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| Pronunciation | /ˌɛθɪnɪlˌɛstrəˈdaɪ.əl/ |
| Other names | Ethynylestradiol; ethinyl estradiol; ethinyl oestradiol; EE; EE2; 17α-ethynylestradiol; 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol; NSC-10973[1] |
| AHFS/Drugs.com | Consumer Drug Information |
| MedlinePlus | a604032 |
| Routes of administration | By mouth,transdermal,vaginal |
| Drug class | Estrogen |
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| Bioavailability | 38–48%[2][3][4] |
| Protein binding | 97–98% (toalbumin;[5] is not bound toSHBGTooltip sex hormone-binding globulin)[6] |
| Metabolism | Liver (primarilyCYP3A4)[9] |
| Metabolites | •Ethinylestradiol sulfate[7][8] • Others[7][8] |
| Eliminationhalf-life | 7–36 hours[9][2][10][11] |
| Excretion | Feces: 62%[10] Urine: 38%[10] |
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| ECHA InfoCard | 100.000.311 |
| Chemical and physical data | |
| Formula | C20H24O2 |
| Molar mass | 296.410 g·mol−1 |
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| Melting point | 182 to 184 °C (360 to 363 °F) |
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Ethinylestradiol (EE) is anestrogen medication which is used widely inbirth control pills in combination withprogestins.[7][8] Ethinylestradiol is widely used for various indications such as the treatment ofmenopausalsymptoms,gynecological disorders, and certainhormone-sensitive cancers. It is usually takenby mouth but is also used as apatch andvaginal ring.[7][12]
The generalside effects of ethinylestradiol includebreast tenderness andenlargement,headache,fluid retention, andnausea among others.[7] In males, ethinylestradiol can additionally causebreast development,feminization in general,hypogonadism, andsexual dysfunction. Rare but serious side effects includeblood clots,liver damage, andcancer of the uterus.[7]
Ethinylestradiol is anestrogen, or anagonist of theestrogen receptors, thebiological target of estrogens likeestradiol.[7] It is asyntheticderivative ofestradiol, anatural estrogen, and differs from it in various ways.[7] Compared to estradiol, ethinylestradiol is more resistant tometabolism, has greatly improvedbioavailability when taken by mouth, and shows relatively increased effects in certain parts of the body like theliver anduterus.[7] These differences make ethinylestradiol 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.[7]
Ethinylestradiol was developed in the 1930s and was introduced for medical use in 1943.[13][14] The medication started being used in birth control pills in the 1960s.[15] Ethinylestradiol is found in almost allcombined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of the most widely used estrogens.[16][17] In 2022, the combination withnorethisterone was the 80th most commonly prescribed medication in the United States with more than 8 million prescriptions.[18][19]Fixed-dose combination medications containing ethinylestradiol with other hormones are available.[18]
Ethinylestradiol is most commonly used ascontraception incombined oral contraceptives (COC), also known asbirth control, to prevent pregnancy after sex. Ethinylestradiol in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during menstruation, andacne.
Ethinylestradiol is also used asmenopausal hormone therapy.[20] The main reason for using HRT in menopausal women is to relieve commonvasomotor symptoms such ashot flashes,night sweats, andflushing. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo.[21] 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, ethinylestradiol has been used as a component offeminizing hormone therapy fortransgender women.[22] However, it is no longer commonly used nor recommended for this purpose, withestradiol having largely superseded it.[22]
Ethinylestradiol can also be used to treathypogonadism in women, prevent osteoporosis in women, and has been used aspalliative care forprostate cancer in men andbreast cancer in women.[8][23] It has also been used to reducesex drive insex offenders.[24][25]
Ethinylestradiol or any estrogen alone is contraindicated for women who have a uterus due to the increased risk ofendometrial cancer; giving aprogestogen with an estrogen mitigates the risk.[26]
Ethinylestradiol is available in combination with a progestin in a vast number of combined oral contraceptives.[27] It is also available in combination with progestins as atransdermalcontraceptive patch and as acontraceptive vaginal ring.[12] In addition, there is a single preparation (brand name FemHRT) containing very low doses of ethinylestradiol (2.5 and 5 μg) plus a progestin in an oraltablet that remains in use for menopausal hormone therapy.[12][20] Ethinylestradiol was previously available by itself under brand names like Estinyl and Lynoral in the form of 0.002, 0.01, 0.02, 0.025, 0.05, 0.1, 0.5, and 1.0 mg (2, 10, 20, 25, 50, 100, 500, and 1000 μg) tablets.[28][29][30][31][32]
The amount of ethinylestradiol in combined oral contraceptives has reduced over the years.[8] Previously, combined oral contraceptives contained high doses of ethinylestradiol of as much as 100 μg/day.[33] Doses of more than 50 μg ethinylestradiol are considered high-dose, doses of 30 and 35 μg ethinylestradiol are considered low-dose, and doses of 10 to 25 μg ethinylestradiol are considered very low dose.[34] Combined oral contraceptives generally contain 10 to 50 μg ethinylestradiol.[34] The higher doses of ethinylestradiol were discontinued due to a high risk of venous thromboembolism and cardiovascular problems.[33]
Ethinylestradiol should be avoided in individuals with a history of or known susceptibility toarterial orvenous thrombosis (blood clots), due to an increased risk ofcardiovascular problems such asvenous thromboembolism (VTE),myocardial infarction, andischemic stroke.[35] This includes women with:
Except when being used to treat it, ethinylestradiol should be avoided in women with currentbreast cancer due to a possible worsening of prognosis.[36]
Ethinylestradiol should also be avoided inbreastfeeding women who are less than 21 dayspostpartum due to an increased risk of venous thromboembolism.[37] Ethinylestradiol 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 ethinylestradiol.[37]
Due to risk ofcholestatic hepatotoxicity, it is widely considered that combined oral contraceptives containing ethinylestradiol should be avoided in women with a history ofcholestasis of pregnancy,hepatic tumors, activehepatitis, and familial defects in biliary excretion.[38]
| Ethinylestradiol dose | No. of VTE cases | Woman-years | VTE rate | AdjustedRRa |
|---|---|---|---|---|
| Low (<50 μg) | 53 | 127,000 | 4.2 in 10,000 woman-years | 1.0 |
| Intermediate (50 μg) | 69 | 98,000 | 7.0 in 10,000 woman-years | 1.5 |
| High (>50 μg) | 20 | 20,000 | 10.0 in 10,000 woman-years | 1.7 |
| All | 142 | 245,000 | 5.8 in 10,000 woman-years | – |
| Footnotes:a = Relative to low-dose (not to non-use).Notes: In birth control pills containing afirst-generation progestin, such asnorethisterone orlevonorgestrel.Sources:Main:[39][40]Additional:[41] | ||||
The severity of side effects can vary based on the dose and administration route of ethinylestradiol.[42] General side effects of ethinylestradiol are the same as for other estrogens and includebreast tenderness,headache,fluid retention (bloating),nausea,dizziness, andweight gain.[10][38] The estrogen component of oral contraceptives, which is almost always ethinylestradiol, can causebreast tenderness andfullness.[28] In males, ethinylestradiol has additional side effects, includinggynecomastia (breast development),feminization in general,hypogonadism,infertility, andsexual dysfunction (e.g., reducedlibido anderectile dysfunction). In men who receivedhigh-dose estrogen therapy with 200 μg/day oral ethinylestradiol for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%.[43]
