Levonorgestrel

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Medication abortion
.
Levonorgestrel
Clinical data
Trade namesPlan B, Julie, Mirena, Plan B One-Step, Liletta, others
Other namesLNG; LNG-EC; d-Norgestrel; d(–)-Norgestrel; D-Norgestrel; WY-5104; SH-90999; NSC-744007; 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.comMonograph
MedlinePlusa610021
Pregnancy
category
Progestin
ATC code
Legal status
Legal status
conjugation)[4][6]
Metabolites• 5α-Dihydro-LNG[4]
Elimination half-life24–32 hours[4]
ExcretionUrine: 20–67%
Feces: 21–34%[6]
Identifiers
  • (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
JSmol)
Melting point235 to 237 °C (455 to 459 °F)
  • CC[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CC(=O)CC[C@H]34
  • 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 checkY
  • Key:WWYNJERNGUHSAO-XUDSTZEESA-N checkY
  (verify)

Levonorgestrel is a

implantation) has occurred.[7] Levonorgestrel works by preventing ovulation or fertilization from occurring.[10] It decreases the chances of pregnancy by 57–93%.[11] In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy.[7] A levonorgestrel-releasing implant is also available in some countries.[12]

Common

progestin and has effects similar to those of the hormone progesterone.[7] It works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.[7]

Levonorgestrel was patented in 1960 and introduced for medical use together with

over the counter (OTC) for all ages.[17] In 2020, it was the 323rd most commonly prescribed medication in the United States, with more than 800 thousand prescriptions.[18]

Medical uses

Birth control

See also: Ethinylestradiol/levonorgestrel

At low doses, levonorgestrel is used in

triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100 to 250 µg, and triphasic doses of 50 µg/75 µg/125 µg.[19] It is combined with the estrogen ethinylestradiol in these formulations.[19]

At very low daily dose of 30 µg, levonorgestrel is used in some

formulations.[19]

Levonorgestrel is the active ingredient in a number of

Jadelle.[19][20]

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.[21]

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 three days of unprotected sex. With one study indicating that beginning as late as 120 hours (5 days) after intercourse could be effective.[medical citation needed] 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."[22]
There is no age, I.D., or prescription required to purchase emergency contraception. Plan B hit the market in 1999 where it could be bought by anyone older than 18. However, in 2013, the rules were changed so that Plan B could be purchased at any age without ID or prescription.

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.[23][24][25][26] 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."[27][28] In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.[29]

Other studies still find the evidence to be unclear.[30] While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.[31]

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]."[29][32][33] 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.[29]

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.[34] These values yield an eight-fold reduction in efficacy for women with BMI over 30 compared to women with BMI under 25. However, emergency contraceptives remain effective regardless of BMI.

Hormone therapy

Levonorgestrel is used in combination with an

menopausal hormone therapy.[19][35] It is used under the brand name Klimonorm as a combined oral tablet with estradiol valerate and under the brand name Climara Pro as a combined transdermal patch with estradiol.[19][35]

Available forms

As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy.[36] 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 mg taken once or 0.75 mg taken 12–24 hours apart.[37] The effectiveness in both methods is similar.[37] The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 mg dosage of levonorgestrel.[36] Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex.[38] 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.[38]

Skin patch

See also: 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 flashes or osteoporosis.[39] The simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.[40][41]

Intrauterine device

The levonorgestrel intrauterine system (LNG-IUS) is a type of long-term birth control that releases the progestin into the uterine cavity.[42][21] Levonorgestrel is released at a constant, gradual rate of 0.02 mg per day by the polydimethylsiloxane membrane of the device, which renders it effective for up to five years.[42] 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 ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35 ng.[42] This high level of levonorgestrel impedes the function of the endometrium, making it hostile for sperm transport, fertilization, and implantation of an ovum.[42]

Implant

birth control implants under the brand names Norplant and Jadelle and are available for use in some countries.[43][19]

Contraindications

Known or suspected pregnancy is a contraindication of levonorgestrel as an emergency contraceptive.[44]

Side effects

See also:
Progestin § Side effects

After an intake of 1.5 mg levonorgestrel in

painful menstruation; these side effects usually disappeared within 48 hours.[45][46] However, the long term side effects common with oral contraceptives such as arterial disease are lower with levonorgestrel than in combination pills.[medical citation needed
]

Levonorgestrel as a contraceptive intrauterine device is associated with a higher risk of breast cancer than with non-use.[47]

Overdose

Overdose of levonorgestrel as an emergency contraceptive has not been described.[44] Nausea and vomiting might be expected.[44]

Interactions

If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.[48] These include, but are not limited to barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John's wort and topiramate.[medical citation needed]

Pharmacology

Pharmacodynamics

Levonorgestrel is a

affinity for the mineralocorticoid receptor, which is as much as 75% of that of aldosterone.[4]

Relative affinities (%) of levonorgestrel and metabolites
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Levonorgestrel 150–162 34a, 45 0 1–8 17–75 50 0
5α-Dihydrolevonorgestrel 50 38a 0 ? ? ? ?
3α,5α-Tetrahydrolevonorgestrel ? ? 0.4 ? ? ? ?
3β,5α-Tetrahydrolevonorgestrel ? ? 2.4 ? ? ? ?
Notes: Values are percentages (%). Reference
CBG
Tooltip Corticosteroid-binding globulin. Sources: See template.

