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Levonorgestrel

Levonorgestrel is a hormonal medication which is used in a number of birth control methods.[1] In pill form, sold under the brand name Plan B among others, it is useful within 120 hours as emergency birth control.[1] It becomes less effective the longer after sex and only works before pregnancy has occurred.[1] It is also combined with an estrogen to make combined oral birth control pills.[2] Within an intrauterine device (IUD), sold as Mirena among others, it is effective for long-term prevention of pregnancy.[1] An implantable form of levonorgestrel is also available in some countries.[3]

Levonorgestrel
Levonorgestrel.svg
Levonorgestrel3D.png
Clinical data
Trade names Plan B, others
Synonyms LNG; L-Norgestrel; WY-5104; 18-Methylnorethisterone; 17α-Ethynyl-18-methyl-19-nortestosterone; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one; 13β-Ethyl-17α-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one
AHFS/Drugs.com Monograph
MedlinePlus a610021
Pregnancy
category
Routes of
administration
By mouth, implant, insert (extended-release)
Drug class Progestogen
ATC code
Legal status
Legal status
  • Rx only, or OTC
Pharmacokinetic data
Bioavailability ~100%
Protein binding 55%
Metabolism Liver via CYP3A4[citation needed]
Biological half-life 36 ± 13 hours
Excretion Kidney: 45%
Feces: 32%
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.011.227
Chemical and physical data
Formula C21H28O2
Molar mass 312.446 g/mol
3D model (JSmol)
  (verify)

Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding.[1] When used as a form of emergency contraception, if pregnancy occurs, there is no evidence its use harms the baby.[1] It is safe to use during breastfeeding.[1] Birth control that contains levonorgestrel will not change the risk of sexually transmitted infections.[1] It is a progestin and has effects similar to those of the hormone progesterone.[1] It works mostly by preventing ovulation and closing off the cervix to prevent the passage of sperm.[1]

Levonorgestrel was first made in the 1960s and its use as a method of birth control began in the 1980s.[4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] It is available as a generic medication.[6] The wholesale cost in the developing world costs between 0.23 and 1.65 USD for the dose required for emergency birth control.[7] In the United States it is over the counter for all ages.[8]

Contents

Medical usesEdit

Birth control pillsEdit

At low doses, levonorgestrel is used in monophasic and triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100–250 µg, and triphasic doses of 50 µg/75 µg/125 µg. It is combined with the estrogen ethinylestradiol in these formulations.

At very low daily dose of 30 µg, levonorgestrel is used in some progestogen only pill formulations.

Emergency birth controlEdit

Levonorgestrel is used in 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 mg (as a single dose or as two 0.75 mg doses 12 hours apart) taken within 3 days of unprotected sex, with one study indicating that beginning as late as 120 hours (5 days) after intercourse could be effective.

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.[9][10][11][12] 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."[13][14] In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.[15]

Other studies still find the evidence to be unclear.[16] While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.[17]

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]."[15][18][19] 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.[15]

Intrauterine deviceEdit

Levonorgestrel is the active ingredient in a number of intrauterine devices including Mirena and Skyla.

Birth control implantEdit

Levonorgestrel is the active ingredient in Norplant and Jadelle.

Hormone therapyEdit

Levonorgestrel is combined with estradiol in the estrogen patch for menopausal hormone therapy.

Side effectsEdit

After intake of 1.5 mg levonorgestrel in clinical trials, very common side effects (reported by 10% or more) included: hives, dizziness, headache, nausea, abdominal pain, uterine pain, delayed menstruation, heavy menstruation, uterine bleeding, and fatigue; common side effects (reported by 1% to 10%) included diarrhea, vomiting, and painful menstruation; these side effects usually disappeared within 48 hours.[20][21]

InteractionsEdit

If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.[22]

