Ethinylestradiol
| Numerous |
| Ethynylestradiol; Ethinyl estradiol; Ethinyl oestradiol; EE; EE2; 17α-Ethynylestradiol; 17α-Ethynylestra-1,3,5[10]-triene-3,17β-diol; NSC-10973[1] |
| International Drug Names |
| a604032 |
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| • By mouth [tablet] • Transdermal [patch] • Vaginal [ring] |
| Estrogen |
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| 38–48%[2][3][4] |
| 97–98% [to albumin;[5] is not bound to SHBG][6] |
| Liver [primarily CYP3A4][9] |
| • Ethinylestradiol
sulfate[7][8] • Others[7][8] |
| 7–36 hours[9][2][10][11] |
| Feces: 62%[10] Urine: 38%[10] |
IUPAC name
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| 100.000.311
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| C20H24O2 |
| 296.410 g·mol−1 |
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| 182 to 184 °C [360 to 363 °F] |
SMILES
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InChI
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| [verify] |
Ethinylestradiol [EE] is an estrogen medication which is used widely in birth control pills in combination with progestins.[7][8] In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.[7][12]
The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others.[7] 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.[7]
EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[7] It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways.[7] 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.[7] 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.[7]
EE 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] 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.[16][17]
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 menstruation, and acne.
EE is also used as menopausal hormone therapy.[18] 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.[19] 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.[20] However, it is no longer commonly used nor recommended for this purpose, with estradiol having largely superseded it.[20]
EE can also be used to treat hypogonadism in women, prevent osteoporosis in women, and has been used as palliative care for prostate cancer in men and breast cancer in women.[8][21] It has also been used to reduce sex drive in sex offenders.[22][23]
EE or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of endometrial cancer; giving a progestogen with an estrogen mitigates the risk.[24]
Available forms[edit]
EE is available in combination with a progestin in a vast number of COCs.[25] It is also available in combination with progestins as a transdermal contraceptive patch and as a contraceptive vaginal ring.[12] In addition, there is a single preparation [brand name FemHRT] containing very low doses of EE [2.5 and 5 µg] plus a progestin in an oral tablet that remains in use for menopausal hormone therapy.[12][18] EE was previously available by itself under the brand name Estinyl in the form of 0.02, 0.05, and 0.5 mg [20, 50, and 500 µg] tablets.[26]
The amount of EE in COCs has reduced over the years.[8] Previously, COCs contained high doses of EE of as much as 100 µg/day.[27] Doses of more than 50 µg EE are considered high-dose, doses of 30 and 35 µg EE are considered low-dose, and doses of 10 to 25 µg EE are considered very low dose.[28] Today, COCs generally contain 10 to 50 µg EE.[28] The higher doses of EE were discontinued due to a high risk of VTE and cardiovascular problems.[27]
Contraindications[edit]
EE should be avoided in individuals with a history of or known susceptibility to arterial or venous thrombosis [blood clots], due to an increased risk of cardiovascular problems such as venous thromboembolism [VTE], myocardial infarction, and ischemic stroke.[29] This includes women with:
- History of deep vein thrombosis [DVT] or pulmonary embolism [PE] not receiving anticoagulants
- Acute DVT/PE
- Prolonged immobilization due to major surgery
- Advanced diabetes mellitus with vascular disease
- Migraine with aura
- Hypertension ≥160/100
- Vascular disease
- Current and history of ischemic heart disease
- Multiple risk factors for atherosclerotic cardiovascular disease [e.g. older age, smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels]
- Age ≥35 and smoking ≥15 cigarettes/day
- History of cerebrovascular accident
- Systemic lupus erythematosus with positive [or unknown] antiphospholipid antibodies
- Complicated valvular heart disease
Except when being used to treat it, EE should be avoided in women with current breast cancer due to a possible worsening of prognosis.[30]
EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE.[31] 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.[31]
