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Ethinylestradiol

April 10, 2024

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]

Ethinylestradiol
Clinical data
Pronunciation/ˌɛθɪnɪlˌɛstrəˈdaɪ.əl/
Trade namesMany
Other namesEthynylestradiol; Ethinyl estradiol; Ethinyl oestradiol; EE; EE2; 17α-Ethynylestradiol; 17α-Ethynylestra-1,3,5(10)-triene-3,17β-diol; NSC-10973[1]
AHFS/Drugs.comInternational Drug Names
MedlinePlusa604032
Routes of
administration		• By mouth, Transdermal, Vaginal
Drug classEstrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability38–48%[2][3][4]
Protein binding97–98% (to albumin;[5] is not bound to SHBGTooltip sex hormone-binding globulin)[6]
MetabolismLiver (primarily CYP3A4)[9]
Metabolites• Ethinylestradiol sulfate[7][8]
• Others[7][8]
Elimination half-life7–36 hours[9][2][10][11]
ExcretionFeces: 62%[10]
Urine: 38%[10]
Identifiers
  • (8R,9S,13S,14S,17R)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-4,17-diol
CAS Number
  • 57-63-6 Y
PubChem CID
  • 5991
IUPHAR/BPS
  • 7071
DrugBank
  • DB00977 Y
ChemSpider
  • 5770 Y
UNII
  • 423D2T571U
KEGG
  • D00554 Y
ChEBI
  • CHEBI:4903 Y
ChEMBL
  • ChEMBL691 Y
CompTox Dashboard (EPA)
  • DTXSID5020576
ECHA InfoCard100.000.311
Chemical and physical data
FormulaC20H24O2
Molar mass296.410 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point182 to 184 °C (360 to 363 °F)
  • Oc1cc4c(cc1)[C@H]3CC[C@]2([C@@H](CC[C@]2(C#C)O)[C@@H]3CC4)C
  • InChI=1S/C20H24O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,5,7,12,16-18,21-22H,4,6,8-11H2,2H3/t16-,17-,18+,19+,20+/m1/s1 Y
  • Key:BFPYWIDHMRZLRN-SLHNCBLASA-N Y
  (verify)

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 is more resistant to metabolism, has greatly improved bioavailability when taken by mouth, 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] Ethinylestradiol 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 the most widely used estrogens.[16][17]

In 2021, the combination with norethisterone was the 52nd most commonly prescribed medication in the United States, with more than 12 million prescriptions;[18][19] the version with norgestimate was the 76th most commonly prescribed medication in the US, with more than 8 million prescriptions;[18][20] the combination with levonorgestrel was the 144th most commonly prescribed medication in the US, with more than 4 million prescriptions;[18][21] the combination with etonogestrel was the 198th most commonly prescribed medication in the US, with more than 2 million prescriptions;[18][22] the combination with norgestrel was the 227th most commonly prescribed medication in the US, with more than 2 million prescriptions;[18][23] the combination with etynodiol was the 276th most commonly prescribed medication in the US, with more than 800,000 prescriptions;[18][24] the combination with drospirenone and levomefolic acid was the 277th most commonly prescribed medication in the US, with more than 800,000 prescriptions;[18][25]

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.[26] 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.[27] 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.[28] However, it is no longer commonly used nor recommended for this purpose, with estradiol having largely superseded it.[28]

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][29] It has also been used to reduce sex drive in sex offenders.[30][31]

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.[32]

Available forms edit

EE is available in combination with a progestin in a vast number of COCs.[33] 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][26] EE 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.[34][35][36][37][38]

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.[39] 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.[40] Today, COCs generally contain 10 to 50 µg EE.[40] The higher doses of EE were discontinued due to a high risk of VTE and cardiovascular problems.[39]

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.[41] This includes women with:

Except when being used to treat it, EE should be avoided in women with current breast cancer due to a possible worsening of prognosis.[42]

EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE.[43] 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.[43]

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.[44]

Side effects edit

Dose of ethinylestradiol in birth control pills and risk of venous thromboembolism (VTE)
Ethinylestradiol dose No. of VTE cases Woman-years VTE rate Adjusted RRa
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 a first-generation progestin, such as norethisterone or levonorgestrel. Sources: Main:[45][46] Additional:[47]

The severity of side effects can vary based on the dose and administration route of EE.[48] 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][44] The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness.[34] 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%.[49]

Long-term effects edit

Beneficial and adverse effects of ethinylestradiol-containing birth control pills
Beneficial effects Adverse effects
Disease RRTooltip Relative risk Disease RRTooltip Relative risk
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: [50][34]

Blood clots edit

VTE is a blood clot in a vein, and includes deep vein thrombosis (DVT) and pulmonary embolism (PE).[7][51][52] Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors.[7][51][52] 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.[53] 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.[53] Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use.[53] 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.[53][54] Pregnancy is associated with about a 4.3-fold increase in risk of VTE.[53] 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.[55]

Modern COCs contain 10 to 35 μg EE, but typically 20, 30, or 35 μg.[53][56] The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 μg EE.[57][47][56] However, it was soon found that EE is associated with increased risk of VTE and that the risk is dose-dependent.[56] Following these events, the dose of EE was greatly reduced, and is now always less than 50 μg.[58][59][60] These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.[56] 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.[45] 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.[53] COCs containing 20 μg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 μg EE.[61] However, discontinuation of COCs is more common with doses of EE from 10 to 20 μg due to problematic changes in bleeding patterns.[62]

Women with thrombophilia have a dramatically higher risk of VTE with EE-containing contraception than women without thrombophilia.[53][54] Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women.[53][54]

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.[63][64][65] 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.[63] Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.[63] 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.[66] Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.[67][68][69][70][71] High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.[70]

Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
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/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.[29][72][73] 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.[72][73] 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][73]

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.[73][74][75] However, significantly increased cardiovascular morbidity has been observed with high-dosage polyestradiol phosphate.[73][74][75] In any case, these estrogens are considered to be much safer than oral synthetic estrogens like EE and diethylstilbestrol.[73][74][75] 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.[73]

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.[76][77] Cholestasis can manifest as pruritus and jaundice.[78] 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.[79] Very high concentrations of estradiol, via its metabolite estradiol glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy.[77] 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.[44][80] 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.[80][78] 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%.[80] However, the values usually remain in the normal range.[80] 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.[80] 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,[78][81][82] as well as greater risk of other liver complications.[83][84] At one time, EE-containing birth control pills were estimated to be responsible for 84% of all drug-related and histologically verified liver damage.[80] However, these risks now are reduced with modern lower-dose EE-containing birth control pills, with contain 35 μg/day EE or less.[78][82]

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.[85] 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.[85] 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.[85] In turn, most studies of modern COCs have found a decreased risk of endometrial cancer.[86]

Ecological Effects edit

Wastewater contains various estrogens, including EE, that are not completely broken down by wastewater treatment procedures.[87] 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.[87] 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.[87] In amphibians, exposure to EE can reduce hatching success and alter gonadal development.[88] Exposure to hormones can change frogs' gonadal development even though it is encoded in their genes.[88] 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.[88]

Overdose edit

See also: Estrogen (medication) § Overdose

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.[89] Thus, inducers of enzymes such as CYP3A4 can decrease circulating concentrations of EE.[44] Examples of inducers include anticonvulsants like phenytoin, primidone, ethosuximide, phenobarbital, and carbamazepine; azole antifungals like fluconazole; and rifamycin antibiotics like rifampin (rifampicin).[44] Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE.[44] An example is troleandomycin, which is a potent and highly selective inhibitor of CYP3A4.[44]

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.[44] The same has been found for ascorbic acid (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.[44]

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.[44] This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.[44] There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.[44]

EE is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, and is possibly an inducer of CYP2A6.[90] As a result, it can affect the metabolism and concentrations of many other drugs.[90] Examples of known interactions include bupropion, caffeine, mephenytoin, midazolam, nicotine, nifedipine, omeprazole, propranolol, proguanil, selegiline, theophylline, and tizanidine.[90][44] One of the most notable interactions is that EE strongly increases levels of selegiline, a substrate of CYP2B6 and CYP2C19.[90] EE may also induce glucuronidation and possibly alter sulfation.[90] It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated.[90] Examples include clofibrate, lamotrigine, lorazepam, oxazepam, and propranolol.[90]

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.[90] Examples include gestodene, desogestrel, and etonogestrel, which are CYP3A4 and CYP2C19 inhibitors.[90] In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself.[44]

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.[91] In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively.[92] 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.[93][94][95][96] Estrogens have antigonadotropic effects through activation of the ERα.[97] 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.[98][99]

EE is a long-acting estrogen, with a nuclear retention of about 24 hours.[46]

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.[100][101][102] 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.[103][104] In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism.[56] Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.[101]

Affinities of estrogen receptor ligands for the ERα and ERβ
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 of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.
Relative affinities of estrogens for steroid hormone receptors and blood proteins
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: Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, testosterone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: See template.
Relative oral potencies of estrogens
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 of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCaTooltip urinary calcium. FSH = Suppression of FSHTooltip follicle-stimulating hormone levels. LH = Suppression of LHTooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
Potencies of oral estrogens[data sources 1]
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 - - - -
Sources and footnotes:
  1. ^ [105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123]
  1. ^ Dosages are given in milligrams unless otherwise noted.
  2. ^ a b c Dosed every 2 to 3 weeks
  3. ^ a b c Dosed daily
  4. ^ a b In divided doses, 3x/day; irregular and atypical proliferation.

Antiandrogenic and antigonadotropic effects edit

 
Testosterone levels with no treatment and with various estrogens in men with prostate cancer.[124] Determinations were made with an early radioimmunoassay (RIA).[124] Source was Shearer et al. (1973).[124]

EE is a potent functional antiandrogen in both women and men.[125] It mediates its antiandrogenic effects by 1) stimulating the production of sex hormone-binding globulin (SHBG) in the liver, which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressing luteinizing hormone (LH) secretion from the pituitary gland, which decreases production of testosterone by the gonads.[125][126][33][127] Birth control pills that contain EE are useful in the treatment of androgen-dependent conditions like acne and hirsutism by virtue of their antiandrogenic effects.[125][128]

Birth control pills containing EE 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%).[129][63][130][33] Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold.[66] This is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy.[66] Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills.[10] In men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis).[126] The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.[7][10][131]

Estrogens are antigonadotropins and are able to suppress the secretion of LH and FSH from the pituitary gland and by extension gonadal testosterone production.[132][133] High-dose estrogen therapy, including with EE, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range.[134][132][133] The dosage of EE required for use as a component of hormone therapy for preoperative transgender women is 50 to 100 µg/day.[135] This high dosage is associated with a high incidence of VTE, particularly in those over the age of 40 years, and it has been said that it should not be used.[135] The dosage of EE used in the treatment of prostate cancer in men is 150 to 1,000 µg/day (0.15–1.0 mg/day).[8][136] A dosage of EE 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 oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress testosterone levels into the castrate range.[137] The ovulation-inhibiting dose of EE by itself and not in combination with a progestin in women is 100 μg/day.[138][139] 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.[140][141][142][143] In another study, ovulation occurred in 25.2% with an EE dose of 50 μg/day.[144]

Lower dosages of EE also have significant antigonadotropic effects.[135] A "very low" dosage of 15 µg/day EE 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 EE.[8] However, other clinical studies have found that 20 µg/day EE increased testosterone levels by 50% in men (as described above)[126] and that dosages of 32 µg/day and 42 µg/day EE 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 mg norgestrel 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 COCs is primarily responsible for inhibition of ovulation in women.[8] A combination of 20 µg/day EE and 10 mg/day methyltestosterone was found to suppress FSH secretion in men to an extent sufficient to stop spermatogenesis.[8] Studies in women have found that 50 µg/day EE suppresses LH and FSH levels both by about 70% in postmenopausal women.[104]

In addition to its antigonadotropic effects, EE can significantly suppress androgen production by the adrenal glands at high concentrations.[8][145][146] One study found that treatment with a high dosage of 100 µg/day EE suppressed circulating adrenal androgen levels by 27 to 48% in transgender women.[8][145][146] This may additionally contribute to suppression of androgen levels by estrogens.[8][145][146]