Venous thromboembolism is ablood clot in avein, and includesdeep vein thrombosis (DVT) andpulmonary embolism (PE).[7][45][46] Estrogens are known to increase the risk of venous thromboembolism due to their effects onliver synthesis ofcoagulation factors.[7][45][46] Ethinylestradiol carries a greater risk of blood clot formation and venous thromboembolism than does naturalestradiol, which is thought to be due tostructural differences between the two compounds and different susceptibilities toliverinactivation.[7]
A 2012meta-analysis estimated that theabsolute risk of venous thromboembolism is 2 per 10,000 women for non-use, 8 per 10,000 women for ethinylestradiol andlevonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing ethinylestradiol and athird- orfourth-generation progestin such asdesogestrel ordrospirenone.[47] For comparison, the absolute risk of venous thromboembolism is generally estimated as 1 to 5 per 10,000 woman–years for non-use, 5 to 20 per 10,000 woman–years for pregnancy, and 40 to 65 per 10,000 woman–years for thepostpartum period.[47] Combined oral contraceptives are associated with about a 2- to 4-fold higher risk of venous thromboembolism than non-use.[47] Theroute of administration of ethinylestradiol does not appear to influence venous thromboembolism risk, as ethinylestradiol/progestin-containingcontraceptive vaginal rings andcontraceptive patches have the same or even higher risk of venous thromboembolism than combined oral contraceptives.[47][48] Pregnancy is associated with about a 4.3-fold increase in risk of venous thromboembolism.[47] It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to venous thromboembolism caused by ethinylestradiol-containing birth control pills.[49]
Combined oral contraceptives contain 10 to 35 μg ethinylestradiol, but typically 20, 30, or 35 μg.[47][50] The initial formulations of combined oral contraceptives that were introduced in the 1960s contained 100 to 150 μg ethinylestradiol.[51][41][50] However, it was soon found that ethinylestradiol is associated with increased risk of venous thromboembolism and that the risk is dose-dependent.[50] Following these events, the dose of ethinylestradiol was greatly reduced, and is now always less than 50 μg.[52][53][54] These lower doses have a significantly reduced risk of venous thromboembolism with no loss of contraceptive effectiveness.[50] Gerstman et al. (1991) found that combined oral contraceptives containing more than 50 μg ethinylestradiol had 1.7-fold and combined oral contraceptives containing 50 μg ethinylestradiol 1.5-fold the risk of venous thromboembolism of combined oral contraceptives containing less than 50 μg.[39] A 2014Cochrane review found that combined oral contraceptives containing 50 μg ethinylestradiol with levonorgestrel had 2.1- to 2.3-fold the risk of combined oral contraceptives containing 30 μg or 20 μg ethinylestradiol with levonorgestrel, respectively.[47] combined oral contraceptives containing 20 μg ethinylestradiol are likewise associated with a significantly lower risk of cardiovascular events than combined oral contraceptives containing 30 or 40 μg ethinylestradiol.[55] However, discontinuation of combined oral contraceptives is more common with doses of ethinylestradiol from 10 to 20 μg due to problematic changes in bleeding patterns.[56]
Women withthrombophilia have a dramatically higher risk of venous thromboembolism with ethinylestradiol-containing contraception than women without thrombophilia.[47][48] Depending on the condition, risk of venous thromboembolism can be increased 5- to 50-fold relative to non-use in such women.[47][48]
Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be asurrogate marker forcoagulation and venous thromboembolism risk with estrogen therapy, although this topic has been debated.[57][58][59] SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold withlevonorgestrel, 2.5- to 4-fold withdesogestrel andgestodene, 3.5- to 4-fold withdrospirenone anddienogest, and 4- to 5-fold withcyproterone acetate.[57]Contraceptive vaginal rings andcontraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.[57] Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.[60] Conversely, increases in SHBG levels are much lower withestradiol, especially when used parenterally.[61][62][63][64][65] High-dose parenteralpolyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.[64]
| Type | Route | Medications | Odds ratio (95%CITooltip confidence interval) |
|---|---|---|---|
| Menopausal hormone therapy | Oral | Estradiol alone ≤1 mg/day >1 mg/day | 1.27 (1.16–1.39)* 1.22 (1.09–1.37)* 1.35 (1.18–1.55)* |
| Conjugated estrogens alone ≤0.625 mg/day >0.625 mg/day | 1.49 (1.39–1.60)* 1.40 (1.28–1.53)* 1.71 (1.51–1.93)* | ||
| Estradiol/medroxyprogesterone acetate | 1.44 (1.09–1.89)* | ||
| Estradiol/dydrogesterone ≤1 mg/dayE2 >1 mg/dayE2 | 1.18 (0.98–1.42) 1.12 (0.90–1.40) 1.34 (0.94–1.90) | ||
| Estradiol/norethisterone ≤1 mg/dayE2 >1 mg/dayE2 | 1.68 (1.57–1.80)* 1.38 (1.23–1.56)* 1.84 (1.69–2.00)* | ||
| Estradiol/norgestrel orestradiol/drospirenone | 1.42 (1.00–2.03) | ||
| Conjugated estrogens/medroxyprogesterone acetate | 2.10 (1.92–2.31)* | ||
| Conjugated estrogens/norgestrel ≤0.625 mg/dayCEEs >0.625 mg/dayCEEs | 1.73 (1.57–1.91)* 1.53 (1.36–1.72)* 2.38 (1.99–2.85)* | ||
| Tibolone alone | 1.02 (0.90–1.15) | ||
| Raloxifene alone | 1.49 (1.24–1.79)* | ||
| Transdermal | Estradiol alone ≤50 μg/day >50 μg/day | 0.96 (0.88–1.04) 0.94 (0.85–1.03) 1.05 (0.88–1.24) | |
| Estradiol/progestogen | 0.88 (0.73–1.01) | ||
| Vaginal | Estradiol alone | 0.84 (0.73–0.97) | |
| Conjugated estrogens alone | 1.04 (0.76–1.43) | ||
| Combined birth control | Oral | Ethinylestradiol/norethisterone | 2.56 (2.15–3.06)* |
| Ethinylestradiol/levonorgestrel | 2.38 (2.18–2.59)* | ||
| Ethinylestradiol/norgestimate | 2.53 (2.17–2.96)* | ||
| Ethinylestradiol/desogestrel | 4.28 (3.66–5.01)* | ||
| Ethinylestradiol/gestodene | 3.64 (3.00–4.43)* | ||
| Ethinylestradiol/drospirenone | 4.12 (3.43–4.96)* | ||
| Ethinylestradiol/cyproterone acetate | 4.27 (3.57–5.11)* | ||
| Notes: (1)Nested case–control studies (2015, 2019) based on data from theQResearch andClinical Practice Research Datalink (CPRD) databases. (2)Bioidenticalprogesterone was not included, but is known to be associated with no additional risk relative to estrogen alone.Footnotes: * =Statistically significant (p < 0.01).Sources: See template. | |||
When used orally at high dosages, for instance as a form of high-dose estrogen therapy in men with prostate cancer and in women with breast cancer,synthetic and non-bioidentical estrogens like ethinylestradiol anddiethylstilbestrol are associated with fairly high rates of severecardiovascular complications such as venous thromboembolism,myocardial infarction, andstroke.[23][66][67] Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of venous thromboembolism in men treated with it for prostate cancer.[66][67] Ethinylestradiol has a to some degree lower risk ofcardiovascular complications than does diethylstilbestrol when used in the treatment of prostate cancer in men.[8] However, both ethinylestradiol and diethylstilbestrol nonetheless have highly disproportionate effects onliver protein synthesis, which is thought to be responsible for their cardiovascular toxicity.[7][67]
In contrast to oral synthetic estrogens like ethinylestradiol and diethylstilbestrol, high-dosagepolyestradiol phosphate andtransdermal estradiol have not been found to increase the risk of cardiovascularmortality orthromboembolism in men with prostate cancer.[67][68][69] However, significantly increased cardiovascularmorbidity has been observed with high-dosage polyestradiol phosphate.[67][68][69] In any case, these estrogens are considered to be much safer than oral synthetic estrogens like ethinylestradiol and diethylstilbestrol.[67][68][69] In addition,ethinylestradiol sulfonate (EES), an oral butparenteral-like long-lasting prodrug of ethinylestradiol, is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than ethinylestradiol.[8]
Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like ethinylestradiol and diethylstilbestrol are no longer used in menopausal hormone therapy.[8] They are also being replaced by parenteral forms of estradiol like polyestradiol phosphate and transdermal estradiol in the treatment of prostate cancer.[67]
