Pharmacology of Levonorgestrel

Introduction/Overview

Levonorgestrel is a synthetic progestogen that represents one of the most widely utilized hormonal agents in clinical practice. As the biologically active levorotatory enantiomer of norgestrel, it possesses potent progestational and antiestrogenic activities. The clinical relevance of levonorgestrel is substantial, underpinning its use across a spectrum of reproductive health applications from contraception to therapeutic management of gynecological disorders. Its importance is further amplified by its role in public health initiatives aimed at reducing unintended pregnancies, particularly through its availability as an emergency contraceptive. The drug’s pharmacology provides a foundation for understanding its diverse effects, therapeutic window, and appropriate clinical application.

Learning Objectives

• Describe the chemical classification of levonorgestrel and its relationship to endogenous progesterone.
• Explain the molecular and cellular mechanisms of action of levonorgestrel across its different clinical formulations and indications.
• Analyze the pharmacokinetic profile of levonorgestrel, including absorption, distribution, metabolism, and excretion, and relate these parameters to dosing regimens.
• Identify the approved therapeutic uses of levonorgestrel and evaluate the evidence supporting common off-label applications.
• Recognize major adverse effects, drug interactions, and special population considerations to ensure safe and effective clinical use.

Classification

Levonorgestrel is classified within several overlapping pharmacological and therapeutic categories, reflecting its multifaceted clinical role.

Therapeutic and Pharmacological Classification

• Progestogen/Progestin: It is a first-generation 19-nortestosterone derivative, specifically a gonane. This classification denotes its primary action as an agonist at the progesterone receptor.
• Contraceptive Agent: It is a key component in numerous hormonal contraceptive methods, including combined oral contraceptives, progestin-only pills, subdermal implants, and intrauterine systems.
• Emergency Contraceptive: It is approved specifically for postcoital interception to prevent pregnancy after unprotected intercourse or contraceptive failure.
• Hormone Replacement Therapy (HRT) Component: In combination with an estrogen, it is used in HRT regimens for menopausal women with an intact uterus to provide endometrial protection.

Chemical Classification

Chemically, levonorgestrel is known as (-)-13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one. It is the biologically active levorotatory enantiomer of the racemic compound norgestrel. Its structure is derived from 19-nortestosterone, which confers greater metabolic stability and oral bioavailability compared to endogenous progesterone. The absence of the C-19 methyl group and the presence of an ethynyl group at the 17α position are critical structural features that inhibit hepatic metabolism, allowing for effective oral administration. The 13β-ethyl substitution enhances its binding affinity for the progesterone receptor. This synthetic structure results in a compound with high progestational potency, minimal estrogenic activity, and moderate antiestrogenic and androgenic properties.

Mechanism of Action

The pharmacological effects of levonorgestrel are mediated primarily through its action as a ligand for the intracellular progesterone receptor (PR), a member of the nuclear receptor superfamily. Its mechanisms, however, vary significantly depending on the dose, timing, and route of administration, particularly distinguishing between regular contraceptive use and emergency contraception.

Receptor Interactions and Genomic Effects

Levonorgestrel binds with high affinity to the human progesterone receptor. Upon binding, the ligand-receptor complex undergoes a conformational change, dissociates from chaperone proteins, dimerizes, and translocates to the cell nucleus. The dimer binds to specific progesterone response elements (PREs) in the promoter regions of target genes, recruiting coactivators or corepressors to modulate gene transcription. This genomic action is responsible for many of its systemic effects, including the transformation of the proliferative endometrium into a secretory state. Levonorgestrel also exhibits affinity for other steroid receptors, including the androgen receptor (AR), through which it may exert mild androgenic effects, and the glucocorticoid receptor (GR), though with much lower affinity and unclear clinical significance at therapeutic doses.

Cellular and Tissue-Level Mechanisms in Regular Contraception

When administered continuously for contraception, levonorgestrel exerts multiple synergistic effects to prevent pregnancy.