Effects on liver protein synthesis edit

EE has marked effects on liver protein synthesis, even at low dosages and regardless of route 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), and thyroxine-binding globulin (TBG), and also affects a broad range of other liver proteins.[8][7] EE affects triglyceride levels at a dose as low as 1 μg/day and LDL and HDL cholesterol levels at a dose as low as 2.5 μg/day.[147] EE affects several hepatic proteins at a dosage as low as 5 µg/day.[8] At doses above 20 µg/day, the incremental effects of EE on liver protein synthesis become continuously smaller.[8]

EE at 5 μg/day has been found to increase SHBG levels by 100% in postmenopausal women, while a dosage of 20 µg/day EE increased them by 200%.[8] Androgens decrease hepatic SHBG production, and have been found to oppose the effects of EE on SHBG levels.[8] This is of particular relevance when it is considered that many progestins used in COCs have varying degrees of weak androgenic activity.[8] A combination of 20 µg/day EE and 0.25 mg/day levonorgestrel, a progestin with relatively high androgenicity, decreases SHBG levels by 50%; 30 µg/day EE and 0.25 mg/day levonorgestrel has no effect on SHBG levels; 30 µg/day EE and 0.15 mg/day levonorgestrel increases SHBG levels by 30%; and triphasic COCs containing EE and levonorgestrel increase SHBG levels by 100 to 150%.[8] The combination of 30 µg/day EE and 150 µg/day desogestrel, a progestin with relatively weak androgenicity than levonorgestrel, increases SHBG levels by 200%, while the combination of 35 µg/day EE and 2 mg/day cyproterone acetate, a progestin with potent antiandrogenic activity, increases SHBG levels by 400%.[8] As such, the type and dosage of progestin contained in COCs potently moderates the effects of EE on SHBG levels.[8]

A dosage of 10 µg/day EE has been found to increase CBG levels by 50%, while a dosage of 20 µg/day EE increased them by 100%.[8] Progestins that are progesterone derivatives have no effect on CBG levels, while androgenic progestins like the 19-nortestosterone derivatives have only a weak effect on CBG levels.[8] COCs may increase CBG levels by 100 to 150%.[8] A dosage of 5 µg/day EE has been found to increase TBG levels by 40%, while a dosage of 20 µg/day EE 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 EE and 1 mg/day norethisterone, a moderately androgenic progestin, have been found to increase TBG levels by 50 to 70%, while the combination of 30 µg/day EE and 150 µg/day desogestrel increased them by 100%.[8]

Differences from estradiol edit

 
Changes in levels of estrogen-sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women.[70][71] FSH is a pituitary protein and represents general/systemic estrogenic effect, while SHBG and PZPTooltip pregnancy zone protein are hepatic proteins and represent liver estrogenic effect.[70][71]
 
SHBG levels in men with 1) intramuscular injection of 320 mg polyestradiol phosphate once every 4 weeks alone; 2) the combination of intramuscular injection of 80 mg polyestradiol phosphate once every 4 weeks plus 150 µg/day oral ethinylestradiol; 3) orchiectomy only.[69]

EE shows strong and disproportionate effects on liver protein synthesis relative to estradiol.[7] The liver as well as the uterus express 17β-hydroxysteroid dehydrogenase (17β-HSD), and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogen estrone (which has approximately 4% of the estrogenic activity of estradiol).[7] In contrast to estradiol, the 17α-ethynyl group of EE prevents oxidation of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them.[7][148][11] This is the mechanism of the disproportionately strong effects of EE on hepatic protein production,[7][148] which results in a greatly increased magnitude of effect on VTE and cardiovascular risks relative to estradiol.[149]

On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison.[7] This is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium.[7] The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol,[3] in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).[150]

EE has been found to have disproportionate effects on liver protein synthesis and VTE risk regardless of whether the route of administration is oral, transdermal, or vaginal, indicating that the use of parenteral routes over the oral route does not result in EE having proportional hepatic actions relative to non-hepatic actions.[148][8] However, the potency of EE on liver protein synthesis is in any case reduced with parenteral administration.[8] A dosage of 10 µg/day vaginal EE has been found to be equivalent to 50 µg oral EE in terms of effects on liver protein synthesis, such as stimulation of hepatic SHBG production.[8] As such, parenteral EE, which bypasses the first pass through the liver that occurs with oral EE, has been found to have a 5-fold lower impact on liver protein synthesis by weight than oral EE.[8] In contrast to EE as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages.[7]

Comparison of estradiol and ethinylestradiol
Parameters Estradiol Ethinylestradiol
ERTooltip Estrogen receptor affinity 1 × 1010 M-1 2–5 × 1011 M-1
Nuclear retention 6–8 hours 24 hours
Elimination half-life 90 minutes 7 hours
Substrate for 17β-HSDTooltip 17β-hydroxysteroid dehydrogenase? Yes No
Bound to SHBGTooltip Sex hormone-binding globulin? Yes No
Relative oral liver potency 1 ~500–1,500
Relative oral pituitary potency 1 200
Sources:[70]

Pharmacokinetics edit

Absorption edit

 
EE levels while fasting or with a high-fat meal following ingestion of tablets containing a single oral dose of 20 µg EE and 2 mg norethisterone acetate in women.[151][7]

The oral bioavailability of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high interindividual variability.[10][4] Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%).[2][10] Following a single 20 μg dose of EE in combination with 2 mg norethisterone acetate in postmenopausal women, EE 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 EE in general further increase by about 50% until steady-state concentrations are reached;[7][151] 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 or estradiol 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 EE that are produced by an oral dose of EE that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol.[100][7] In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels.[7][152] A dosage of EE of 50 μg/day has been found to achieve a wide range of circulating EE levels of about 100 to 2,000 pg/mL.[153][152] Taking EE in combination with a high-fat meal has been found to significantly decrease its peak concentrations.[151][7]

EE levels after a single 50 μg dose by intravenous injection are several times higher than levels of EE after a single 50 mg dose given orally.[153] Besides the difference in levels, the course of elimination is similar for the two routes.[153]

There may be gender-specific differences in the pharmacokinetics of EE, such that EE may have greater oral potency in women than in men.[8] A study found that a combination of 60 μg/day EE and 0.25 mg/day levonorgestrel in women and men resulted in peak levels of EE of 495 pg/mL and 251 pg/mL, area-under-the-curve levels of EE of 6.216 pg/mL/hour and 2.850 pg/mL/hour, and elimination 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 against environmental estrogen exposure.[8]

Distribution edit

The plasma protein binding of EE is 97 to 98%, and it is bound almost exclusively to albumin.[5][7][10][154] Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein, about 2% of that of estradiol, and hence does not bind to it importantly.[155]

Metabolism edit

Due to high first-pass metabolism in the intestines and liver, only 1% of an oral dose of an EE appears in the circulation as EE itself.[7] During first-pass metabolism, EE is extensively conjugated via glucuronidation and sulfation into the hormonally inert ethinylestradiol glucuronides and ethinylestradiol sulfate (EE sulfate), and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE.[7][4] For comparison, with oral administration of 2 mg micronized estradiol, levels of estrone and estrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively.[7] In contrast to estradiol, EE, due to steric 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 EE relative to oral estradiol.[7] EE is also not metabolized into estradiol.[156]

Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens.[7] This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4.[10] Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent.[10] 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE.[7] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α.[10][7] The ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters.[7] A review found that the range of the reported elimination half-life of EE in the literature was 13.1 to 27.0 hours.[2] Another review reported an elimination half-life of EE of 10 to 20 hours.[10] However, the elimination half-life of EE 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 EE 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 EE sulfate reservoir for EE is much smaller in comparison.[7][4] In any case, due to the formation of EE sulfate, enterohepatic recirculation is involved in the pharmacokinetics of EE similarly to estradiol, although to a lesser extent.[7][157] The contribution of enterohepatic recirculation to total circulating EE levels appears to be 12 to 20% or less, and is not observed consistently.[8][157] A secondary peak in EE levels 10 to 14 hours after administration can often be observed with oral EE.[157]

EE, following oxidative formation of a very reactive metabolite, irreversibly inhibits cytochrome P450 enzymes involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol.[7] Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable.[154] A 2-fold accumulation in EE levels with an EE-containing COC has been observed following 1 year of therapy.[157]

Elimination edit

EE is eliminated 62% in the feces and 38% in the urine.[10]

Chemistry edit

EE, also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol, is a synthetic estrane steroid and a derivative of estradiol with an ethynyl substitution at the C17α position.[1][158] The 17α-ethynylation of estradiol to create EE is analogous to the 17α-substitution of testosterone to make testosterone derivatives such as 17α-ethynylated progestins like ethisterone (17α-ethynyltestosterone) and norethisterone (17α-ethynyl-19-nortestosterone) as well as 17α-alkylated androgens/anabolic steroids like methyltestosterone (17α-methyltestosterone).

Analogues edit

See also: List of estrogens § 17α-Substituted estradiol derivatives

A number of derivatives of EE exist.[1][158] These include mestranol (EE 3-methyl ether), quinestrol (EE 3-cyclopentyl ether), ethinylestradiol sulfonate (EE 3-isopropylsulfonate), and moxestrol (11β-methoxy-EE).[1][158][8] The former three are prodrugs of EE, while the latter one is not.[8] A few analogues of EE with other substitutions at the C17α position exist.[1][158] Examples include the estradiol derivatives methylestradiol (17α-methylestradiol) and ethylestradiol (17α-ethylestradiol), and the estriol derivatives ethinylestriol (17α-ethynylestriol) and nilestriol (17α-ethynylestriol 3-cyclopentyl ether).[1][158] Androstane analogues of EE with significant although weak estrogenic activity include ethinylandrostenediol (17α-ethynyl-5-androstenediol), 17α-ethynyl-3β-androstanediol, 17α-ethynyl-3α-androstanediol, and methandriol (17α-methyl-5-androstenediol).

History edit

EE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of Schering AG in Berlin.[159][160][161][162][163] It was approved by the US Food and Drug Administration (FDA) in June 1943, and marketed by Schering under the brand name Estinyl.[14] The FDA withdrew approval of Estinyl effective 4 June 2004 at the request of Schering, which had discontinued marketing it.[164]

EE was never introduced for use by intramuscular injection.[165]

EE was first used in COCs, as an alternative to mestranol, in 1964, and shortly thereafter superseded mestranol in COCs.[15]

Early COCs contained 40 to 100 μg/day EE and 50 to 150 μg/day mestranol.[166][167]

Society and culture edit

Generic names edit

Ethinylestradiol is the English generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[168][1][169][158] It has also been spelled as ethynylestradiol, ethynyloestradiol, and ethinyloestradiol (all having the same pronunciation), and the latter was formerly its BANTooltip British Approved Name but was eventually changed.[168][1][158] In addition, a space is often included in the name of EE such that it is written as ethinyl estradiol (as well as variations thereof), and this is its USPTooltip United States Pharmacopeia name.[168][158] The generic name of EE in French and its DCFTooltip Dénomination Commune Française are éthinylestradiol, in Spanish is etinilestradiol, in Italian and its DCITTooltip Denominazione Comune Italiana are etinilestradiolo, and in Latin is ethinylestradiolum.[168][158]

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

Brand names edit

EE has been marketed as a standalone oral drug under the brand names Esteed, Estinyl, Feminone, Lynoral, Menolyn, Novestrol, Palonyl, Spanestrin, and Ylestrol among others, although most or all of these formulations are now discontinued.[170][171][158] It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive.[168] In addition, EE is marketed in the U.S. in combination with norelgestromin under the brand names Ortho Evra and Xulane as a contraceptive patch, in combination with etonogestrel under the brand name NuvaRing as a contraceptive vaginal ring, and in combination with norethisterone acetate under the brand name FemHRT in oral hormone replacement therapy for the treatment of menopausal symptoms.[12]

Availability edit

Ethinylestradiol is marketed throughout the world.[168][158] It is marketed exclusively or almost exclusively in combination with progestins.[168]

References edit

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  162. ^ Sneader W (2005). "Hormone analogues". Drug discovery: a history. Hoboken, NJ: John Wiley & Sons. pp. 188–225. ISBN 978-0-471-89980-8.
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  168. ^ a b c d e f g "Ethinylestradiol - Drugs.com".
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  171. ^ American Society of Hospital Pharmacists. Committee on Pharmacy and Pharmaceuticals (1983). American Hospital Formulary Service: A Two-volume Collection of Drug Monographs and Other Information. American Society of Hospital Pharmacists. ISBN 978-0-930530-02-0. ETHINYL ESTRADIOL U.S.P. (Esteed®, Estinyl®, Lynoral®, Menolyn®, Novestrol®, Palonyl®, Spanestrin®, Ylestrol®)

Further reading edit

  • Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 4, 10, 15, 165, 247–248, 276–291, 363–408, 424, 514, 540, 543, 581. ISBN 978-3-642-60107-1.
  • Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  • Stanczyk FZ, Archer DF, Bhavnani BR (June 2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. PMID 23375353.
  • Mattison DR, Karyakina N, Goodman M, LaKind JS (September 2014). "Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: a review of the data and identification of knowledge gaps". Critical Reviews in Toxicology. 44 (8): 696–724. doi:10.3109/10408444.2014.930813. PMID 25099693. S2CID 11212469.