At the lower dosages that are now used in birth control pills, ethinylestradiol has been associated rarely withcholestatichepatotoxicity similarly to17α-alkylatedandrogens/anabolic steroids and 17α-ethynylated19-nortestosterone progestins.[70][71] Cholestasis can manifest aspruritus andjaundice.[72]Glucuronidemetabolites of ethinylestradiol, via effects on theABCB11 (BSEP) andMRP2 (ABCC2)proteins and consequent changes inbile flow andbile saltexcretion, appear to be responsible for the cholestasis.[73] Very high concentrations of estradiol, via its metaboliteestradiol glucuronide, are also implicated in cholestasis, for instance incholestasis of pregnancy.[71] However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with ethinylestradiol than with estradiol, which is thought to be due to the reactive C17α ethynyl substitution in ethinylestradiol as well as its greatly reduced susceptibility to hepatic metabolism.[38][74] Whereas abnormalliver function tests (LFTs) are normally found in about 1% of women not on birth control pills or taking lower-dose ethinylestradiol-containing birth control pills, this increases to more than 10% of women taking birth control pills containing 50 μg/day ethinylestradiol or more.[74][72] With birth control pills containing 50 μg/day ethinylestradiol,alanine aminotransferase (ALT) levels increase by 50%,hematocrit by 19%, andleukocytes by 50%, whilegamma-glutamyltransferase (GGT) decreases by 30%.[74] However, the values usually remain in the normal range.[74] In addition to abnormal LFTs, pathological changes in partial liver functions and livermorphology can be observed in half of women on birth control pills with 50 μg/day ethinylestradiol.[74] Ethinylestradiol-containing birth control pills have also been associated with a 25- to 50-fold increase in the risk of rarebenign liver tumors and a 3- to 6-fold increase in the risk ofhepatocellular carcinoma,[72][75][76] as well as greater risk of other liver complications.[77][78] At one time, ethinylestradiol-containing birth control pills were estimated to be responsible for 84% of all drug-related and histologically verified liver damage.[74] However, these risks now are reduced with modern lower-dose ethinylestradiol-containing birth control pills, with contain 35 μg/day ethinylestradiol or less.[72][76]
The high doses of ethinylestradiol that were used in early combined oral contraceptives were associated with a significantly increased risk ofendometrial cancer in certain preparations, for instance those containing the progestogendimethisterone.[79] Unopposed estrogens like ethinylestradiol 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 ethinylestradiol, in turn resulting in the increased risk of endometrial cancer.[79] Combined oral contraceptives containing dimethisterone have been discontinued (with more potent progestogens used instead) and doses of ethinylestradiol in combined oral contraceptives in general have been dramatically reduced, abrogating the risk.[79] In turn, most studies of combined oral contraceptives have found a decreased risk of endometrial cancer.[80]
Wastewater contains various estrogens, including ethinylestradiol, that are not completely broken down bywastewater treatment procedures.[81] The input of artificial estrogens intofreshwater ecosystems affectsfish andamphibian populations. Chronic exposure to low levels of ethinylestradiol over seven years led to the collapse offathead minnow populations in anexperimental lake inOntario, Canada.[81] Ethinylestradiol changedoogenesis in female fish and feminized male fish such that they produced a protein associated with egg maturation,vitellogenin, as well as early-stage eggs.[81] In amphibians, exposure to ethinylestradiol can reduce hatching success and altergonadal development.[82] Exposure to hormones can change frogs' gonadal development even though it isencoded in theirgenes.[82] A study ofmink frogs found moreintersextadpoles in those experimentally exposed to ethinylestradiol than those not exposed to ethinylestradiol, andgreen frogs showed much lower rates of hatching success.[82]
Estrogens like ethinylestradiol are relatively safe in acuteoverdose.[citation needed]
Ethinylestradiol is metabolized by certaincytochrome P450 isoforms, includingCYP3A4 andCYP2C9.[83] Thus,inducers of enzymes such as CYP3A4 can decrease circulating concentrations of ethinylestradiol.[38] Examples of inducers includeanticonvulsants likephenytoin,primidone,ethosuximide,phenobarbital, andcarbamazepine;azoleantifungals likefluconazole; andrifamycinantibiotics likerifampin (rifampicin).[38] Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of ethinylestradiol.[38] An example istroleandomycin, which is a potent and highly selective inhibitor of CYP3A4.[38]
Paracetamol (acetaminophen) has been found tocompetitively inhibit the sulfation of ethinylestradiol, with pretreatment of 1,000 mg of paracetamol significantly increasing theAUC levels of ethinylestradiol (by 22%) and decreasing the AUC levels ofethinylestradiol sulfate (EE sulfate) in women.[38] The same has been found forascorbic acid (vitamin C) and ethinylestradiol, although the significance of the interaction has been regarded as dubious.[38]
In contrast to estradiol, it is unlikely that there is a pharmacokinetic interaction betweensmoking (which potently induces certaincytochrome P450enzymes and markedly increases the 2-hydroxylation of estradiol) and ethinylestradiol.[38] This suggests that estradiol and ethinylestradiol are metabolized by different cytochrome P450 enzymes.[38] There is, however, an increased risk of cardiovascular complications with smoking and ethinylestradiol, similarly to the case of smoking and other estrogens.[38]
Ethinylestradiol is known toinhibit severalcytochrome P450 enzymes, includingCYP1A2,CYP2B6,CYP2C9,CYP2C19, andCYP3A4, and is possibly aninducer ofCYP2A6.[84] As a result, it can affect the metabolism and concentrations of many other drugs.[84] Examples of known interactions includebupropion,caffeine,mephenytoin,midazolam,nicotine,nifedipine,omeprazole,propranolol,proguanil,selegiline,theophylline, andtizanidine.[84][38] One of the most notable interactions is that ethinylestradiol strongly increases levels ofselegiline, a substrate of CYP2B6 and CYP2C19.[84] Ethinylestradiol may also induceglucuronidation and possibly altersulfation.[84] It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated.[84] Examples includeclofibrate,lamotrigine,lorazepam,oxazepam, andpropranolol.[84]
Progestins, which are often used in combination with ethinylestradiol, are also known to inhibit cytochrome P450 enzymes, and this may contribute to drug interactions with ethinylestradiol-containing contraceptives as well.[84] Examples includegestodene,desogestrel, andetonogestrel, which are CYP3A4 and CYP2C19 inhibitors.[84] In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of ethinylestradiol itself.[38]
Ethinylestradiol is anestrogen similarly to natural estrogens like estradiol andconjugated estrogens (Premarin) and synthetic estrogens likediethylstilbestrol. It binds to and activates bothisoforms of theestrogen receptor,ERα andERβ.[8] In one study, ethinylestradiol was found to have 233% and 38% of theaffinity ofestradiol for the ERα and ERβ, respectively.[85] In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively.[86] Ethinylestradiol also appears to act as apotent agonist of theG protein-coupled estrogen receptor (GPER) (affinity unknown), amembrane estrogen receptor, similarly to estradiol.[87][88][89][90] Estrogens haveantigonadotropic effects through activation of the ERα.[91] As a contraceptive, ethinylestradiol acts in concert with a progestin to inhibit the mid-cycle surge inluteinizing hormone (LH) andfollicle-stimulating hormone (FSH) via its antigonadotropic effects, thereby inhibitingfolliculogenesis and preventingovulation and hence the possibility ofpregnancy.[92][93]
Ethinylestradiol is a long-acting estrogen, with a nuclear retention of about 24 hours.[40]
