Levonorgestrel

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Levonorgestrel
220px
220px
Systematic (IUPAC) name
(8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one
Clinical data
Trade names Plan B, others
AHFS/Drugs.com monograph
MedlinePlus a610021
Pregnancy
category
  • X
Legal status
  • Rx-OTC
Routes of
administration		 Implant, insert (extended-release), by mouth
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 797-63-7 YesY
ATC code G03AC03 (WHO) G03AD01
PubChem CID: 13109
IUPHAR/BPS 2881
DrugBank DB00367 YesY
ChemSpider 12560 YesY
UNII 5W7SIA7YZW YesY
KEGG D00950 YesY
ChEBI CHEBI:6443 YesY
ChEMBL CHEMBL1389 YesY
Chemical data
Formula C21H28O2
Molecular mass 312.446 g/mol
  • [H][C@]12CCC(=O)C=C1CC[C@]1([H])[C@]2([H])CC[C@@]2(CC)[C@@]1([H])CC[C@@]2(O)C#C
  • InChI=1S/C21H28O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23H,3,5-12H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1 YesY
  • Key:WWYNJERNGUHSAO-XUDSTZEESA-N YesY
  (verify)

Levonorgestrel is a manufactured hormone 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. 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 pill.[2] Within an IUD with progestogen, 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]

Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding. If used as a form of emergency contraception during pregnancy there is no evidence it affects the baby. It is safe to use during breastfeeding. Levonorgestrel containing birth control does not change the risk of sexually transmitted infections. It works by decreasing 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 important medication needed in a basic health system.[5] It is available as a generic medication.[6] Wholesale it 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 those over 16 years of age.[6]

Usage

Oral birth control

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.

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

Emergency birth control

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.[8][9][10][11] 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."[12][13] In November 2013, the European Medicines Agency (EMA) approved a change to the label for HRA Pharma's NorLevo saying it cannot prevent implantation of a fertilized egg.[14]

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]."[14][15][16] 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.[14]

Intrauterine device

Levonorgestrel is the active ingredient in the Mirena & Skyla (Jaydess) intrauterine system.

Contraceptive implants

Levonorgestrel is the active ingredient in Norplant and Jadelle.

Hormone replacement therapy

Levenorgestrel is combined with 17-beta estradiol in the estrogen patch.

Side effects

After intake of levonorgestrel 1.5 mg in clinical trials, very common effects (reported by 10% or more) included: dizziness, headache, nausea, abdominal pain, uterine pain, delay of menstruation, heavy menstruation, uterine bleeding, or fatigue; common effects (reported by 1% to 10%) included diarrhea, vomiting, or painful menstruation; these effects usually disappeared within 48 hours.[17]

Chemistry

Levonorgestrel (levo=left) is one form of a hormone that exists in two mirror image left and right forms. (See Chirality (chemistry).)

Chemically, it is a hormonally active levorotatory enantiomer of the racemic mixture norgestrel. It is a gonane progestin derived from 19-nortestosterone.[18]

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.[19]

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

Society and culture

Names

Levonorgestrel is also chemically known as l-norgestrel and D-norgestrel. It is often referred to as the "morning after pill".

There are many brand names for levonorgestrel-only ECPs, including: Nogestat, AfterPill, Escapelle, Plan B, Levonelle, Glanique, NorLevo, Postinor-2, i-pill, Next Choice, 72-HOURS.[20]

Behind-the-counter

In 2013 the FDA approved Plan B One-Step to be sold without a prescription to women of all ages.[21]

Indian Health Services

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.[22]

References

  1. ↑ 1.0 1.1 1.2 1.3 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found. 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

  9. ↑ Lua error in package.lua at line 80: module 'strict' not found. 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

  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.

    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

  11. ↑ Lua error in package.lua at line 80: module 'strict' not found. p. 155:

    Emergency postcoital contraception
    Levonorgestrel
    Mechanism and efficacy

  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
    Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.

    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.

  14. ↑ 14.0 14.1 14.2 Lua error in package.lua at line 80: module 'strict' not found.
    Lua error in package.lua at line 80: module 'strict' not found.
    Lua error in package.lua at line 80: module 'strict' not found.
    Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm358082.htm
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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