How does etonogestrel (Nexplanon) prevent pregnancy in women?

Mechanism of Action of Etonogestrel (Nexplanon)

Etonogestrel prevents pregnancy primarily by suppressing ovulation through inhibition of the mid-cycle luteinizing hormone surge, while also thickening cervical mucus to block sperm penetration and altering the endometrium to create an unfavorable environment for implantation. 1, 2

Primary Contraceptive Mechanisms

Ovulation Suppression (Most Important)

• Etonogestrel achieves contraceptive levels within 8 hours of insertion, reaching peak serum concentrations of 813 pg/ml at 4 days, then stabilizing at steady-state levels around 200 pg/ml after 4-6 months. 1
• The implant prevents the mid-cycle LH (luteinizing hormone) peak that triggers ovulation, which is the dominant mechanism of pregnancy prevention. 1
• Initially, etonogestrel completely suppresses follicular development and estradiol production, though ovarian activity gradually increases after 6 months with FSH and estradiol levels approaching normal ranges. 1
• Despite this partial recovery of ovarian function, endogenous progesterone levels remain in the subovulatory range for more than 3 years in most users, confirming continued ovulation suppression. 1
• Ultrasound studies demonstrate that ovulation occurs in less than 5% of users even after 30 months of use, reflecting the sustained effectiveness of ovulation inhibition. 1
• Recent research confirms that when inserted mid-cycle with a dominant follicle present, the implant suppresses ovulation in 65% of cases within 5 days, demonstrating rapid onset of action. 3

Cervical Mucus Changes (Secondary Mechanism)

• Etonogestrel thickens cervical mucus, creating a physical barrier that restricts or completely suppresses the access of fertile spermatozoa to the site of fertilization in the fallopian tubes. 2
• This mucus effect provides an important backup mechanism even in the rare instances when ovulation occurs. 2

Endometrial Effects (Tertiary Mechanism)

• The progestin exerts direct effects on the endometrium through endometrial progestin receptors, causing alterations in endometrial histology, thickness, and development. 4
• These endometrial changes create an unfavorable environment for implantation, though the exact contribution of this mechanism to overall contraceptive efficacy is difficult to quantify. 4, 2
• The endometrial effects also modify vascular, angiogenic, steroid receptor, and proto-oncogene function, which may explain the irregular bleeding patterns some users experience. 4

Clinical Efficacy and Reversibility

Contraceptive Effectiveness

• The combined mechanisms result in exceptional contraceptive efficacy with a failure rate of less than 0.05% during the 3-year approved duration, making it one of the most effective reversible methods available. 5
• Clinical trials demonstrate a zero pregnancy rate over 5,629 woman-years of use, reflecting the reliability of these multiple mechanisms working together. 1

Rapid Reversibility

• Etonogestrel becomes undetectable within 1 week of implant removal, allowing rapid return to fertility. 1
• Ovulation resumes in most women within 3-4 weeks after removal, demonstrating that the contraceptive effects are completely reversible. 1

Important Clinical Considerations

Timing and Backup Contraception

• When inserted within the first 5 days of menstrual bleeding, no additional contraception is needed as ovulation suppression is immediate. 6
• If inserted 6 or more days after menstrual bleeding started, backup contraception (condoms or abstinence) should be used for at least 7 days to ensure full contraceptive protection. 6, 5

Drug Interactions

• Hepatic enzyme-inducing drugs (efavirenz, nevirapine, most protease inhibitors) can reduce etonogestrel effectiveness by increasing its metabolism, requiring alternative or additional contraceptive methods. 5
• Standard oral antibiotics do not interfere with Nexplanon's effectiveness, unlike combined oral contraceptives. 5