Ethinylestradiol is a synthetic form of the natural hormone estradiol, a type of estrogen. It is widely used in combination with progestins in oral contraceptive pills, hormone replacement therapy (HRT), and for the treatment of menstrual disorders, acne, and estrogen deficiency. Due to its high oral bioavailability and potency, ethinylestradiol has become a key component in hormonal therapies. Ethinylestradiol was first introduced in the 1960s as part of the first generation of combined oral contraceptives (COCs). It has since received regulatory approval from health authorities such as the U.S. FDA, EMA (European Medicines Agency), and other national agencies for various indications related to contraception, hormone therapy, and gynecological conditions. It is included in numerous combination products rather than as a standalone drug in most countries.
BRAND NAMES
Yaz: Yaz is a combined oral contraceptive containing ethinylestradiol (20 mcg) and drospirenone (3 mg). It is used for pregnancy prevention, acne treatment, and premenstrual dysphoric disorder.
Microgynon: Microgynon is a combined oral contraceptive containing ethinylestradiol (30 mcg) and levonorgestrel (150 mcg). It is used to prevent pregnancy and regulate menstrual cycles.
MECHANISM OF ACTION
Ethinylestradiol is a synthetic estrogen that exerts its effects by binding to estrogen receptors in various target tissues, leading to modulation of gene expression and promotion of estrogenic activity. In hormonal contraceptives, its primary mechanism involves the suppression of the hypothalamic-pituitary-gonadal axis, resulting in decreased secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This inhibition prevents ovulation, the release of an egg from the ovary. Ethinylestradiol also helps stabilize the endometrial lining, reducing the risk of irregular bleeding, and increases the expression of progesterone receptors, enhancing the effectiveness of co-administered progestins. When used in combination with a progestin, it contributes to changes in cervical mucus and endometrial structure, making it more difficult for sperm to reach the egg and for a fertilized egg to implant, thereby ensuring effective contraception.
PHARMACOKINETICS
Absorption:
Ethinylestradiol is rapidly and efficiently absorbed after oral administration, with a bioavailability of ~40–45% due to first-pass hepatic metabolism.
Distribution:
Widely distributed in body tissues and highly bound to albumin in plasma (not to sex hormone-binding globulin).
Metabolism:
Undergoes extensive hepatic metabolism, primarily via CYP3A4 and subjected to enterohepatic recirculation, prolonging its presence in the body, metabolized into inactive hydroxylated and conjugated forms (glucuronides and sulfates).
Elimination:
Eliminated mainly via urine (60%) and feces (40%) as metabolites and terminal half-life approximately 13–27 hours
DOSAGE AND ADMINISTRATION
Ethinylestradiol is taken orally once daily, most often as part of a combined oral contraceptive (COC) with a progestin. It is typically administered in 28-day regimens consisting of 21 active hormone tablets followed by 7 placebo tablets, or in some cases, 24 active and 4 placebo tablets to improve cycle control. The usual dose ranges from 20 to 35 micrograms of ethinylestradiol per tablet. For continuous contraceptive protection, it's important to start the next pack immediately after finishing the last, without gaps between cycles.
DRUG INTERACTIONS
- CYP3A4 inducers (e.g., rifampin, phenytoin) ↓ contraceptive effectiveness.
- CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) ↑ estrogen levels and side effects.
- Antibiotics (e.g., ampicillin, tetracyclines) may reduce efficacy via gut flora disruption.
- Lamotrigine: Levels may decrease, reducing seizure control.
- Warfarin: Estrogen may reduce its anticoagulant effect.
CONTRAINDICATIONS
- Pregnancy: Hormonal contraceptives should not be used during pregnancy as they offer no benefit and may pose risks.
- Thromboembolic disorders: History or current deep vein thrombosis (DVT), pulmonary embolism (PE), retinal vein thrombosis, or arterial thrombosis (e.g., stroke, myocardial infarction).
- Known thrombophilia: Inherited or acquired conditions such as Factor V Leiden, antithrombin III deficiency, protein C/S deficiency.
- Liver disease: Severe hepatic dysfunction, active liver disease, or hepatic tumors (benign or malignant).
- Uncontrolled hypertension: Especially if systolic >160 mmHg or diastolic >100 mmHg.
- Migraine with aura: Increased risk of stroke in users with this type of migraine.
- Hypersensitivity: To ethinylestradiol or any excipients in the formulation.
SIDE EFFECTS
- Nausea
- Headache
- Breast tenderness
- Breakthrough bleeding or spotting
- Weight changes
- Mood changes (e.g., depression, irritability)
- Bloating
- Changes in libido
- Skin changes
- Increased risk of thromboembolism
TOXICITY
Ethinylestradiol generally has a low risk of acute toxicity, and overdose typically results in mild symptoms such as nausea, vomiting, breast tenderness, or breakthrough bleeding, which are usually self-limiting. However, long-term or high-dose exposure can lead to serious toxicities, including an increased risk of thromboembolic events (such as deep vein thrombosis, pulmonary embolism, stroke, or myocardial infarction.
Prolonged use is also associated with a higher risk of developing liver tumors and estrogen-dependent cancers like breast or cervical cancer. Use during pregnancy is contraindicated, as it may potentially affect fetal development, although the teratogenic risk in humans is considered low. Due to these chronic risks, especially related to cancer and vascular complications, ethinylestradiol (in combination products) is classified as a Group 1 carcinogen by the International Agency for Research on Cancer.
