Levonorgestrel

Levonorgestrel
Systematic (IUPAC) name
	(–)-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	Norplant
MedlinePlus	a610021
Pregnancy cat.	X
Legal status	Rx-OTC
Routes	Implant; insert (extended-release); oral
Pharmacokinetic data
Bioavailability	~100%
Protein binding	55%
Metabolism	Hepatic via CYP3A4
Half-life	36 ± 13 hours
Excretion	Renal: 45%; Fecal:32%
Identifiers
CAS number	797-63-7
ATC code	G03AC03 G03AD01
PubChem	CID 13109
IUPHAR ligand	2881
DrugBank	DB00367
ChemSpider	12560
UNII	5W7SIA7YZW
KEGG	D00950
ChEBI	CHEBI:6443
ChEMBL	CHEMBL1389
Chemical data
Formula	C21H28O2
Mol. mass	312.446 g/mol
	SMILES [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 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 ; Key:WWYNJERNGUHSAO-XUDSTZEESA-N ;
(what is this?) (verify);

Levonorgestrel (or l-norgestrel or D-norgestrel) (Plan B, Next Choice, and others^[1]) is a second generation synthetic progestogen used as an active ingredient in some hormonal contraceptives, including combined oral contraceptive pills, progestogen only pills, emergency contraceptive pills, intrauterine systems, contraceptive implants, and hormone replacement therapy.

Chemistry [edit]

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

Chemically, it is a hormonally active levorotatory enantiomer of the racemic mixture norgestrel. It is a gonane progestin derived from 19-nortestosterone.^[2]

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.^[3]

If taken together with drugs that induce the CYP3A4 cytochrome liver enzyme, the levonorgestrel will be metabolized faster and have lower efficacy, and a larger dose will be needed.^{[citation needed]}

Usage [edit]

Oral contraception [edit]

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 contraception [edit]

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 .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.

There are many brand names of levonorgestrel-only ECPs, including: Escapelle, Plan B, Levonelle, Glanique, NorLevo, Postinor-2, i-pill, "Next Choice" and 72-HOURS.^[4]

The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is to prevent fertilization by inhibition of ovulation.^[5]^[6]^[7]^[8] The International Federation of Gynecology and Obstetrics (FIGO) has issued a statement 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."^[9]^[10] In June 2012, a New York Times editorial called on the FDA to remove from the label the unsupported suggestion that levonorgestrel emergency contraceptive pills inhibit implantation.^[11]

Intrauterine system [edit]

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

Contraceptive implants [edit]

Levonorgestrel is the active ingredient in Norplant and Jadelle.

Hormone replacement therapy [edit]

Levenorgestrel is combined with 17-beta estradiol in the Climara Pro hormonal patch.

Side effects [edit]

Possible side effects of levonorgestrel include nausea, vomiting, stomach pain, dizziness, breast tenderness, tiredness and weakness, headache, menstrual changes, and diarrhea.^[12]

It decreases total and free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT) and sex hormone–binding globulin (SHBG), but has no effect on sexual function or markers of androgen bioactivity.^[13]

References [edit]

^ http://ec.princeton.edu/questions/dose.html#dose
^ Edgren RA, Stanczyk FZ (1999). "Nomenclature of the gonane progestins". Contraception 60 (6): 313. doi:10.1016/S0010-7824(99)00101-8. PMID 10715364.
^ Sitruk-Ware R (2006). "New progestagens for contraceptive use". Hum Reprod Update 12 (2): 169–78. doi:10.1093/humupd/dmi046. PMID 16291771.
^ Trussell, James; Cleland, Kelly (2007-04-10). "Emergency Contraceptive Pills Worldwide". Princeton University. Retrieved 2007-05-28.
^ 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
^ RCOG Faculty of Sexual & Reproductive Healthcare, Clinical Effectiveness Unit (January 2012). Clinical guidance: emergency contraception. London: Royal College of Obstetricians and Gynaecologists. ISSN 1755-103X. 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
^ 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)". Geneva: World Health Organization.

