What is the role of ethinyl estradiol (EE) alone and in combination with levonorgestrel (progestin) in contraception?

Role of Ethinyl Estradiol Alone and in Combination with Levonorgestrel in Contraception

Ethinyl estradiol (EE) is never used alone for contraception; it must be combined with a progestin like levonorgestrel to prevent pregnancy effectively. 1

Why Ethinyl Estradiol Cannot Be Used Alone

• Ethinyl estradiol alone does not suppress ovulation reliably and lacks the progestational effects necessary for contraception, including cervical mucus thickening and endometrial changes that prevent sperm penetration and implantation 1
• The FDA-approved indication for ethinyl estradiol is exclusively in combination formulations with progestins for pregnancy prevention 1
• No clinical evidence supports the use of ethinyl estradiol monotherapy for contraceptive purposes

Mechanism of Action: Combined Ethinyl Estradiol/Levonorgestrel

Combined oral contraceptives containing ethinyl estradiol and levonorgestrel prevent pregnancy through multiple complementary mechanisms:

• Primary mechanism: Suppression of gonadotropins (FSH and LH), which inhibits ovulation 1, 2
• Secondary mechanisms: Changes in cervical mucus that increase difficulty of sperm entry into the uterus, and alterations in the endometrium that reduce likelihood of implantation 1
• Levonorgestrel demonstrates high progestational activity with minimal androgenic effects, contributing to the overall contraceptive efficacy 1

Contraceptive Efficacy

Low-dose ethinyl estradiol/levonorgestrel combinations (20-35 μg EE) provide highly effective contraception with Pearl Index values of 0.88-1.26 per 100 woman-years:

• The typical-use failure rate for combined oral contraceptives is approximately 5%, while perfect-use failure rate is 0.1% 1
• A large trial of continuous-use ethinyl estradiol 20 μg/levonorgestrel 90 μg demonstrated a Pearl Index of 1.26 over 12 months 2
• Standard cyclic ethinyl estradiol 20 μg/levonorgestrel 100 μg showed a Pearl Index of 0.88 in a 3-year trial with 26,554 evaluable cycles 3
• Contraceptive efficacy is comparable across different low-dose formulations (20-35 μg ethinyl estradiol) when used correctly 4, 3

Available Formulations and Dosing

Multiple formulations exist with varying doses of ethinyl estradiol (20-35 μg) combined with levonorgestrel:

• Standard monophasic pills: Most commonly prescribed are formulations containing 30-35 μg ethinyl estradiol with levonorgestrel, recommended as first-line for adolescents 4
• Low-dose options: 20 μg ethinyl estradiol combined with 90-100 μg levonorgestrel provides effective contraception with potentially fewer estrogen-related side effects 4, 2, 3
• Extended-cycle regimens: Continuous-use formulations (e.g., 20 μg EE/90 μg levonorgestrel) eliminate hormone-free intervals, optimizing ovarian suppression and potentially increasing effectiveness, especially among adolescents who frequently miss pills 4, 2
• Standard pill packs: Contain 21-24 hormone pills and 4-7 placebo pills in 28-day cycles 4

Clinical Algorithm for Prescribing

Start with a monophasic combined oral contraceptive containing 30-35 μg ethinyl estradiol and levonorgestrel for most patients:

1. Initial selection: Choose the formulation with the lowest copay on patient's insurance, as no clear data suggest superiority of one low-dose formulation over another for general use 4

2. Consider 20 μg ethinyl estradiol formulations for:

   • Patients concerned about estrogen-related side effects
   • Those who prefer lower hormone exposure
   • Note: Efficacy remains comparable to higher-dose formulations 3, 5

3. Consider extended-cycle regimens for:

   • Adolescents with compliance concerns (eliminates weekly pill-taking variations) 4
   • Patients with menstrual-related symptoms that worsen cyclically 4
   • Those desiring fewer withdrawal bleeds 2

4. Adjust based on response:

   • If breakthrough bleeding occurs, consider switching to different progestin or extending cycles 4
   • If adverse effects develop, consider lower estrogen dose (20 μg) formulations 4

Safety Considerations and Contraindications

Absolute contraindications (WHO Category 4) include:

