Levonorgestrel what is it. Levonorgestrel: A Comprehensive Guide to the Emergency Contraceptive Pill

29.06.202324.06.2023 by alexxlab

What is levonorgestrel. How does it work as an emergency contraceptive. When should levonorgestrel be taken. What are the side effects of levonorgestrel. Who can use levonorgestrel. How effective is levonorgestrel as a morning-after pill. What are the different forms of levonorgestrel available.

Содержание

Understanding Levonorgestrel: The Morning-After Pill

Levonorgestrel, commonly known as the morning-after pill, is a crucial emergency contraceptive approved by the World Health Organization and the FDA. This synthetic progestogen plays a vital role in preventing unintended pregnancies when taken within a specific timeframe after unprotected sexual intercourse or contraceptive failure.

Is levonorgestrel only available as an emergency contraceptive. No, it’s also used in various forms of long-term birth control methods, including combination pills with estradiol, implants, transdermal patches, and intrauterine devices (IUDs).

Key Features of Levonorgestrel

FDA-approved for use within 72 hours of unprotected sex
Available over-the-counter without a prescription
Approved for all age groups
Can be effective for up to 96 hours in some cases (off-label use)
Used in various forms of long-term birth control

The Science Behind Levonorgestrel’s Mechanism of Action

How does levonorgestrel prevent pregnancy. Levonorgestrel works through multiple mechanisms to prevent conception:

Delays or inhibits ovulation by preventing follicular rupture
Thickens cervical mucus, interfering with sperm motility
Alters the release of gonadotropin-releasing hormone from the hypothalamus
Blunts the luteinizing hormone surge during the pre-ovulation stage

Contrary to some beliefs, recent studies have not found significant evidence that levonorgestrel alters the endometrium to prevent pregnancy. Its primary mode of action is through the prevention of ovulation and fertilization.

Pharmacokinetics of Levonorgestrel

Does levonorgestrel undergo significant first-pass metabolism. No, studies have shown that levonorgestrel is not subject to significant first-pass metabolism. Instead, it undergoes metabolism via hydroxylation, conjugation, and reduction in the liver. Its bioavailability is impressively high, ranging from 85% to 100%.

Administration and Dosage Guidelines for Levonorgestrel

When should levonorgestrel be taken for emergency contraception. The recommended dose is a 1.5 mg oral tablet taken within 72 hours of unprotected sexual intercourse. Alternatively, two 0.75 mg tablets can be taken 24 hours apart.

Special Considerations for Dosage

A 3 mg dose is recommended for patients taking CYP3A4 cytochrome p450 liver enzyme-inducing drugs
If vomiting occurs within two hours of administration, the dose should be repeated
For long-term birth control, levonorgestrel is available in various forms with different dosages

Are there any special instructions for taking levonorgestrel. Yes, it’s crucial to take the pill as soon as possible within the 72-hour window for maximum efficacy. If using the two-dose regimen, the second dose must be taken exactly 24 hours after the first.

Efficacy and Factors Affecting Levonorgestrel’s Performance

How effective is levonorgestrel as an emergency contraceptive. Levonorgestrel’s efficacy can vary depending on several factors, including:

Timing of administration (earlier is better)
Body weight of the user
Ovulation stage at the time of intake
Concurrent use of other medications

Research indicates that levonorgestrel is most effective when taken in the pre-ovulation stage. Its efficacy decreases as the time between unprotected intercourse and administration increases.

Impact of Body Weight on Efficacy

Does body weight affect the effectiveness of levonorgestrel. Yes, studies have shown that the efficacy of levonorgestrel may be reduced in women with a BMI greater than 26 kg/mÂ². However, this reduction is not significant enough to restrict its use in this patient subset. The lower efficacy is likely due to the reduced bioavailability of the standard 1.5 mg dose in patients with higher body weight.

Side Effects and Safety Profile of Levonorgestrel

What are the common side effects of levonorgestrel? The most frequently reported side effects include:

Menstrual abnormalities (amenorrhea, dysmenorrhea, oligomenorrhea)
Headaches
Acne
Nausea and vomiting

It’s important to note that while these side effects can occur, they are generally mild and transient. The safety profile of levonorgestrel is considered favorable, which is why it’s approved for over-the-counter use and for all age groups.

