|Systematic (IUPAC) name|
|AHFS/Drugs.com||International Drug Names|
|Protein binding||97–98% (to albumin; does not bind to SHBG)|
|Biological half-life||10–36 hours|
|ATC code||G03CA01 (WHO) L02AA03 (WHO)|
|Molar mass||296.403 g/mol|
Ethinyl estradiol (EE) (USP) (former brand name Estinyl), or ethinylestradiol (INN, USAN, JAN), also spelled as ethinylœstradiol (BAN), is a synthetic, steroidal estrogen. It is a derivative of estradiol, the major endogenous estrogen in humans; specifically, EE is 17α-ethynylestradiol. EE is an orally active estrogen used in many formulations of combined oral contraceptives (COCs), and is the most commonly used estrogen for this purpose.
As Estinyl, EE was formerly used for hormone replacement therapy in menopause and the treatment of female hypogonadism, loss of menstruation, dysmenorrhea, acne, prostate cancer, and breast cancer. However, in more recent times, EE is mainly used in COCs. In contraception, due to concerns of unopposed estrogen action and the possible increased risk of endometrial cancer that accompanies this, EE is formulated in combination with progestins. EE is no longer used in menopausal hormone replacement therapy.
The original formulations of combined oral contraceptives contained as much as 150 μg EE. However, it was soon found that EE is associated with incidence of venous thromboembolism and that the risk is dose-dependent. Subsequently, the dosage of EE was greatly reduced, and is now generally between 25 and 35 μg, in some cases less than 20 μg, and not more than 50 μg. These lower dosages have a significantly reduced risk of venous thromboembolism with no loss of contraceptive effectiveness. According to a bulletin posted by the U.S. FDA, the rate of deep vein thrombosis in women taking COCs containing 20 to 40 μg EE is 4 per 10,000, which is approximately equivalent to the rate of 3 per 10,000 in women not taking a COC. No study has shown a further reduced risk of venous thromboembolism below an EE dosage of 30 or 35 μg.
EE carries a greater risk of blood clot formation and venous thromboembolism than natural estradiol, which has been theorized to be related to different amounts of hepatic metabolism after absorption. The same contraindications and precautions apply for EE as with other estrogens.
EE is an estrogen similarly to natural estrogens like estradiol and conjugated equine estrogens and synthetic estrogens like diethylstilbestrol. It binds to and activates both isoforms of the estrogen receptor, ERα and ERβ, with similar affinity to that of estradiol.
Orally, EE is about 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated equine estrogens. This appears to be true in regards to both modification of hepatic protein synthesis and antigonadotropic activity. In contrast, the potencies of EE and natural estrogens are reportedly similar when they are administered intravenously, due to bypassing of first-pass hepatic metabolism. Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.
The oral bioavailability of EE is 38–48%, with a large range of 20% to 65% (mean 45%) due to high inter-individual variability. Although relatively low, the oral bioavailability of EE is considerably higher than that of estradiol (5%). EE is metabolized mainly by 2-hydroxylation, primarily by CYP3A4. Hydroxylation of EE at the C4, C6, and C16β positions have also been reported, but appear to contribute to its metabolism to only a small extent. Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, presumably owing to steric hindrance of its ethinyl group at C17α. A literature review found that the range of the reported terminal half-life of EE in the literature was 13.1 to 27.0 hours. However, the terminal half-life of EE has also been reported as 36 ± 13 hours Another review reported a terminal half-life of EE of 10–20 hours. Steady-state concentrations are reached after one week of daily administration. Unlike estradiol, which binds with high affinity to sex hormone-binding globulin, EE does not bind to this protein and is instead bound mainly to albumin (97–98%).
The first orally active semisynthetic steroidal estrogen, EE (17α-ethynylestradiol), the 17α-ethynyl analogue of estradiol, was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin. EE was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering as Estinyl. The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.
- Ethinyl estradiol sulfonate
- Cloxestradiol acetate
- Ethinyl estriol
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The binding affinity of EE for the estrogen receptor is similar to that of estradiol. [...] During daily intake, the EE levels increase up to a steady state which is reached after about 1 week.
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Following a recommendation by its Fertility and Maternal Health Drugs Advisory Committee, the Food and Drug Administration (FDA) recently ordered the removal from the market of all oral contraceptives with [ethinyl estradiol] contents greater than 50 μg.
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Oral contraceptive formulations containing greater than 50 ug ethinyl estradiol were removed from the United States market in 1989, and currently marketed formulations generally contain between 20 and 35 μg ethinyl estradiol.
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Low-dose COCs contain <50 μg of estrogen and are the primary choice for oral contraception. COCs containing ≥50 μg of estrogen should no longer be routinely used for contraception.
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The synthetic estrogen, ethinyl estradiol, more commonly used in oral contraceptives, has a biological activity 100 times that of the native and conjugated substances.
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EE has about 100 times the potency of an equivalent weight of conjugated equine estrogen or estrone sulfate for stimulating synthesis of hepatic proteins. [...] EE is about 1.7 times as potent as the same weight of mestranol.
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Meyer et al. found that ethinyl estradiol was 75 to 100 times more potent than conjugated estrogen on the basis of the doses required to lower testosterone to the adult female range, 0.1 mg of the former and 7.5 to 10 mg of the latter being necessary.
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