• History of venous thromboembolism or pulmonary embolism 4
• Ischemic heart disease (current or history) 4
• History of cerebrovascular accident 4
• Migraine with focal neurologic symptoms at any age, or migraine without aura if ≥35 years 4
• Active viral hepatitis, severe decompensated cirrhosis, or liver tumor 4
• Breast cancer history with <5 years disease-free 4
• Major surgery with prolonged immobilization 4

Relative contraindications (WHO Category 3) requiring careful consideration:

• Breast cancer history with ≥5 years disease-free 4
• Mild compensated cirrhosis 4
• History of cholestasis related to COC use 4
• Concurrent use of drugs affecting liver enzymes 4

Stroke risk considerations:

• Combined hormonal contraceptives containing ≤20 μg ethinyl estradiol have lower stroke risk compared to preparations with higher estrogen content (OR 1.19 per 10 μg increase) 4
• For women with hypertension, smoking, or migraine with aura, progestin-only methods should be strongly considered instead 4
• The absolute stroke risk remains lower than stroke risk from pregnancy (8.8 vs 30 per 100,000) 4

Emergency Contraception Use

The Yuzpe regimen uses combined ethinyl estradiol/levonorgestrel for emergency contraception, but is now considered inferior to other options:

• Dosing: Two doses of 100 μg ethinyl estradiol plus 0.50 mg levonorgestrel, taken 12 hours apart 4
• Effectiveness: 57% success rate with 3.2% failure rate, significantly less effective than levonorgestrel-only (85% success rate, 1.1% failure rate) or ulipristal acetate 4, 6
• Side effects: More frequent nausea and vomiting compared to levonorgestrel-only regimens 4
• Current recommendation: Levonorgestrel 1.5 mg single dose or ulipristal acetate 30 mg are preferred over the combined regimen for emergency contraception 4, 7, 8

Patients already on combined oral contraceptives can and should use emergency contraception if:

• Unprotected intercourse occurred during the first week of pill pack or when ≥2 consecutive pills were missed 4, 8
• Unprotected intercourse occurred in the previous 5 days with missed doses 8
• The existing hormonal contraception does not interfere with emergency contraception effectiveness 8

Missed Pill Instructions

Critical timing determines the need for backup contraception:

• One pill late (<24 hours): Take as soon as remembered, continue as usual, no backup needed 4

• One pill missed (24-48 hours): Take most recent missed pill immediately, discard other missed pills, continue remaining pills at usual time, use backup contraception or abstain for 7 consecutive days 4

• Two or more pills missed (>48 hours): Take most recent missed pill immediately, discard other missed pills, use backup contraception or abstain for 7 consecutive days; if pills were missed in the last week of hormonal pills, omit hormone-free interval and start new pack immediately 4

• Emergency contraception should be considered if hormonal pills were missed during the first week and unprotected intercourse occurred in the previous 5 days 4

Return to Fertility

Fertility returns rapidly after discontinuation:

• Hormonal and ultrasound changes indicative of reinstated ovulation occur within one month of discontinuation 2
• Menstruation begins again in most women within 90 days 2
• Combined oral contraceptives have no negative effect on long-term fertility and are completely reversible 4

Long-Term Benefits

Extended use provides significant non-contraceptive benefits:

• Use for more than 3 years provides significant protection against endometrial and ovarian cancers 4
• No increased risk of breast cancer with COC use 4
• Improvement in menstrual cycle-related symptoms with continuous-use regimens 2

Common Pitfalls to Avoid

• Never prescribe ethinyl estradiol alone for contraception—it is ineffective without a progestin component 1
• Do not assume all low-dose formulations are equivalent for stroke risk—each 10 μg increase in ethinyl estradiol increases stroke risk (OR 1.19) 4
• Do not use combined estrogen/progestin regimen for emergency contraception when levonorgestrel-only or ulipristal acetate are available—it is less effective and causes more side effects 4, 7
• Do not overlook laboratory-verified noncompliance (11-12.6% of users have undetectable plasma drug levels), which significantly impacts real-world efficacy 5
• Do not forget that obesity may reduce effectiveness of emergency contraception with levonorgestrel, requiring consideration of ulipristal acetate or copper IUD 4, 7