Orally, ethinylestradiol is on the order of 100 times as potent by weight as natural estrogens likemicronized estradiol and conjugated estrogens, which is largely due to substantially greater resistance tofirst-pass metabolism.[94][95][96] It is specifically in the range of 80 to 200 times as potent asestropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, in terms of systemic estrogenic potency.[97][98] In contrast, the potencies of ethinylestradiol and natural estrogens are similar when they are administeredintravenously, due to the bypassing of first-pass metabolism.[50] Relative to itsprodrugmestranol, ethinylestradiol is about 1.7 times as potent by weight orally.[95]
| Ligand | Other names | Relative binding affinities (RBA, %)a | Absolute binding affinities (Ki, nM)a | Action | ||
|---|---|---|---|---|---|---|
| ERα | ERβ | ERα | ERβ | |||
| Estradiol | E2; 17β-Estradiol | 100 | 100 | 0.115 (0.04–0.24) | 0.15 (0.10–2.08) | Estrogen |
| Estrone | E1; 17-Ketoestradiol | 16.39 (0.7–60) | 6.5 (1.36–52) | 0.445 (0.3–1.01) | 1.75 (0.35–9.24) | Estrogen |
| Estriol | E3; 16α-OH-17β-E2 | 12.65 (4.03–56) | 26 (14.0–44.6) | 0.45 (0.35–1.4) | 0.7 (0.63–0.7) | Estrogen |
| Estetrol | E4; 15α,16α-Di-OH-17β-E2 | 4.0 | 3.0 | 4.9 | 19 | Estrogen |
| Alfatradiol | 17α-Estradiol | 20.5 (7–80.1) | 8.195 (2–42) | 0.2–0.52 | 0.43–1.2 | Metabolite |
| 16-Epiestriol | 16β-Hydroxy-17β-estradiol | 7.795 (4.94–63) | 50 | ? | ? | Metabolite |
| 17-Epiestriol | 16α-Hydroxy-17α-estradiol | 55.45 (29–103) | 79–80 | ? | ? | Metabolite |
| 16,17-Epiestriol | 16β-Hydroxy-17α-estradiol | 1.0 | 13 | ? | ? | Metabolite |
| 2-Hydroxyestradiol | 2-OH-E2 | 22 (7–81) | 11–35 | 2.5 | 1.3 | Metabolite |
| 2-Methoxyestradiol | 2-MeO-E2 | 0.0027–2.0 | 1.0 | ? | ? | Metabolite |
| 4-Hydroxyestradiol | 4-OH-E2 | 13 (8–70) | 7–56 | 1.0 | 1.9 | Metabolite |
| 4-Methoxyestradiol | 4-MeO-E2 | 2.0 | 1.0 | ? | ? | Metabolite |
| 2-Hydroxyestrone | 2-OH-E1 | 2.0–4.0 | 0.2–0.4 | ? | ? | Metabolite |
| 2-Methoxyestrone | 2-MeO-E1 | <0.001–<1 | <1 | ? | ? | Metabolite |
| 4-Hydroxyestrone | 4-OH-E1 | 1.0–2.0 | 1.0 | ? | ? | Metabolite |
| 4-Methoxyestrone | 4-MeO-E1 | <1 | <1 | ? | ? | Metabolite |
| 16α-Hydroxyestrone | 16α-OH-E1; 17-Ketoestriol | 2.0–6.5 | 35 | ? | ? | Metabolite |
| 2-Hydroxyestriol | 2-OH-E3 | 2.0 | 1.0 | ? | ? | Metabolite |
| 4-Methoxyestriol | 4-MeO-E3 | 1.0 | 1.0 | ? | ? | Metabolite |
| Estradiol sulfate | E2S; Estradiol 3-sulfate | <1 | <1 | ? | ? | Metabolite |
| Estradiol disulfate | Estradiol 3,17β-disulfate | 0.0004 | ? | ? | ? | Metabolite |
| Estradiol 3-glucuronide | E2-3G | 0.0079 | ? | ? | ? | Metabolite |
| Estradiol 17β-glucuronide | E2-17G | 0.0015 | ? | ? | ? | Metabolite |
| Estradiol 3-gluc. 17β-sulfate | E2-3G-17S | 0.0001 | ? | ? | ? | Metabolite |
| Estrone sulfate | E1S; Estrone 3-sulfate | <1 | <1 | >10 | >10 | Metabolite |
| Estradiol benzoate | EB; Estradiol 3-benzoate | 10 | ? | ? | ? | Estrogen |
| Estradiol 17β-benzoate | E2-17B | 11.3 | 32.6 | ? | ? | Estrogen |
| Estrone methyl ether | Estrone 3-methyl ether | 0.145 | ? | ? | ? | Estrogen |
| ent-Estradiol | 1-Estradiol | 1.31–12.34 | 9.44–80.07 | ? | ? | Estrogen |
| Equilin | 7-Dehydroestrone | 13 (4.0–28.9) | 13.0–49 | 0.79 | 0.36 | Estrogen |
| Equilenin | 6,8-Didehydroestrone | 2.0–15 | 7.0–20 | 0.64 | 0.62 | Estrogen |
| 17β-Dihydroequilin | 7-Dehydro-17β-estradiol | 7.9–113 | 7.9–108 | 0.09 | 0.17 | Estrogen |
| 17α-Dihydroequilin | 7-Dehydro-17α-estradiol | 18.6 (18–41) | 14–32 | 0.24 | 0.57 | Estrogen |
| 17β-Dihydroequilenin | 6,8-Didehydro-17β-estradiol | 35–68 | 90–100 | 0.15 | 0.20 | Estrogen |
| 17α-Dihydroequilenin | 6,8-Didehydro-17α-estradiol | 20 | 49 | 0.50 | 0.37 | Estrogen |
| Δ8-Estradiol | 8,9-Dehydro-17β-estradiol | 68 | 72 | 0.15 | 0.25 | Estrogen |
| Δ8-Estrone | 8,9-Dehydroestrone | 19 | 32 | 0.52 | 0.57 | Estrogen |
| Ethinylestradiol | EE; 17α-Ethynyl-17β-E2 | 120.9 (68.8–480) | 44.4 (2.0–144) | 0.02–0.05 | 0.29–0.81 | Estrogen |
| Mestranol | EE 3-methyl ether | ? | 2.5 | ? | ? | Estrogen |
| Moxestrol | RU-2858; 11β-Methoxy-EE | 35–43 | 5–20 | 0.5 | 2.6 | Estrogen |
| Methylestradiol | 17α-Methyl-17β-estradiol | 70 | 44 | ? | ? | Estrogen |
| Diethylstilbestrol | DES; Stilbestrol | 129.5 (89.1–468) | 219.63 (61.2–295) | 0.04 | 0.05 | Estrogen |
| Hexestrol | Dihydrodiethylstilbestrol | 153.6 (31–302) | 60–234 | 0.06 | 0.06 | Estrogen |
| Dienestrol | Dehydrostilbestrol | 37 (20.4–223) | 56–404 | 0.05 | 0.03 | Estrogen |
| Benzestrol (B2) | – | 114 | ? | ? | ? | Estrogen |
| Chlorotrianisene | TACE | 1.74 | ? | 15.30 | ? | Estrogen |
| Triphenylethylene | TPE | 0.074 | ? | ? | ? | Estrogen |
| Triphenylbromoethylene | TPBE | 2.69 | ? | ? | ? | Estrogen |
| Tamoxifen | ICI-46,474 | 3 (0.1–47) | 3.33 (0.28–6) | 3.4–9.69 | 2.5 | SERM |
| Afimoxifene | 4-Hydroxytamoxifen; 4-OHT | 100.1 (1.7–257) | 10 (0.98–339) | 2.3 (0.1–3.61) | 0.04–4.8 | SERM |
| Toremifene | 4-Chlorotamoxifen; 4-CT | ? | ? | 7.14–20.3 | 15.4 | SERM |
| Clomifene | MRL-41 | 25 (19.2–37.2) | 12 | 0.9 | 1.2 | SERM |
| Cyclofenil | F-6066; Sexovid | 151–152 | 243 | ? | ? | SERM |
| Nafoxidine | U-11,000A | 30.9–44 | 16 | 0.3 | 0.8 | SERM |
| Raloxifene | – | 41.2 (7.8–69) | 5.34 (0.54–16) | 0.188–0.52 | 20.2 | SERM |
| Arzoxifene | LY-353,381 | ? | ? | 0.179 | ? | SERM |
| Lasofoxifene | CP-336,156 | 10.2–166 | 19.0 | 0.229 | ? | SERM |
| Ormeloxifene | Centchroman | ? | ? | 0.313 | ? | SERM |
| Levormeloxifene | 6720-CDRI; NNC-460,020 | 1.55 | 1.88 | ? | ? | SERM |
| Ospemifene | Deaminohydroxytoremifene | 0.82–2.63 | 0.59–1.22 | ? | ? | SERM |
| Bazedoxifene | – | ? | ? | 0.053 | ? | SERM |
| Etacstil | GW-5638 | 4.30 | 11.5 | ? | ? | SERM |
| ICI-164,384 | – | 63.5 (3.70–97.7) | 166 | 0.2 | 0.08 | Antiestrogen |
| Fulvestrant | ICI-182,780 | 43.5 (9.4–325) | 21.65 (2.05–40.5) | 0.42 | 1.3 | Antiestrogen |
| Propylpyrazoletriol | PPT | 49 (10.0–89.1) | 0.12 | 0.40 | 92.8 | ERα agonist |
| 16α-LE2 | 16α-Lactone-17β-estradiol | 14.6–57 | 0.089 | 0.27 | 131 | ERα agonist |
| 16α-Iodo-E2 | 16α-Iodo-17β-estradiol | 30.2 | 2.30 | ? | ? | ERα agonist |
| Methylpiperidinopyrazole | MPP | 11 | 0.05 | ? | ? | ERα antagonist |
| Diarylpropionitrile | DPN | 0.12–0.25 | 6.6–18 | 32.4 | 1.7 | ERβ agonist |
| 8β-VE2 | 8β-Vinyl-17β-estradiol | 0.35 | 22.0–83 | 12.9 | 0.50 | ERβ agonist |
| Prinaberel | ERB-041; WAY-202,041 | 0.27 | 67–72 | ? | ? | ERβ agonist |
| ERB-196 | WAY-202,196 | ? | 180 | ? | ? | ERβ agonist |
| Erteberel | SERBA-1; LY-500,307 | ? | ? | 2.68 | 0.19 | ERβ agonist |
| SERBA-2 | – | ? | ? | 14.5 | 1.54 | ERβ agonist |
| Coumestrol | – | 9.225 (0.0117–94) | 64.125 (0.41–185) | 0.14–80.0 | 0.07–27.0 | Xenoestrogen |
| Genistein | – | 0.445 (0.0012–16) | 33.42 (0.86–87) | 2.6–126 | 0.3–12.8 | Xenoestrogen |
| Equol | – | 0.2–0.287 | 0.85 (0.10–2.85) | ? | ? | Xenoestrogen |
| Daidzein | – | 0.07 (0.0018–9.3) | 0.7865 (0.04–17.1) | 2.0 | 85.3 | Xenoestrogen |
| Biochanin A | – | 0.04 (0.022–0.15) | 0.6225 (0.010–1.2) | 174 | 8.9 | Xenoestrogen |
| Kaempferol | – | 0.07 (0.029–0.10) | 2.2 (0.002–3.00) | ? | ? | Xenoestrogen |
| Naringenin | – | 0.0054 (<0.001–0.01) | 0.15 (0.11–0.33) | ? | ? | Xenoestrogen |
| 8-Prenylnaringenin | 8-PN | 4.4 | ? | ? | ? | Xenoestrogen |
| Quercetin | – | <0.001–0.01 | 0.002–0.040 | ? | ? | Xenoestrogen |
| Ipriflavone | – | <0.01 | <0.01 | ? | ? | Xenoestrogen |
| Miroestrol | – | 0.39 | ? | ? | ? | Xenoestrogen |
| Deoxymiroestrol | – | 2.0 | ? | ? | ? | Xenoestrogen |
| β-Sitosterol | – | <0.001–0.0875 | <0.001–0.016 | ? | ? | Xenoestrogen |
| Resveratrol | – | <0.001–0.0032 | ? | ? | ? | Xenoestrogen |
| α-Zearalenol | – | 48 (13–52.5) | ? | ? | ? | Xenoestrogen |
| β-Zearalenol | – | 0.6 (0.032–13) | ? | ? | ? | Xenoestrogen |
| Zeranol | α-Zearalanol | 48–111 | ? | ? | ? | Xenoestrogen |
| Taleranol | β-Zearalanol | 16 (13–17.8) | 14 | 0.8 | 0.9 | Xenoestrogen |
| Zearalenone | ZEN | 7.68 (2.04–28) | 9.45 (2.43–31.5) | ? | ? | Xenoestrogen |
| Zearalanone | ZAN | 0.51 | ? | ? | ? | Xenoestrogen |
| Bisphenol A | BPA | 0.0315 (0.008–1.0) | 0.135 (0.002–4.23) | 195 | 35 | Xenoestrogen |
| Endosulfan | EDS | <0.001–<0.01 | <0.01 | ? | ? | Xenoestrogen |
| Kepone | Chlordecone | 0.0069–0.2 | ? | ? | ? | Xenoestrogen |
