What is the effect of ethinyl estradiol (EE) in contraception?

Effect of Ethinyl Estradiol in Contraception

Ethinyl estradiol (EE) is the essential estrogen component in combined oral contraceptives that prevents pregnancy by suppressing ovulation through inhibition of gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone, with typical doses of 30-35 μg providing highly effective contraception when used correctly. 1, 2

Mechanism of Contraceptive Action

Ethinyl estradiol works synergistically with progestins in combined oral contraceptives through multiple mechanisms 1:

• Ovulation suppression: EE inhibits the hypothalamic-pituitary-gonadal axis, preventing the mid-cycle LH surge necessary for ovulation 1, 2
• Endometrial effects: Combined with progestins, EE creates an endometrial environment less favorable for implantation 1
• Cervical mucus changes: The hormonal combination thickens cervical mucus, impeding sperm penetration 1

Dosing Considerations for Contraceptive Efficacy

The standard first-line dose is 30-35 μg of ethinyl estradiol combined with a progestin such as levonorgestrel or norgestimate, as this provides optimal contraceptive effectiveness with an acceptable safety profile. 2

Lower-Dose Formulations (20 μg EE)

• Require stricter adherence: Seven consecutive days of pill-taking is necessary to reliably prevent ovulation, and studies show more follicular activity when 20 μg pills are missed compared to 30 μg formulations 1, 2
• Higher discontinuation rates: 20 μg EE formulations result in increased early discontinuation due to irregular bleeding and breakthrough bleeding compared to higher-dose pills 3
• Contraceptive effectiveness: While pregnancy rates remain low (0-2 per 5,000 cycles), the margin for error with missed pills is narrower 4

Standard-Dose Formulations (30-35 μg EE)

• More forgiving with missed doses: Provide greater ovulation suppression, allowing for occasional missed pills without immediate loss of contraceptive protection 1, 2
• Better cycle control: Result in fewer bleeding disturbances and lower discontinuation rates 3
• Established safety profile: Second-generation progestins combined with 30-35 μg EE demonstrate the safest coagulation profile 2

Cardiovascular and Thrombotic Risks

All COCs containing ethinyl estradiol increase the risk of venous thromboembolism (VTE) from a baseline of 1-5 per 10,000 woman-years to 3-9 per 10,000 woman-years, though this remains significantly lower than the VTE risk during pregnancy (10-20 per 10,000 woman-years). 1, 2

Dose-Related Effects

• Historical context: Doses above 50 μg EE (no longer available in the US) were associated with higher VTE risks 1
• Current evidence: COCs with 35 μg or more EE show statistically higher odds ratios for VTE than lower doses, though the absolute risk difference is small 2
• Hepatic protein effects: EE causes dose-dependent increases in factor VII:Ag, factor VIII:C, and other coagulation factors, creating a hypercoagulable state 5, 6

Route of Administration

• Oral vs. vaginal delivery: Hemostatic changes and hepatic protein alterations are similar regardless of delivery route, indicating these effects are intrinsic to EE itself rather than first-pass metabolism 6

Additional Cardiovascular Considerations

• Myocardial infarction: Risk is strongly associated with cigarette smoking and other cardiovascular risk factors; healthy, normotensive, nondiabetic nonsmokers show no increased MI risk at any age 1
• Stroke risk: Increased risk of both ischemic and hemorrhagic stroke, particularly in women with hypertension, smoking history, or age ≥35 years 1
• Blood pressure effects: Newer formulations with drospirenone may help mitigate blood pressure increases due to anti-mineralocorticoid effects 2

Contraindications to EE-Containing Contraceptives

Do not prescribe COCs with ethinyl estradiol to patients with the following conditions 2:

• Severe and uncontrolled hypertension
• Ongoing hepatic dysfunction
• Complicated valvular heart disease
• Migraines with aura or focal neurologic symptoms
• History of thromboembolism or thrombophilia
• Complications of diabetes
• Smoking in women ≥35 years old (though smoking alone is not a contraindication in women <35 years) 2

Drug Interactions Affecting Contraceptive Efficacy

Certain medications reduce ethinyl estradiol levels, potentially compromising contraceptive effectiveness and requiring alternative or additional contraceptive methods 1, 2:

• Ritonavir-boosted protease inhibitors: Significantly decrease hormonal levels; alternative contraception should be considered 1
• NNRTIs: Nevirapine and efavirenz induce EE metabolism and reduce hormonal levels, though etravirine and rilpivirine do not cause the same reduction 1
• No interactions: Nucleoside reverse transcriptase inhibitors, integrase inhibitors (raltegravir, dolutegravir), entry inhibitors (maraviroc), and fusion inhibitors (enfuvirtide) 1

Clinical Management Pearls

Initiation Protocol

• Quick start method: COCs can be started on the same day as the visit in healthy, nonpregnant individuals, with backup contraception used for the first 7 days 2
• Timing considerations: If starting more than 5 days after menstrual bleeding began, use backup contraception for the first 7 days 2

Missed Pill Management

For one missed pill (24 to <48 hours late) 1:

• Take the missed pill immediately
• Continue remaining pills at usual time
• Use backup contraception for 7 consecutive days
• Consider emergency contraception if pills were missed in the first week and unprotected intercourse occurred in the previous 5 days

For two or more consecutive missed pills (≥48 hours late) 1:

• Take the most recent missed pill immediately
• Use backup contraception until 7 consecutive days of pills have been taken
• If missed in the last week of hormonal pills, omit the hormone-free interval and start a new pack immediately

Prescribing Practices

• Duration: Prescribe up to 1 year of COCs at a time to improve adherence and reduce barriers to access 2
• Formulation selection: Among low-dose pills, no clear data suggest one formulation is superior for most users; the lowest copay option on insurance formulary is often appropriate 2
• Monitoring: Blood pressure should be monitored regularly throughout treatment 2

Non-Contraceptive Benefits

Beyond pregnancy prevention, ethinyl estradiol in COCs provides 1, 2:

• Acne treatment: Anti-androgenic properties decrease ovarian androgen production, increase sex hormone-binding globulin, and reduce free testosterone 1
• Menstrual benefits: Decreased cramping, reduced blood loss, and predictable bleeding patterns 2
• Cancer protection: Long-term use (>3 years) provides significant protection against endometrial and ovarian cancers 2
• Treatment of medical conditions: Beneficial for anemia, severe dysmenorrhea, endometriosis, abnormal uterine bleeding, and bleeding disorders 2

Common Pitfalls to Avoid

• Do not arbitrarily limit COC use based on age: Healthy, nonsmoking women can safely use EE-containing COCs throughout their reproductive years 2
• Do not assume lower EE doses are safer: While theoretically appealing, no evidence supports improved safety with 20 μg vs. 30-35 μg formulations, and lower doses have higher discontinuation rates due to bleeding irregularities 3, 4
• Do not overlook drug interactions: Always review antiretroviral therapy, anticonvulsants, and other medications that may reduce EE levels 1, 2
• Do not forget backup contraception: Seven consecutive days of hormone pills are required to reliably prevent ovulation after missed pills or when starting COCs 1, 2