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Clinical data
Pronunciation /ˌɛθɪnɪlˌstrəˈd.əl/
Trade names Numerous
Synonyms 17α-Ethynylestradiol; 17α-Ethynylestra-1,3,5(10)-triene-3,17β-diol; NSC-10973[1]
AHFS/ International Drug Names
MedlinePlus a604032
License data
Routes of
By mouth (tablet)
Transdermal (patch)
Vaginal (ring)
Drug class Estrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 38–48%[3][4][5]
Protein binding 97–98% (to albumin;[6] is not bound to SHBG)[7]
Metabolism Liver (primarily CYP3A4)[2]
Elimination half-life 7–36 hours[8][3][2][9]
Excretion Feces: 62%[8]
Urine: 38%[8]
CAS Number
PubChem CID
ECHA InfoCard 100.000.311 Edit this at Wikidata
Chemical and physical data
Formula C20H24O2
Molar mass 296.403 g/mol
3D model (JSmol)
 NoYesY (what is this?)  (verify)

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins.[10] It is also occasionally used as a component of menopausal hormone therapy for the treatment of menopausal symptoms in combination with progestins.[10] In the past, EE was widely used alone for various indications such as the treatment of gynecological disorders and prostate cancer, but this is no longer the case, it is usually taken by mouth.[10]

The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others.[10] In men, EE can additionally cause breast development, feminization in general, hypogonadism, and sexual dysfunction. Rare but serious side effects include blood clots, liver damage, and cancer of the uterus.[10]

EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[10] It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways.[10] Compared to estradiol, EE has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus.[10] These differences make EE more favorable for use in birth control pills than estradiol, though also result in an increased risk of blood clots and certain other rare adverse effects.[10]

EE was developed in the 1930s and was introduced for medical use in 1943,[11][12] the drug started being used in birth control pills in the 1960s.[13] Today, EE is found in almost all combined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of if not the most widely used estrogens.[14][15]

Medical uses[edit]

There are many uses for EE, it is most commonly used as contraception in combined oral contraceptives (COC), also known as birth control, to prevent pregnancy after sex. EE in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during mensturation, and acne, the amount of EE in COCs has reduced over the years.[medical citation needed]

EE is also used as menopausal hormone therapy, the main reason for using HRT in menopausal women is to relieve common vasomotor symptoms such as hot flashes, night sweats, and flushing. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo.[16] Other common menopause symptoms such as vaginal dryness (which can cause pain during sexual intercourse), vaginal itching, and depressed mood, can benefit from HRT; in addition to treatment of menopausal symptoms, EE has been used as a component of feminizing hormone therapy for transgender women.[17] However, it is no longer commonly used nor recommended for this purpose, with estradiol having largely superseded it.[17]

EE or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of endometrial cancer; giving a progestin with an estrogen mitigates the risk.[18]

Moreover, EE can also be used to treat female hypogonadism, prevent osteoporosis in women, and has been used as palliative care for prostate cancer in men.[citation needed]


EE should be avoided in women with a history of or known susceptibility to arterial or venous thrombosis (blood clots), due to an increased risk of venous thromboembolism (VTE), myocardial infarction and ischemic stroke.[19] This includes women with:

EE should be avoided in women with current breast cancer due to a possible worsening of prognosis.[20]

EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE.[21] EE use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using EE.[21]

Due to risk of cholestatic hepatotoxicity, it is widely considered that COCs containing EE should be avoided in women with a history of cholestasis of pregnancy, hepatic tumors, active hepatitis, and familial defects in biliary excretion.[22]

Side effects[edit]

The severity of side effects can vary based on the dose and administration route of EE.[23] General side effects of EE are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain.[8][22] The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness;[24] in males, EE has additional side effects, including gynecomastia (breast development), feminization in general, hypogonadism, infertility, and sexual dysfunction (e.g., reduced libido and erectile dysfunction).

Rare reactions[edit]

Venous thromboembolism[edit]

EE carries a greater risk of blood clot formation and VTE than does natural estradiol, which is thought to be due to different degrees of hepatic metabolism between the two drugs (see below).

