Levonorgestrel

Template:Short description Template:Distinguish Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

|preview=

}}{{Infobox drug/maintenance categoriesTemplate:Yesno | drug_name = | INN = | _drugtype =

| _has_physiological_data= | _has_gene_therapy=

| vaccine_type= | mab_type= | _number_of_combo_chemicals={{#invoke:ParameterCount |main |component1 |component2 |component3 |component4|component5|component6 }} | _vaccine_data= | _mab_data= | _mab_vaccine_data= | _mab_other_data=21282CC[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CC(=O)CC[C@H]341S/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/s1WWYNJERNGUHSAO-XUDSTZEESA-NTemplate:StdinchiciteTemplate:Stdinchicite235237 | _combo_data= | _physiological_data= | _clinical_data=Template:Drugs.coma610021 <ref name="Drugs.com pregnancy">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>B3Contraindicated<ref name="Drugs.com pregnancy" />By mouth, transdermal patch, intrauterine device, subcutaneous implantPlan B, Plan B One-Step, othersProgestogen (medication); ProgestinG03Template:ATC | _legal_data=/ OTC<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>POM/ OTC<ref name="Plan B One-Step FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-onlyRx/OTC

| _other_data=(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

| _image_0_or_2 = Levonorgestrel.svgLevonorgestrel molecule ball.png | _image_LR =

| _datapage = Levonorgestrel (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=Rx-onlyPOMRx-onlyRx/OTC | _ATC_prefix_supplemental=G03Template:ATC | _has_EMA_link = | CAS_number=797-63-7 | PubChem=13109 | ChemSpiderID=12560 | ChEBI=6443 | ChEMBL=1389 | DrugBank=DB00367 | KEGG=D00950 | _hasInChI_or_Key={{#if: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/s1WWYNJERNGUHSAO-XUDSTZEESA-N |yes}} | UNII=5W7SIA7YZW | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=462091161}} Levonorgestrel is a hormonal medication used in a number of birth control methods.<ref name="Plan B One-Step FDA label" /><ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is combined with an estrogen to make combination birth control pills.<ref>Template:Cite book</ref> As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex.<ref name="Plan B One-Step FDA label" /><ref name=AHFS2015/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The more time that has passed since sex, the less effective the medication becomes.<ref name=AHFS2015/> Levonorgestrel works by preventing or delaying ovulation so an egg cannot be released. The dosage used for emergency contraception is ineffective when ovulation has already occurred, and has been found to have no effect on implantation.<ref>Template:Cite journal</ref> It decreases the chances of pregnancy by 57–93%.<ref name="Gem2010">Template:Cite journal</ref> In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy.<ref name=AHFS2015/> A levonorgestrel-releasing implant is also available in some countries.<ref>Template:Cite book</ref>

Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding.<ref name=AHFS2015/> When used as an emergency contraceptive, if pregnancy occurs, there is no evidence that its use harms the fetus.<ref name=AHFS2015/> It is safe to use during breastfeeding.<ref name=AHFS2015/> Birth control that contains levonorgestrel will not change the risk of sexually transmitted infections.<ref name=AHFS2015/> It is a progestin and has effects similar to those of the hormone progesterone.<ref name=AHFS2015/> It works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.<ref name=AHFS2015/>

Levonorgestrel was patented in 1960 and introduced for medical use together with ethinylestradiol in 1970.<ref name=Fis2006>Template:Cite book</ref><ref name=Roth2014/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> It is available as a generic medication.<ref name=Ric2014>Template:Cite book</ref> In the United States, levonorgestrel-containing emergency contraceptives are available over the counter (OTC) for all ages.<ref>Template:Cite press release</ref> In 2020, it was the 323rd most commonly prescribed medication in the United States, with more than 800Template:Nbspthousand prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:TOC limit

Medical uses

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 to 250 μg, and triphasic doses of 50 μg, 75 μg, and 125 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 μg, levonorgestrel is used in some progestogen-only pill 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 implants Norplant and 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">Template:Cite journal</ref>