| o,p'-DDT | – | 0.0073–0.4 | ? | ? | ? | Xenoestrogen |
| p,p'-DDT | – | 0.03 | ? | ? | ? | Xenoestrogen |
| Methoxychlor | p,p'-Dimethoxy-DDT | 0.01 (<0.001–0.02) | 0.01–0.13 | ? | ? | Xenoestrogen |
| HPTE | Hydroxychlor;p,p'-OH-DDT | 1.2–1.7 | ? | ? | ? | Xenoestrogen |
| Testosterone | T; 4-Androstenolone | <0.0001–<0.01 | <0.002–0.040 | >5000 | >5000 | Androgen |
| Dihydrotestosterone | DHT; 5α-Androstanolone | 0.01 (<0.001–0.05) | 0.0059–0.17 | 221–>5000 | 73–1688 | Androgen |
| Nandrolone | 19-Nortestosterone; 19-NT | 0.01 | 0.23 | 765 | 53 | Androgen |
| Dehydroepiandrosterone | DHEA; Prasterone | 0.038 (<0.001–0.04) | 0.019–0.07 | 245–1053 | 163–515 | Androgen |
| 5-Androstenediol | A5; Androstenediol | 6 | 17 | 3.6 | 0.9 | Androgen |
| 4-Androstenediol | – | 0.5 | 0.6 | 23 | 19 | Androgen |
| 4-Androstenedione | A4; Androstenedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
| 3α-Androstanediol | 3α-Adiol | 0.07 | 0.3 | 260 | 48 | Androgen |
| 3β-Androstanediol | 3β-Adiol | 3 | 7 | 6 | 2 | Androgen |
| Androstanedione | 5α-Androstanedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
| Etiocholanedione | 5β-Androstanedione | <0.01 | <0.01 | >10000 | >10000 | Androgen |
| Methyltestosterone | 17α-Methyltestosterone | <0.0001 | ? | ? | ? | Androgen |
| Ethinyl-3α-androstanediol | 17α-Ethynyl-3α-adiol | 4.0 | <0.07 | ? | ? | Estrogen |
| Ethinyl-3β-androstanediol | 17α-Ethynyl-3β-adiol | 50 | 5.6 | ? | ? | Estrogen |
| Progesterone | P4; 4-Pregnenedione | <0.001–0.6 | <0.001–0.010 | ? | ? | Progestogen |
| Norethisterone | NET; 17α-Ethynyl-19-NT | 0.085 (0.0015–<0.1) | 0.1 (0.01–0.3) | 152 | 1084 | Progestogen |
| Norethynodrel | 5(10)-Norethisterone | 0.5 (0.3–0.7) | <0.1–0.22 | 14 | 53 | Progestogen |
| Tibolone | 7α-Methylnorethynodrel | 0.5 (0.45–2.0) | 0.2–0.076 | ? | ? | Progestogen |
| Δ4-Tibolone | 7α-Methylnorethisterone | 0.069–<0.1 | 0.027–<0.1 | ? | ? | Progestogen |
| 3α-Hydroxytibolone | – | 2.5 (1.06–5.0) | 0.6–0.8 | ? | ? | Progestogen |
| 3β-Hydroxytibolone | – | 1.6 (0.75–1.9) | 0.070–0.1 | ? | ? | Progestogen |
| Footnotes:a = (1)Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety ofin-vitro systems withlabeled estradiol and humanERα andERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ).Sources: See template page. | ||||||
| Estrogen | Relative binding affinities (%) | ||||||
|---|---|---|---|---|---|---|---|
| ERTooltip Estrogen receptor | ARTooltip Androgen receptor | PRTooltip Progesterone receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin | |
| Estradiol | 100 | 7.9 | 2.6 | 0.6 | 0.13 | 8.7–12 | <0.1 |
| Estradiol benzoate | ? | ? | ? | ? | ? | <0.1–0.16 | <0.1 |
| Estradiol valerate | 2 | ? | ? | ? | ? | ? | ? |
| Estrone | 11–35 | <1 | <1 | <1 | <1 | 2.7 | <0.1 |
| Estrone sulfate | 2 | 2 | ? | ? | ? | ? | ? |
| Estriol | 10–15 | <1 | <1 | <1 | <1 | <0.1 | <0.1 |
| Equilin | 40 | ? | ? | ? | ? | ? | 0 |
| Alfatradiol | 15 | <1 | <1 | <1 | <1 | ? | ? |
| Epiestriol | 20 | <1 | <1 | <1 | <1 | ? | ? |
| Ethinylestradiol | 100–112 | 1–3 | 15–25 | 1–3 | <1 | 0.18 | <0.1 |
| Mestranol | 1 | ? | ? | ? | ? | <0.1 | <0.1 |
| Methylestradiol | 67 | 1–3 | 3–25 | 1–3 | <1 | ? | ? |
| Moxestrol | 12 | <0.1 | 0.8 | 3.2 | <0.1 | <0.2 | <0.1 |
| Diethylstilbestrol | ? | ? | ? | ? | ? | <0.1 | <0.1 |
| Notes: Referenceligands (100%) wereprogesterone for thePRTooltip progesterone receptor,testosterone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources: See template. | |||||||
| Estrogen | HFTooltip Hot flashes | VETooltip Vaginal epithelium | UCaTooltip Urinary calcium | FSHTooltip Follicle-stimulating hormone | LHTooltip Luteinizing hormone | HDLTooltip High-density lipoprotein-CTooltip Cholesterol | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid-binding globulin | AGTTooltip Angiotensinogen | Liver |
|---|---|---|---|---|---|---|---|---|---|---|
| Estradiol | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
| Estrone | ? | ? | ? | 0.3 | 0.3 | ? | ? | ? | ? | ? |
| Estriol | 0.3 | 0.3 | 0.1 | 0.3 | 0.3 | 0.2 | ? | ? | ? | 0.67 |
| Estrone sulfate | ? | 0.9 | 0.9 | 0.8–0.9 | 0.9 | 0.5 | 0.9 | 0.5–0.7 | 1.4–1.5 | 0.56–1.7 |
| Conjugated estrogens | 1.2 | 1.5 | 2.0 | 1.1–1.3 | 1.0 | 1.5 | 3.0–3.2 | 1.3–1.5 | 5.0 | 1.3–4.5 |
| Equilin sulfate | ? | ? | 1.0 | ? | ? | 6.0 | 7.5 | 6.0 | 7.5 | ? |
| Ethinylestradiol | 120 | 150 | 400 | 60–150 | 100 | 400 | 500–600 | 500–600 | 350 | 2.9–5.0 |
| Diethylstilbestrol | ? | ? | ? | 2.9–3.4 | ? | ? | 26–28 | 25–37 | 20 | 5.7–7.5 |
Sources and footnotes Notes: Values are ratios, with estradiol as standard (i.e., 1.0).Abbreviations:HF = Clinical relief ofhot flashes.VE = Increasedproliferation ofvaginal epithelium.UCa = Decrease inUCaTooltip urinary calcium.FSH = Suppression ofFSHTooltip follicle-stimulating hormone levels.LH = Suppression ofLHTooltip luteinizing hormone levels.HDL-C,SHBG,CBG, andAGT = Increase in the serum levels of theseliver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins).Sources: See template. | ||||||||||
| Compound | Dosage for specific uses (mg usually)[a] | ||||||
|---|---|---|---|---|---|---|---|
| ETD[b] | EPD[b] | MSD[b] | MSD[c] | OID[c] | TSD[c] | ||
| Estradiol (non-micronized) | 30 | ≥120–300 | 120 | 6 | - | - | |
| Estradiol (micronized) | 6–12 | 60–80 | 14–42 | 1–2 | >5 | >8 | |
| Estradiol valerate | 6–12 | 60–80 | 14–42 | 1–2 | - | >8 | |
| Estradiol benzoate | - | 60–140 | - | - | - | - | |
| Estriol | ≥20 | 120–150[d] | 28–126 | 1–6 | >5 | - | |
| Estriol succinate | - | 140–150[d] | 28–126 | 2–6 | - | - | |
| Estrone sulfate | 12 | 60 | 42 | 2 | - | - | |
| Conjugated estrogens | 5–12 | 60–80 | 8.4–25 | 0.625–1.25 | >3.75 | 7.5 | |
| Ethinylestradiol | 200 μg | 1–2 | 280 μg | 20–40 μg | 100 μg | 100 μg | |
| Mestranol | 300 μg | 1.5–3.0 | 300–600 μg | 25–30 μg | >80 μg | - | |
| Quinestrol | 300 μg | 2–4 | 500 μg | 25–50 μg | - | - | |
| Methylestradiol | - | 2 | - | - | - | - | |
| Diethylstilbestrol | 2.5 | 20–30 | 11 | 0.5–2.0 | >5 | 3 | |
| DES dipropionate | - | 15–30 | - | - | - | - | |
| Dienestrol | 5 | 30–40 | 42 | 0.5–4.0 | - | - | |
| Dienestrol diacetate | 3–5 | 30–60 | - | - | - | - | |
| Hexestrol | - | 70–110 | - | - | - | - | |
| Chlorotrianisene | - | >100 | - | - | >48 | - | |
| Methallenestril | - | 400 | - | - | - | - | |
Ethinylestradiol is a potent functionalantiandrogen in both women and men.[119] It mediates its antiandrogenic effects by 1) stimulating theproduction ofsex hormone-binding globulin (SHBG) in theliver, which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressingluteinizing hormone (LH)secretion from thepituitary gland, which decreases production of testosterone by thegonads.[119][120][27][121] Birth control pills that contain ethinylestradiol are useful in the treatment ofandrogen-dependent conditions likeacne andhirsutism by virtue of their antiandrogenic effects.[119][122]
Birth control pills containing ethinylestradiol have been found in women to reduce total testosterone levels by 30% on average, to increase circulating SHBG levels by about 3-fold on average (but variable depending on progestin, range 1.5- to 5-fold increase), and to reduce free testosterone concentrations by 60% on average (range 40 to 80%).[123][57][124][27] Birth control pills containing high doses of ethinylestradiol can increase SHBG levels in women by as much as 5- to 10-fold.[60] This is similar to the 5- to 10-fold increase in SHBG levels that occurs duringpregnancy.[60] Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with ethinylestradiol-containing birth control pills.[10] In men, a study found that treatment with a relatively low dosage of 20 μg/day ethinylestradiol 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 reducednegative feedback by androgens on thehypothalamic–pituitary–gonadal axis).[120] The stimulation of hepatic SHBG production by ethinylestradiol is far stronger than with other estrogens like estradiol, owing to the high resistance of ethinylestradiol to inactivation in the liver and hence its disproportionate effects in this part of the body.[7][10][125]