PharmacologyEdit

PharmacodynamicsEdit

Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone.[23] It is also a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone.[23] Levonorgestrel has no other hormonal activity of significance, including antiprogestogenic or antiandrogenic, estrogenic or antiestrogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid.[23] Its in vitro relative binding affinities at human steroid hormone receptors are: 323% that of progesterone at the progesterone receptor, 58% that of testosterone at the androgen receptor, 17% that of aldosterone at the mineralocorticoid receptor, 7.5% that of cortisol at the glucocorticoid receptor, and <0.02% that of estradiol at the estrogen receptor.[24]

Levonorgestrel is a weakly androgenic progestin and may cause androgenic side effects such as decreased sex hormone-binding globulin (SHBG) levels, decreased HDL cholesterol levels, weight gain, and acne.[23][25] In combination with a potent estrogen like ethinylestradiol however, all contraceptives containing androgenic progestins are negligibly androgenic in clinical practice and can in fact be used to treat androgen-dependent conditions like acne and hirsutism.[25] This is because ethinylestradiol causes a marked increase in SHBG levels and thereby decreases levels of free and hence bioactive testosterone, acting as a functional antiandrogen.[25] Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater relative extent and are more effective for such indications.[25] Levonorgestrel is the most androgenic progestin that is used in contraceptives, and contraceptives containing levonorgestrel may not be as effective for such indications relative to those containing other progestins that are less androgenic.[26][27][28]

ChemistryEdit

Levonorgestrel, also known as 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone.[29][30] It is the C13β or levorotatory stereoisomer and enantiopure form of norgestrel, the C13α or dextrorotatory isomer being inactive.[31][32] Levonorgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins.[33]

HistoryEdit

Levonorgestrel was first introduced in 1968, as an oral contraceptive in combination with ethinylestradiol.[34]

Society and cultureEdit

Generic namesEdit

Levonorgestrel is the generic name of the drug and its INN, USAN, USP, BAN, DCIT, and JAN, while lévonorgestrel is its DCF.[29][30][35]

Brand namesEdit

Levonorgestrel is marketed alone or in combination with an estrogen (specifically ethinylestradiol, estradiol, or estradiol valerate under a multitude of brand names throughout the world, including Alesse, Altavera, Alysena, Amethia, Amethyst, Ashlyna, Aviane, Camrese, Chateal, Climara Pro, Daysee, Emerres, Enpresse, Erlibelle, Escapelle, Falmina, Introvale, Isteranda, Jadelle, Jaydess, Jolessa, Klimonorm, Kurvelo, Kyleena, Lessina, Levlen, Levodonna, Levonelle, Levonest, Levosert, Levora, Liletta, Loette, Logynon, LoSeasonique, Lutera, Lybrel, Marlissa, Microgynon, Microlut, Min-Ovral, Miranova, Mirena, My Way, Myzilra, Next Choice, Nordette, Norgeston, NorLevo, Norplant, Option 2, Orsythia, Ovima, Ovranette, Plan B, Plan B One-Step, Portia, Postinor, Postinor-2, Ramonna, Rigevidon, Quartette, Quasense, Seasonale, Seasonique, Skyla, Sronyx, Tri-Levlen, Trinordiol, Triphasil, Triquilar, Tri-Regol, Trivora, and Upostelle, among many others.[30][35][36] These formulations are used as emergency contraceptives, normal contraceptives, or in menopausal hormone therapy for the treatment of menopausal symptoms.

As an emergency contraceptive, levonorgestrel is often referred to colloquially as the "morning-after pill".[37][38]

AvailabilityEdit

Levonorgestrel is very widely marketed throughout the world and is available in almost every country.[30][35]

Over-the-counterEdit

In 2013, the FDA approved Plan B One-Step for sale over-the-counter without a prescription or age restriction.[39]

Indian Health ServicesEdit

A policy update in 2015 required all Indian Health Services-run pharmacies, clinics, and emergency departments to have Plan B One-Step in stock, to distribute it to any woman (or her representative) who asked for it without a prescription, age verification, registration or any other requirement, to provide orientation training to all staff regarding the medication, to provide unbiased and medically accurate information about emergency contraception, and to make someone available at all times to distribute the pill in case the primary staffer objected to providing it on religious or moral grounds.[40]