The original formulations of COCs contained as much as 150 μg EE.[25] However, it was soon found that EE is associated with incidence of VTE and that the risk is dose-dependent.[25] Subsequently, the dosage of EE was greatly reduced, and is now generally between 25 and 35 μg,[25] in some cases less than 20 μg,[25] and not more than 50 μg.[26][27][24] These lower dosages have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.[25] However, discontinuation of OCs are common with doses of estrogen from 10 to 20 μg due to its association "with higher rates of bleeding pattern disruptions."[23] 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.[28] No study has shown a further reduced risk of VTE below an EE dosage of 30 or 35 μg.[25]

Cholestatic hepatotoxicity[edit]

EE has, albeit rarely (at the low dosages that are now used in COCs), been associated with cholestatic hepatotoxicity similarly to 17α-alkylated anabolic–androgenic steroids and 17α-ethynylated 19-nortestosterone progestins.[29][30] Glucuronide metabolites of EE, via effects on the ABCB11 (BSEP) and MRP2 (ABCC2) proteins and consequent changes in bile flow and bile salt excretion, appear to be responsible for the cholestasis.[31] High concentrations of estradiol, via its metabolite estradiol D-glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy.[30] However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with EE than with estradiol, which is due to its 17α-ethynyl substitution and consequent reduced metabolism.[22]

Endometrial cancer[edit]

The high doses of EE that were used in early COCs were associated with a significantly increased risk of endometrial cancer in certain preparations, for instance those containing the progestogen dimethisterone.[32] Unopposed estrogens like EE have carcinogenic effects in the endometrium and progestogens protect against these effects, but dimethisterone is a relatively weak progestogen and was unable to adequately antagonize the endometrial carcinogenic effects of EE, in turn resulting in the increased risk of endometrial cancer.[32] COCs containing dimethisterone have since been discontinued (with more potent progestogens used instead) and doses of EE in COCs in general have been dramatically reduced, abrogating the risk;[32] in turn, most studies of modern COCs have found a decreased risk of endometrial cancer.[33]


EE is metabolized by certain cytochrome P450 isoforms, including CYP3A4 and CYP2C9.[34] Thus, inducers of enzymes such as CYP3A4 can decrease circulating concentrations of EE.[22] Examples of inducers include anticonvulsants like phenytoin, primidone, ethosuximide, phenobarbital, and carbamazepine; azole antifungals like fluconazole; and rifamycin antibiotics like rifampin (rifampicin).[22] Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE.[22] An example is troleandomycin, which is a potent and highly selective inhibitor of CYP3A4.[22]

Paracetamol (acetaminophen) has been found to competitively inhibit the sulfation of EE, with pretreatment of 1,000 mg of paracetamol significantly increasing the AUC levels of EE (by 22%) and decreasing the AUC levels of EE sulfate in women.[22] The same has been found for ascorbic acid (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.[22]

In contrast to estradiol, it is unlikely that there is a pharmacokinetic interaction between smoking (which potently induces certain cytochrome P450 enzymes and markedly increases the 2-hydroxylation of estradiol) and EE.[22] This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.[22] There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.[22]

The 19-nortestosterone progestins, gestodene and, to a lesser extent, desogestrel, have been found to inhibit cytochrome P450 enzymes and to progressively inhibit the metabolism and increase the concentrations of EE.[22]

EE has been found to significantly increase (by 38%) the AUC of omeprazole (which is metabolized by CYP2C19).[22]



EE is an estrogen similarly to natural estrogens like estradiol and conjugated estrogens (Premarin) and synthetic estrogens like diethylstilbestrol, it binds to and activates both isoforms of the estrogen receptor, ERα and ERβ.[35] In one study, EE was found to have 233% and 38% of the affinity of estradiol for the ERα and ERβ, respectively;[36] in another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively.[37] EE also appears to signal through the GPER, a membrane estrogen receptor, similarly to estradiol.[38][39][40] Estrogens have antigonadotropic effects through activation of the ERα,[41] as a contraceptive, EE acts in concert with a progestin to inhibit the mid-cycle surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via its antigonadotropic effects, thereby inhibiting folliculogenesis and preventing ovulation and hence the possibility of pregnancy.[42][43]