Long-term Safety Considerations

Are there any long-term risks associated with levonorgestrel use? Current research has not identified significant long-term risks associated with occasional use of levonorgestrel as an emergency contraceptive. However, as with any medication, it’s important to use it as directed and consult with a healthcare provider if there are concerns.

Contraindications and Precautions for Levonorgestrel Use

Who should not use levonorgestrel? While levonorgestrel is generally safe for most women, there are some contraindications and precautions to consider:

Known or suspected pregnancy (as it will not terminate an existing pregnancy)
Hypersensitivity to any component of the product
Undiagnosed abnormal vaginal bleeding
Severe liver disease

It’s crucial to note that levonorgestrel does not protect against sexually transmitted infections (STIs). Healthcare providers should advise patients to use condoms for STI protection.

Drug Interactions

Are there any significant drug interactions with levonorgestrel? Yes, certain medications can affect the efficacy of levonorgestrel:

CYP3A4 enzyme inducers (e.g., rifampicin, St. John’s wort, carbamazepine, phenobarbital)
Certain antiretroviral medications
Some anti-epileptic drugs

In these cases, a higher dose of levonorgestrel may be recommended to ensure its effectiveness.

Different Forms of Levonorgestrel for Long-term Contraception

While levonorgestrel is widely known as an emergency contraceptive, it’s also used in various forms of long-term birth control. What are the different forms of levonorgestrel available for ongoing contraception?

Oral combination pills with estradiol
Levonorgestrel-releasing intrauterine devices (IUDs)
Implants
Transdermal patches

Levonorgestrel-Releasing Intrauterine Device (IUD)

How does the levonorgestrel-releasing IUD work? This T-shaped device contains 52 mg of levonorgestrel covered by a rate-controlling membrane. It slowly releases the hormone over time, providing effective contraception for up to five years. This method is often referred to as a “low maintenance” birth control option due to its long-lasting effects and minimal user intervention required.

Off-Label Uses of Levonorgestrel in Gynecological Conditions

Beyond its primary use as a contraceptive, levonorgestrel has shown efficacy in treating various gynecological conditions. What are some off-label uses of levonorgestrel?

Treatment of endometrial hyperplasia
Management of menorrhagia (heavy menstrual bleeding)
Alleviation of endometriosis symptoms
Use in menopausal hormone therapy

These off-label uses highlight the versatility of levonorgestrel in addressing a range of women’s health issues. However, it’s important to note that these applications should be discussed with and supervised by a healthcare provider.

Levonorgestrel in Endometriosis Management

How does levonorgestrel help in managing endometriosis? Levonorgestrel can help reduce the growth of endometrial tissue outside the uterus and alleviate associated pain. It does this by suppressing ovulation and thinning the endometrial lining, which can help reduce the severity of endometriosis symptoms.

The Role of Healthcare Providers in Levonorgestrel Administration

While levonorgestrel is available over-the-counter, healthcare providers play a crucial role in its effective and safe use. What responsibilities do healthcare providers have regarding levonorgestrel?

Educating patients about proper use and timing
Discussing potential side effects and what to expect
Addressing concerns about efficacy and safety
Providing information on long-term contraceptive options
Screening for contraindications and potential drug interactions

Healthcare providers should also emphasize the importance of regular contraceptive methods and discuss strategies for preventing unintended pregnancies in the future.

Counseling on STI Prevention

Why is it important for healthcare providers to discuss STI prevention when prescribing levonorgestrel? Levonorgestrel does not protect against sexually transmitted infections. Therefore, it’s crucial for healthcare providers to remind patients about the importance of using barrier methods like condoms to prevent STIs, even when using emergency contraception or other hormonal birth control methods.

Future Developments and Research in Emergency Contraception

The field of emergency contraception is continually evolving, with ongoing research aimed at improving efficacy, reducing side effects, and expanding access. What are some areas of current research in emergency contraception?

Development of new formulations with improved bioavailability
Studies on extending the window of efficacy beyond 72 hours
Investigation of potential interactions with new medications
Research on the impact of body weight on efficacy and potential dosage adjustments
Exploration of combination therapies for enhanced effectiveness

These research efforts aim to enhance the effectiveness and accessibility of emergency contraception, potentially leading to new options and improved guidelines for use in the future.