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.[32]
Side effects[edit]
Dose of ethinylestradiol in birth control pills and risk of venous thromboembolism [VTE]| Low [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 a first-generation progestin, such as norethisterone or levonorgestrel. Sources: Main:[33][34] Additional:[35] |
The severity of side effects can vary based on the dose and administration route of EE.[36] 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.[10][32] The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness.[26] 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]. In men who received high-dose estrogen therapy with 200 μg/day oral EE for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%.[37]
Long-term effects[edit]
Beneficial and adverse effects of ethinylestradiol-containing birth control pills| Iron-deficiency anemia | 0.58 | Cardiovascular diseases [total] | 1.5 |
| Menorrhagia | 0.52 | Myocardial infarction [heart attack] [total] | 3.3 |
| Irregular menstruation | 0.65 | Myocardial infarction [non-smokers] | 1.0 |
| Intermenstrual bleeding | 0.72 | Myocardial infarction [light smokers] | 3.5 |
| Dysmenorrhea | 0.37 | Myocardial infarction [heavy smokers] | 20 |
| Pelvic inflammatory disease [incidence] | 0.50 | Cerebrovascular diseases [total] | 1.4 |
| Pelvic inflammatory disease [hospitalization] | 0.22 | Cerebral thromboses [strokes] | 2.5 |
| Trichomonas vaginitis | 0.56 | Subarachnoidal bleeding [heavy smokers] | 10 |
| Benign breast disease | 0.69 | Pulmonary embolism | 3.0 |
| Fibrocystic breast disease | 0.66 | Deep vein thromboses | 2.5 |
| Benign breast fibroadenomas | 0.35 | Gall-bladder diseases | 3.0 |
| Rheumatoid arthritis | 0.49 | Benign liver tumors | 50 |
| Endometrial cancer | 0.40–0.50 | Hepatocellular carcinoma | 3.0 |
| Ovarian cancer [incidence] | 0.37–0.64 | Erythema nodosum et multiforme | 3.0 |
| Ovarian cancer [death] | 0.20 | Pruritus [itching] | 2.0 |
| Benign follicular cysts [high-dose COCs] | 0.24 | Photosensitive eczema | 4.0 |
| Acne vulgaris | 0.44 | Irritant agent eczema | 2.0 |
| Low bone mineral density [later in life] | 0.35a | Dermatitis [eczema] | 2.0 |
| Ectopic pregnancy | 0.19 | Chloasma [melasma] | 1.5 |
| Cervicitis [6 years of use] | 3.0 | ||
| Chlamydia infections | 2.5 | ||
| Footnotes: a = Odds ratio. Sources: [38][26] |
Blood clots[edit]
VTE is a blood clot in a vein, and includes deep vein thrombosis [DVT] and pulmonary embolism [PE].[7][39][40] Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors.[7][39][40] EE carries a greater risk of blood clot formation and VTE than does natural estradiol, which is thought to be due to structural differences between the two compounds and different susceptibilities to liver inactivation.[7]
A 2012 meta-analysis estimated that the absolute risk of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for EE and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing EE and a third- or fourth-generation progestin such as desogestrel or drospirenone.[41] For comparison, the absolute risk of VTE 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 the postpartum period.[41] Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use.[41] The route of administration of EE does not appear to influence VTE risk, as EE/progestin-containing contraceptive vaginal rings and contraceptive patches have the same or even higher risk of VTE than COCs.[41][42] Pregnancy is associated with about a 4.3-fold increase in risk of VTE.[41] It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to VTE caused by EE-containing birth control pills.[43]
Modern COCs contain 10 to 35 μg EE, but typically 20, 30, or 35 μg.[41][44] The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 μg EE.[45][35][44] However, it was soon found that EE is associated with increased risk of VTE and that the risk is dose-dependent.[44] Following these events, the dose of EE was greatly reduced, and is now always less than 50 μg.[46][47][48] These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.[44] Gerstman et al. [1991] found that COCs containing more than 50 μg EE had 1.7-fold and COCs containing 50 μg EE 1.5-fold the risk of VTE of COCs containing less than 50 μg.[33] A 2014 Cochrane review found that COCs containing 50 μg EE with levonorgestrel had 2.1- to 2.3-fold the risk of COCs containing 30 μg or 20 μg EE with levonorgestrel, respectively.[41] COCs containing 20 μg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 μg EE.[49] However, discontinuation of COCs is more common with doses of EE from 10 to 20 μg due to problematic changes in bleeding patterns.[50]