Orally, EE is about 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated estrogens, which is largely due to substantially greater resistance to first-pass metabolism.[44][45][46] In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism.[25] Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.[45]

Antiandrogenic effects[edit]

EE is a potent functional antiandrogen in both women and men,[52] it mediates its antiandrogenic effects by 1) stimulating the production of sex hormone-binding globulin (SHBG) in the liver, which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressing luteinizing hormone (LH) secretion from the pituitary gland, which decreases production of testosterone by the gonads.[52][53][54][55] Birth control pills that contain EE are useful in the treatment of androgen-dependent conditions like acne and hirsutism by virtue of their antiandrogenic effects.[52][56]

Birth control pills containing EE have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%.[54] Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold,[57] this is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy.[57] Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills;[8] in men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis).[53] The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.[58][8][59]

Estrogens are antigonadotropins and are able to suppress the secretion of LH from the pituitary gland and by extension gonadal testosterone production.[60][61] High-dose estrogen therapy, including with EE, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range.[62][60][61]

Differences from estradiol[edit]

Comparison of estradiol and ethinylestradiol[63]
Parameters Estradiol Ethinylestradiol
ER affinity 1 × 1010 M-1 2–5 × 1011 M-1
Nuclear retention 6–8 hours 24 hours
Blood half-life 90 minutes 7 hours
Substrate for 17β-HSD Yes No
Bound to SHBG Yes No
Relative liver potency 1 ~500–1,500
Relative pituitary potency 1 200

As can be seen in the tables, EE shows strong and disproportionate effects on hepatic protein production relative to estradiol,[10] the liver as well as the uterus express 17β-hydroxysteroid dehydrogenase (17β-HSD), and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues (analogously but in the opposite manner to potentiation of testosterone by 5α-reductase into the more potent dihydrotestosterone in so-called androgenic tissues like the skin, hair follicles, and prostate gland)[64] by reversibly converting it into the far less potent estrogen estrone (which has approximately 4% of the estrogenic activity of estradiol, most of which is actually due to conversion into estradiol).[10] In contrast to estradiol, the 17α-ethynyl group of EE prevents oxidation of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them.[10][65][9] This is the mechanism of the disproportionately strong effects of EE on hepatic protein production,[10][65] which results in a greatly increased magnitude of effect on VTE risk relative to estradiol.[66]

On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison,[10] this is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium.[10] The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol,[4] in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).[67]

EE has been found to have similar effects on hepatic protein production and VTE risk regardless of whether the route of administration is oral, transdermal, or vaginal, indicating that oral versus non-oral routes do not reduce the hepatic actions of EE relative to non-hepatic actions;[65] in contrast, at typical menopausal dosages, oral estradiol shows significant effects on hepatic protein production whereas transdermal estradiol shows few or no such effects.[10]



The oral bioavailability of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high interindividual variability.[8][5] Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%).[3][8] Following a single 20 μg dose of EE in combination with 1 mg norethisterone in postmenopausal women, EE concentrations have been found to reach a maximum of 50 pg/mL within an average of 1.5 hours.[10] Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached;[10] steady-state is reached after one week of daily administration.[35] For comparison, the mean peak levels of estradiol achieved with 2 mg micronized estradiol or estradiol valerate are 40 pg/mL following the first dose and 80 pg/mL after three weeks of administration.[10] These concentrations of estradiol are in the same range as the concentrations of EE that are produced by an oral dose of EE that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol;[44][10] in accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels.[10]


Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein of about 2% of that of estradiol, and hence does not bind to it importantly.[51] Instead, EE is bound almost exclusively to albumin (97–98%).[6][10][8][68] As estradiol that is bound to SHBG is considered to be hormonally inactive,[69] the lack of binding of EE to SHBG may in part be involved in its increased comparative potency.[citation needed]


Due to high first-pass metabolism in the intestines and liver, only 1% of an oral dose of an EE appears in the circulation as EE itself,[10] during first-pass metabolism, EE is extensively conjugated via sulfation into the hormonally inert EE sulfate, and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE.[10] For comparison, with oral administration of 2 mg micronized estradiol, levels of estrone and estrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively.[10] In contrast to estradiol, EE, due to steric hindrance by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD,[9] and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol.[10] Due to the formation of EE sulfate, enterohepatic circulation is involved in the pharmacokinetics of EE similarly to estradiol, although to a lesser extent.[10]

Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens,[10] this is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4.[8] Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent.[8] 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE.[10] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α,[8][10] the ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters.[10] A review found that the range of the reported terminal half-life of EE in the literature was 13.1 to 27.0 hours.[3] Another review reported a terminal half-life of EE of 10–20 hours.[8] However, the terminal half-life of EE has also been reported by other sources to be as short as 7 hours[9] and as long as 36 hours.[2]

Unlike the case of estradiol, in which there is a rapid rise in its levels and which remain elevated in a plateau-like curve for many hours, levels of EE fall rapidly after peaking,[10] this is thought to be because estrone and estrone sulfate can be reversibly converted back into estradiol and serve as a hormonally inert reservoir for estradiol, whereas the EE sulfate reservoir for EE is much smaller in comparison.[10]

EE, following oxidative formation of a very reactive metabolite, irreversibly inhibits cytochrome P450 enzymes involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol.[10] Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable.[68]


EE is eliminated 62% in the feces and 38% in the urine.[8]


EE is a synthetic estrane steroid and a derivative of estradiol with an ethynyl substitution at the C17α position.[1][70] It is also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol,[1][70] the 17α-ethynylation of EE is analogous to the 17α-substitution of testosterone derivatives such as 17α-ethynylated progestins like ethisterone (17α-ethynyltestosterone) and norethisterone (17α-ethynyl-19-nortestosterone) as well as 17α-alkylated anabolic steroids like methyltestosterone (17α-methyltestosterone).


A number of derivatives of EE exist,[1][70] these include mestranol (EE 3-methyl ether), quinestrol (EE 3-cyclopentyl ether), ethinylestradiol sulfonate (EE 3-isopropylsulfonate), and moxestrol (11β-methoxy-EE).[1][70] The former three are prodrugs of EE, while the latter one is not. A few 17α-substituted analogues of EE exist.[1][70] Examples include methylestradiol (17α-methylestradiol), ethylestradiol (17α-ethylestradiol), ethinylestriol (17α-ethynylestriol), and nilestriol (17α-ethynylestriol 3-cyclopentyl ether).[1][70]


EE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of Schering AG in Berlin.[71][72][73][74][75] It was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering under the brand name Estinyl.[12] The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.[76]

EE was first used in COCs, as an alternative to mestranol, in 1964, and shortly thereafter superseded mestranol in COCs.[13]

Society and culture[edit]

Generic names[edit]

Ethinylestradiol is the English generic name of the drug and its INN, USAN, BAN, and JAN.[77][1][78][70] It has also been spelled as ethynylestradiol, ethynyloestradiol, and ethinyloestradiol (all having the same pronunciation), and the latter was formerly its BAN but was eventually changed.[77][1][70] In addition, a space is often included in the name of EE such that it is written as ethinyl estradiol (as well as variations thereof), and this is its USP name.[77][70] The generic name of EE in French and its DCF are éthinylestradiol, in Spanish is etinilestradiol, in Italian and its DCIT are etinilestradiolo, and in Latin is ethinylestradiolum.[77][70]

The name of the drug is often abbreviated as EE or as EE2 in the medical literature.

Brand names[edit]

EE has been marketed as a standalone oral drug under the brand names Esteed, Estinyl, Feminone, Lynoral, Menolyn, Novestrol, Palonyl, Spanestrin, and Ylestrol among others, although most or all of these formulations are now discontinued.[79][80][70] It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive;[77] in addition, EE is marketed in the U.S. in combination with norelgestromin under the brand names Ortho Evra and Xulane as a contraceptive patch, in combination with etonogestrel under the brand name NuvaRing as a contraceptive vaginal ring, and in combination with norethisterone acetate under the brand name FemHRT in oral hormone replacement therapy for the treatment of menopausal symptoms.[81]


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Further reading[edit]

  • Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–27. doi:10.1016/j.contraception.2012.12.011. PMID 23375353.