Addressing Barriers to Access

What steps are being taken to improve access to emergency contraception? Researchers and policymakers are working on several fronts to enhance access:

Advocating for over-the-counter availability in more countries
Developing educational programs to increase awareness and reduce stigma
Exploring telemedicine options for prescription and counseling
Investigating cost-reduction strategies to make emergency contraception more affordable

These efforts aim to ensure that emergency contraception is readily available to all who need it, regardless of geographic location, age, or socioeconomic status.

Levonorgestrel – StatPearls – NCBI Bookshelf

Continuing Education Activity

Objectives:

Summarize the mechanism of action of levonorgestrel.
Review the effective and correct administration of levonorgestrel for morning-after birth control.
Describe the contraindications for using levonorgestrel.
Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with levonorgestrel.

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Indications

Levonorgestrel, also known as the morning-after pill, is a first-line oral emergency contraceptive pill with approval from the World Health Organization to prevent pregnancy. It is FDA-approved to be used within 72 hours of unprotected sexual intercourse or when a presumed contraceptive failure has occurred. There have been cases of off-label efficacy for up to 96 hours.[1] A prescription is not needed, and it is available over the counter at local pharmacies. The FDA has also approved levonorgestrel availability for all age groups due to its lack of life-threatening contraindications and side-effect profile.[2] Levonorgestrel can be used as an oral combination pill with estradiol as a long-term option for birth control and is available in other forms, such as implants or transdermal patches. There is a levonorgestrel-releasing intrauterine device considered to be a “low maintenance” birth control option for women that is efficacious for up to five years.[3] It has also been used off-label effects to treat endometrial hyperplasia, menorrhagia, endometriosis, and menopausal hormone therapy.

Mechanism of Action

Levonorgestrel (LNG—17alpha-ethynyl-18-methylestr-4-en-17beta-ol-3-one) is a second-generation synthetic progestogen that is the active component of the racemic mixture of norgestrel. It binds to progesterone and androgen receptors, where it can delay gonadotropin-releasing hormone from being released from the hypothalamus. This action blunts the luteinizing hormone surge that occurs during the pre-ovulation stage. Ultimately, it can delay or inhibit ovulation by preventing fertilization via inhibiting follicular rupture and releasing a viable egg from the ovaries. Optimal efficacy is achievable when it is taken in the pre-ovulation stage as well. Levonorgestrel also induces the thickening of cervical mucus, which helps by interfering with sperm motility and passage. There has been no evidence in recent studies that levonorgestrel significantly affects the endometrium to alter it to prevent pregnancy.[4]

Studies have shown that levonorgestrel is not subject to significant first-pass metabolism. Levonorgestrel undergoes metabolism via hydroxylation, conjugation, and reduction in the liver. Its bioavailability varies from 85 to 100%.[5]

Administration

For emergency contraceptive use, the recommended dose is 1.5 mg oral tablet within 72 hours. There is also a 0.75 mg oral tablet that can be given with a second 0.75 mg dose if needed 24 hours later. A 3 mg oral levonorgestrel is for patients concomitantly taking a CYP3A4 cytochrome p450 liver enzyme-inducing drug, e.g., rifampicin, St. John’s wort, carbamazepine, or phenobarbital due to these agents increasing hepatic clearance of levonorgestrel. Vomiting can occur within two hours of administration, at which case the patient would need to repeat the initial dose taken.[6]

For the long-term birth control options, the levonorgestrel intrauterine T-shaped device has 52 mg of levonorgestrel covered by a rate-controlling membrane that regulates the rate of release of hormones. 2, but not significant enough to restrict this subset of patients from using levonorgestrel, which appears to be due to the lower bioavailability of a standard 1.5 mg dose given of levonorgestrel, free plus albumin-bound, in these patients. The most common side effects are menstrual abnormalities, amenorrhea, dysmenorrhea, oligomenorrhea, headaches, and acne. Other side effects that can occur are nausea and vomiting. Importantly, this drug does not protect any patient from sexually transmitted infections and diseases, and the advice to patients is to use condoms for protection from such.[7][8]

For the intrauterine device, there is 0.1% of pregnancy occurring within the first year of use. The intrauterine device most commonly causes menstrual irregularities, including amenorrhea and oligomenorrhea. Other side effects of the intrauterine device are similar to those of the combined oral contraceptive pill route, such as ovarian cysts, weight gain, depression, acne, and low libido.[3]

Drug-Drug Interactions:

The following may diminish the therapeutic effect of progestins: acitretin, anticoagulants, antidiabetic agents, barbiturates, carbamazepine, fosphenytoin, griseofulvin, mifepristone, phenytoin, primidone, retinoic acid derivatives, and St. John’s wort.