• Central Inhibition of Ovulation: The primary mechanism of regular progestin-only contraception is the suppression of the mid-cycle luteinizing hormone (LH) surge from the anterior pituitary. This is achieved through negative feedback on the hypothalamic-pituitary-ovarian axis, inhibiting the release of gonadotropin-releasing hormone (GnRH). Without the LH surge, follicular maturation is disrupted, and ovulation is prevented.
• Cervical Mucus Alteration: Levonorgestrel induces a thickening and reduction in the quantity of cervical mucus. This change creates a viscous, impenetrable barrier that significantly hinders sperm penetration and ascent into the uterine cavity.
• Endometrial Effects: The drug causes endometrial atrophy and alters the endometrial lining, making it less receptive to blastocyst implantation. Glandular development is suppressed, and the stroma becomes decidualized.
• Fallopian Tube Motility: There is evidence that progestins may alter tubal motility and ciliary function, potentially affecting ovum and sperm transport, though this is considered a secondary mechanism.

Mechanism in Emergency Contraception

The mechanism of action for the single high-dose (1.5 mg) regimen used for emergency contraception is distinct and time-dependent. Efficacy is highest when administered within 72 hours after unprotected intercourse, with declining effectiveness over time.

• Pre-Ovulatory Administration: If taken before the LH surge, the primary mechanism is the delay or inhibition of ovulation. Levonorgestrel appears to disrupt the follicular development process, preventing the follicle from reaching the point of maturity and rupture required for ovulation.
• Peri-Ovulatory Administration: If administered around the time of the LH surge, it may interfere with the ovulatory process itself, potentially leading to luteinized unruptured follicle syndrome, where the follicle luteinizes but fails to release an oocyte.
• Post-Ovulatory Administration: Evidence does not support that levonorgestrel emergency contraception is effective by preventing implantation of a fertilized egg. It does not appear to have significant effects on the endometrium that would impair implantation when administered after ovulation has occurred. Therefore, it is not considered an abortifacient.

Mechanism in Intrauterine Systems (IUS)

When delivered via an intrauterine system (e.g., Mirena®, Kyleena®), the mechanism is predominantly local. High local concentrations of levonorgestrel within the uterine cavity lead to profound endometrial suppression, causing glandular atrophy and stromal decidualization. This creates a hostile environment for sperm survival and implantation. While systemic absorption occurs, ovulation is often inhibited initially in many users, but over time, a significant proportion of women using the 52 mg IUS resume ovulatory cycles, with the contraceptive effect maintained primarily through the local endometrial actions. The foreign body effect of the IUS frame also contributes to a sterile inflammatory response that is spermicidal.

Pharmacokinetics

The pharmacokinetic profile of levonorgestrel is influenced by its formulation, dose, and route of administration. Understanding these parameters is essential for predicting its onset, duration of action, and potential for interactions.

Absorption

Levonorgestrel is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration. However, it undergoes significant first-pass metabolism in the liver, which reduces its absolute bioavailability to approximately 85-90% for the active enantiomer. Absorption is not significantly affected by food. Following oral administration of a 1.5 mg emergency contraceptive dose, peak plasma concentrations (C_max) ranging from 15 to 20 ng/mL are typically achieved within 1 to 2 hours (t_max). For lower daily doses (e.g., 30 µg in progestin-only pills), C_max is proportionally lower. Non-oral routes bypass first-pass metabolism. Subdermal implants provide slow, sustained release over years. Intrauterine systems achieve very high local endometrial concentrations (ng/g tissue) with much lower systemic levels (pg/mL to low ng/mL in plasma). Intramuscular administration in oil solutions results in a prolonged release profile.

Distribution

Levonorgestrel is widely distributed throughout the body. Its volume of distribution is approximately 1.5 to 2.0 L/kg, indicating extensive tissue binding. The drug is highly bound to plasma proteins (>95%), primarily to sex hormone-binding globulin (SHBG) and, to a lesser extent, albumin. Only the unbound fraction is pharmacologically active. Levonorgestrel increases the hepatic synthesis of SHBG, which can alter its own binding kinetics over time with continuous use. It distributes into breast milk, saliva, and crosses the placental barrier.

Metabolism

Levonorgestrel is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, with CYP3A4 being the major isoform involved. The metabolic pathways include reduction of the Δ⁴-3-keto group and hydroxylation at various positions (C2, C16α, C16β), followed by conjugation. The major reduced metabolites are 3α,5β-tetrahydro-levonorgestrel and 3β,5α-tetrahydro-levonorgestrel. These metabolites are generally considered to possess minimal progestogenic activity compared to the parent compound. The ethynyl group at C17 contributes to metabolic stability by blocking oxidation at this site.