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. One study indicated that beginning as late as 120 hours (5 days) after intercourse could be effective.Template: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."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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">Template:Cite book 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 shown 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

</ref><ref name="FSRH EC 2012">Template:Cite journal 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

</ref><ref name="WHO 2010">{{#invoke:citation/CS1|citation

|CitationClass=web

}}

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

</ref><ref name="Speroff 2011">Template:Cite book p. 155:

Emergency postcoital contraception
Levonorgestrel
Mechanism and efficacy

</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">Template:Cite news
Template:Cite news</ref><ref name="FIGO 2011">{{#invoke:citation/CS1|citation

|CitationClass=web

}}

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.

</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">Template:Cite news
{{#invoke:citation/CS1|citation

|CitationClass=web }}
{{#invoke:citation/CS1|citation |CitationClass=web }}
Template:Cite news</ref>

Other studies still find the evidence to be unclear.<ref>Template:Cite journal</ref> While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.<ref>Template:Cite journal</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">Template:Cite journal</ref><ref name="Trussell 2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</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 in menopausal hormone therapy.<ref name="Drugs.com" /><ref name="Kubíková2014" /> 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.<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">{{#invoke:citation/CS1|citation |CitationClass=web }}</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 mg taken once or 0.75 mg taken 12–24 hours apart.<ref name=":0">Template:Cite journal</ref> The effectiveness in both methods is similar.<ref name=":0" /> The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 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">Template:Cite journal</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

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.<ref name=":2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.<ref name=":3">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</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>Template:Cite journal</ref><ref name="Bao Q 2018"/> 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.<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 ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35 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 implants of levonorgestrel have been marketed as birth control implants under the brand names Norplant and Jadelle and are available for use in some countries.<ref name="pmid18803473">Template:Cite journal</ref><ref name="Drugs.com" />

Contraindications

Known or suspected pregnancy is a contraindication of levonorgestrel as an emergency contraceptive.<ref name="PlanB_One-Step-Label" />

Side effects

After an intake of 1.5 mg levonorgestrel in clinical trials, very common side effects (reported by 10% or more) included: hives, dizziness, hair loss, 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid24708811">Template:Cite journal</ref> However, the long term side effects common with oral contraceptives such as arterial disease are lower with levonorgestrel than in combination pills.Template:Medical citation needed

Levonorgestrel as a contraceptive intrauterine device has been associated with a slightly higher risk of breast cancer than with non-use in select studies.<ref name="pmid31990981">Template:Cite journal</ref>

Overdose

Overdose of levonorgestrel as an emergency contraoceptive has not been described.<ref name="PlanB_One-Step-Label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Nausea and vomiting might be expected.<ref name="PlanB_One-Step-Label" />

Interactions

If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These include, but are not limited to barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John's wort and topiramate.Template:Medical citation needed

Pharmacology

Pharmacodynamics

Levonorgestrel is a progestogen with weak androgenic activity.<ref name="pmid16112947">Template:Cite journal</ref> It has no other important hormonal activity, including no estrogenic, glucocorticoid, or antimineralocorticoid activity.<ref name="pmid16112947" /> The lack of significant mineralocorticoid or antimineralocorticoid activity with levonorgestrel is in spite of it having relatively high affinity for the mineralocorticoid receptor, which is as much as 75% of that of aldosterone.<ref name="pmid16112947" />

Progestogenic activity

Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone.<ref name="pmid16112947" /> It has effects similar to those of the hormone progesterone.<ref name=AHFS2015/> As a contraceptive, it works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.<ref name=AHFS2015/> The endometrial transformation dose of levonorgestrel is 150 to 250Template:Nbspμg/day or 2.5 to 6Template:Nbspmg per cycle.<ref name="pmid16112947" /><ref name="pmid14670641">Template:Cite journal</ref><ref name="KnörrKnörr-Gärtner2013">Template:Cite book</ref><ref name="pmid2215269">Template:Cite journal</ref>