ReferencesEdit

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  4. ^ Science and Political Controversy. Santa Barbara: ABC-CLIO. 2014. p. 97. ISBN 9781610693202. Archived from the original on 2017-08-07. 
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  6. ^ Hamilton, Richard J. (2014). Tarascon pocket pharmacopoeia : 2014 deluxe lab-pocket edition (15th ed.). Sudbury: Jones & Bartlett Learning. pp. 310–312. ISBN 9781284053999. Archived from the original on 2015-09-26. 
  7. ^ "Levonorgestrel". International Drug Price Indicator Guide. Retrieved 21 August 2015. [permanent dead link]
  8. ^ "FDA approves Plan B One-Step emergency contraceptive for use without a prescription for all women of child-bearing potential". June 20, 2013. Archived from the original on 14 January 2016. Retrieved 2 February 2016. 
  9. ^ Trussell, James; Schwarz, Eleanor Bimla (2011). "Emergency contraception". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 113–145. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734.  p. 121:

    Mechanism of action
    Copper-releasing IUCs
    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%.2,3 This very high level of effectiveness implies that emergency insertion of a copper IUC must prevent some pregnancies after fertilization.
    Emergency contraceptive pills
    To make an informed choice, women must know that ECPs—like the birth control pill, patch, ring, shot, and implant,76 and even like breastfeeding77—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.
    ECPs do not cause abortion78 or harm an established pregnancy. Pregnancy begins with implantation according to medical authorities such as the US FDA, the National Institutes of Health79 and the American College of Obstetricians and Gynecologists (ACOG).80
    Ulipristal acetate (UPA). One study has demonstrated that UP can delay ovulation.81... Another study found that UPA altered the endometrium, but whether this change would inhibit implantation is unknown.82
    p. 122:
    Progestin-only emergency contraceptive pills. Early treatment with ECPs containing only the progestin levonorgestrel has been show to impair the ovulatory process and luteal function.83–87
    p. 123:
    Combined emergency contraceptive pills. Several clinical studies have shown that combined ECPs containing ethinyl estradiol and levonorgestrel can inhibit or delay ovulation.107–110

  10. ^ RCOG Faculty of Sexual; Reproductive Healthcare; Clinical Effectiveness Unit (January 2012). Clinical guidance: emergency contraception (PDF). London: Royal College of Obstetricians and Gynaecologists. ISSN 1755-103X. Archived (PDF) from the original on 2012-05-26. Retrieved 2012-04-30.  p.3:

    How does EC work?
    In 2002, a judicial review ruled that pregnancy begins at implantation, not fertilisation.8 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.
    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.9–11 A systematic review on mechanisms of action of IUDs showed that both pre- and postfertilisation effects contribute to efficacy.11 If fertilisation has already occurred, it is accepted that there is an anti-implantation effect,12,13
    Levonorgestrel (LNG). The precise mode of action of levonorgestrel (LNG) is incompletely understood but it is thought to work primarily by inhibition of ovulation.16,17
    Ulipristal acetate (UPA). UPA’s primary mechanism of action is thought to be inhibition or delay of ovulation.2

  11. ^ UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) (March 25, 2010). "Fact sheet on the safety of levonorgestrel-alone emergency contraceptive pills (LNG ECPs)" (PDF). Geneva: World Health Organization. Archived (PDF) from the original on March 16, 2012. 