Excretion

The elimination of levonorgestrel and its metabolites occurs via both renal and biliary/fecal routes. Following conjugation (primarily glucuronidation and sulfation), approximately 40-50% of a dose is excreted in the urine and 30-40% in the feces. The elimination is biphasic. The terminal elimination half-life (t_1/2) after a single oral dose is approximately 24 to 32 hours. However, with continuous daily dosing, an effective steady-state is maintained due to the accumulation predicted by its half-life. Clearance (CL) of levonorgestrel is relatively slow, estimated at about 1.5 to 2.0 mL/min/kg.

Pharmacokinetic Parameters and Dosing Considerations

The relationship between dose, systemic exposure, and effect is non-linear for some parameters due to saturable binding to SHBG. At higher doses, the increase in plasma concentration may be less than proportional to the dose increase. For emergency contraception, the single 1.5 mg dose is designed to achieve rapidly high plasma levels to exert its pre-ovulatory effects. For continuous contraception, the low daily doses (e.g., 30 µg) maintain steady-state concentrations sufficient to exert central and peripheral effects without the peaks associated with the emergency dose. The pharmacokinetics of the subdermal implant (e.g., Norplant®, Jadelle®) and intrauterine systems are characterized by near-zero-order release kinetics, providing stable plasma levels over extended periods (years), which gradually decline as the reservoir is depleted.

Therapeutic Uses/Clinical Applications

Levonorgestrel is employed in a variety of clinical settings, with its use dictated by formulation, dose, and regimen.

Approved Indications

• Emergency Contraception: This is the most recognized indication for single-dose (1.5 mg) oral levonorgestrel. It is indicated for use within 72-120 hours (depending on the specific product license) after unprotected intercourse or contraceptive failure (e.g., condom breakage).
• Progestin-Only Contraception (Mini-Pill): Daily administration of a low-dose (typically 30 µg) levonorgestrel pill is used for continuous contraception, particularly suitable for women who cannot use estrogen-containing contraceptives (e.g., during lactation, with history of thromboembolism, or with migraine with aura).
• Combined Hormonal Contraception: Levonorgestrel is combined with an estrogen (usually ethinyl estradiol) in numerous combined oral contraceptive (COC) formulations, transdermal patches, and vaginal rings. These provide highly effective contraception through synergistic mechanisms.
• Long-Acting Reversible Contraception (LARC):
  • Subdermal Implants: Rods containing levonorgestrel (e.g., Jadelle® with 2 rods, 150 mg total) provide contraception for up to 5 years.
  • Intrauterine Systems (IUS): Devices like Mirena® (52 mg), Liletta® (52 mg), Kyleena® (19.5 mg), and Skyla® (13.5 mg) release levonorgestrel directly into the uterine cavity, providing contraception for 3 to 8 years depending on the dose. Mirena® is also approved for the treatment of heavy menstrual bleeding.
• Hormone Replacement Therapy (HRT): In combination with estrogens, levonorgestrel is used in sequential or continuous-combined HRT regimens to protect the endometrium from the hyperplastic effects of unopposed estrogen in postmenopausal women with a uterus.
• Treatment of Heavy Menstrual Bleeding: The 52 mg levonorgestrel-releasing IUS is specifically approved for the reduction of heavy menstrual bleeding in women who choose intrauterine contraception.

Common Off-Label Uses

• Endometrial Protection during Tamoxifen Therapy: The levonorgestrel-IUS may be used in women with breast cancer on tamoxifen to prevent drug-induced endometrial hyperplasia and polyps, though this requires careful risk-benefit assessment.
• Management of Endometriosis-Associated Pain: The levonorgestrel-IUS has been shown to reduce dysmenorrhea and pelvic pain associated with endometriosis, likely through local endometrial suppression and reduction in inflammatory mediators.
• Treatment of Endometrial Hyperplasia without Atypia: The levonorgestrel-IUS is often used as a first-line medical treatment to induce regression of simple or complex hyperplasia without atypia in women wishing to preserve fertility or avoid surgery.
• Premenstrual Dysphoric Disorder (PMDD): Some combined oral contraceptives containing levonorgestrel in a 24/4 regimen are used to manage symptoms of PMDD.
• Acne: Certain combined oral contraceptives containing levonorgestrel are approved for the treatment of moderate acne in women seeking contraception, who are at least 14-15 years old, and have had menarche.