April 10, 2024
ethinylestradiol, estrogen, medication, which, used, widely, birth, control, pills, combination, with, progestins, past, widely, used, various, indications, such, treatment, menopausal, symptoms, gynecological, disorders, certain, hormone, sensitive, cancers, . 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 EthinylestradiolClinical dataPronunciation ˌ ɛ 8 ɪ n ɪ l ˌ ɛ s t r e ˈ d aɪ el Trade namesManyOther namesEthynylestradiol Ethinyl estradiol Ethinyl oestradiol EE EE2 17a Ethynylestradiol 17a Ethynylestra 1 3 5 10 triene 3 17b diol NSC 10973 1 AHFS Drugs comInternational Drug NamesMedlinePlusa604032Routes ofadministration By mouth Transdermal VaginalDrug classEstrogenATC codeG03CA01 WHO L02AA03 WHO Legal statusLegal statusIn general Prescription only Pharmacokinetic dataBioavailability38 48 2 3 4 Protein binding97 98 to albumin 5 is not bound to SHBGTooltip sex hormone binding globulin 6 MetabolismLiver primarily CYP3A4 9 Metabolites Ethinylestradiol sulfate 7 8 Others 7 8 Elimination half life7 36 hours 9 2 10 11 ExcretionFeces 62 10 Urine 38 10 IdentifiersIUPAC name 8R 9S 13S 14S 17R 17 ethynyl 13 methyl 7 8 9 11 12 14 15 16 octahydro 6H cyclopenta a phenanthrene 4 17 diolCAS Number57 63 6 YPubChem CID5991IUPHAR BPS7071DrugBankDB00977 YChemSpider5770 YUNII423D2T571UKEGGD00554 YChEBICHEBI 4903 YChEMBLChEMBL691 YCompTox Dashboard EPA DTXSID5020576ECHA InfoCard100 000 311Chemical and physical dataFormulaC 20H 24O 2Molar mass296 410 g mol 13D model JSmol Interactive imageMelting point182 to 184 C 360 to 363 F SMILES Oc1cc4c cc1 C H 3CC C 2 C H CC C 2 C C O C H 3CC4 CInChI InChI 1S C20H24O2 c1 3 20 22 11 9 18 17 6 4 13 12 14 21 5 7 15 13 16 17 8 10 19 18 20 2 h1 5 7 12 16 18 21 22H 4 6 8 11H2 2H3 t16 17 18 19 20 m1 s1 YKey BFPYWIDHMRZLRN SLHNCBLASA N Y verify 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 is more resistant to metabolism has greatly improved bioavailability when taken by mouth 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 Ethinylestradiol 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 the most widely used estrogens 16 17 In 2021 the combination with norethisterone was the 52nd most commonly prescribed medication in the United States with more than 12 million prescriptions 18 19 the version with norgestimate was the 76th most commonly prescribed medication in the US with more than 8 million prescriptions 18 20 the combination with levonorgestrel was the 144th most commonly prescribed medication in the US with more than 4 million prescriptions 18 21 the combination with etonogestrel was the 198th most commonly prescribed medication in the US with more than 2 million prescriptions 18 22 the combination with norgestrel was the 227th most commonly prescribed medication in the US with more than 2 million prescriptions 18 23 the combination with etynodiol was the 276th most commonly prescribed medication in the US with more than 800 000 prescriptions 18 24 the combination with drospirenone and levomefolic acid was the 277th most commonly prescribed medication in the US with more than 800 000 prescriptions 18 25 Contents 1 Medical uses 1 1 Available forms 2 Contraindications 3 Side effects 3 1 Long term effects 3 1 1 Blood clots 3 1 2 Cardiovascular issues 3 1 3 Liver damage 3 1 4 Uterine cancer 3 2 Ecological Effects 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Antiandrogenic and antigonadotropic effects 6 1 2 Effects on liver protein synthesis 6 1 3 Differences from estradiol 6 2 Pharmacokinetics 6 2 1 Absorption 6 2 2 Distribution 6 2 3 Metabolism 6 2 4 Elimination 7 Chemistry 7 1 Analogues 8 History 9 Society and culture 9 1 Generic names 9 2 Brand names 9 3 Availability 10 References 11 Further readingMedical uses editThere 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 26 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 27 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 28 However it is no longer commonly used nor recommended for this purpose with estradiol having largely superseded it 28 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 29 It has also been used to reduce sex drive in sex offenders 30 31 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 32 Available forms edit EE is available in combination with a progestin in a vast number of COCs 33 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 26 EE 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 34 35 36 37 38 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 39 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 40 Today COCs generally contain 10 to 50 µg EE 40 The higher doses of EE were discontinued due to a high risk of VTE and cardiovascular problems 39 Contraindications editEE 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 41 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 diseaseExcept when being used to treat it EE should be avoided in women with current breast cancer due to a possible worsening of prognosis 42 EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE 43 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 43 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 44 Side effects editDose of ethinylestradiol in birth control pills and risk of venous thromboembolism VTE Ethinylestradiol dose No of VTE cases Woman years VTE rate Adjusted RRaLow lt 50 mg 53 127 000 4 2 in 10 000 woman years 1 0Intermediate 50 mg 69 98 000 7 0 in 10 000 woman years 1 5High gt 50 mg 20 20 000 10 0 in 10 000 woman years 1 7All 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 45 46 Additional 47 The severity of side effects can vary based on the dose and administration route of EE 48 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 44 The estrogen component of oral contraceptives which is almost always EE can cause breast tenderness and fullness 34 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 mg day oral EE for more than three months gynecomastia occurred in 98 and decreased libido occurred in 42 to 73 49 Long term effects edit Beneficial and adverse effects of ethinylestradiol containing birth control pills Beneficial effects Adverse effectsDisease RRTooltip Relative risk Disease RRTooltip Relative riskIron deficiency anemia 0 58 Cardiovascular diseases total 1 5Menorrhagia 0 52 Myocardial infarction heart attack total 3 3Irregular menstruation 0 65 Myocardial infarction non smokers 1 0Intermenstrual bleeding 0 72 Myocardial infarction light smokers 3 5Dysmenorrhea 0 37 Myocardial infarction heavy smokers 20Pelvic inflammatory disease incidence 0 50 Cerebrovascular diseases total 1 4Pelvic inflammatory disease hospitalization 0 22 Cerebral thromboses strokes 2 5Trichomonas vaginitis 0 56 Subarachnoidal bleeding heavy smokers 10Benign breast disease 0 69 Pulmonary embolism 3 0Fibrocystic breast disease 0 66 Deep vein thromboses 2 5Benign breast fibroadenomas 0 35 Gall bladder diseases 3 0Rheumatoid arthritis 0 49 Benign liver tumors 50Endometrial cancer 0 40 0 50 Hepatocellular carcinoma 3 0Ovarian cancer incidence 0 37 0 64 Erythema nodosum et multiforme 3 0Ovarian cancer death 0 20 Pruritus itching 2 0Benign follicular cysts high dose COCs 0 24 Photosensitive eczema 4 0Acne vulgaris 0 44 Irritant agent eczema 2 0Low bone mineral density later in life 0 35a Dermatitis eczema 2 0Ectopic pregnancy 0 19 Chloasma melasma 1 5Cervicitis 6 years of use 3 0Chlamydia infections 2 5Footnotes a Odds ratio Sources 50 34 Blood clots edit VTE is a blood clot in a vein and includes deep vein thrombosis DVT and pulmonary embolism PE 7 51 52 Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors 7 51 52 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 53 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 53 Modern COCs are associated with about a 2 to 4 fold higher risk of VTE than non use 53 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 53 54 Pregnancy is associated with about a 4 3 fold increase in risk of VTE 53 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 55 Modern COCs contain 10 to 35 mg EE but typically 20 30 or 35 mg 53 56 The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 mg EE 57 47 56 However it was soon found that EE is associated with increased risk of VTE and that the risk is dose dependent 56 Following these events the dose of EE was greatly reduced and is now always less than 50 mg 58 59 60 These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness 56 Gerstman et al 1991 found that COCs containing more than 50 mg EE had 1 7 fold and COCs containing 50 mg EE 1 5 fold the risk of VTE of COCs containing less than 50 mg 45 A 2014 Cochrane review found that COCs containing 50 mg EE with levonorgestrel had 2 1 to 2 3 fold the risk of COCs containing 30 mg or 20 mg EE with levonorgestrel respectively 53 COCs containing 20 mg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 mg EE 61 However discontinuation of COCs is more common with doses of EE from 10 to 20 mg due to problematic changes in bleeding patterns 62 Women with thrombophilia have a dramatically higher risk of VTE with EE containing contraception than women without thrombophilia 53 54 Depending on the condition risk of VTE can be increased 5 to 50 fold relative to non use in such women 53 54 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 63 64 65 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 63 Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2 5 fold and 3 5 fold respectively 63 Birth control pills containing high doses of ethinylestradiol gt 50 mg can increase SHBG levels by 5 to 10 fold which is similar to the increase that occurs during pregnancy 66 Conversely increases in SHBG levels are much lower with estradiol especially when used parenterally 67 68 69 70 71 High dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1 5 fold 70 vte Risk of venous thromboembolism VTE with hormone therapy and birth control QResearch CPRD Type Route Medications Odds ratio 95 CITooltip confidence interval Menopausal hormone therapy Oral Estradiol alone 1 mg day gt 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 gt 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 gt 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 gt 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 gt 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 mg day gt 50 mg 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 lt 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 29 72 73 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 72 73 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 73 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 73 74 75 However significantly increased cardiovascular morbidity has been observed with high dosage polyestradiol phosphate 73 74 75 In any case these estrogens are considered to be much safer than oral synthetic estrogens like EE and diethylstilbestrol 73 74 75 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 73 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 17a alkylated androgens anabolic steroids and 17a ethynylated 19 nortestosterone progestins 76 77 Cholestasis can manifest as pruritus and jaundice 78 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 79 Very high concentrations of estradiol via its metabolite estradiol glucuronide are also implicated in cholestasis for instance in cholestasis of pregnancy 77 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 C17a ethynyl substitution in EE as well as its greatly reduced susceptibility to hepatic metabolism 44 80 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 mg day EE or more 80 78 With birth control pills containing 50 mg day EE alanine