Women with thrombophilia have a dramatically higher risk of VTE with EE-containing contraception than women without thrombophilia.[41][42] Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women.[41][42]
Sex hormone-binding globulin [SHBG] levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated.[51][52][53] SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate.[51] Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.[51] 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.[54] Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.[55][56][57][58][59] High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.[58]
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| 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/day E2 >1 mg/day E2 | 1.18 [0.98–1.42] 1.12 [0.90–1.40] 1.34 [0.94–1.90] | ||
| Estradiol/norethisterone ≤1 mg/day E2 >1 mg/day E2 | 1.68 [1.57–1.80]* 1.38 [1.23–1.56]* 1.84 [1.69–2.00]* | ||
| Estradiol/norgestrel or estradiol/drospirenone | 1.42 [1.00–2.03] | ||
| Conjugated estrogens/medroxyprogesterone acetate | 2.10 [1.92–2.31]* | ||
| Conjugated estrogens/norgestrel ≤0.625 mg/day CEEs >0.625 mg/day CEEs | 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 the QResearch and Clinical Practice Research Datalink [CPRD] databases. [2] Bioidentical progesterone 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. |
Cardiovascular issues[edit]
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 EE and diethylstilbestrol are associated with fairly high rates of severe cardiovascular complications such as VTE, myocardial infarction, and stroke.[21][60][61] Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer.[60][61] EE has a to some degree lower risk of cardiovascular complications than does diethylstilbestrol when used in the treatment of prostate cancer in men.[8] However, both EE and diethylstilbestrol nonetheless have highly disproportionate effects on liver protein synthesis, which is thought to be responsible for their cardiovascular toxicity.[7][61]
In contrast to oral synthetic estrogens like EE and diethylstilbestrol, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer.[61][62][63] However, significantly increased cardiovascular morbidity has been observed with high-dosage polyestradiol phosphate.[61][62][63] In any case, these estrogens are considered to be much safer than oral synthetic estrogens like EE and diethylstilbestrol.[61][62][63] In addition, ethinylestradiol sulfonate [EES], an oral but parenteral-like long-lasting prodrug of EE, is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than EE.[8]
Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like EE 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.[61]
Liver damage[edit]
At the lower dosages that are now used in birth control pills, EE has been associated rarely with cholestatic hepatotoxicity similarly to 17α-alkylated androgens/anabolic steroids and 17α-ethynylated 19-nortestosterone progestins.[64][65] Cholestasis can manifest as pruritus and jaundice.[66] 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.[67] Very high concentrations of estradiol, via its metabolite estradiol glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy.[65] However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with EE than with estradiol, which is thought to be due to the reactive C17α ethynyl substitution in EE as well as its greatly reduced susceptibility to hepatic metabolism.[32][68] Whereas abnormal liver function tests [LFTs] are normally found in about 1% of women not on birth control pills or taking lower-dose EE-containing birth control pills, this increases to more than 10% of women taking birth control pills containing 50 μg/day EE or more.[68][66] With birth control pills containing 50 μg/day EE, alanine aminotransferase [ALT] levels increase by 50%, hematocrit by 19%, and leukocytes by 50%, while gamma-glutamyltransferase [GGT] decreases by 30%.[68] However, the values usually remain in the normal range.[68] In addition to abnormal LFTs, pathological changes in partial liver functions and liver morphology can be observed in half of women on birth control pills with 50 μg/day EE.[68] EE-containing birth control pills have also been associated with a 25- to 50-fold increase in the risk of rare benign liver tumors and a 3- to 6-fold increase in the risk of hepatocellular carcinoma,[66][69][70] as well as greater risk of other liver complications.[71][72] At one time, EE-containing birth control pills were estimated to be responsible for 84% of all drug-related and histologically verified liver damage.[68] However, these risks now are reduced with modern lower-dose EE-containing birth control pills, with contain 35 μg/day EE or less.[66][70]