Adverse Effects

The adverse effect profile of levonorgestrel is generally favorable, particularly with low-dose and local delivery systems, but it encompasses a range of predictable, progestin-related effects.

Common Side Effects

These effects are often dose-dependent and tend to diminish with continued use over several months.

• Menstrual Irregularities: This is the most frequently reported side effect, especially with progestin-only methods. Patterns include irregular spotting or breakthrough bleeding, amenorrhea, prolonged bleeding, or changes in menstrual flow. Amenorrhea is very common with the levonorgestrel-IUS and is often a desired effect.
• Androgenic Effects: Due to its structural relation to norethindrone and mild androgenic activity, levonorgestrel may cause acne, seborrhea, hirsutism, or, rarely, alopecia. This is more common with older, higher-dose oral formulations.
• Central Nervous System Effects: Headache, dizziness, mood changes (including depression or mood swings), fatigue, and nervousness have been reported. Changes in libido can occur in either direction.
• Gastrointestinal Effects: Nausea and abdominal pain are common, particularly with the high single dose used for emergency contraception. Vomiting may occur; if vomiting happens within 2-3 hours of taking the emergency dose, a repeat dose may be required.
• Breast Symptoms: Tenderness, pain, and enlargement are possible.
• Local Effects (with IUS or implant): Pain during insertion, expulsion of the IUS, or complications related to implant insertion/removal (e.g., infection, bruising). Ovarian cysts may be detected on ultrasound and are usually functional and asymptomatic.
• Weight Change: Minor weight gain or fluid retention may occur, though significant weight gain is not consistently supported by clinical evidence for modern low-dose formulations.

Serious/Rare Adverse Reactions

• Ectopic Pregnancy: While levonorgestrel-containing contraceptives significantly reduce the absolute risk of pregnancy, if a pregnancy does occur with a progestin-only method (particularly the mini-pill or IUS), the relative proportion that is ectopic may be increased. However, the absolute risk of ectopic pregnancy is far lower than in women using no contraception. Emergency contraception does not increase the risk of ectopic pregnancy in a subsequent cycle.
• Thromboembolic Events: The risk of venous thromboembolism (VTE) with progestin-only contraceptives, including levonorgestrel, is considered very low and significantly lower than with combined estrogen-progestin contraceptives. Any risk is likely confined to underlying patient factors.
• Cardiovascular Events: The risk of arterial events (myocardial infarction, stroke) is extremely low in healthy, non-smoking women using progestin-only methods and is primarily associated with underlying risk factors (e.g., hypertension, smoking, diabetes).
• Hepatic Effects: Benign hepatic adenomas and, very rarely, hepatocellular carcinoma have been associated with long-term use of high-dose hormonal steroids. Jaundice may occur in susceptible individuals.
• Hypersensitivity Reactions: True anaphylaxis is rare but possible. Urticaria, rash, and angioedema have been reported.
• Intrauterine System-Specific Risks: Uterine perforation (rare, occurs at insertion), pelvic inflammatory disease (risk highest in the first 20 days after insertion), and embedment of the IUS in the myometrium.
• Vision Changes: Discontinuation should be considered if there is a onset of migraine, or if there is any sudden partial or complete loss of vision, diplopia, or papilledema.

Black Box Warnings and Contraindications

Levonorgestrel itself does not carry a specific FDA Black Box Warning. However, cigarette smoking increases the risk of serious cardiovascular side effects from combined oral contraceptives containing levonorgestrel; this is boxed for COCs, not for progestin-only products. Contraindications are largely shared with other hormonal contraceptives and include known or suspected pregnancy (for continuous contraception, not for emergency use), undiagnosed abnormal genital bleeding, known or suspected carcinoma of the breast or other progestin-sensitive neoplasms, active liver disease or liver tumors (benign or malignant), and hypersensitivity to any component of the formulation.