Antigonadotropic effects

Due to its progestogenic activity, levonorgestrel has antigonadotropic effects and is able to suppress the secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland.<ref name="pmid16112947" /> This in turn, results in suppression of gonadal activity, including reduction of fertility and gonadal sex hormone production in both women and men.<ref name="pmid16112947" /><ref name="pmid20933120">Template:Cite journal</ref> The ovulation-inhibiting dose of levonorgestrel in premenopausal women is 50 to 60Template:Nbspμg/day.<ref name="pmid16112947" /><ref name="pmid14670641" /><ref name="pmid22078182">Template:Cite journal</ref>

In men, levonorgestrel causes marked suppression of circulating testosterone levels secondary to its antigonadotropic effects.<ref name="pmid12826683">Template:Cite journal</ref> In healthy young men, levonorgestrel alone at a dose of 120 to 240 μg/day orally for 2 weeks suppressed testosterone levels from ~450 ng/dL to ~248 ng/dL (–45%).<ref name="pmid28189123">Template:Cite journal</ref> Because of its effects on testosterone levels, and due to its androgenic activity being only weak and hence insufficient for purposes of androgen replacement in males, levonorgestrel has potent functional antiandrogenic effects in men.<ref name="pmid12826683" /> Consequently, it can produce adverse effects like decreased libido and erectile dysfunction, among others.<ref name="pmid12826683" /> Levonorgestrel has been combined with an androgen like testosterone or dihydrotestosterone when it has been studied as a hormonal contraceptive in men.<ref name="pmid20933120" /><ref name="pmid12826683" />

Androgenic activity

Levonorgestrel is a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone.<ref name="pmid16112947" /> It is a weakly androgenic progestin and in women may cause androgenic biochemical changes and side effects such as decreased sex hormone-binding globulin (SHBG) levels, decreased [[HDL cholesterol|Template:Abbr cholesterol]] levels, weight gain, and acne.<ref name="pmid16112947" /><ref name="pmid7825629">Template:Cite journal</ref>

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.<ref name="pmid7825629" /> 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.<ref name="pmid7825629" /> Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater extent and may be more effective for such indications.<ref name="pmid7825629" /> 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.<ref name="KnausIsaacs2012">Template:Cite book</ref><ref name="GolanTashjian2011">Template:Cite book</ref><ref name="BreastCancer1991">Template:Cite book</ref>

Other activity

Levonorgestrel stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).<ref name="pmid23758160">Template:Cite journal</ref><ref name="pmid22335423">Template:Cite journal</ref> Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.<ref name="pmid23758160" /><ref name="pmid22335423" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.<ref name="pmid31512725">Template:Cite journal</ref>

Pharmacokinetics

The bioavailability of levonorgestrel is approximately 95% (range 85 to 100%).<ref name="pmid16112947" /><ref name="pmid8842581">Template:Cite journal</ref> The plasma protein binding of levonorgestrel is about 98%.<ref name="pmid16112947" /> It is bound 50% to albumin and 48% to SHBG.<ref name="pmid16112947" /> Levonorgestrel is metabolized in the liver, via reduction, hydroxylation, and conjugation (specifically glucuronidation and sulfation).<ref name="pmid16112947" /><ref name="ShoupeHaseltine2012">Template:Cite book</ref> Oxidation occurs primarily at the C2α and C16β positions, while reduction occurs in the A ring.<ref name="ShoupeHaseltine2012" /> 5α-Dihydrolevonorgestrel is produced as an active metabolite of levonorgestrel by 5α-reductase.<ref name="pmid16112947" /> 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.<ref name="pmid16112947" /><ref name="ShoupeHaseltine2012" /> About 20 to 67% of a single oral dose of levonorgestrel is eliminated in urine and 21 to 34% in feces.<ref name="ShoupeHaseltine2012" />