Uterine 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.[73] 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.[73] 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.[73] In turn, most studies of modern COCs have found a decreased risk of endometrial cancer.[74]
Ecological Effects[edit]
Wastewater contains various estrogens, including EE, that are not completely broken down by wastewater treatment procedures.[75] The input of artificial estrogens into freshwater ecosystems affects fish and amphibian populations. Chronic exposure to low levels of EE over seven years led to the collapse of fathead minnow populations in an experimental lake in Ontario, Canada.[75] EE changed oogenesis in female fish and feminized male fish such that they produced a protein associated with egg maturation, vitellogenin, as well as early-stage eggs.[75] In amphibians, exposure to EE can reduce hatching success and alter gonadal development.[76] Exposure to hormones can change frogs' gonadal development even though it is encoded in their genes.[76] A study of mink frogs found more intersex tadpoles in those experimentally exposed to EE than those not exposed to EE, and green frogs showed much lower rates of hatching success.[76]
Overdose[edit]
Estrogens like EE are relatively safe in acute overdose.[citation needed]
Interactions[edit]
EE is metabolized by certain cytochrome P450 isoforms, including CYP3A4 and CYP2C9.[77] Thus, inducers of enzymes such as CYP3A4 can decrease circulating concentrations of EE.[32] Examples of inducers include anticonvulsants like phenytoin, primidone, ethosuximide, phenobarbital, and carbamazepine; azole antifungals like fluconazole; and rifamycin antibiotics like rifampin [rifampicin].[32] Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE.[32] An example is troleandomycin, which is a potent and highly selective inhibitor of CYP3A4.[32]
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 ethinylestradiol sulfate [EE sulfate] in women.[32] The same has been found for ascorbic acid [vitamin C] and EE, although the significance of the interaction has been regarded as dubious.[32]
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.[32] This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.[32] There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.[32]
EE is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, and is possibly an inducer of CYP2A6.[78] As a result, it can affect the metabolism and concentrations of many other drugs.[78] Examples of known interactions include bupropion, caffeine, mephenytoin, midazolam, nicotine, nifedipine, omeprazole, propranolol, proguanil, selegiline, theophylline, and tizanidine.[78][32] One of the most notable interactions is that EE strongly increases levels of selegiline, a substrate of CYP2B6 and CYP2C19.[78] EE may also induce glucuronidation and possibly alter sulfation.[78] It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated.[78] Examples include clofibrate, lamotrigine, lorazepam, oxazepam, and propranolol.[78]
Progestins, which are often used in combination with EE, are also known to inhibit cytochrome P450 enzymes, and this may contribute to drug interactions with EE-containing contraceptives as well.[78] Examples include gestodene, desogestrel, and etonogestrel, which are CYP3A4 and CYP2C19 inhibitors.[78] In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself.[32]
Pharmacology[edit]
Pharmacodynamics[edit]
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.[8] In one study, EE was found to have 233% and 38% of the affinity of estradiol for the ERα and ERβ, respectively.[79] In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively.[80] EE also appears to act as a potent agonist of the G protein-coupled estrogen receptor [GPER] [affinity unknown], a membrane estrogen receptor, similarly to estradiol.[81][82][83][84] Estrogens have antigonadotropic effects through activation of the ERα.[85] 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.[86][87]
EE is a long-acting estrogen, with a nuclear retention of about 24 hours.[34]
Orally, EE is on the order of 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.[88][89][90] It is specifically in the range of 80 to 200 times as potent as estropipate [piperazine estrone sulfate], which has similar potency to micronized estradiol, in terms of systemic estrogenic potency.[91][92] In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism.[44] Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.[89]
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| 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 | Chủ Đề |