aminotransferase ALT levels increase by 50 hematocrit by 19 and leukocytes by 50 while gamma glutamyltransferase GGT decreases by 30 80 However the values usually remain in the normal range 80 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 mg day EE 80 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 78 81 82 as well as greater risk of other liver complications 83 84 At one time EE containing birth control pills were estimated to be responsible for 84 of all drug related and histologically verified liver damage 80 However these risks now are reduced with modern lower dose EE containing birth control pills with contain 35 mg day EE or less 78 82 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 85 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 85 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 85 In turn most studies of modern COCs have found a decreased risk of endometrial cancer 86 Ecological Effects edit Wastewater contains various estrogens including EE that are not completely broken down by wastewater treatment procedures 87 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 87 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 87 In amphibians exposure to EE can reduce hatching success and alter gonadal development 88 Exposure to hormones can change frogs gonadal development even though it is encoded in their genes 88 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 88 Overdose editSee also Estrogen medication Overdose Estrogens like EE are relatively safe in acute overdose citation needed Interactions editEE is metabolized by certain cytochrome P450 isoforms including CYP3A4 and CYP2C9 89 Thus inducers of enzymes such as CYP3A4 can decrease circulating concentrations of EE 44 Examples of inducers include anticonvulsants like phenytoin primidone ethosuximide phenobarbital and carbamazepine azole antifungals like fluconazole and rifamycin antibiotics like rifampin rifampicin 44 Conversely inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE 44 An example is troleandomycin which is a potent and highly selective inhibitor of CYP3A4 44 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 44 The same has been found for ascorbic acid vitamin C and EE although the significance of the interaction has been regarded as dubious 44 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 44 This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes 44 There is however an increased risk of cardiovascular complications with smoking and EE similarly to the case of smoking and other estrogens 44 EE is known to inhibit several cytochrome P450 enzymes including CYP1A2 CYP2B6 CYP2C9 CYP2C19 and CYP3A4 and is possibly an inducer of CYP2A6 90 As a result it can affect the metabolism and concentrations of many other drugs 90 Examples of known interactions include bupropion caffeine mephenytoin midazolam nicotine nifedipine omeprazole propranolol proguanil selegiline theophylline and tizanidine 90 44 One of the most notable interactions is that EE strongly increases levels of selegiline a substrate of CYP2B6 and CYP2C19 90 EE may also induce glucuronidation and possibly alter sulfation 90 It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated 90 Examples include clofibrate lamotrigine lorazepam oxazepam and propranolol 90 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 90 Examples include gestodene desogestrel and etonogestrel which are CYP3A4 and CYP2C19 inhibitors 90 In addition these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself 44 Pharmacology editPharmacodynamics 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 ERa and ERb 8 In one study EE was found to have 233 and 38 of the affinity of estradiol for the ERa and ERb respectively 91 In another study it was found to possess 194 and 151 of the affinity of estradiol for the ERa and ERb respectively 92 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 93 94 95 96 Estrogens have antigonadotropic effects through activation of the ERa 97 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 98 99 EE is a long acting estrogen with a nuclear retention of about 24 hours 46 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 100 101 102 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 103 104 In contrast the potencies of EE and natural estrogens are similar when they are administered intravenously due to the bypassing of first pass metabolism 56 Relative to its prodrug mestranol EE is about 1 7 times as potent by weight orally 101 vte Affinities of estrogen receptor ligands for the ERa and ERb Ligand Other names Relative binding affinities RBA a Absolute binding affinities Ki nM a ActionERa ERb ERa ERbEstradiol E2 17b Estradiol 100 100 0 115 0 04 0 24 0 15 0 10 2 08 EstrogenEstrone 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 EstrogenEstriol E3 16a OH 17b E2 12 65 4 03 56 26 14 0 44 6 0 45 0 35 1 4 0 7 0 63 0 7 EstrogenEstetrol E4 15a 16a Di OH 17b E2 4 0 3 0 4 9 19 EstrogenAlfatradiol 17a Estradiol 20 5 7 80 1 8 195 2 42 0 2 0 52 0 43 1 2 Metabolite16 Epiestriol 16b Hydroxy 17b estradiol 7 795 4 94 63 50 Metabolite17 Epiestriol 16a Hydroxy 17a estradiol 55 45 29 103 79 80 Metabolite16 17 Epiestriol 16b Hydroxy 17a estradiol 1 0 13 Metabolite2 Hydroxyestradiol 2 OH E2 22 7 81 11 35 2 5 1 3 Metabolite2 Methoxyestradiol 2 MeO E2 0 0027 2 0 1 0 Metabolite4 Hydroxyestradiol 4 OH E2 13 8 70 7 56 1 0 1 9 Metabolite4 Methoxyestradiol 4 MeO E2 2 0 1 0 Metabolite2 Hydroxyestrone 2 OH E1 2 0 4 0 0 2 0 4 Metabolite2 Methoxyestrone 2 MeO E1 lt 0 001 lt 1 lt 1 Metabolite4 Hydroxyestrone 4 OH E1 1 0 2 0 1 0 Metabolite4 Methoxyestrone 4 MeO E1 lt 1 lt 1 Metabolite16a Hydroxyestrone 16a OH E1 17 Ketoestriol 2 0 6 5 35 Metabolite2 Hydroxyestriol 2 OH E3 2 0 1 0 Metabolite4 Methoxyestriol 4 MeO E3 1 0 1 0 MetaboliteEstradiol sulfate E2S Estradiol 3 sulfate lt 1 lt 1 MetaboliteEstradiol disulfate Estradiol 3 17b disulfate 0 0004 MetaboliteEstradiol 3 glucuronide E2 3G 0 0079 MetaboliteEstradiol 17b glucuronide E2 17G 0 0015 MetaboliteEstradiol 3 gluc 17b sulfate E2 3G 17S 0 0001 MetaboliteEstrone sulfate E1S Estrone 3 sulfate lt 1 lt 1 gt 10 gt 10 MetaboliteEstradiol benzoate EB Estradiol 3 benzoate 10 EstrogenEstradiol 17b benzoate E2 17B 11 3 32 6 EstrogenEstrone methyl ether Estrone 3 methyl ether 0 145 Estrogenent Estradiol 1 Estradiol 1 31 12 34 9 44 80 07 EstrogenEquilin 7 Dehydroestrone 13 4 0 28 9 13 0 49 0 79 0 36 EstrogenEquilenin 6 8 Didehydroestrone 2 0 15 7 0 20 0 64 0 62 Estrogen17b Dihydroequilin 7 Dehydro 17b estradiol 7 9 113 7 9 108 0 09 0 17 Estrogen17a Dihydroequilin 7 Dehydro 17a estradiol 18 6 18 41 14 32 0 24 0 57 Estrogen17b Dihydroequilenin 6 8 Didehydro 17b estradiol 35 68 90 100 0 15 0 20 Estrogen17a Dihydroequilenin 6 8 Didehydro 17a estradiol 20 49 0 50 0 37 EstrogenD8 Estradiol 8 9 Dehydro 17b estradiol 68 72 0 15 0 25 EstrogenD8 Estrone 8 9 Dehydroestrone 19 32 0 52 0 57 EstrogenEthinylestradiol EE 17a Ethynyl 17b E2 120 9 68 8 480 44 4 2 0 144 0 02 0 05 0 29 0 81 EstrogenMestranol EE 3 methyl ether 2 5 EstrogenMoxestrol RU 2858 11b Methoxy EE 35 43 5 20 0 5 2 6 EstrogenMethylestradiol 17a Methyl 17b estradiol 70 44 EstrogenDiethylstilbestrol DES Stilbestrol 129 5 89 1 468 219 63 61 2 295 0 04 0 05 EstrogenHexestrol Dihydrodiethylstilbestrol 153 6 31 302 60 234 0 06 0 06 EstrogenDienestrol Dehydrostilbestrol 37 20 4 223 56 404 0 05 0 03 EstrogenBenzestrol B2 114 EstrogenChlorotrianisene TACE 1 74 15 30 EstrogenTriphenylethylene TPE 0 074 EstrogenTriphenylbromoethylene TPBE 2 69 EstrogenTamoxifen ICI 46 474 3 0 1 47 3 33 0 28 6 3 4 9 69 2 5 SERMAfimoxifene 4 Hydroxytamoxifen 4 OHT 100 1 1 7 257 10 0 98 339 2 3 0 1 3 61 0 04 4 8 SERMToremifene 4 Chlorotamoxifen 4 CT 7 14 20 3 15 4 SERMClomifene MRL 41 25 19 2 37 2 12 0 9 1 2 SERMCyclofenil F 6066 Sexovid 151 152 243 SERMNafoxidine U 11 000A 30 9 44 16 0 3 0 8 SERMRaloxifene 41 2 7 8 69 5 34 0 54 16 0 188 0 52 20 2 SERMArzoxifene LY 353 381 0 179 SERMLasofoxifene CP 336 156 10 2 166 19 0 0 229 SERMOrmeloxifene Centchroman 0 313 SERMLevormeloxifene 6720 CDRI NNC 460 020 1 55 1 88 SERMOspemifene Deaminohydroxytoremifene 0 82 2 63 0 59 1 22 SERMBazedoxifene 0 053 SERMEtacstil GW 5638 4 30 11 5 SERMICI 164 384 63 5 3 70 97 7 166 0 2 0 08 AntiestrogenFulvestrant ICI 182 780 43 5 9 4 325 21 65 2 05 40 5 0 42 1 3 AntiestrogenPropylpyrazoletriol PPT 49 10 0 89 1 0 12 0 40 92 8 ERa agonist16a LE2 16a Lactone 17b estradiol 14 6 57 0 089 0 27 131 ERa agonist16a Iodo E2 16a Iodo 17b estradiol 30 2 2 30 ERa agonistMethylpiperidinopyrazole MPP 11 0 05 ERa antagonistDiarylpropionitrile DPN 0 12 0 25 6 6 18 32 4 1 7 ERb agonist8b VE2 8b Vinyl 17b estradiol 0 35 22 0 83 12 9 0 50 ERb agonistPrinaberel ERB 041 WAY 202 041 0 27 67 72 ERb agonistERB 196 WAY 202 196 180 ERb agonistErteberel SERBA 1 LY 500 307 2 68 0 19 ERb agonistSERBA 2 14 5 1 54 ERb agonistCoumestrol 9 225 0 0117 94 64 125 0 41 185 0 14 80 0 0 07 27 0 XenoestrogenGenistein 0 445 0 0012 16 33 42 0 86 87 2 6 126 0 3 12 8 XenoestrogenEquol 0 2 0 287 0 85 0 10 2 85 XenoestrogenDaidzein 0 07 0 0018 9 3 0 7865 0 04 17 1 2 0 85 3 XenoestrogenBiochanin A 0 04 0 022 0 15 0 6225 0 010 1 2 174 8 9 XenoestrogenKaempferol 0 07 0 029 0 10 2 2 0 002 3 00 XenoestrogenNaringenin 0 0054 lt 0 001 0 01 0 15 0 11 0 33 Xenoestrogen8 Prenylnaringenin 8 PN 4 4 XenoestrogenQuercetin lt 0 001 0 01 0 002 0 040 XenoestrogenIpriflavone lt 0 01 lt 0 01 XenoestrogenMiroestrol 0 39 XenoestrogenDeoxymiroestrol 2 0 Xenoestrogenb Sitosterol lt 0 001 0 0875 lt 0 001 0 016 XenoestrogenResveratrol lt 0 001 0 0032 Xenoestrogena Zearalenol 48 13 52 5 Xenoestrogenb Zearalenol 0 6 0 032 13 XenoestrogenZeranol a Zearalanol 48 111 XenoestrogenTaleranol b Zearalanol 16 13 17 8 14 0 8 0 9 XenoestrogenZearalenone ZEN 7 68 2 04 28 9 45 2 43 31 5 XenoestrogenZearalanone ZAN 0 51 XenoestrogenBisphenol A BPA 0 0315 0 008 1 0 0 135 0 002 4 23 195 35 XenoestrogenEndosulfan EDS lt 0 001 lt 0 01 lt 0 01 XenoestrogenKepone Chlordecone 0 0069 0 2 Xenoestrogeno p DDT 0 0073 0 4 Xenoestrogenp p DDT 0 03 XenoestrogenMethoxychlor p p Dimethoxy DDT 0 01 lt 0 001 0 02 0 01 0 13 XenoestrogenHPTE Hydroxychlor p p OH DDT 1 2 1 7 XenoestrogenTestosterone T 4 Androstenolone lt 0 0001 lt 0 01 lt 0 002 0 040 gt 5000 gt 5000 AndrogenDihydrotestosterone DHT 5a Androstanolone 0 01 lt 0 001 0 05 0 0059 0 17 221 gt 5000 73 1688 AndrogenNandrolone 19 Nortestosterone 19 NT 0 01 0 23 765 53 AndrogenDehydroepiandrosterone DHEA Prasterone 0 038 lt 0 001 0 04 0 019 0 07 245 1053 163 515 Androgen5 Androstenediol A5 Androstenediol 6 17 3 6 0 9 Androgen4 Androstenediol 0 5 0 6 23 19 Androgen4 Androstenedione A4 Androstenedione lt 0 01 lt 0 01 gt 10000 gt 10000 Androgen3a Androstanediol 3a Adiol 0 07 0 3 260 48 Androgen3b Androstanediol 3b Adiol 3 7 6 2 AndrogenAndrostanedione 5a Androstanedione lt 0 01 lt 0 01 gt 10000 gt 10000 AndrogenEtiocholanedione 5b Androstanedione lt 0 01 lt 0 01 gt 10000 gt 10000 AndrogenMethyltestosterone 17a Methyltestosterone lt 0 0001 AndrogenEthinyl 3a androstanediol 17a Ethynyl 3a adiol 4 0 lt 0 07 EstrogenEthinyl 3b androstanediol 17a Ethynyl 3b adiol 50 5 6 EstrogenProgesterone P4 4 Pregnenedione lt 0 001 0 6 lt 0 001 0 010 ProgestogenNorethisterone NET 17a Ethynyl 19 NT 0 085 0 0015 lt 0 1 0 1 0 01 0 3 152 1084 ProgestogenNorethynodrel 5 10 Norethisterone 0 5 0 3 0 7 lt 0 1 0 22 14 53 ProgestogenTibolone 7a Methylnorethynodrel 0 5 0 45 2 0 0 2 0 076 ProgestogenD4 Tibolone 7a Methylnorethisterone 0 069 lt 0 1 0 027 lt 0 1 Progestogen3a Hydroxytibolone 2 5 1 06 5 0 0 6 0 8 Progestogen3b Hydroxytibolone 1 6 0 75 1 9 0 070 0 1 ProgestogenFootnotes 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 