    Can LNG ECPs cause an abortion?
    LNG ECPs do not interrupt an established pregnancy or harm a developing embryo.15 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.16

  12. ^ Speroff, Leon; Darney, Philip D. (2011). "Special uses of oral contraception: emergency contraception, the progestin-only minipill". A clinical guide for contraception (5th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 153–166. ISBN 978-1-60831-610-6.  p. 155:

    Emergency postcoital contraception
    Levonorgestrel
    Mechanism and efficacy

  13. ^ Belluck, Pam (June 6, 2012). "No abortion role seen for morning-after pill". The New York Times. p. A1. Archived from the original on February 27, 2017. 
    Belluck, Pam (June 6, 2012). "Drug's nickname may have aided politicization". The New York Times. p. A14. 
  14. ^ International Federation of Gynecology and Obstetrics (FIGO) and International Consortium for Emergency Contraception (ICEC) (April 4, 2011). "Mechanism of action: How do levonorgestrel-only emergency contraceptive pills (LNG ECPs) prevent pregnancy?" (PDF). London: International Federation of Gynecology and Obstetrics. Archived (PDF) from the original on December 29, 2014. 

    Levonorgestrel-only emergency contraceptive pills:
    • Interfere with the process of ovulation;
    • May possibly prevent the sperm and the egg from meeting.
    Implications of the research:
    • Inhibition or delay of ovulation is LNG ECPs principal and possibly only mechanism of action.
    • 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.
    • 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.
    • 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.

  15. ^ a b c Belluck, Pam (November 26, 2013). "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". The New York Times. Archived from the original on March 4, 2014. Retrieved March 5, 2014. 
    HRA Pharma (November 2013). "NorLevo 1.5 mg tablet Patient Information Leaflet (PIL)" (PDF). Dublin: Irish Medicines Board. Archived (PDF) from the original on March 5, 2014. Retrieved March 5, 2014. NorLevo works by stopping your ovaries from releasing an egg. It cannot stop a fertilized egg from attaching to the womb. 
    HRA Pharma (November 2013). "NorLevo 1.5 mg tablet Summary of Product Characteristics (SPC)". Dublin: Irish Pharmaceutical Healthcare Association. Retrieved March 5, 2014.  |chapter= ignored (help)
    European Medicines Agency (January 24, 2014). "Review of emergency contraceptives started". London: European Medicines Agency. Archived from the original on March 27, 2014. Retrieved March 5, 2014. 
  16. ^ Mozzanega, B; Cosmi, E (June 2011). "How do levonorgestrel-only emergency contraceptive pills prevent pregnancy? Some considerations". Gynecological Endocrinology. 27 (6): 439–42. doi:10.3109/09513590.2010.501885. PMID 20670097. 
  17. ^ Leung, VW; Levine, M; Soon, JA (February 2010). "Mechanisms of action of hormonal emergency contraceptives". Pharmacotherapy. 30 (2): 158–68. doi:10.1592/phco.30.2.158. PMID 20099990. 
  18. ^ Glasier, Anna; Cameron, Sharon T.; Blithe, Diana; Scherrer, Bruno; Mathe, Henri; Levy, Delphine; Gainer, Erin; Ulmann, Andre (October 2011). "Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel". Contraception. 84 (4): 363–367. doi:10.1016/j.contraception.2011.02.009. PMID 21920190. 
  19. ^ Trussell, James; Raymond, Elizabeth G.; Cleland, Kelly (February 2014). "Emergency contraception: a last chance to prevent unintended pregnancy" (PDF). Princeton: Office of Population Research at Princeton University, Association of Reproductive Health Professionals. Archived (PDF) from the original on September 23, 2010. Retrieved April 9, 2014. 
  20. ^ HRA Pharma (November 2013). "NorLevo 1.5 mg tablet Summary of Product Characteristics (SPC)". Dublin: Irish Pharmaceutical Healthcare Association. Retrieved April 9, 2014.  |chapter= ignored (help)
  21. ^ Chen X, Wu X, Zhu H. "Acute urticaria as a side effect of the Mirena® (levonorgestrel-releasing intrauterine system): a case report". BMC Res Notes. 7: 209. doi:10.1186/1756-0500-7-209. PMC 3992142 . PMID 24708811. 
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  25. ^ a b c d Darney PD (1995). "The androgenicity of progestins". Am. J. Med. 98 (1A): 104S–110S. PMID 7825629. 
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External linksEdit