The following may decrease the serum concentration of progestins: aprepitant, artemether, bexarotene, bile acid sequestrants, bosentan, brigatinib, clobazam, CYP3A4 inducers, dabrafenib, darunavir, efavirenz, encorafenib, eslicarbazepine, exenatide, felbamate, fosaprepitant, ixazomib, lamotrigine, lesinurad, lixisenatide, lopinavir, lorlatinib, lumacaftor, metreleptin, mycophenolate, nelfinavir, nevirapine, oxcarbazepine, perampanel, rifamycin derivatives, saquinavir, sugammadex, and topiramate.

The following may increase the serum concentration of progestins: atazanavir, cobicistat, tipranavir, and voriconazole.

The following may enhance the thrombogenic effect of progestins: C1-inhibitors and carfilzomib.

Contraindications

There are several contraindications for the emergency contraceptive form, including allergy, hypersensitivity, severe liver disease, pregnancy, and drug-drug interactions with liver enzyme-inducing drugs.[9]

For the intrauterine device, the contraindications include uterine anomalies (fibroids, cysts), breast carcinoma, active cervicitis/vaginitis, suspected cervical dysplasia, and pregnancy. [3]

Emergency contraceptive form: The medication is not for use in women confirmed to be pregnant; however, there is no proof nor reports of adverse effects on the mother or fetus following inadvertent exposure during pregnancy.[10]

Pregnancy for the IUD: Use during pregnancy or suspected pregnancy is contraindicated.

Combined ethinylestradiol and levonorgestrel is pregnancy category X.

Breastfeeding: levonorgestrel is present in breast milk; however, the relative infant dose is 8%. Breastfeeding is acceptable when the relative infant dose of a medication is less than 10%.[11]

Monitoring

Routine examinations with a gynecologist are encouraged for the long-term combined oral pill or intrauterine device birth control options to monitor side effects and possible pregnancy. Levonorgestrel undergoes metabolism by the liver and is subject to impairment in patients with liver dysfunction. Therefore, monitoring liver function tests at the time of administration may be beneficial. Also, drugs containing CYP3A4 cytochrome p450 liver-enzyme inducing properties require close vigilance when a patient takes levonorgestrel. Patients may need to consider another emergency contraceptive method to avoid drug-drug interactions. These liver-enzyme-inducing drugs can cause rapid metabolism and decrease the efficacy of levonorgestrel when there is concomitant use.[12]

Toxicity

There is a lack of research regarding the toxic levels and effects in humans. While there could be toxicity seen in patients with liver disease, there is not enough research to support this. More human trial studies will be necessary. There have been studies that show LD50 to be over 5000 mg/kg in rats when given orally, with a significant decrease in white blood cell counts.[13]

Enhancing Healthcare Team Outcomes

While levonorgestrel is a first-line emergency contraceptive for unwanted pregnancy, communication and teamwork between primary care physicians, gynecologists, obstetricians, pharmacists, nurse practitioners, physician assistants, and nursing staff working together in an interprofessional team approach to care can make a tangible difference in a patient’s experience while taking levonorgestrel. There has been controversy about the morning after pill being available without a prescription and sold over the counter at any local pharmacy. This agent can be deemed a drug that promotes risky sexual behavior and can also be a drug of convenience for both perceived and verifiable contraceptive failures. This issue is how healthcare teams can combine patient education with adequate treatment plans to promote levonorgestrel use in the most effective way without compromising patient safety.[14] [Level 5]

Primary care physicians and gynecologists should routinely ask the patient about pertinent sexual history to help monitor sexual behavior and document any changes.
Maintenance of a strong physician-patient relationship so that the patients trust the physicians and can be open and honest about their sexual practices and potentially risky behavior in a judgment-free atmosphere.
Pharmacists should emphasize the side effects of levonorgestrel, its strict timeline to achieve optimal drug efficacy, and how it will not prevent sexually transmitted infections and diseases.