of in vitro systems with labeled estradiol and human ERa and ERb proteins except the ERb values from Kuiper et al 1997 which are rat ERb Sources See template page vte Relative affinities of estrogens for steroid hormone receptors and blood proteins 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 globulinEstradiol 100 7 9 2 6 0 6 0 13 8 7 12 lt 0 1Estradiol benzoate lt 0 1 0 16 lt 0 1Estradiol valerate 2 Estrone 11 35 lt 1 lt 1 lt 1 lt 1 2 7 lt 0 1Estrone sulfate 2 2 Estriol 10 15 lt 1 lt 1 lt 1 lt 1 lt 0 1 lt 0 1Equilin 40 0Alfatradiol 15 lt 1 lt 1 lt 1 lt 1 Epiestriol 20 lt 1 lt 1 lt 1 lt 1 Ethinylestradiol 100 112 1 3 15 25 1 3 lt 1 0 18 lt 0 1Mestranol 1 lt 0 1 lt 0 1Methylestradiol 67 1 3 3 25 1 3 lt 1 Moxestrol 12 lt 0 1 0 8 3 2 lt 0 1 lt 0 2 lt 0 1Diethylstilbestrol lt 0 1 lt 0 1Notes Reference ligands 100 were progesterone for the PRTooltip progesterone receptor testosterone for the ARTooltip androgen receptor estradiol for the ERTooltip estrogen receptor dexamethasone for the GRTooltip glucocorticoid receptor aldosterone for the MRTooltip mineralocorticoid receptor dihydrotestosterone for SHBGTooltip sex hormone binding globulin and cortisol for CBGTooltip Corticosteroid binding globulin Sources See template vte Relative oral potencies of estrogens 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 LiverEstradiol 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0Estrone 0 3 0 3 Estriol 0 3 0 3 0 1 0 3 0 3 0 2 0 67Estrone 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 7Conjugated 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 5Equilin 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 0Diethylstilbestrol 2 9 3 4 26 28 25 37 20 5 7 7 5Sources and footnotesNotes Values are ratios with estradiol as standard i e 1 0 Abbreviations HF Clinical relief of hot flashes VE Increased proliferation of vaginal epithelium UCa Decrease in UCaTooltip urinary calcium FSH Suppression of FSHTooltip follicle stimulating hormone levels LH Suppression of LHTooltip luteinizing hormone levels HDL C SHBG CBG and AGT Increase in the serum levels of these liver proteins Liver Ratio of liver estrogenic effects to general systemic estrogenic effects hot flashes gonadotropins Sources See template vte Potencies of oral estrogens data sources 1 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 gt 5 gt 8Estradiol valerate 6 12 60 80 14 42 1 2 gt 8Estradiol benzoate 60 140 Estriol 20 120 150 d 28 126 1 6 gt 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 gt 3 75 7 5Ethinylestradiol 200 mg 1 2 280 mg 20 40 mg 100 mg 100 mgMestranol 300 mg 1 5 3 0 300 600 mg 25 30 mg gt 80 mg Quinestrol 300 mg 2 4 500 mg 25 50 mg Methylestradiol 2 Diethylstilbestrol 2 5 20 30 11 0 5 2 0 gt 5 3DES dipropionate 15 30 Dienestrol 5 30 40 42 0 5 4 0 Dienestrol diacetate 3 5 30 60 Hexestrol 70 110 Chlorotrianisene gt 100 gt 48 Methallenestril 400 Sources and footnotes 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 Dosages are given in milligrams unless otherwise noted a b c Dosed every 2 to 3 weeks a b c Dosed daily a b In divided doses 3x day irregular and atypical proliferation Antiandrogenic and antigonadotropic effects edit nbsp Testosterone levels with no treatment and with various estrogens in men with prostate cancer 124 Determinations were made with an early radioimmunoassay RIA 124 Source was Shearer et al 1973 124 EE is a potent functional antiandrogen in both women and men 125 It mediates its antiandrogenic effects by 1 stimulating the production of sex hormone binding globulin SHBG in the liver which decreases free and thus bioactive concentrations of testosterone in the blood and by 2 suppressing luteinizing hormone LH secretion from the pituitary gland which decreases production of testosterone by the gonads 125 126 33 127 Birth control pills that contain EE are useful in the treatment of androgen dependent conditions like acne and hirsutism by virtue of their antiandrogenic effects 125 128 Birth control pills containing EE 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 80 129 63 130 33 Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5 to 10 fold 66 This is similar to the 5 to 10 fold increase in SHBG levels that occurs during pregnancy 66 Due to the marked increase in SHBG levels free testosterone levels become very low during treatment with EE containing birth control pills 10 In men a study found that treatment with a relatively low dosage of 20 mg day EE for five weeks increased circulating SHBG levels by 150 and due to the accompanying decrease in free testosterone levels increased total circulating levels of testosterone by 50 via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic pituitary gonadal axis 126 The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body 7 10 131 Estrogens are antigonadotropins and are able to suppress the secretion of LH and FSH from the pituitary gland and by extension gonadal testosterone production 132 133 High dose estrogen therapy including with EE is able to suppress testosterone levels in men by around 95 or into the castrate female range 134 132 133 The dosage of EE required for use as a component of hormone therapy for preoperative transgender women is 50 to 100 µg day 135 This high dosage is associated with a high incidence of VTE particularly in those over the age of 40 years and it has been said that it should not be used 135 The dosage of EE used in the treatment of prostate cancer in men is 150 to 1 000 µg day 0 15 1 0 mg day 8 136 A dosage of EE of 50 mg twice daily 100 mg day total has been found to suppress testosterone levels in men to an equivalent extent as 3 mg day oral diethylstilbestrol which is the minimum dosage of diethylstilbestrol required to consistently suppress testosterone levels into the castrate range 137 The ovulation inhibiting dose of EE by itself and not in combination with a progestin in women is 100 mg day 138 139 However it has been found to be about 75 to 90 effective at inhibiting ovulation at a dosage of 20 mg day and about 97 or 98 effective at a dosage of 50 mg day 140 141 142 143 In another study ovulation occurred in 25 2 with an EE dose of 50 mg day 144 Lower dosages of EE also have significant antigonadotropic effects 135 A very low dosage of 15 µg day EE 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 EE 8 However other clinical studies have found that 20 µg day EE increased testosterone levels by 50 in men as described above 126 and that dosages of 32 µg day and 42 µg day EE 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 mg norgestrel 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 COCs is primarily responsible for inhibition of ovulation in women 8 A combination of 20 µg day EE and 10 mg day methyltestosterone was found to suppress FSH secretion in men to an extent sufficient to stop spermatogenesis 8 Studies in women have found that 50 µg day EE suppresses LH and FSH levels both by about 70 in postmenopausal women 104 In addition to its antigonadotropic effects EE can significantly suppress androgen production by the adrenal glands at high concentrations 8 145 146 One study found that treatment with a high dosage of 100 µg day EE suppressed circulating adrenal androgen levels by 27 to 48 in transgender women 8 145 146 This may additionally contribute to suppression of androgen levels by estrogens 8 145 146 Effects on liver protein synthesis edit EE has marked effects on liver protein synthesis even at low dosages and regardless of route 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 and thyroxine binding globulin TBG and also affects a broad range of other liver proteins 8 7 EE affects triglyceride levels at a dose as low as 1 mg day and LDL and HDL cholesterol levels at a dose as low as 2 5 mg day 147 EE affects several hepatic proteins at a dosage as low as 5 µg day 8 At doses above 20 µg day the incremental effects of EE on liver protein synthesis become continuously smaller 8 EE at 5 mg day has been found to increase SHBG levels by 100 in postmenopausal women while a dosage of 20 µg day EE increased them by 200 8 Androgens decrease hepatic SHBG production and have been found to oppose the effects of EE on SHBG levels 8 This is of particular relevance when it is considered that many progestins used in COCs have varying degrees of weak androgenic activity 8 A combination of 20 µg day EE and 0 25 mg day levonorgestrel a progestin with relatively high androgenicity decreases SHBG levels by 50 30 µg day EE and 0 25 mg day levonorgestrel has no effect on SHBG levels 30 µg day EE and 0 15 mg day levonorgestrel increases SHBG levels by 30 and triphasic COCs containing EE and levonorgestrel increase SHBG levels by 100 to 150 8 The combination of 30 µg day EE and 150 µg day desogestrel a progestin with relatively weak androgenicity than levonorgestrel increases SHBG levels by 200 while the combination of 35 µg day EE and 2 mg day cyproterone acetate a progestin with potent antiandrogenic activity increases SHBG levels by 400 8 As such the type and dosage of progestin contained in COCs potently moderates the effects of EE on SHBG levels 8 A dosage of 10 µg day EE has been found to increase CBG levels by 50 while a dosage of 20 µg day EE increased them by 100 8 Progestins that are progesterone derivatives have no effect on CBG levels while androgenic progestins like the 19 nortestosterone derivatives have only a weak effect on CBG levels 8 COCs may increase CBG levels by 100 to 150 8 A dosage of 5 µg day EE has been found to increase TBG levels by 40 while a dosage of 20 µg day EE 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 EE and 1 mg day norethisterone a moderately androgenic progestin have been found to increase TBG levels by 50 to 70 while the combination of 30 µg day EE and 150 µg day desogestrel increased them by 100 8 Differences from estradiol edit nbsp Changes in levels of estrogen sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women 70 71 FSH is a pituitary protein and represents general systemic estrogenic effect while SHBG and PZPTooltip pregnancy zone protein are hepatic proteins and represent liver estrogenic effect 70 71 nbsp SHBG levels in men with 1 intramuscular injection of 320 mg polyestradiol phosphate once every 4 weeks alone 2 the combination of intramuscular injection of 80 mg polyestradiol phosphate once every 4 weeks plus 150 µg day oral ethinylestradiol 3 orchiectomy only 69 EE shows strong and disproportionate effects on liver protein synthesis relative to estradiol 7 The liver as well as the uterus express 17b hydroxysteroid dehydrogenase 17b HSD and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogen estrone which has approximately 4 of the estrogenic activity of estradiol 7 In contrast to estradiol the 17a ethynyl group of EE prevents oxidation of the C17b position of EE by 17b HSD and for this reason EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them 7 148 11 This is the mechanism of the disproportionately strong effects of EE on hepatic protein production 7 148 which results in a greatly increased magnitude of effect on VTE and cardiovascular risks relative to estradiol 149 On the other hand due to the loss of inactivation of EE by 17b HSD in the endometrium uterus EE is relatively more active than estradiol in the endometrium and for this reason is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison 7 This is particularly so in the case of combined estrogen and progestogen therapy as in COCs or menopausal HRT as progestogens induce the expression of 17b HSD in the endometrium 7 The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol 3 