Chemistry

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.<ref name="Elks2014">Template:Cite book</ref><ref name="IndexNominum2000">Template:Cite book</ref> It is the C13β or levorotatory stereoisomer and enantiopure form of norgestrel, the C13α or dextrorotatory isomer being inactive.<ref name="AlldredgeCorelli2012">Template:Cite book</ref><ref name="LaverySanfilippo2012">Template:Cite book</ref> Levonorgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane or 13β-ethylgonane) subgroup of the 19-nortestosterone family of progestins.<ref name="OffermannsRosenthal2008">Template:Cite book</ref> Besides levonorgestrel itself, this group includes desogestrel, dienogest, etonogestrel, gestodene, norelgestromin, norgestimate, and norgestrel.<ref name="pmid24333799">Template:Cite journal</ref> Levonorgestrel acetate and levonorgestrel butanoate are C17β esters of levonorgestrel.<ref name="GWU1987">Template:Cite book</ref><ref name="pmid6658872">Template:Cite journal</ref> Levonorgestrel has a molecular weight of 312.45 g/mol and a partition coefficient (log P) of 3.8.<ref name="PubChem">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="DrugBank">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

Norgestrel (rac-13-ethyl-17α-ethynyl-19-nortestosterone), the racemic mixture containing levonorgestrel and dextronorgestrel, was discovered by Hughes and colleagues at Wyeth in 1963 via structural modification of norethisterone (17α-ethynyl-19-nortestosterone).<ref name="Meikle1999">Template:Cite book</ref><ref name="SzejtliSzente2012">Template:Cite book</ref><ref name="FilshieGuillebaud2013">Template:Cite book</ref><ref name="Marks2010">Template:Cite book</ref> It was the first progestogen to be manufactured via total chemical synthesis.<ref name="FilshieGuillebaud2013" /><ref name="Marks2010" /> Norgestrel was introduced for medical use as a combined birth control pill with ethinylestradiol under the brand name Eugynon in Germany in 1966 and under the brand name Ovral in the United States 1968, and as a progestogen-only pill under the brand name Ovrette in the United States in 1973.<ref name="Marks2010" /><ref name="Pohl2004" /><ref name="Ortiz-GómezSantesmases2016" /><ref name="ToneWatkins2007">Template:Cite book</ref> Following its discovery, norgestrel had been licensed by Wyeth to Schering AG, which separated the racemic mixture into its two optical isomers and identified levonorgestrel (13β-ethyl-17α-ethynyl-19-nortestosterone) as the active component of the mixture.<ref name="Roth2014" /><ref name="FilshieGuillebaud2013" /><ref name="Marks2010" /> 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.<ref name="Roth2014">Template:Cite book</ref><ref name="Pohl2004">Template:Cite book</ref><ref name="Ortiz-GómezSantesmases2016">Template:Cite book</ref><ref name="Albach1993">Template:Cite book</ref><ref name="ApeloVeloso1970">Template:Cite journal</ref><ref name="BrosensVanAssche1971">Template:Cite journal</ref> A more widely used formulation, containing lower doses of ethinylestradiol and levonorgestrel, was introduced under the brand name Microgynon by 1973.<ref name="Drugs.com" /><ref name="SchneiderSpona1974">Template:Cite journal</ref><ref name="pmid4614952">Template:Cite journal</ref> In addition to combined formulations, levonorgestrel was introduced as a progestogen-only pill under the brand names Microlut by 1972 and Microval by 1974.<ref name="Scharff1972">Template:Cite journal</ref><ref name="pmid4817042">Template:Cite journal</ref> Many other formulations and brand names of levonorgestrel-containing birth control pills have also been marketed.<ref name="Drugs.com" />