Estrogens areantigonadotropins and are able to suppress the secretion of LH and FSH from the pituitary gland and by extension gonadal testosterone production.[126][127]High-dose estrogen therapy, including with ethinylestradiol, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range.[128][126][127] The dosage of ethinylestradiol required for use as a component ofhormone therapy for preoperativetransgender women is 50 to 100 μg/day.[129] This high dosage is associated with a high incidence of venous thromboembolism, particularly in those over the age of 40 years, and it has been said that it should not be used.[129] The dosage of ethinylestradiol used in the treatment of prostate cancer in men is 150 to 1,000 μg/day (0.15–1.0 mg/day).[8][130] A dosage of ethinylestradiol of 50 μg twice daily (100 μg/day total) has been found to suppress testosterone levels in men to an equivalent extent as 3 mg/day oraldiethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress testosterone levels into the castrate range.[131] The ovulation-inhibiting dose of ethinylestradiol by itself and not in combination with a progestin in women is 100 μg/day.[132][133] However, it has been found to be about 75 to 90% effective at inhibiting ovulation at a dosage of 20 μg/day and about 97 or 98% effective at a dosage of 50 μg/day.[134][135][136][137] In another study, ovulation occurred in 25.2% with an ethinylestradiol dose of 50 μg/day.[138]
Lower dosages of ethinylestradiol also have significant antigonadotropic effects.[129] A "very low" dosage of 15 μg/day ethinylestradiol has been described as the "borderline" amount required for suppression of LH and testosterone levels in men, and a study found that LH and testosterone levels were "reliably" suppressed in men by a dosage of 30 μg/day ethinylestradiol.[8] However, other clinical studies have found that 20 μg/day ethinylestradiol increased testosterone levels by 50% in men (as described above)[120] and that dosages of 32 μg/day and 42 μg/day ethinylestradiol suppressed FSH levels in men but did not significantly affect LH levels.[8] A stronger suppression of testosterone levels was observed in men following daily treatment with a combined oral contraceptive containing 50 μg ethinylestradiol and 0.5 mgnorgestrel for 9 days.[8] However, investigation revealed that the progestin was the more important component responsible for the suppression in testosterone levels.[8] In accordance, the progestin component of combined oral contraceptives is primarily responsible for inhibition ofovulation in women.[8] A combination of 20 μg/day ethinylestradiol and 10 mg/daymethyltestosterone was found to suppress FSH secretion in men to an extent sufficient to stopspermatogenesis.[8] Studies in women have found that 50 μg/day ethinylestradiol suppresses LH and FSH levels both by about 70% in postmenopausal women.[98]
In addition to its antigonadotropic effects, ethinylestradiol can significantly suppress androgen production by theadrenal glands at high concentrations.[8][139][140] One study found that treatment with a high dosage of 100 μg/day ethinylestradiol suppressed circulatingadrenal androgen levels by 27 to 48% in transgender women.[8][139][140] This may additionally contribute to suppression of androgen levels by estrogens.[8][139][140]
Ethinylestradiol has marked effects onliver protein synthesis, even at low dosages and regardless ofroute of administration.[8][7] These effects are mediated by its estrogenic activity.[8][7] The medication dose-dependently increases circulating levels of SHBG,corticosteroid-binding globulin (CBG), andthyroxine-binding globulin (TBG), and also affects a broad range of other liver proteins.[8][7] Ethinylestradiol affectstriglyceride levels at a dose as low as 1 μg/day andLDL andHDL cholesterol levels at a dose as low as 2.5 μg/day.[141] Ethinylestradiol affects several liver proteins at a dosage as low as 5 μg/day.[8] At doses above 20 μg/day, the incremental effects of ethinylestradiol on liver protein synthesis become continuously smaller.[8]
Ethinylestradiol at 5 μg/day has been found to increase SHBG levels by 100% in postmenopausal women, while a dosage of 20 μg/day ethinylestradiol increased them by 200%.[8] Androgens decrease hepatic SHBG production, and have been found to oppose the effects of ethinylestradiol on SHBG levels.[8] This is of particular relevance when it is considered that many progestins used in combined oral contraceptives have varying degrees of weak androgenic activity.[8] A combination of 20 μg/day ethinylestradiol and 0.25 mg/daylevonorgestrel, a progestin with relatively high androgenicity, decreases SHBG levels by 50%; 30 μg/day ethinylestradiol and 0.25 mg/day levonorgestrel has no effect on SHBG levels; 30 μg/day ethinylestradiol and 0.15 mg/day levonorgestrel increases SHBG levels by 30%; andtriphasic combined oral contraceptives containing ethinylestradiol and levonorgestrel increase SHBG levels by 100 to 150%.[8] The combination of 30 μg/day ethinylestradiol and 150 μg/daydesogestrel, a progestin with relatively weak androgenicity than levonorgestrel, increases SHBG levels by 200%, while the combination of 35 μg/day ethinylestradiol and 2 mg/daycyproterone acetate, a progestin with potentantiandrogenic activity, increases SHBG levels by 400%.[8] As such, the type and dosage of progestin contained in combined oral contraceptives potently moderates the effects of ethinylestradiol on SHBG levels.[8]
A dosage of 10 μg/day ethinylestradiol has been found to increase CBG levels by 50%, while a dosage of 20 μg/day ethinylestradiol increased them by 100%.[8] Progestins that are progesterone derivatives have no effect on CBG levels, while androgenic progestins like the19-nortestosterone derivatives have only a weak effect on CBG levels.[8] Combined oral contraceptives may increase CBG levels by 100 to 150%.[8] A dosage of 5 μg/day ethinylestradiol has been found to increase TBG levels by 40%, while a dosage of 20 μg/day ethinylestradiol increased them by 60%.[8] Progestins that are progesterone derivatives do not affect TBG levels, while progestins with androgenic activity may decrease TBG levels.[8] A combination of 30 μg/day ethinylestradiol and 1 mg/daynorethisterone, a moderately androgenic progestin, have been found to increase TBG levels by 50 to 70%, while the combination of 30 μg/day ethinylestradiol and 150 μg/day desogestrel increased them by 100%.[8]
Ethinylestradiol shows strong and disproportionate effects onliver protein synthesis relative to estradiol.[7] Theliver as well as theuterus express17β-hydroxysteroid dehydrogenase (17β-HSD), and thisenzyme serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogenestrone (which has approximately 4% of the estrogenic activity of estradiol).[7] In contrast to estradiol, the 17α-ethynyl group of ethinylestradiol preventsoxidation of the C17β position of ethinylestradiol by 17β-HSD, and for this reason, ethinylestradiol is not inactivated in these tissues and has much stronger relative estrogenic activity in them.[7][142][11] This is the mechanism of the disproportionately strong effects of ethinylestradiol on hepatic protein production,[7][142] which results in a greatly increased magnitude of effect on venous thromboembolism and cardiovascular risks relative to estradiol.[143]
On the other hand, due to the loss of inactivation of ethinylestradiol by 17β-HSD in theendometrium (uterus), ethinylestradiol is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence ofvaginal bleeding and spotting in comparison.[7] This is particularly so in the case of combined estrogen and progestogen therapy (as in combined oral contraceptives or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium.[7] The reduced vaginal bleeding and spotting with ethinylestradiol is one of the main reasons that it is used in combined oral contraceptives instead of estradiol,[3] in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and venous thromboembolism incidence).[144]