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
^ 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
^ Belluck, Pam (June 6, 2012). "No abortion role seen for morning-after pill". The New York Times. p. A1.
Belluck, Pam (June 6, 2012). "Drug's nickname may have aided politicization". The New York Times. p. A14.
^ 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?". London: International Federation of Gynecology and Obstetrics.

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 ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling.
• The fact that LNG ECPs 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 ECPs 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.
^ editorial (June 9, 2012). "How morning-after pills really work". The New York Times. p. A20. "The F.D.A. now acknowledges that the emerging data suggest the morning-after pill, often called Plan B, does not inhibit implantation. It should remove that unsupported suggestion from the label."
^ MedicineNet.com > LEVONORGESTREL - ORAL (lee-voh-nor-JEST-rell) Retrieved on April 3, 2010
^ Kovalevsky G, Ballagh SA, Stanczyk FZ, Lee J, Cooper J, Archer DF (April 2010). "Levonorgestrel effects on serum androgens, sex hormone-binding globulin levels, hair shaft diameter, and sexual function". Fertil. Steril. 93 (6): 1997–2003. doi:10.1016/j.fertnstert.2008.12.095. PMID 19394598.

External links [edit]

Levonelle manufacturer's product information from Schering
Monograph for levonorgestrel - Uk Medicines Information
U.S. National Library of Medicine: Drug Information Portal - Levonorgestrel

[1] ttp://ec.princeton.edu/questions/dose.html#dose

[2] Edgren RA, Stanczyk FZ (1999). "Nomenclature of the gonane progestins". Contraception 60 (6): 313. doi:10.1016/S0010-7824(99)00101-8. PMID 10715364.

[3] Sitruk-Ware R (2006). "New progestagens for contraceptive use". Hum Reprod Update 12 (2): 169–78. doi:10.1093/humupd/dmi046. PMID 16291771.

[ecp_worldwide-4] Trussell, James; Cleland, Kelly (2007-04-10). "Emergency Contraceptive Pills Worldwide". Princeton University. Retrieved 2007-05-28.

[Trussell_2011-5] 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

[FSRH_EC_2012-6] RCOG Faculty of Sexual & Reproductive Healthcare, Clinical Effectiveness Unit (January 2012). Clinical guidance: emergency contraception. London: Royal College of Obstetricians and Gynaecologists. ISSN 1755-103X. 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

[WHO_2010-7] 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)". Geneva: World Health Organization.

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

[Speroff_2011-8] 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

[Belluck_2012b-9] Belluck, Pam (June 6, 2012). "No abortion role seen for morning-after pill". The New York Times. p. A1.
Belluck, Pam (June 6, 2012). "Drug's nickname may have aided politicization". The New York Times. p. A14.

[FIGO_2011-10] 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?". London: International Federation of Gynecology and Obstetrics.

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 ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling.
• The fact that LNG ECPs 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 ECPs 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.

[NYT_2012-11] torial (June 9, 2012). "How morning-after pills really work". The New York Times. p. A20. "The F.D.A. now acknowledges that the emerging data suggest the morning-after pill, often called Plan B, does not inhibit implantation. It should remove that unsupported suggestion from the label."

[12] MedicineNet.com > LEVONORGESTREL - ORAL (lee-voh-nor-JEST-rell) Retrieved on April 3, 2010

[13] Kovalevsky G, Ballagh SA, Stanczyk FZ, Lee J, Cooper J, Archer DF (April 2010). "Levonorgestrel effects on serum androgens, sex hormone-binding globulin levels, hair shaft diameter, and sexual function". Fertil. Steril. 93 (6): 1997–2003. doi:10.1016/j.fertnstert.2008.12.095. PMID 19394598.

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Levonorgestrel

Contents

Chemistry [edit]

Usage [edit]

Oral contraception [edit]

Emergency contraception [edit]

Intrauterine system [edit]

Contraceptive implants [edit]

Hormone replacement therapy [edit]

Side effects [edit]

References [edit]

External links [edit]

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