Levonorgestrel, taken alone in a single high dose, was first evaluated as a form of emergency contraception in 1973.<ref name="KesserüLarrañaga1973">Template:Cite journal</ref> It was the second progestin to be evaluated for such purposes, following a study of quingestanol acetate in 1970.<ref name="KesserüLarrañaga1973" /><ref name="RubioBerman1970">Template:Cite journal</ref> In 1974, the Yuzpe regimen, which consisted of high doses of a combined birth control pill containing ethinylestradiol and norgestrel, was described as a method of emergency contraception by A. Albert Yuzpe and colleagues, and saw widespread interest.<ref name="Balaji2009">Template:Cite book</ref><ref name="pmid4844513">Template:Cite journal</ref> Levonorgestrel-only emergency contraception was introduced under the brand name Postinor by 1978.<ref name="Farkas1978">Template:Cite journal</ref> Ho and Kwan published the first study comparing levonorgestrel only and the Yuzpe regimen as methods of emergency contraception in 1993 and found that they had similar effectiveness but that levonorgestrel alone was better-tolerated.<ref name="ArtiniGenazzani2001">Template:Cite book</ref><ref name="pmid8473453">Template:Cite journal</ref> In relation to this, the Yuzpe regimen has largely been replaced as a method of emergency contraception by levonorgrestrel-only preparations.<ref name="King2013">Template:Cite book</ref> Levonorgestrel-only emergency contraception was approved in the United States under the brand name Plan B in 1999, and has also been marketed widely elsewhere throughout the world under other brand names such as Levonelle and NorLevo in addition to Postinor.<ref name="Drugs.com" /><ref name="Harrison-Woolrych2015">Template:Cite book</ref> In 2013, the Food and Drug Administration approved Plan B One-Step for sale over-the-counter in the United States without a prescription or age restriction.<ref name="CBSNews2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Levonorgestrel has also been introduced for use as a progestogen-only intrauterine device under the brand names Mirena and Skyla among others, as a progestogen-only birth control implant under the brand names Norplant and Jadelle, as a combined oral tablet with estradiol valerate for menopausal hormone therapy under the brand name Klimonorm, and as a combined transdermal patch with estradiol for menopausal hormone therapy under the brand name Climara Pro.<ref name="Drugs.com" /><ref name="pmid26732558">Template:Cite journal</ref><ref name="Kubíková2014">Template:Cite journal</ref> Ester prodrugs of levonorgestrel such as levonorgestrel acetate and levonorgestrel butanoate have been developed and studied as other forms of birth control such as long-acting progestogen-only injectable contraceptives and contraceptive vaginal rings, but have not been marketed for medical use.<ref name="GWU1987"/><ref name="pmid6658872"/>

Society and culture

Generic names

Levonorgestrel is the generic name of the drug and its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, Template:Abbrlink, and Template:Abbrlink, while lévonorgestrel is its Template:Abbrlink.<ref name="Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Elks2014" /><ref name="IndexNominum2000" /> 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).<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Scharff1972" />

Brand names

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, Cycle 21, 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, Microvlar, Min-Ovral, Miranova, Mirena, My Way, Myzilra, Next Choice, Nordette, Norgeston, NorLevo, Norplant, One Pill, Option 2, Orsythia, Ovima, Ovranette, Plan B, Plan B One-Step, Portia, Postinor, Postinor-2, Preventeza, Ramonna, Rigevidon, Quartette, Quasense, Seasonale, Seasonique, Skyla, Sronyx, Tri-Levlen, Trinordiol, Triphasil, Triquilar, Tri-Regol, Trivora, and Upostelle, among many others.<ref name="Drugs.com" /><ref name="IndexNominum2000" /><ref name="Princeton2017">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These formulations are used as emergency contraceptives, normal contraceptives, or in menopausal hormone therapy for the treatment of menopausal symptoms.Template:Medical citation needed

As an emergency contraceptive, levonorgestrel is often referred to colloquially as the "morning-after pill".<ref name="OatsAbraham2011">Template:Cite book</ref><ref name="CarlsonEisenstat2004">Template:Cite book</ref>

Availability

Levonorgestrel is very widely marketed throughout the world and is available in almost every country.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

Accessibility

Levonorgestrel-containing emergency contraception is available over-the-counter in some countries, such as the United States.<ref name="CBSNews2013" /> On some college campuses, Plan B is available from vending machines.<ref>Template:Cite news</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Levonorgestrel has been studied in combination with androgens such as testosterone and dihydrotestosterone as a hormonal contraceptive for men.<ref name="pmid20933120" /><ref name="pmid12826683" />