These examples of interprofessional strategies can optimize the benefits of therapy with levonorgestrel. [Level 5]

Review Questions

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References

1.: Chao YS, Frey N. Ulipristal versus Levonorgestrel for Emergency Contraception: A Review of Comparative Clinical Effectiveness and Guidelines [Internet]. Canadian Agency for Drugs and Technologies in Health; Ottawa (ON): Nov 29, 2018. [PubMed: 30883064]
2.: David M, Berends L, Bartley J. Current Opinion of Obstetricians on the Prescription of Emergency Contraception: A German-American Comparison. Geburtshilfe Frauenheilkd. 2012 Nov;72(11):1004-1008. [PMC free article: PMC4168318] [PubMed: 25258456]
3.: Beatty MN, Blumenthal PD. The levonorgestrel-releasing intrauterine system: Safety, efficacy, and patient acceptability. Ther Clin Risk Manag. 2009 Jun;5(3):561-74. [PMC free article: PMC2724187] [PubMed: 19707273]
4.: Kahlenborn C, Peck R, Severs WB. Mechanism of action of levonorgestrel emergency contraception. Linacre Q. 2015 Feb;82(1):18-33. [PMC free article: PMC4313438] [PubMed: 25698840]
5.: Basaraba CN, Westhoff CL, Pike MC, Nandakumar R, Cremers S. Estimating systemic exposure to levonorgestrel from an oral contraceptive. Contraception. 2017 Apr;95(4):398-404. [PMC free article: PMC5376510] [PubMed: 28041990]
6.: Black KI, Hussainy SY. Emergency contraception: Oral and intrauterine options. Aust Fam Physician. 2017 Oct;46(10):722-726. [PubMed: 29036770]
7.: Festin MPR, Peregoudov A, Seuc A, Kiarie J, Temmerman M. Effect of BMI and body weight on pregnancy rates with LNG as emergency contraception: analysis of four WHO HRP studies. Contraception. 2017 Jan;95(1):50-54. [PMC free article: PMC5357708] [PubMed: 27527670]
8.: Shen J, Che Y, Showell E, Chen K, Cheng L. Interventions for emergency contraception. Cochrane Database Syst Rev. 2019 Jan 20;1(1):CD001324. [PMC free article: PMC7055045] [PubMed: 30661244]
9.: Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet. 1990 Jun;18(6):472-84. [PubMed: 2191822]
10.: Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, Simmons KB, Pagano HP, Jamieson DJ, Whiteman MK. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep. 2016 Jul 29;65(3):1-103. [PubMed: 27467196]
11.: Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000 Jul 13;343(2):118-26. [PubMed: 10891521]
12.: Coricovac D, Farcas C, Nica C, Pinzaru I, Simu S, Stoian D, Soica C, Proks M, Avram S, Navolan D, Dumitru C, Popovici RA, Dehelean CA. Ethinylestradiol and Levonorgestrel as Active Agents in Normal Skin, and Pathological Conditions Induced by UVB Exposure: In Vitro and In Ovo Assessments. Int J Mol Sci. 2018 Nov 14;19(11) [PMC free article: PMC6275072] [PubMed: 30441863]
13.: Kim SK, Shin SJ, Yoo Y, Kim NH, Kim DS, Zhang D, Park JA, Yi H, Kim JS, Shin HC. Oral toxicity of isotretinoin, misoprostol, methotrexate, mifepristone and levonorgestrel as pregnancy category X medications in female mice. Exp Ther Med. 2015 Mar;9(3):853-859. [PMC free article: PMC4316989] [PubMed: 25667641]
14.: Brandão ER. [Long-acting reversible contraception methods in the Brazilian Unified National Health System: the debate on women’s (in)discipline]. Cien Saude Colet. 2019 Mar;24(3):875-879. [PubMed: 30892508]

: Disclosure: Christina Vrettakos declares no relevant financial relationships with ineligible companies.
: Disclosure: Tushar Bajaj declares no relevant financial relationships with ineligible companies.