Ethinylestradiol has been found to have disproportionate effects on liver protein synthesis and venous thromboembolism risk regardless of whether theroute of administration is oral, transdermal, or vaginal, indicating that the use ofparenteral routes over the oral route does not result in ethinylestradiol having proportional hepatic actions relative to non-hepatic actions.[142][8] However, the potency of ethinylestradiol on liver protein synthesis is in any case reduced with parenteral administration.[8] A dosage of 10 μg/day vaginal ethinylestradiol has been found to be equivalent to 50 μg oral ethinylestradiol in terms of effects on liver protein synthesis, such as stimulation of hepatic SHBG production.[8] As such, parenteral ethinylestradiol, which bypasses the first pass through the liver that occurs with oral ethinylestradiol, has been found to have a 5-fold lower impact on liver protein synthesis by weight than oral ethinylestradiol.[8] In contrast to ethinylestradiol as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages.[7]
| Parameters | Estradiol | Ethinylestradiol |
|---|---|---|
| ERTooltip Estrogen receptoraffinity | 1 × 1010 M-1 | 2–5 × 1011 M-1 |
| Nuclear retention | 6–8 hours | 24 hours |
| Elimination half-life | 90 minutes | 7 hours |
| Substrate for17β-HSDTooltip 17β-hydroxysteroid dehydrogenase? | Yes | No |
| Bound toSHBGTooltip Sex hormone-binding globulin? | Yes | No |
| Relativeoralliverpotency | 1 | ~500–1,500 |
| Relativeoralpituitary potency | 1 | 200 |
| Sources:[64] | ||
Theoralbioavailability of ethinylestradiol is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to highinterindividual variability.[10][4] Although relatively low, the oral bioavailability of ethinylestradiol is considerably higher than that of micronized estradiol (5%).[2][10] Following a single 20 μg dose of ethinylestradiol in combination with 2 mgnorethisterone acetate in postmenopausal women, ethinylestradiol concentrations have been found to reach a maximum of 50 pg/mL within an average of 1.5 hours.[7] Following the first dose, mean levels of ethinylestradiol in general further increase by about 50% untilsteady-state concentrations are reached;[7][145] steady-state is reached after one week of daily administration.[8] For comparison, the mean peak levels of estradiol achieved with 2 mg micronized estradiol orestradiol valerate are 40 pg/mL following the first dose and 80 pg/mL after three weeks of administration.[7] These maximal concentrations of estradiol are in the same range as the concentrations of ethinylestradiol that are produced by an oral dose of ethinylestradiol that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of ethinylestradiol relative to estradiol.[94][7] In accordance with the high interindividual variability in the oral bioavailability of ethinylestradiol, there is a large degree of interindividual variation in ethinylestradiol levels.[7][146] A dosage of ethinylestradiol of 50 μg/day has been found to achieve a wide range of circulating ethinylestradiol levels of about 100 to 2,000 pg/mL.[147][146] Taking ethinylestradiol in combination with a high-fat meal has been found to significantly decrease its peak concentrations.[145][7]
Ethinylestradiol levels after a single 50 μg dose by intravenous injection are several times higher than levels of ethinylestradiol after a single 50 mg dose given orally.[147] Besides the difference in levels, the course of elimination is similar for the two routes.[147]
There may be gender-specific differences in thepharmacokinetics of ethinylestradiol, such that ethinylestradiol may have greater oral potency in women than in men.[8] A study found that a combination of 60 μg/day ethinylestradiol and 0.25 mg/daylevonorgestrel in women and men resulted in peak levels of ethinylestradiol of 495 pg/mL and 251 pg/mL,area-under-the-curve levels of ethinylestradiol of 6.216 pg/mL/hour and 2.850 pg/mL/hour, andelimination half-lives of 16.5 hours and 10.2 hours, respectively.[8] It has been suggested that this phenomenon could represent a "protection mechanism" of males againstenvironmental estrogen exposure.[8]
Theplasma protein binding of ethinylestradiol is 97 to 98%, and it is bound almost exclusively toalbumin.[5][7][10][148] Unlike estradiol, which binds with high affinity to SHBG, ethinylestradiol has very low affinity for this protein, about 2% of that of estradiol, and hence does not bind to it importantly.[149]
Due to high first-pass metabolism in theintestines andliver, only 1% of an oral dose of an ethinylestradiol appears in the circulation as ethinylestradiol itself.[7] During first-pass metabolism, ethinylestradiol is extensivelyconjugated viaglucuronidation andsulfation into the hormonally inert ethinylestradiolglucuronides andethinylestradiol sulfate (EE sulfate), and levels of ethinylestradiol sulfate in circulation are between 6- and 22-fold higher than those of ethinylestradiol.[7][4] For comparison, with oral administration of 2 mg micronized estradiol, levels ofestrone andestrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively.[7] In contrast to estradiol, ethinylestradiol, due tosteric hindrance by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD,[11] and this is the primary factor responsible for the dramatically increased potency of oral ethinylestradiol relative to oral estradiol.[7] Ethinylestradiol is also not metabolized into estradiol.[150]
Aside from sulfate conjugation, ethinylestradiol is mainlymetabolized byhydroxylation intocatechol estrogens.[7] This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily byCYP3A4.[10] Hydroxylation of ethinylestradiol 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.[10] 2- and 4-methoxy-EE are also formed via transformation bycatechol O-methyltransferase of 2- and 4-hydroxy-EE.[7] Unlike the case of estradiol, 16α-hydroxylation does not occur with ethinylestradiol, owing tosteric hindrance by its ethynyl group at C17α.[10][7] The ethynylation of ethinylestradiol is largely irreversible, and so ethinylestradiol is not metabolized into estradiol, unlikeestradiol esters.[7] A review found that the range of the reportedelimination half-life of ethinylestradiol in the literature was 13.1 to 27.0 hours.[2] Another review reported an elimination half-life of ethinylestradiol of 10 to 20 hours.[10] However, the elimination half-life of ethinylestradiol has also been reported by other sources to be as short as 7 hours[11] and as long as 36 hours.[9]
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 ethinylestradiol fall rapidly after peaking.[7] 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 ethinylestradiol sulfate reservoir for ethinylestradiol is much smaller in comparison.[7][4] In any case, due to the formation of ethinylestradiol sulfate,enterohepatic recirculation is involved in thepharmacokinetics of ethinylestradiol similarly to estradiol, although to a lesser extent.[7][151] The contribution of enterohepatic recirculation to total circulating ethinylestradiol levels appears to be 12 to 20% or less, and is not observed consistently.[8][151] A secondary peak in ethinylestradiol levels 10 to 14 hours after administration can often be observed with oral ethinylestradiol.[151]
Ethinylestradiol, followingoxidative formation of a very reactivemetabolite,irreversibly inhibitscytochrome P450enzymes involved in its metabolism, and this may also play a role in the increased potency of ethinylestradiol relative to estradiol.[7] Indeed, ethinylestradiol 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.[148] A 2-fold accumulation in ethinylestradiol levels with an ethinylestradiol-containing COC has been observed following 1 year of therapy.[151]
Ethinylestradiol iseliminated 62% in thefeces and 38% in theurine.[10]
Ethinylestradiol, also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol, is asyntheticestranesteroid and aderivative ofestradiol with anethynyl substitution at the C17α position.[1][152] The 17α-ethynylation of estradiol to create ethinylestradiol is analogous to the 17α-substitution oftestosterone to make testosterone derivatives such as 17α-ethynylated progestins likeethisterone (17α-ethynyltestosterone) andnorethisterone (17α-ethynyl-19-nortestosterone) as well as17α-alkylatedandrogens/anabolic steroids likemethyltestosterone (17α-methyltestosterone).