Progestogenic activity

Levonorgestrel is a

endometrial transformation dose of levonorgestrel is 150 to 250 μg/day or 2.5 to 6 mg per cycle.[4][49][50][51]

Antigonadotropic effects

Due to its progestogenic activity, levonorgestrel has

premenopausal women is 50 to 60 μg/day.[4][49][53]

In men, levonorgestrel causes marked suppression of circulating testosterone levels secondary to its antigonadotropic effects.

hormonal contraceptive in men.[52][54]

Androgenic activity

Levonorgestrel is a weak agonist of the

HDL cholesterol levels, weight gain, and acne.[4][56]

In combination with a potent estrogen like ethinylestradiol however, all contraceptives containing androgenic progestins are negligibly androgenic in practice and in fact can be used to treat androgen-dependent conditions like acne and hirsutism in women.[56] 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.[56] Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater extent and may be more effective for such indications.[56] Levonorgestrel is currently the most androgenic progestin that is used in contraceptives, and contraceptives containing levonorgestrel may be less effective for androgen-dependent conditions relative to those containing other progestins that are less androgenic.[57][58][59]

Other activity

Levonorgestrel stimulates the

progesterone receptor membrane component-1 (PGRMC1).[60][61] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[60][61] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[62]

Pharmacokinetics

The

elimination half-life of levonorgestrel is 24 to 32 hours, although values as short as 8 hours and as great as 45 hours have been reported.[4][6] About 20 to 67% of a single oral dose of levonorgestrel is eliminated in urine and 21 to 34% in feces.[6]

Chemistry

See also:
List of androgens/anabolic steroids, and Norgestrel

Levonorgestrel, also known as 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a

molecular weight of 312.45 g/mol and a partition coefficient (log P) of 3.8.[71][72]

History

optical isomers and identified levonorgestrel (13β-ethyl-17α-ethynyl-19-nortestosterone) as the active component of the mixture.[14][75][76] Levonorgestrel was first studied in humans by 1970, and was introduced for medical use in Germany as a combined birth control pill with ethinylestradiol under the brand name Neogynon in August 1970.[14][77][78][80][81][82] A more widely used formulation, containing lower doses of ethinylestradiol and levonorgestrel, was introduced under the brand name Microgynon by 1973.[19][83][84] In addition to combined formulations, levonorgestrel was introduced as a progestogen-only pill under the brand names Microlut by 1972 and Microval by 1974.[85][86] Many other formulations and brand names of levonorgestrel-containing birth control pills have also been marketed.[19]

Levonorgestrel, taken alone in a single high dose, was first evaluated as a form of

over-the-counter in the United States without a prescription or age restriction.[96]

Levonorgestrel has also been introduced for use as a

progestogen-only injectable contraceptives and contraceptive vaginal rings, but have not been marketed for medical use.[69][70]

Society and culture

Generic names

Levonorgestrel is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name, while lévonorgestrel is its DCFTooltip Dénomination Commune Française.[19][63][64] It is also known as d-norgestrel, d(–)-norgestrel, or D-norgestrel, as well as by its developmental code names WY-5104 (Wyeth) and SH-90999 (Schering AG).[19][63][64][85]

Brand names

Levonorgestrel is marketed alone or in combination with an

Rigevidon, Quartette, Quasense, Seasonale, Seasonique, Skyla, Sronyx, Tri-Levlen, Trinordiol, Triphasil, Triquilar, Tri-Regol, Trivora, and Upostelle, among many others.[19][64][97] These formulations are used as emergency contraceptives, normal contraceptives, or in menopausal hormone therapy for the treatment of menopausal symptoms.[medical citation needed
]

As an emergency contraceptive, levonorgestrel is often referred to colloquially as the "morning-after pill".[98][99]

Availability

See also: List of progestogens available in the United States

Levonorgestrel is very widely marketed throughout the world and is available in almost every country.[19][64]

Accessibility

Levonorgestrel-containing emergency contraception is available

over-the-counter in some countries, such as the United States.[96] On some college campuses, Plan B is available from vending machines.[100]

A policy update in 2015, required all pharmacies, clinics, and emergency departments run by

Indian Health Services (for Native Americans) 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.[101]

Research

Levonorgestrel has been studied in combination with

hormonal contraceptive for men.[52][54]

References

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    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
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    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.83–87
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    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

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    Can LNG ECPs cause an abortion?
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    Levonorgestrel-only emergency contraceptive pills:
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    from the original on 28 August 2021. Retrieved 15 April 2018. [Norgestrel] was discovered by Hughes et al. (1963).
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External links

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