Levonorgestrel

Indications

Levonorgestrel is primarily indicated for emergency contraception to prevent pregnancy following contraceptive failure or unprotected sexual intercourse. For individuals aged 17 and below, it is available by prescription, while those over 17 can access it over the counter. This levonorgestrel-only contraceptive is specifically formulated for emergency use and should be administered as promptly as possible, ideally within 72 hours post-intercourse. Its effectiveness decreases when used off-label beyond 96 hours. Additionally, levonorgestrel is effective when combined with other contraceptives, such as ethinyl estradiol, for regular contraceptive use, including hormone-releasing intrauterine devices and subdermal implants for long-term prevention. It is also utilized in hormone therapy during menopause and is occasionally prescribed off-label for conditions like menorrhagia, endometrial hyperplasia, and endometriosis.

Pharmacodynamics

Levonorgestrel exerts its contraceptive effects by disrupting ovulation, fertilization, and implantation processes. When used as directed within 72 hours of intercourse, the levonorgestrel-only emergency contraceptive tablet is approximately 89% effective. In contrast, levonorgestrel dispensed via intrauterine or implantable devices exhibits efficacy rates exceeding 99% in pregnancy prevention. Additionally, its role in hormonal therapy assists in preventing endometrial carcinoma associated with unopposed estrogen usage.

Absorption

The absorption of levonorgestrel varies depending on the mode of administration. Orally administered levonorgestrel is absorbed through the gastrointestinal tract, whereas intrauterine devices facilitate absorption directly in the endometrial lining. Subdermal implants enable immediate absorption into the interstitial fluids. Peak plasma concentration (Cmax) for oral administration is typically reached within an hour following a 0.75 mg dose. Conversely, the subdermal implant achieves Cmax within 2-3 days post-insertion. Factors such as body mass index (BMI) affect pharmacokinetic parameters, with normal BMI individuals exhibiting higher mean Cmax and area under the curve (AUC) values compared to those categorized as obese. The bioavailability of orally administered levonorgestrel approaches 100%, although obesity may diminish its contraceptive efficacy.

Metabolism

Once absorbed, orally administered levonorgestrel undergoes conjugation to form numerous sulfate and glucuronide conjugates detectable in plasma. The metabolic pathway includes 16β-hydroxylation, leading to the formation of both 3α, 5β-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel, albeit no active metabolites have been identified. The rate of metabolism is subject to individual variability, influencing levonorgestrel clearance. Metabolic processes primarily involve the liver enzymes CYP3A4 and CYP3A5.

Mechanism of Action

Levonorgestrel functions as an oral contraceptive by suppressing gonadotropin activity to inhibit ovulation. It achieves this by binding to progesterone and androgen receptors, subsequently reducing the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This suppression disrupts the normal physiological surge of luteinizing hormone (LH) that typically precedes ovulation, thereby preventing the rupture of follicles and the release of a viable egg from the ovaries. The efficacy of levonorgestrel is notably higher when administered prior to ovulation.