A number ofderivatives of ethinylestradiol exist.[1][152] These includemestranol (EE 3-methyl ether),quinestrol (EE 3-cyclopentyl ether),ethinylestradiol sulfonate (EE 3-isopropylsulfonate), andmoxestrol (11β-methoxy-EE).[1][152][8] The former three areprodrugs of ethinylestradiol, while the latter one is not.[8] A fewanalogues of ethinylestradiol with othersubstitutions at the C17α position exist.[1][152] Examples include the estradiol derivativesmethylestradiol (17α-methylestradiol) andethylestradiol (17α-ethylestradiol), and theestriol derivativesethinylestriol (17α-ethynylestriol) andnilestriol (17α-ethynylestriol 3-cyclopentyl ether).[1][152]Androstane analogues of ethinylestradiol with significant although weak estrogenic activity includeethinylandrostenediol (17α-ethynyl-5-androstenediol),17α-ethynyl-3β-androstanediol,17α-ethynyl-3α-androstanediol, andmethandriol (17α-methyl-5-androstenediol).
Ethinylestradiol was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg ofSchering AG inBerlin.[153][154][155][156][157] It was approved by the USFood and Drug Administration (FDA) in June 1943, and marketed bySchering under the brand name Estinyl.[14] The FDA withdrew approval of Estinyl effective 4 June 2004 at the request ofSchering, which had discontinued marketing it.[158]
Ethinylestradiol was never introduced for use byintramuscular injection.[159]
Ethinylestradiol was first used in combined oral contraceptives, as an alternative tomestranol, in 1964, and shortly thereafter superseded mestranol in combined oral contraceptives.[15]
Early combined oral contraceptives contained 40 to 100 μg/day ethinylestradiol and 50 to 150 μg/day mestranol.[160][161]
Ethinylestradiol is theEnglishgeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[162][1][163][152] It has also been spelled asethynylestradiol,ethynyloestradiol, andethinyloestradiol (all having the same pronunciation), and the latter was formerly itsBANTooltip British Approved Name but was eventually changed.[162][1][152] In addition, a space is often included in the name of ethinylestradiol such that it is written asethinyl estradiol (as well as variations thereof), and this is itsUSPTooltip United States Pharmacopeia name.[162][152] The generic name of ethinylestradiol inFrench and itsDCFTooltip Dénomination Commune Française areéthinylestradiol, inSpanish isetinilestradiol, inItalian and itsDCITTooltip Denominazione Comune Italiana areetinilestradiolo, and inLatin isethinylestradiolum.[162][152]
The name of the drug is often abbreviated asEE or asEE2 in themedical literature.
Ethinylestradiol has been marketed as a standalone oral drug under the brand namesEsteed,Estinyl,Feminone,Lynoral,Menolyn,Novestrol,Palonyl,Spanestrin, andYlestrol among others, although most or all of these formulations are now discontinued.[164][165][152] It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive.[162] In addition, ethinylestradiol is marketed in theU.S. in combination withnorelgestromin under the brand namesOrtho Evra andXulane as acontraceptive patch, in combination withetonogestrel under the brand nameNuvaRing as acontraceptive vaginal ring, and in combination withnorethisterone acetate under the brand nameFemHRT in oral hormone replacement therapy for the treatment of menopausal symptoms.[12]
Ethinylestradiol is marketed throughout the world.[162][152] It is marketed exclusively or almost exclusively in combination with progestins.[162]
Combination medications with additional hormones are common medications in the US.[18]
| Other components | Rank | Total prescriptions | Additional sources |
|---|---|---|---|
| Norethisterone ornorethisterone acetate | 80 | 8 million | [19] |
| Norgestimate | 99 | 6 million | [166] |
| Levonorgestrel | 128 | 4 million | [167] |
| Drospirenone | 142 | 4 million | [168] |
| Desogestrel | 161 | 3 million | [169] |
| Etonogestrel | 194 | 2 million | [170] |
| Norgestrel | 264 | 1 million | [171] |
| Drospirenone andlevomefolic acid | 285 | 500,000 | [172] |
| Etynodiol | 294 | 400,000 | [173] |
The binding affinity of EE2 for the estrogen receptor is similar to that of estradiol. [...] During daily intake, the EE2 levels increase up to a steady state which is reached after about 1 week.
Ethinyl estradiol is a synthetic and comparatively potent estrogen. As a result of the alkylation in 17-C position it is not a substrate for 17β dehydrogenase, an enzyme which transforms natural estradiol-17β to the less potent estrone in target organs.
In 1964, ethinyl estradiol was introduced as an alternative to mestranol as the estrogenic component, [...]
ETHINYL ESTRADIOL: TABLET; ORAL: ESTINYL: SCHERING: 0.02MG; 0.05MG; 0.5MG
Ethinyl oestradiol 0,05mg cpr 0,05 mg ethinylestradiol (G03CA01) (FR) Ethinylestradiol tablets 50 mcg Ethinylestradiol (G03CA01) (RUS) Ethinylestradiol 25μg (Jenapharm) Dragees: Ethinylestradiol 25μg (G03CA01) (DE) Ethinylestradiol pch 0,002mg cpr 0,002 mg ethinylestradiol (FR) Ethinylestradiolum tablet 0,05mg ethinylestradiol 0,05 mg (G03CA01) (NL) [...] Etifollin tab 0,5mg (Nycomed pharma a/s) ethinylestradiol (L02AA03) (NO) Etifollin tab 50mcg (Nycomed pharma a/s) ethinylestradiol (G03CA01) (NO)
Ethinyloestradiol (Lynoral, 0.05-mg, 0.1-mg, 1-mg tablets)
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. [...] The estrogen component of COCs can cause breast fullness and tenderness.
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 [ethinylestradiol] contents greater than 50 μg.
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.
Further research showed that the therapeutic effect of ethynylestradiol in established EAE was mediated via GPER, but not via ERα, and possibly involved production of the anti-inflammatory cytokine Il‑10.115
In addition, the therapeutic effect of ethinyl estradiol in established disease was demonstrated to require expression of GPER but not ERα, and was associated with the production of the anti-inflammatory cytokine IL-10 (Yates et al., 2010).
The synthetic estrogen, ethinyl estradiol, more commonly used in oral contraceptives, has a biological activity 100 times that of the native and conjugated substances.
EE2 has about 100 times the potency of an equivalent weight of conjugated equine estrogen or estrone sulfate for stimulating synthesis of hepatic proteins. [...] EE2 is about 1.7 times as potent as the same weight of mestranol.
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.
The relative potency of several estrogens has been assayed by determination of effects on plasma FSH, a measure of the systemic effect, and by increases in SHBG, CBG, and angiotensinogen, all of which indicate the hepatic effect. Piperazine estrone sulfate and micronized estradiol were equipotent with respect to increases in SHBG, whereas conjugated estrogens were 3.2-fold more potent, DES was 28.4-fold more potent, and ethinyl estradiol was 600-fold more potent. With respect to decreased FSH, conjugated estrogens were 1.4-fold, DES was 3.8-fold, and ethinyl estradiol was 80 to 200-fold more potent than was piperazine estrone sulfate.
There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
{{cite book}}: CS1 maint: DOI inactive as of July 2025 (link)Ethinyl Estradiol [Estinyl, Feminone, Lynoral, Novestrol, Palonyl]
ETHINYL ESTRADIOL U.S.P. (Esteed®, Estinyl®, Lynoral®, Menolyn®, Novestrol®, Palonyl®, Spanestrin®, Ylestrol®)
