developing embryo.<sup>15</sup> The evidence available to date shows that LNG ECP use does not prevent a fertilized egg from attaching to the uterine lining. The primary mechanism of action is to stop or disrupt ovulation; LNG ECP use may also prevent the sperm and egg from meeting.<sup>16</sup></blockquote></ref><ref name="Speroff 2011">{{cite book| vauthors = Speroff L, Darney PD |year=2011|chapter=Special uses of oral contraception: emergency contraception, the progestin-only minipill|title=A clinical guide for contraception|edition=5th|location=Philadelphia|publisher=Lippincott Williams & Wilkins|pages=153–166|isbn=978-1-60831-610-6}} p. 155: <blockquote>Emergency postcoital contraception<br />Levonorgestrel<br />Mechanism and efficacy</blockquote></ref> FIGO has stated that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling."<ref name="Belluck 2012b">{{cite news| vauthors = Belluck P |date=6 June 2012|title=No abortion role seen for morning-after pill|newspaper=The New York Times|page=A1|url=https://www.nytimes.com/2012/06/06/health/research/morning-after-pills-dont-block-implantation-science-suggests.html?pagewanted=all|url-status=live|archive-url=https://web.archive.org/web/20170227112421/http://www.nytimes.com/2012/06/06/health/research/morning-after-pills-dont-block-implantation-science-suggests.html?pagewanted=all|archive-date=27 February 2017}}<br />{{cite news| vauthors = Belluck P |date=6 June 2012|title=Drug's nickname may have aided politicization|newspaper=The New York Times |page=A14 |url= https://www.nytimes.com/2012/06/06/health/research/medications-nickname-may-have-helped-in-its-politcization.html}}</ref><ref name="FIGO 2011">{{cite web|author=[[International Federation of Gynecology and Obstetrics]] (FIGO) and International Consortium for Emergency Contraception (ICEC)|date=4 April 2011|title=Mechanism of action: How do levonorgestrel-only emergency contraceptive pills (LNG ECPs) prevent pregnancy?|location=London|publisher=International Federation of Gynecology and Obstetrics|url=http://www.figo.org/sites/default/files/uploads/MOA_FINAL_2011_ENG.pdf|url-status=live|archive-url=https://web.archive.org/web/20141229024754/http://www.figo.org/sites/default/files/uploads/MOA_FINAL_2011_ENG.pdf|archive-date=29 December 2014}}<blockquote>Levonorgestrel-only emergency contraceptive pills:<br />• Interfere with the process of ovulation;<br />• May possibly prevent the sperm and the egg from meeting.<br />Implications of the research:<br />• Inhibition or delay of ovulation is LNG ECPs principal and possibly only mechanism of action.<br />• Review of the evidence suggests that LNG-ECs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling.<br />• The fact that LNG-ECs have no demonstrated effect on implantation explains why they are not 100% effective in preventing pregnancy and are less effective the later they are taken. Women should be given a clear message that LNG-ECs are more effective the sooner they are taken.<br />• LNG ECPs do not interrupt a pregnancy (by any definition of the beginning of pregnancy). However, LNG ECPs can prevent abortions by reducing unwanted pregnancies.</blockquote></ref> In November 2013, the [[European Medicines Agency]] (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.<ref name="Belluck 2013">{{cite news| vauthors = Belluck P |date=26 November 2013|title=New birth control label counters lawsuit claim; European authorities found that a drug like Plan B One-Step cannot prevent fertilized eggs from implanting in the womb|newspaper=The New York Times|url=https://www.nytimes.com/2013/11/27/us/shift-on-birth-control-pill-may-affect-court-cases.html|access-date=5 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140304233807/http://www.nytimes.com/2013/11/27/us/shift-on-birth-control-pill-may-affect-court-cases.html|archive-date=4 March 2014}}<br />{{cite web|author=HRA Pharma|author-link=HRA Pharma|date=November 2013|title=NorLevo 1.5 mg tablet Patient Information Leaflet (PIL)|location=Dublin|publisher=Irish Medicines Board|url=http://www.imb.ie/images/uploaded/swedocuments/2126041.PA1166_002_001.a60606c0-00f0-4866-bc34-91bdfd679b1e.000001PACKAGE%20LEAFLET%201.5.131128.pdf|access-date=5 March 2014|quote=NorLevo works by stopping your ovaries from releasing an egg. It cannot stop a fertilized egg from attaching to the womb.|url-status=live|archive-url=https://web.archive.org/web/20140305170311/http://www.imb.ie/images/uploaded/swedocuments/2126041.PA1166_002_001.a60606c0-00f0-4866-bc34-91bdfd679b1e.000001PACKAGE%20LEAFLET%201.5.131128.pdf|archive-date=5 March 2014}}<br />{{cite web|author=HRA Pharma|author-link=HRA Pharma|date=November 2013<!--|chapter=5.1 Pharmacodynamic properties-->|title=NorLevo 1.5 mg tablet Summary of Product Characteristics (SPC)|location=Dublin|publisher=Irish Pharmaceutical Healthcare Association|url=http://www.medicines.ie/medicine/11933/SPC/Norlevo+1.5mg+tablet/#PHARMACODYNAMIC_PROPS|access-date=5 March 2014|archive-url=https://web.archive.org/web/20120615184048/http://www.medicines.ie/medicine/11933/SPC/Norlevo+1.5mg+tablet#PHARMACODYNAMIC_PROPS|archive-date=15 June 2012|url-status=dead}}<br />{{cite news|author=European Medicines Agency|date=24 January 2014|title=Review of emergency contraceptives started|location=London|publisher=European Medicines Agency|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/01/news_detail_002010.jsp&mid=WC0b01ac058004d5c1|access-date=5 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140327002519/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2014%2F01%2Fnews_detail_002010.jsp&mid=WC0b01ac058004d5c1|archive-date=27 March 2014}}</ref>

