Ethinyl estradiol

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Ethinyl estradiol
Ethinyl estradiol.svg
Systematic (IUPAC) name
Clinical data
Pronunciation /ˌɛθnlˌstrəˈd.əl/
Trade names Numerous
AHFS/ International Drug Names
MedlinePlus a604032
Routes of
Oral, transdermal
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 38–48%[1][2]
Protein binding 97–98% (to albumin;[3] does not bind to SHBG)[4]
Metabolism Liver (CYP3A4)[5]
Biological half-life 7–36 hours[6][1][5][7]
Excretion Feces: 62%[6]
Urine: 38%[6]
CAS Number 57-63-6 YesY
ATC code G03CA01 (WHO) L02AA03 (WHO)
PubChem CID 5991
DrugBank DB00977 YesY
ChemSpider 5770 YesY
UNII 423D2T571U YesY
KEGG D00554 YesY
Synonyms (17α)-19-Norpregna-1,3,5(10)-trien-20-yne-3,17β-diol
Chemical data
Formula C20H24O2
Molar mass 296.403 g/mol

Ethinyl estradiol (EE) (USP) (former brand name Estinyl), or ethinylestradiol (INN, USAN, JAN), also spelled as ethinylœstradiol (BAN) and also known as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol, is a synthetic, steroidal estrogen.[8][9][10] It is a derivative of estradiol, the major endogenous estrogen in humans; specifically, EE is 17α-ethynylestradiol.[8] EE is an orally active estrogen used in almost all formulations of combined oral contraceptives (COCs), being nearly the exclusive estrogen used for this purpose.[11]

Medical uses[edit]

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.[12] 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 little used in menopausal hormone replacement therapy.[13]

EE has been used at very high dosages (1–2 mg/day) in the treatment of prostate cancer.[14]


EE should be avoided in women with a history of or known susceptibility to thrombosis (blood clots), particularly venous thromboembolism (VTE).

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.[15]

Side effects[edit]

Side effects of EE are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain.[6][15] The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness.[16]

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.[17] However, it was soon found that EE is associated with incidence of VTE and that the risk is dose-dependent.[17] Subsequently, the dosage of EE was greatly reduced, and is now generally between 25 and 35 μg,[17] in some cases less than 20 μg,[17] and not more than 50 μg.[18][19][16] These lower dosages have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.[17] 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.[20] No study has shown a further reduced risk of VTE below an EE dosage of 30 or 35 μg.[17]

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.[21][22] 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.[23] High concentrations of estradiol, via its metabolite estradiol D-glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy.[22] 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.[15]

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.[24] 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.[24] 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.[24] In turn, most studies of modern COCs have found a decreased risk of endometrial cancer.[25]


Inducers of certain cytochrome P450 enzymes such as CYP3A4 can decrease circulating concentrations of EE.[15] Examples include anticonvulsants like phenytoin, primidone, ethosuximide, phenobarbital, and carbamazepine, azole antifungals like fluconazole, and rifamycin antibiotics like rifampin and rifampicin.[15] Conversely, inhibitors of CYP3A4 and certain other cytochrome P450 enzymes may increase circulating levels of EE.[15] An example is troleandomycin, which is a potent and highly selective inhibitor of CYP3A4.[15]

Paracetamol has been found to competitively inhibit the sulfation of EE, with pretreatment of 1 g paracetamol significantly increasing the AUC levels of EE (by 22%) and decreasing the AUC levels of EE sulfate in women.[15] The same has been found for ascorbic acid (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.[15]

Unlike the case of estradiol, there is probably no pharmacokinetic interaction between smoking (which potently induces certain cytochrome P450 enzymes and markedly increases the 2-hydroxylation of estradiol) and EE.[15] This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.[15] There is however still an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.[15]

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.[15]

EE has been found to significantly increase (by 38%) the AUC of omeprazole (which is metabolized by CYP2C19).[15]


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.[13] In one study, EE was found to have 233% and 37.8% of the affinity of estradiol for the ERα and ERβ, respectively.[26] EE appears to signal through the GPER membrane estrogen receptor similarly to estradiol.[27][28][29]