Drug Interactions

Interactions can alter the pharmacokinetics or pharmacodynamics of levonorgestrel, potentially reducing its efficacy or increasing toxicity.

Major Drug-Drug Interactions

• Enzyme Inducers: Drugs that induce hepatic cytochrome P450 enzymes, particularly CYP3A4, can significantly increase the metabolism of levonorgestrel, leading to subtherapeutic plasma levels and contraceptive failure. This is a critical interaction for both regular and emergency contraception. Potent inducers include:
  • Anticonvulsants: Carbamazepine, phenytoin, phenobarbital, primidone, topiramate (at doses >200 mg/day).
  • Antimicrobials: Rifampicin, rifabutin, griseofulvin.
  • Antiretrovirals: Efavirenz, nevirapine, ritonavir-boosted protease inhibitors (some may inhibit).
  • Others: Modafinil, St. John’s wort (Hypericum perforatum).

  Concomitant use requires a significant increase in the dose of levonorgestrel (which is often not feasible with fixed-dose products) or, more commonly, the use of a non-hormonal backup contraceptive method or a switch to a non-oral contraceptive less affected by metabolism (e.g., IUS).

• Enzyme Inhibitors: Drugs that inhibit CYP3A4, such as ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, and grapefruit juice, may increase levonorgestrel plasma concentrations. This interaction is less clinically concerning but could theoretically increase the risk of progestin-related side effects.
• Other Hormonal Agents: Concurrent use of other systemic hormonal therapies may alter the bleeding profile or overall hormonal milieu, but does not typically reduce contraceptive efficacy of progestin-only methods.
• Drugs Affecting Gastrointestinal Motility or Flora: Broad-spectrum antibiotics (other than enzyme inducers) are not conclusively proven to reduce the efficacy of progestin-only pills, as their primary mechanism does not depend on enterohepatic recirculation. However, clinical prudence often suggests using backup contraception during and for 7 days after a course of antibiotics if diarrhea or vomiting occurs.

Effects of Levonorgestrel on Other Drugs

Levonorgestrel may influence the metabolism of other drugs, though these effects are usually modest.

• Anticoagulants: Progestins may potentially affect the synthesis of clotting factors and could theoretically alter the response to anticoagulants like warfarin, requiring closer monitoring of INR.
• Antidiabetic Agents: Progestins may decrease glucose tolerance and increase insulin resistance, potentially necessitating adjustment of insulin or oral hypoglycemic drug doses.
• Cyclosporine: Hormonal contraceptives may inhibit the metabolism of cyclosporine, potentially increasing its plasma levels and risk of toxicity.
• Seizure Threshold: The effect on seizure threshold is variable; some reports suggest progestins may have anticonvulsant properties, while others note potential for increased seizure frequency.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy: Levonorgestrel is contraindicated for continuous contraception during known pregnancy (Pregnancy Category X for this indication) due to a lack of necessity and theoretical risks. However, numerous cohort studies have found no increased risk of teratogenicity or adverse pregnancy outcomes following accidental exposure during early pregnancy. Importantly, emergency contraception is not contraindicated in pregnancy because it is not effective after implantation has occurred. If a woman is already pregnant, taking levonorgestrel emergency contraception will not harm the fetus or cause an abortion.

Lactation: Levonorgestrel is considered compatible with breastfeeding. It is excreted in breast milk in small quantities, with estimates suggesting an infant would receive less than 1% of the maternal weight-adjusted dose. No adverse effects on infant growth, development, or health have been demonstrated. Progestin-only pills, including those containing levonorgestrel, are a preferred contraceptive choice for breastfeeding women, typically initiated 4-6 weeks postpartum. The levonorgestrel-IUS and implant are also suitable options. Combined products containing levonorgestrel are usually deferred until at least 4-6 weeks postpartum due to theoretical concerns about estrogen effects on milk supply.

Pediatric and Adolescent Considerations

Levonorgestrel-containing contraceptives are commonly used in adolescents. The World Health Organization (WHO) states that there are no medical restrictions (Medical Eligibility Criteria Category 1 or 2) for the use of most progestin-only methods, including levonorgestrel, in adolescents from menarche onward. Counseling should address adherence (crucial for the daily mini-pill), management of irregular bleeding, and reassurance about safety. The 1.5 mg emergency contraceptive is approved for use in adolescents without age restrictions. The levonorgestrel-IUS is highly effective and appropriate for nulliparous adolescents, though insertion may be more challenging and require cervical preparation.