in spite of its potentially inferior safety profile related to its adverse effects on hepatic protein synthesis and VTE incidence 150 EE has been found to have disproportionate effects on liver protein synthesis and VTE risk regardless of whether the route of administration is oral transdermal or vaginal indicating that the use of parenteral routes over the oral route does not result in EE having proportional hepatic actions relative to non hepatic actions 148 8 However the potency of EE on liver protein synthesis is in any case reduced with parenteral administration 8 A dosage of 10 µg day vaginal EE has been found to be equivalent to 50 µg oral EE in terms of effects on liver protein synthesis such as stimulation of hepatic SHBG production 8 As such parenteral EE which bypasses the first pass through the liver that occurs with oral EE has been found to have a 5 fold lower impact on liver protein synthesis by weight than oral EE 8 In contrast to EE as well as to oral estradiol transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages 7 Comparison of estradiol and ethinylestradiol Parameters Estradiol EthinylestradiolERTooltip Estrogen receptor affinity 1 1010 M 1 2 5 1011 M 1Nuclear retention 6 8 hours 24 hoursElimination half life 90 minutes 7 hoursSubstrate for 17b HSDTooltip 17b hydroxysteroid dehydrogenase Yes NoBound to SHBGTooltip Sex hormone binding globulin Yes NoRelative oral liver potency 1 500 1 500Relative oral pituitary potency 1 200Sources 70 Pharmacokinetics edit Absorption edit nbsp EE levels while fasting or with a high fat meal following ingestion of tablets containing a single oral dose of 20 µg EE and 2 mg norethisterone acetate in women 151 7 The oral bioavailability of EE is 45 on average with a wide range of 20 to 74 though most commonly between 38 and 48 that is due to high interindividual variability 10 4 Although relatively low the oral bioavailability of EE is considerably higher than that of micronized estradiol 5 2 10 Following a single 20 mg dose of EE in combination with 2 mg norethisterone acetate in postmenopausal women EE 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 EE in general further increase by about 50 until steady state concentrations are reached 7 151 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 or estradiol 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 EE that are produced by an oral dose of EE that is 100 times lower by weight which is in accordance with the approximately 100 fold increased oral potency of EE relative to estradiol 100 7 In accordance with the high interindividual variability in the oral bioavailability of EE there is a large degree of interindividual variation in EE levels 7 152 A dosage of EE of 50 mg day has been found to achieve a wide range of circulating EE levels of about 100 to 2 000 pg mL 153 152 Taking EE in combination with a high fat meal has been found to significantly decrease its peak concentrations 151 7 EE levels after a single 50 mg dose by intravenous injection are several times higher than levels of EE after a single 50 mg dose given orally 153 Besides the difference in levels the course of elimination is similar for the two routes 153 There may be gender specific differences in the pharmacokinetics of EE such that EE may have greater oral potency in women than in men 8 A study found that a combination of 60 mg day EE and 0 25 mg day levonorgestrel in women and men resulted in peak levels of EE of 495 pg mL and 251 pg mL area under the curve levels of EE of 6 216 pg mL hour and 2 850 pg mL hour and elimination 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 against environmental estrogen exposure 8 Distribution edit The plasma protein binding of EE is 97 to 98 and it is bound almost exclusively to albumin 5 7 10 154 Unlike estradiol which binds with high affinity to SHBG EE has very low affinity for this protein about 2 of that of estradiol and hence does not bind to it importantly 155 Metabolism edit Due to high first pass metabolism in the intestines and liver only 1 of an oral dose of an EE appears in the circulation as EE itself 7 During first pass metabolism EE is extensively conjugated via glucuronidation and sulfation into the hormonally inert ethinylestradiol glucuronides and ethinylestradiol sulfate EE sulfate and levels of EE sulfate in circulation are between 6 and 22 fold higher than those of EE 7 4 For comparison with oral administration of 2 mg micronized estradiol levels of estrone and estrone sulfate are 4 to 6 fold and 200 fold higher than those of estradiol respectively 7 In contrast to estradiol EE due to steric hindrance by its C17a ethynyl group is not metabolized or inactivated by 17b HSD 11 and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol 7 EE is also not metabolized into estradiol 156 Aside from sulfate conjugation EE is mainly metabolized by hydroxylation into catechol estrogens 7 This is mainly by 2 hydroxylation into 2 hydroxy EE which is catalyzed primarily by CYP3A4 10 Hydroxylation of EE at the C4 C6a and C16b positions into 4 6a and 16b 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 by catechol O methyltransferase of 2 and 4 hydroxy EE 7 Unlike the case of estradiol 16a hydroxylation does not occur with EE owing to steric hindrance by its ethynyl group at C17a 10 7 The ethynylation of EE is largely irreversible and so EE is not metabolized into estradiol unlike estradiol esters 7 A review found that the range of the reported elimination half life of EE in the literature was 13 1 to 27 0 hours 2 Another review reported an elimination half life of EE of 10 to 20 hours 10 However the elimination half life of EE 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 EE 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 EE sulfate reservoir for EE is much smaller in comparison 7 4 In any case due to the formation of EE sulfate enterohepatic recirculation is involved in the pharmacokinetics of EE similarly to estradiol although to a lesser extent 7 157 The contribution of enterohepatic recirculation to total circulating EE levels appears to be 12 to 20 or less and is not observed consistently 8 157 A secondary peak in EE levels 10 to 14 hours after administration can often be observed with oral EE 157 EE following oxidative formation of a very reactive metabolite irreversibly inhibits cytochrome P450 enzymes involved in its metabolism and this may also play a role in the increased potency of EE relative to estradiol 7 Indeed EE is said to have a marked effect on hepatic metabolism and this is one of the reasons among others that natural estrogens like estradiol may be preferable 154 A 2 fold accumulation in EE levels with an EE containing COC has been observed following 1 year of therapy 157 Elimination edit EE is eliminated 62 in the feces and 38 in the urine 10 Chemistry editEE also known as 17a ethynylestradiol or as 17a ethynylestra 1 3 5 10 triene 3 17b diol is a synthetic estrane steroid and a derivative of estradiol with an ethynyl substitution at the C17a position 1 158 The 17a ethynylation of estradiol to create EE is analogous to the 17a substitution of testosterone to make testosterone derivatives such as 17a ethynylated progestins like ethisterone 17a ethynyltestosterone and norethisterone 17a ethynyl 19 nortestosterone as well as 17a alkylated androgens anabolic steroids like methyltestosterone 17a methyltestosterone Analogues edit See also List of estrogens 17a Substituted estradiol derivatives A number of derivatives of EE exist 1 158 These include mestranol EE 3 methyl ether quinestrol EE 3 cyclopentyl ether ethinylestradiol sulfonate EE 3 isopropylsulfonate and moxestrol 11b methoxy EE 1 158 8 The former three are prodrugs of EE while the latter one is not 8 A few analogues of EE with other substitutions at the C17a position exist 1 158 Examples include the estradiol derivatives methylestradiol 17a methylestradiol and ethylestradiol 17a ethylestradiol and the estriol derivatives ethinylestriol 17a ethynylestriol and nilestriol 17a ethynylestriol 3 cyclopentyl ether 1 158 Androstane analogues of EE with significant although weak estrogenic activity include ethinylandrostenediol 17a ethynyl 5 androstenediol 17a ethynyl 3b androstanediol 17a ethynyl 3a androstanediol and methandriol 17a methyl 5 androstenediol History editEE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of Schering AG in Berlin 159 160 161 162 163 It was approved by the US Food and Drug Administration FDA in June 1943 and marketed by Schering under the brand name Estinyl 14 The FDA withdrew approval of Estinyl effective 4 June 2004 at the request of Schering which had discontinued marketing it 164 EE was never introduced for use by intramuscular injection 165 EE was first used in COCs as an alternative to mestranol in 1964 and shortly thereafter superseded mestranol in COCs 15 Early COCs contained 40 to 100 mg day EE and 50 to 150 mg day mestranol 166 167 Society and culture editGeneric names edit Ethinylestradiol is the English generic name of the drug and its INNTooltip International Nonproprietary Name USANTooltip United States Adopted Name BANTooltip British Approved Name and JANTooltip Japanese Accepted Name 168 1 169 158 It has also been spelled as ethynylestradiol ethynyloestradiol and ethinyloestradiol all having the same pronunciation and the latter was formerly its BANTooltip British Approved Name but was eventually changed 168 1 158 In addition a space is often included in the name of EE such that it is written as ethinyl estradiol as well as variations thereof and this is its USPTooltip United States Pharmacopeia name 168 158 The generic name of EE in French and its DCFTooltip Denomination Commune Francaise are ethinylestradiol in Spanish is etinilestradiol in Italian and its DCITTooltip Denominazione Comune Italiana are etinilestradiolo and in Latin is ethinylestradiolum 168 158 The name of the drug is often abbreviated as EE or as EE2 in the medical literature Brand names edit EE has been marketed as a standalone oral drug under the brand names Esteed Estinyl Feminone Lynoral Menolyn Novestrol Palonyl Spanestrin and Ylestrol among others although most or all of these formulations are now discontinued 170 171 158 It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive 168 In addition EE is marketed in the U S in combination with norelgestromin under the brand names Ortho Evra and Xulane as a contraceptive patch in combination with etonogestrel under the brand name NuvaRing as a contraceptive vaginal ring and in combination with norethisterone acetate under the brand name FemHRT in oral hormone replacement therapy for the treatment of menopausal symptoms 12 Availability edit Ethinylestradiol is marketed throughout the world 168 158 It is marketed exclusively or almost exclusively in combination with progestins 168 References edit a b c d e f g h Elks J 14 November 2014 The Dictionary of Drugs Chemical Data Chemical Data Structures and Bibliographies Springer pp 522 ISBN 978 1 4757 2085 3 a b c d Goldzieher JW Brody SA December 1990 Pharmacokinetics of ethinyl estradiol and mestranol American Journal of Obstetrics and Gynecology 163 6 Pt 2 2114 2119 doi 10 1016 0002 9378 90 90550 Q PMID 2256522 a b Fruzzetti F Tremollieres F Bitzer J May 2012 An overview of the development of combined oral contraceptives containing estradiol focus on estradiol valerate dienogest Gynecological Endocrinology 28 5 400 408 doi 10 3109 09513590 2012 662547 PMC 3399636 PMID 22468839 a b c d Fotherby K August 1996 Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy Contraception 54 2 59 69 doi 10 1016 0010 7824 96 