Orally, EE is about 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated equine estrogens.[30][31][32] In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism.[17] Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.[31]

As can be seen in the table below, EE shows strong and disproportionate effects on hepatic protein production relative to estradiol.[33] 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)[34] 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).[33] 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.[33][35][7] This is the mechanism of the disproportionately strong effects of EE on hepatic protein production,[33][35] which results in a greatly increased magnitude of effect on VTE risk relative to estradiol.[36]

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.[33] 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.[33] The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol,[2] in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).[37]

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.[35] In contrast, at typical menopausal dosages, whereas oral estradiol shows significant effects on hepatic protein production, transdermal estradiol shows little or no such effects.[33]

Relative oral potency (by weight) of EE and various other estrogens[33]
Estrogen Hot flashes FSH HDL cholesterol SHBG CBG Angiotensinogen
Estradiol 100 100 100 100 100 100
Estriol 30 30 20  ?  ?  ?
Estrone sulfate  ? 90 50 90 70 150
CEEs 120 110 150 300 150 500
Equilin sulfate  ?  ? 600 750 600 750
Ethinyl estradiol 12,000 12,000 40,000 50,000 60,000 35,000
Diethylstilbestrol  ? 340  ? 2,560 2,450 1,950
Hot flashes = clinical relief of hot flashes; FSH = suppression of FSH levels; HDL cholesterol, SHBG, CBG,
and angiotensinogen = increase in the serum levels of these hepatic proteins.



The oral bioavailability of EE is between 38 to 48%, with a wide range of 20% to 65% (mean 45%) that is due to high interindividual variability.[6] Although relatively low, the oral bioavailability of EE is considerably higher than that of estradiol (5%).[1][6] 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.[33] Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached;[33] steady-state is reached after one week of daily administration.[13] 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.[33] 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.[30][33] In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels.[33]


Unlike estradiol, which binds with high affinity to sex hormone-binding globulin (SHBG), EE has no affinity for this protein and is instead bound almost exclusively to albumin (97–98%).[3][33][6][38] As estradiol that is bound to SHBG is considered to be hormonally inactive,[39] the lack of binding of EE to SHBG may 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.[33] 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.[33] 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.[33] In contrast to estradiol, EE, due to steric hindrance by its 17α-ethynyl group, is not converted by 17β-HSD into the estrone equivalent (ethinyl estrone),[7] and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol.[33] Due to the formation of EE sulfate, enterohepatic circulation is involved in the pharmacokinetics of EE similarly to estradiol, although to a lesser extent.[33]

Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens.[33] This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4.[6] 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.[6] 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE.[33] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α.[6][33] A review found that the range of the reported terminal half-life of EE in the literature was 13.1 to 27.0 hours.[1] Another review reported a terminal half-life of EE of 10–20 hours.[6] However, the terminal half-life of EE has also been reported by other sources to be as short as 7 hours[7] and as long as 36 hours[5]

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.[33] 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.[33]

EE, following oxidative formation of a very reactive metabolite, irreversibly inhibits cytochrome P450 enzymes involved in its metabolism, and this may also role in the increased potency of EE relative to estradiol.[33] 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.[38]


EE is eliminated 62% in the feces and 38% in the urine.[6]


EE is an estrane (C18) steroid and derivative of estradiol with an ethynyl substitution at the C17α position. It is also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol. The 17α-ethynylation of EE is analogous to the 17α-substitution of testosterone derivatives such as 17α-ethynylated progestins like ethisterone and norethisterone and 17α-alkylated anabolic-androgenic steroids like methyltestosterone.


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.[40][41][42][43][44] EE was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering as Estinyl.[45] The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.[46] EE has been marketed as a standalone drug under the brand names Estinyl, Feminone, Lynoral, Novestrol, and Palonyl, although most or all of these formulations are now discontinued.[47][10]

EE was introduced as an alternative to mestranol in oral contraceptives in 1964.[48]

See also[edit]


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External links[edit]