Geriatric Considerations

Formal use of levonorgestrel for contraception ceases at menopause (age 50-55). However, it remains relevant in perimenopausal women for contraception and management of heavy bleeding. In postmenopausal women, low-dose levonorgestrel is used as the progestogenic component in HRT. Age-related declines in hepatic and renal function are not considered clinically significant barriers to use at standard doses, as the drug has a wide therapeutic index. Cardiovascular risk factors, which increase with age, should be assessed, particularly if considering a combined estrogen-levonorgestrel product.

Renal and Hepatic Impairment

Renal Impairment: No specific dose adjustments are recommended for levonorgestrel in patients with renal impairment. Since renal excretion accounts for a portion of elimination, accumulation could theoretically occur in severe renal failure, but clinical data are lacking. The drug is not dialyzable due to high protein binding. Use with caution and monitor for side effects.

Hepatic Impairment: Levonorgestrel is contraindicated in acute or severe hepatic disease (including liver tumors, active viral hepatitis, decompensated cirrhosis) because the liver is the primary site of its metabolism. Impaired hepatic function can lead to decreased clearance and significant accumulation of the drug, increasing the risk of adverse effects. In mild chronic liver disease (e.g., compensated cirrhosis), the benefits of progestin-only contraception may outweigh risks (WHO Category 2 or 3), but careful monitoring is advised. The levonorgestrel-IUS, with its low systemic exposure, may be a preferred option in some cases of mild hepatic impairment.

Summary/Key Points

• Levonorgestrel is a potent first-generation synthetic progestin derived from 19-nortestosterone, used across a wide spectrum of reproductive health applications.
• Its mechanism of action is context-dependent: it primarily inhibits ovulation and alters cervical mucus in regular contraception, while emergency contraception works mainly by delaying or inhibiting ovulation if administered pre-ovulation.
• Pharmacokinetically, it is well-absorbed orally with high first-pass metabolism, extensively protein-bound (to SHBG), metabolized by CYP3A4, and eliminated with a half-life of 24-32 hours. Formulations range from oral tablets to long-acting implants and intrauterine systems, each with distinct PK profiles.
• Major therapeutic uses include emergency contraception, progestin-only and combined oral contraception, long-acting reversible contraception (implants, IUS), and endometrial protection in HRT. The levonorgestrel-IUS is also approved for heavy menstrual bleeding.
• Common adverse effects are menstrual irregularities, headache, nausea, and androgenic symptoms like acne. Serious risks are rare but include ectopic pregnancy (if method fails) and, with combined products, thromboembolism.
• Clinically significant drug interactions primarily involve hepatic enzyme inducers (e.g., rifampin, certain anticonvulsants, St. John’s wort), which can drastically reduce levonorgestrel levels and compromise contraceptive efficacy.
• It is considered safe during lactation and is a preferred contraceptive for breastfeeding women. Accidental use during pregnancy is not associated with teratogenicity. Use requires caution in severe hepatic impairment.

Clinical Pearls

• For emergency contraception, efficacy is time-critical; administer as soon as possible after unprotected intercourse, ideally within 72 hours, though some formulations are labeled for up to 120 hours.
• When prescribing regular levonorgestrel contraception (especially the mini-pill), emphasize the necessity of strict adherence to a consistent daily dosing time (within a 3-hour window) to maintain contraceptive efficacy.
• Always inquire about concomitant medications, particularly enzyme inducers, before prescribing levonorgestrel for contraception. For women on long-term enzyme inducers, a non-oral method (e.g., IUS, implant) is often the most reliable choice.
• Counsel patients initiating a levonorgestrel method (especially progestin-only pills, implant, or IUS) about the high likelihood of irregular bleeding or spotting in the first 3-6 months, which typically improves with continued use.
• Recognize that the levonorgestrel-releasing IUS has therapeutic benefits beyond contraception, including first-line medical management for heavy menstrual bleeding and endometrial hyperplasia without atypia.

References

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