00136 9 PMID 8842581 a b Facts and Comparisons Firm Ovid Technologies Inc 2005 Drug Facts and Comparisons 2005 Pocket Version Facts and Comparisons p 121 ISBN 978 1 57439 179 4 Micromedex 1 January 2003 USP DI 2003 Drug Information for Healthcare Professionals Thomson Micromedex pp 1253 1258 1266 ISBN 978 1 56363 429 1 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au Oettel M Schillinger E 6 December 2012 Estrogens and Antiestrogens II Pharmacology and Clinical Application of Estrogens and Antiestrogen Springer Science amp Business Media pp 4 10 15 165 247 248 276 291 363 408 424 514 540 543 581 ISBN 978 3 642 60107 1 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 a b c Hughes CL Waters MD 23 March 2016 Translational Toxicology Defining a New Therapeutic Discipline Humana Press pp 73 ISBN 978 3 319 27449 2 a b c d e f g h i j k l m n Stanczyk FZ Archer DF Bhavnani BR June 2013 Ethinyl estradiol and 17b estradiol in combined oral contraceptives pharmacokinetics pharmacodynamics and risk assessment Contraception 87 6 706 727 doi 10 1016 j contraception 2012 12 011 PMID 23375353 a b c d Shellenberger TE 1986 Pharmacology of estrogens The Climacteric in Perspective pp 393 410 doi 10 1007 978 94 009 4145 8 36 ISBN 978 94 010 8339 3 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 17b dehydrogenase an enzyme which transforms natural estradiol 17b to the less potent estrone in target organs a b c d Drugs FDA FDA Approved Drug Products U S Food and Drug Administration FDA Retrieved 22 December 2016 Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 482 ISBN 978 3 527 60749 5 a b U S Food and Drug Administration FDA 2007 Approval history Estinyl ethinyl estradiol NDA 005292 search Estinyl a b Gruhn JG Kazer RR 11 November 2013 Hormonal Regulation of the Menstrual Cycle The Evolution of Concepts Springer Science amp Business Media pp 185 ISBN 978 1 4899 3496 3 In 1964 ethinyl estradiol was introduced as an alternative to mestranol as the estrogenic component Evans G Sutton EL May 2015 Oral contraception The Medical Clinics of North America 99 3 479 503 doi 10 1016 j mcna 2015 01 004 PMID 25841596 Shoupe D Haseltine FP 6 December 2012 Contraception Springer Science amp Business Media pp 112 ISBN 978 1 4612 2730 4 a b c d e f g The Top 300 of 2021 ClinCalc Archived from the original on 15 January 2024 Retrieved 14 January 2024 Ethinyl Estradiol Norethindrone Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Ethinyl Estradiol Norgestimate Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Ethinyl Estradiol Levonorgestrel Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Ethinyl Estradiol Etonogestrel Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Ethinyl Estradiol Norgestrel Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Ethinyl Estradiol Ethynodiol Drug Usage Statistics ClinCalc Archived from the original on 18 January 2024 Retrieved 14 January 2024 Drospirenone EthinylEstradiol Levomefolate Drug Usage Statistics ClinCalc Retrieved 14 January 2024 a b Rowan JP Simon JA Speroff L Ellman H June 2006 Effects of low dose norethindrone acetate plus ethinyl estradiol 0 5 mg 2 5 microg in women with postmenopausal symptoms updated analysis of three randomized controlled trials Clinical Therapeutics 28 6 921 932 doi 10 1016 j clinthera 2006 06 013 PMID 16860174 Hamoda H Panay N Arya R Savvas M December 2016 The British Menopause Society amp Women s Health Concern 2016 recommendations on hormone replacement therapy in menopausal women Post Reproductive Health 22 4 165 183 doi 10 1177 2053369116680501 hdl 1983 d96e4479 2ccc 44c3 963c d3918b1e325b a b Unger CA December 2016 Hormone therapy for transgender patients Translational Andrology and Urology 5 6 877 884 doi 10 21037 tau 2016 09 04 PMC 5182227 PMID 28078219 a b Coelingh Bennink HJ Verhoeven C Dutman AE Thijssen J January 2017 The use of high dose estrogens for the treatment of breast cancer Maturitas 95 11 23 doi 10 1016 j maturitas 2016 10 010 PMID 27889048 Thibaut F De La Barra F Gordon H Cosyns P Bradford JM June 2010 The World Federation of Societies of Biological Psychiatry WFSBP guidelines for the biological treatment of paraphilias The World Journal of Biological Psychiatry 11 4 604 655 doi 10 3109 15622971003671628 PMID 20459370 S2CID 14949511 Bancroft J Tennent G Loucas K Cass J September 1974 The control of deviant sexual behaviour by drugs I Behavioural changes following oestrogens and anti androgens The British Journal of Psychiatry 125 586 310 315 doi 10 1192 bjp 125 3 310 PMID 4607733 S2CID 10971754 Menopausal Hormone Therapy and Cancer Risk American Cancer Society 13 February 2015 a b c IARC Working Group on the Evaluation of Carcinogenic Risks to Humans World Health Organization International Agency for Research on Cancer 2007 Combined Estrogen progestogen Contraceptives and Combined Estrogen progestogen Menopausal Therapy World Health Organization pp 157 433 ISBN 978 92 832 1291 1 a b c Becker KL 2001 Principles and Practice of Endocrinology and Metabolism Lippincott Williams amp Wilkins p 1027 ISBN 978 0 7817 1750 2 DIANE Publishing Company 1995 Approved Drug Products with Therapeutic Evaluations DIANE Publishing p 3 122 ISBN 978 0 7881 0405 3 ETHINYL ESTRADIOL TABLET ORAL ESTINYL SCHERING 0 02MG 0 05MG 0 5MG Approved Prescription Drug Products with Therapeutic Equivalence Evaluations U S Department of Health and Human Services Public Health Service Food and Drug Administration Bureau of Drugs 1980 OCLC 7074861 Muller 19 June 1998 European Drug Index European Drug Registrations Fourth Edition 4 ed CRC Press pp 457 ISBN 978 3 7692 2114 5 Ethinyl oestradiol 0 05mg cpr 0 05 mg ethinylestradiol G03CA01 FR Ethinylestradiol tablets 50 mcg Ethinylestradiol G03CA01 RUS Ethinylestradiol 25mg Jenapharm Dragees Ethinylestradiol 25mg 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 S Monfardini K Brunner D Crowther S Eckhardt D Olive S Tanneberger A Veronesi J M A Whitehouse R Wittes eds 6 December 2012 Manual of Adult and Paediatric Medical Oncology Springer Science amp Business Media pp 78 ISBN 978 3 642 82489 0 OCLC 1058058829 Ethinyloestradiol Lynoral 0 05 mg 0 1 mg 1 mg tablets a b Lip GY Hall JE 28 June 2007 Comprehensive Hypertension E Book Elsevier Health Sciences pp 865 ISBN 978 0 323 07067 6 a b Alldredge BK Corelli RL Ernst ME 1 February 2012 Koda Kimble and Young s Applied Therapeutics The Clinical Use of Drugs Lippincott Williams amp Wilkins pp 1072 ISBN 978 1 60913 713 7 U S Selected Practice Recommendations for Contraceptive Use 2016 PDF Recommendations and Reports Vol 65 no 4 Centers for Disease Control and Prevention 29 July 2016 U S Selected Practice Recommendations for Contraceptive Use 2016 PDF Recommendations and Reports Vol 65 no 4 Centers for Disease Control and Prevention 29 July 2016 a b U S Medical Eligibility Criteria for Contraceptive Use 2016 PDF Recommendations and Reports Vol 65 no 3 Centers for Disease Control and Prevention 29 July 2016 a b c d e f g h i j k l m n Aronson JK 21 February 2009 Meyler s Side Effects of Endocrine and Metabolic Drugs Elsevier pp 177 219 223 224 230 232 239 242 ISBN 978 0 08 093292 7 a b Gerstman BB Piper JM Tomita DK Ferguson WJ Stadel BV Lundin FE January 1991 Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease American Journal of Epidemiology 133 1 32 37 doi 10 1093 oxfordjournals aje a115799 PMID 1983896 a b Runnebaum B Rabe T eds 17 April 2013 Kontrazeption Gynakologische Endokrinologie und Fortpflanzungsmedizin Band 1 Gynakologische Endokrinologie Springer Verlag pp 411 512 ISBN 978 3 662 07635 4 a b Gerstman BB Gross TP Kennedy DL Bennett RC Tomita DK Stadel BV January 1991 Trends in the content and use of oral contraceptives in the United States 1964 88 American Journal of Public Health 81 1 90 96 doi 10 2105 ajph 81 1 90 PMC 1404924 PMID 1983923 Gallo MF Nanda K Grimes DA Lopez LM Schulz KF August 2013 20 µg versus gt 20 µg estrogen combined oral contraceptives for contraception The Cochrane Database of Systematic Reviews 2013 8 CD003989 doi 10 1002 14651858 CD003989 pub5 PMC 7173696 PMID 23904209 Pincus G 22 October 2013 Hormones and Atherosclerosis Proceedings of the Conference Held in Brighton Utah March 11 14 1958 Elsevier Science pp 411 ISBN 978 1 4832 7064 7 Oettel M Schillinger E 6 December 2012 Estrogens and Antiestrogens II Pharmacology and Clinical Application of Estrogens and Antiestrogen Springer Science amp Business Media p 390 ISBN 978 3 642 60107 1 a b Legato MJ 29 October 2009 Principles of Gender Specific Medicine Academic Press pp 225 234 ISBN 978 0 08 092150 1 a b Stein PD 5 April 2016 Pulmonary Embolism Wiley pp 187 ISBN 978 1 119 03909 9 a b c d e f g h i Pfeifer S Butts S Dumesic D Fossum G Gracia C La Barbera A et al Practice Committee of the American Society for Reproductive Medicine January 2017 Combined hormonal contraception and the risk of venous thromboembolism a guideline Fertility and Sterility 107 1 43 51 doi 10 1016 j fertnstert 2016 09 027 PMID 27793376 a b c Plu Bureau G Maitrot Mantelet L Hugon Rodin J Canonico M February 2013 Hormonal contraceptives and venous thromboembolism an epidemiological update Best Practice amp Research Clinical Endocrinology amp Metabolism 27 1 25 34 doi 10 1016 j beem 2012 11 002 PMID 23384743 Keenan L Kerr T Duane M Van Gundy K November 2018 Systematic Review of Hormonal Contraception and Risk of Venous Thrombosis The Linacre Quarterly 85 4 470 477 doi 10 1177 0024363918816683 PMC 6322116 PMID 32431379 a b c d e Falcone T Hurd WW 2007 Clinical Reproductive Medicine and Surgery Elsevier Health Sciences pp 388 ISBN 978 0 323 03309 1 Christin Maitre S 2017 Use of Hormone Replacement in Females with Endocrine Disorders Hormone Research in Paediatrics 87 4 215 223 doi 10 1159 000457125 PMID 28376481 Becker KL 2001 Principles and Practice of Endocrinology and Metabolism Lippincott Williams amp Wilkins pp 1024 1027 1035 2153 ISBN 978 0 7817 1750 2 Low dose COCs contain lt 50 mg of estrogen and are the primary choice for oral contraception COCs containing 50 mg of estrogen should no longer be routinely used for contraception The estrogen component of COCs can cause breast fullness and tenderness Committee on the Relationship Between Oral Contraceptives and BreastCancer 1 January 1991 Oral Contraceptives and Breast Cancer National Academies pp 143 ISBN 978 0 309 04493 6 NAP 13774 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 mg Multigenerational Reproductive Toxicology Study of Ethinyl Estradiol CAS No 57636 in SpragueDawley Rats Feed Studies DIANE Publishing pp 27 ISBN 978 1 4379 4231 6 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 mg ethinyl estradiol Sitruk Ware R November 2016 Hormonal contraception and thrombosis Fertility and Sterility 106 6 1289 1294 doi 10 1016 j fertnstert 2016 08 039 PMID 27678035 Gallo MF Nanda K Grimes DA Lopez LM Schulz KF August 2013 20 µg versus gt 20 µg estrogen combined oral contraceptives for contraception The Cochrane Database of Systematic Reviews 2013 8 CD003989 doi 10 1002 14651858 CD003989 pub5 PMC 7173696 PMID 23904209 a b c d Odlind V Milsom I Persson I Victor A June 2002 Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills Acta Obstetricia et Gynecologica Scandinavica 81 6 482 490 PMID 12047300 Raps M Helmerhorst F Fleischer K Thomassen S Rosendaal F Rosing J et al June 2012 Sex hormone binding globulin as a marker for the thrombotic risk of hormonal contraceptives Journal of Thrombosis and Haemostasis 10 6 992 997 doi 10 1111 j 1538 7836 2012 04720 x PMID 22469296 S2CID 20803995 Stanczyk FZ Grimes DA September 2008 Sex hormone binding globulin not a surrogate marker for venous