Other studies still find the evidence to be unclear.<ref>{{cite journal | vauthors = Mozzanega B, Cosmi E | s2cid = 6431709 | title = How do levonorgestrel-only emergency contraceptive pills prevent pregnancy? Some considerations | journal = Gynecological Endocrinology | volume = 27 | issue = 6 | pages = 439–42 | date = June 2011 | pmid = 20670097 | doi = 10.3109/09513590.2010.501885 | hdl = 11577/2476296 }}</ref> While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.<ref>{{cite journal | vauthors = Leung VW, Levine M, Soon JA | title = Mechanisms of action of hormonal emergency contraceptives | journal = Pharmacotherapy | volume = 30 | issue = 2 | pages = 158–68 | date = February 2010 | pmid = 20099990 | doi = 10.1592/phco.30.2.158 | s2cid = 41337748 }}</ref>

In November 2013, the EMA also approved a change to the label for [[HRA Pharma]]'s ''NorLevo'' saying: "In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg [165 pounds] or more, and levonorgestrel was not effective in women who weighed more than 80 kg [176 pounds]."<ref name="Belluck 2013"/><ref name="Glasier 2011">{{cite journal | vauthors = Glasier A, Cameron ST, Blithe D, Scherrer B, Mathe H, Levy D, Gainer E, Ulmann A | title = Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel | journal = Contraception | volume = 84 | issue = 4 | pages = 363–7 | date = October 2011 | pmid = 21920190 | doi = 10.1016/j.contraception.2011.02.009 }}</ref><ref name="Trussell 2014">{{cite web| vauthors = Trussell J, Raymond EG, Cleland K |date=February 2014|title=Emergency contraception: a last chance to prevent unintended pregnancy|location=Princeton|publisher=Office of Population Research at Princeton University, Association of Reproductive Health Professionals|url=http://ec.princeton.edu/questions/ec-review.pdf|access-date=9 April 2014|url-status=dead|archive-url=https://web.archive.org/web/20100923040101/http://ec.princeton.edu/questions/ec-review.pdf|archive-date=23 September 2010}}</ref> In November 2013 and January 2014, the FDA and the EMA said they were reviewing whether increased weight and [[body mass index]] (BMI) reduce the efficacy of emergency contraceptives.<ref name="Belluck 2013"/>

An analysis of four WHO randomised clinical trials, published in January 2017, showed pregnancy rates of 1.25% (68/5428) in women with BMI under 25, 0.61% (7/1140) in women with BMI between 25 and 30, and 2.03% (6/295) in women with BMI over 30.<ref>{{cite journal | vauthors = Festin MP, Peregoudov A, Seuc A, Kiarie J, Temmerman M | title = Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies | journal = Contraception | volume = 95 | issue = 1 | pages = 50–54 | date = January 2017 | pmid = 27527670 | pmc = 5357708 | doi = 10.1016/j.contraception.2016.08.001 }}</ref> These values yield an eight-fold reduction in efficacy for women with a BMI over 30 compared to women with a BMI under 25. However, emergency contraceptives remain effective regardless of BMI.

===Hormone therapy===
Levonorgestrel is used in combination with an [[estrogen (medication)|estrogen]] in [[menopausal hormone therapy]].<ref name="Drugs.com" /><ref name="Kubíková2014" /> It is used under the brand name ''Klimonorm'' as a [[tablet (pharmacy)|combined oral tablet]] with [[estradiol valerate]] and under the brand name ''Climara Pro'' as a [[transdermal patch|combined transdermal patch]] with [[estradiol (medication)|estradiol]].<ref name="Drugs.com" /><ref name="Kubíková2014" />

===Available forms===
As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy.<ref name="Emergency Contraception - ACOG">{{Cite web|url=https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins-Gynecology/Emergency-Contraception?IsMobileSet=false|title=Emergency Contraception - ACOG|website=www.acog.org|access-date=1 June 2019|archive-date=9 October 2019|archive-url=https://web.archive.org/web/20191009072551/https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins-Gynecology/Emergency-Contraception?IsMobileSet=false|url-status=live}}</ref> However, it can serve different hormonal purposes in its different methods of delivery. It is available for use in a variety of forms:

====By mouth====
Levonorgestrel can be taken by mouth as a form of emergency birth control. The typical dosage is either 1.5&nbsp;mg taken once or 0.75&nbsp;mg taken 12–24 hours apart.<ref name=":0">{{cite journal | vauthors = Hansen LB, Saseen JJ, Teal SB | title = Levonorgestrel-only dosing strategies for emergency contraception | journal = Pharmacotherapy | volume = 27 | issue = 2 | pages = 278–84 | date = February 2007 | pmid = 17253917 | doi = 10.1592/phco.27.2.278 | s2cid = 24229915 }}</ref> The effectiveness in both methods is similar.<ref name=":0" /> The most widely used form of oral emergency contraception is the [[Progestogen-only pill|progestin-only pill]], which contains a 1.5&nbsp;mg dosage of levonorgestrel.<ref name="Emergency Contraception - ACOG"/> Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex.<ref name=":1">{{cite journal | vauthors = Shohel M, Rahman MM, Zaman A, Uddin MM, Al-Amin MM, Reza HM | title = A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception | journal = BMC Women's Health | volume = 14 | pages = 54 | date = April 2014 | pmid = 24708837 | pmc = 3977662 | doi = 10.1186/1472-6874-14-54 | doi-access = free }}</ref> The efficacy of the drug decreases by 50% for each 12-hour delay in taking the dose after the emergency contraceptive regimen has been started.<ref name=":1" />

====Skin patch====
{{See also|Estradiol/levonorgestrel}}

[[Estradiol/levonorgestrel|Estradiol with levonorgestrel]] in the form of a skin patch is used under the brand name Climara Pro for [[hormone replacement therapy]] in postmenstrual women, treating symptoms such as [[hot flash]]es or [[osteoporosis]].<ref name=":2">{{Cite web|url=https://www.mayoclinic.org/drugs-supplements/estradiol-and-levonorgestrel-transdermal-route/description/drg-20112971|title=Estradiol And Levonorgestrel (Transdermal Route) Description and Brand Names - Mayo Clinic|website=www.mayoclinic.org|access-date=1 June 2019|archive-date=31 May 2019|archive-url=https://web.archive.org/web/20190531172016/https://www.mayoclinic.org/drugs-supplements/estradiol-and-levonorgestrel-transdermal-route/description/drg-20112971|url-status=live}}</ref> The simultaneous delivery of a [[progestogen (medication)|progestogen]] such as levonorgestrel is necessary for the protection of the [[endometrium]].<ref name=":3">{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021885lbl.pdf|title=Climara Pro® (Estradiol/Levonorgestrel Transdermal System)|website=Food and Drug Administration|access-date=1 June 2019|archive-date=28 February 2021|archive-url=https://web.archive.org/web/20210228161531/https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021885lbl.pdf|url-status=dead}}</ref><ref>{{cite journal | vauthors = Mueck AO, Römer T | s2cid = 51886877 | title = Choice of progestogen for endometrial protection in combination with transdermal estradiol in menopausal women | journal = Hormone Molecular Biology and Clinical Investigation | volume = 37 | issue = 2 | date = July 2018 | pmid = 30063464 | doi = 10.1515/hmbci-2018-0033 | doi-access = free }}</ref>

====Intrauterine device====
The levonorgestrel intrauterine system (LNG-IUS) is a type of long-term birth control that releases the progestin into the uterine cavity.<ref name=Jeff2005>{{cite journal | vauthors = Jensen JT | s2cid = 43177026 | title = Contraceptive and therapeutic effects of the levonorgestrel intrauterine system: an overview | language = en-US | journal = Obstetrical & Gynecological Survey | volume = 60 | issue = 9 | pages = 604–12 | date = September 2005 | pmid = 16121115 | doi = 10.1097/01.ogx.0000175805.90122.af }}</ref><ref name="Bao Q 2018"/> Levonorgestrel is released at a constant, gradual rate of 0.02&nbsp;mg per day by the polydimethylsiloxane membrane of the device, which renders it effective for up to five years.<ref name=Jeff2005 /> Because it is inserted directly into the uterus, levonorgestrel is present in the endometrium in much higher concentrations that would result from a LNG-containing oral pill; the LNG-IUS delivers 391&nbsp;ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35&nbsp;ng.<ref name=Jeff2005 /> This high level of levonorgestrel impedes the function of the endometrium, making it hostile for sperm transport, fertilization, and implantation of an ovum.<ref name=Jeff2005 />

====Implant====
[[Subcutaneous implant]]s of levonorgestrel have been marketed as [[birth control implant]]s under the brand names Norplant and Jadelle and are available for use in some countries.<ref name="pmid18803473">{{cite journal | vauthors = Benagiano G, Gabelnick H, Farris M | title = Contraceptive devices: subcutaneous delivery systems | journal = Expert Review of Medical Devices | volume = 5 | issue = 5 | pages = 623–637 | date = September 2008 | pmid = 18803473 | doi = 10.1586/17434440.5.5.623 | s2cid = 207201811 }}</ref><ref name="Drugs.com" />