thromboembolism in women using oral contraceptives Contraception 78 3 201 203 doi 10 1016 j contraception 2008 04 004 PMID 18692609 a b c Winters SJ Huhtaniemi IT 25 April 2017 Male Hypogonadism Basic Clinical and Therapeutic Principles Humana Press pp 307 ISBN 978 3 319 53298 1 Notelovitz M March 2006 Clinical opinion the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause MedGenMed 8 1 85 PMC 1682006 PMID 16915215 Goodman MP February 2012 Are all estrogens created equal A review of oral vs transdermal therapy Journal of Women s Health 21 2 161 169 doi 10 1089 jwh 2011 2839 PMID 22011208 a b Stege R Carlstrom K Collste L Eriksson A Henriksson P Pousette A 1988 Single drug polyestradiol phosphate therapy in prostatic cancer American Journal of Clinical Oncology 11 Suppl 2 S101 S103 doi 10 1097 00000421 198801102 00024 PMID 3242384 S2CID 32650111 a b c d e von Schoultz B Carlstrom K Collste L Eriksson A Henriksson P Pousette A et al 1989 Estrogen therapy and liver function metabolic effects of oral and parenteral administration The Prostate 14 4 389 395 doi 10 1002 pros 2990140410 PMID 2664738 S2CID 21510744 a b c Ottosson UB Carlstrom K Johansson BG von Schoultz B 1986 Estrogen induction of liver proteins and high density lipoprotein cholesterol comparison between estradiol valerate and ethinyl estradiol Gynecologic and Obstetric Investigation 22 4 198 205 doi 10 1159 000298914 PMID 3817605 a b Turo R Smolski M Esler R Kujawa ML Bromage SJ Oakley N et al February 2014 Diethylstilboestrol for the treatment of prostate cancer past present and future Scandinavian Journal of Urology 48 1 4 14 doi 10 3109 21681805 2013 861508 PMID 24256023 S2CID 34563641 dead link a b c d e f g Phillips I Shah SI Duong T Abel P Langley RE 2014 Androgen Deprivation Therapy and the Re emergence of Parenteral Estrogen in Prostate Cancer Oncology amp Hematology Review 10 1 42 47 doi 10 17925 ohr 2014 10 1 42 PMC 4052190 PMID 24932461 a b c Hong WK Holland JK 2010 Holland Frei Cancer Medicine 8 PMPH USA pp 753 ISBN 978 1 60795 014 1 a b c Russell N Cheung A Grossmann M August 2017 Estradiol for the mitigation of adverse effects of androgen deprivation therapy Endocrine Related Cancer 24 8 R297 R313 doi 10 1530 ERC 17 0153 PMID 28667081 Trauner M Jansen PJ 2004 Molecular Pathogenesis of Cholestasis Springer Science amp Business Media pp 260 ISBN 978 0 306 48240 3 a b Clavien PA Baillie J 15 April 2008 Diseases of the Gallbladder and Bile Ducts Diagnosis and Treatment John Wiley amp Sons pp 363 ISBN 978 0 470 98697 4 a b c d Kuhl H 1999 Hormonal Contraception Estrogens and Antiestrogens II Handbook of Experimental Pharmacology Vol 135 2 Springer Berlin Heidelberg pp 363 407 doi 10 1007 978 3 642 60107 1 18 eISSN 1865 0325 ISBN 978 3 642 64261 6 ISSN 0171 2004 O Brien PJ Bruce WR 2010 Endogenous Toxins Diet Genetics Disease and Treatment John Wiley amp Sons pp 302 ISBN 978 3 527 32363 0 a b c d e f Kuhl H December 1990 Ovulation inhibitors the significance of estrogen dose Ovulation inhibitors the significance of estrogen dose Geburtshilfe und Frauenheilkunde in German 50 12 910 922 doi 10 1055 s 2008 1026392 PMID 2086334 S2CID 73398961 Shreenath AP Kahloon A January 2022 Hepatic Adenoma StatPearls PMID 30020636 a b Giannitrapani L Soresi M La Spada E Cervello M D Alessandro N Montalto G November 2006 Sex hormones and risk of liver tumor Annals of the New York Academy of Sciences 1089 1 228 236 Bibcode 2006NYASA1089 228G doi 10 1196 annals 1386 044 PMID 17261770 S2CID 7932937 Ponnatapura J Kielar A Burke LM Lockhart ME Abualruz AR Tappouni R et al July 2019 Hepatic complications of oral contraceptive pills and estrogen on MRI Controversies and update Adenoma and beyond Magnetic Resonance Imaging 60 110 121 doi 10 1016 j mri 2019 04 010 PMID 31009688 S2CID 128359413 Perarnau JM Bacq Y August 2008 Hepatic vascular involvement related to pregnancy oral contraceptives and estrogen replacement therapy Seminars in Liver Disease 28 3 315 327 doi 10 1055 s 0028 1085099 PMID 18814084 S2CID 260318275 a b c Blaustein A 11 November 2013 Pathology of the Female Genital Tract Springer Science amp Business Media pp 291 ISBN 978 1 4757 1767 9 Surwit EA Alberts D 6 December 2012 Endometrial Cancer Springer Science amp Business Media pp 11 ISBN 978 1 4613 0867 6 a b c Kidd KA Blanchfield PJ Mills KH Palace VP Evans RE Lazorchak JM et al May 2007 Collapse of a fish population after exposure to a synthetic estrogen Proceedings of the National Academy of Sciences of the United States of America 104 21 8897 8901 Bibcode 2007PNAS 104 8897K doi 10 1073 pnas 0609568104 PMC 1874224 PMID 17517636 a b c Park BJ Kidd K August 2005 Effects of the synthetic estrogen ethinylestradiol on early life stages of mink frogs and green frogs in the wild and in situ Environmental Toxicology and Chemistry 24 8 2027 2036 doi 10 1897 04 227R 1 PMID 16152976 S2CID 32669410 Wang B Sanchez RI Franklin RB Evans DC Huskey SE November 2004 The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha ethinylestradiol Drug Metabolism and Disposition 32 11 1209 1212 doi 10 1124 dmd 104 000182 PMID 15304426 S2CID 86245855 a b c d e f g h i Zhang H Cui D Wang B Han YH Balimane P Yang Z et al 2007 Pharmacokinetic drug interactions involving 17alpha ethinylestradiol a new look at an old drug Clinical Pharmacokinetics 46 2 133 157 doi 10 2165 00003088 200746020 00003 PMID 17253885 S2CID 71784426 Escande A Pillon A Servant N Cravedi JP Larrea F Muhn P et al May 2006 Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta Biochemical Pharmacology 71 10 1459 1469 doi 10 1016 j bcp 2006 02 002 PMID 16554039 Jeyakumar M Carlson KE Gunther JR Katzenellenbogen JA April 2011 Exploration of dimensions of estrogen potency parsing ligand binding and coactivator binding affinities The Journal of Biological Chemistry 286 15 12971 12982 doi 10 1074 jbc M110 205112 PMC 3075970 PMID 21321128 Prossnitz ER Arterburn JB July 2015 International Union of Basic and Clinical Pharmacology XCVII G Protein Coupled Estrogen Receptor and Its Pharmacologic Modulators Pharmacological Reviews 67 3 505 540 doi 10 1124 pr 114 009712 PMC 4485017 PMID 26023144 Yates MA Li Y Chlebeck PJ Offner H April 2010 GPR30 but not estrogen receptor alpha is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol BMC Immunology 11 20 doi 10 1186 1471 2172 11 20 PMC 2864220 PMID 20403194 Prossnitz ER Barton M August 2011 The G protein coupled estrogen receptor GPER in health and disease Nature Reviews Endocrinology 7 12 715 726 doi 10 1038 nrendo 2011 122 PMC 3474542 PMID 21844907 Further research showed that the therapeutic effect of ethynylestradiol in established EAE was mediated via GPER but not via ERa and possibly involved production of the anti inflammatory cytokine Il 10 115 Prossnitz ER Barton M May 2014 Estrogen biology new insights into GPER function and clinical opportunities Molecular and Cellular Endocrinology 389 1 2 71 83 doi 10 1016 j mce 2014 02 002 PMC 4040308 PMID 24530924 In addition the therapeutic effect of ethinyl estradiol in established disease was demonstrated to require expression of GPER but not ERa and was associated with the production of the anti inflammatory cytokine IL 10 Yates et al 2010 Quaynor SD Stradtman EW Kim HG Shen Y Chorich LP Schreihofer DA et al July 2013 Delayed puberty and estrogen resistance in a woman with estrogen receptor a variant The New England Journal of Medicine 369 2 164 171 doi 10 1056 NEJMoa1303611 PMC 3823379 PMID 23841731 Craig CR Stitzel RE 2004 Modern Pharmacology with Clinical Applications Lippincott Williams amp Wilkins pp 708 ISBN 978 0 7817 3762 3 Allahbadia G Agrawal R 2007 Polycystic Ovary Syndrome Anshan pp 257 ISBN 978 1 904798 74 3 a b Gomel V Munro MG Rowe TC 1990 Gynecology a practical approach Williams amp Wilkins p 132 134 ISBN 978 0 683 03631 2 The synthetic estrogen ethinyl estradiol more commonly used in oral contraceptives has a biological activity 100 times that of the native and conjugated substances a b Shoupe D 7 November 2007 The Handbook of Contraception A Guide for Practical Management Springer Science amp Business Media pp 23 ISBN 978 1 59745 150 5 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 McConaghy N 21 November 2013 Sexual Behavior Problems and Management Springer Science amp Business Media pp 177 ISBN 978 1 4899 1133 9 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 Chabner B Longo DL 1996 Cancer Chemotherapy and Biotherapy Principles and Practice Lippincott Raven Publishers p 186 ISBN 978 0 397 51418 2 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 a b Mashchak CA Lobo RA Dozono Takano R Eggena P Nakamura RM Brenner PF et al November 1982 Comparison of pharmacodynamic properties of various estrogen formulations American Journal of Obstetrics and Gynecology 144 5 511 518 doi 10 1016 0002 9378 82 90218 6 PMID 6291391 Lauritzen C September 1990 Clinical use of oestrogens and progestogens Maturitas 12 3 199 214 doi 10 1016 0378 5122 90 90004 P PMID 2215269 Lauritzen C June 1977 Estrogen thearpy in practice 3 Estrogen preparations and combination preparations Estrogen therapy in practice 3 Estrogen preparations and combination preparations Fortschritte Der Medizin in German 95 21 1388 92 PMID 559617 Wolf AS Schneider HP 12 March 2013 Ostrogene in Diagnostik und Therapie Springer Verlag pp 78 ISBN 978 3 642 75101 1 Goretzlehner G Lauritzen C Romer T Rossmanith W 1 January 2012 Praktische Hormontherapie in der Gynakologie Walter de Gruyter pp 44 ISBN 978 3 11 024568 4 Knorr K Beller FK Lauritzen C 17 April 2013 Lehrbuch der Gynakologie Springer Verlag pp 212 213 ISBN 978 3 662 00942 0 Horsky J Presl J 1981 Hormonal Treatment of Disorders of the Menstrual Cycle In Horsky J Presl J eds Ovarian Function and its Disorders Diagnosis and Therapy Springer Science amp Business Media pp 309 332 doi 10 1007 978 94 009 8195 9 11 ISBN 978 94 009 8195 9 Pschyrembel W 1968 Praktische Gynakologie fur Studierende und Arzte Walter de Gruyter pp 598 599 ISBN 978 3 11 150424 7 Lauritzen CH January 1976 The female climacteric syndrome significance problems treatment Acta Obstetricia Et Gynecologica Scandinavica Supplement 51 47 61 doi 10 3109 00016347509156433 PMID 779393 Lauritzen C 1975 The Female Climacteric Syndrome Significance Problems Treatment Acta Obstetricia et Gynecologica Scandinavica 54 s51 48 61 doi 10 3109 00016347509156433 ISSN 0001 6349 Kopera H 1991 Hormone der Gonaden Hormonelle Therapie fur die Frau Kliniktaschenbucher pp 59 124 doi 10 1007 978 3 642 95670 6 6 ISBN 978 3 540 54554 5 ISSN 0172 777X Scott WW Menon M Walsh PC April 1980 Hormonal Therapy of Prostatic Cancer Cancer 45 Suppl 7 1929 1936 doi 10 1002 cncr 1980 45 s7 1929 PMID 29603164 Leinung MC Feustel PJ Joseph J 2018 Hormonal Treatment of Transgender Women with Oral Estradiol Transgender Health 3 1 74 81 doi 10 1089 trgh 2017 0035 PMC 5944393 PMID 29756046 Ryden AB 1950 Natural and synthetic oestrogenic substances their relative effectiveness when administered orally Acta Endocrinologica 4 2 121 39 doi 10 1530 acta 0 0040121 PMID 15432047 Ryden AB 1951 The effectiveness of natural and synthetic oestrogenic substances in women Acta Endocrinologica 8 2 175 91 doi 10 1530 acta 0 0080175 PMID 14902290 Kottmeier HL 1947 Ueber blutungen in der menopause Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung Part I Acta Obstetricia et Gynecologica Scandinavica 27 s6 1 121 doi 10 3109 00016344709154486 ISSN 0001 6349 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 Rietbrock N Staib AH Loew D 11 March 2013 Klinische Pharmakologie Arzneitherapie Springer Verlag pp 426 ISBN 978 3 642 57636 2 Martinez Manautou J Rudel HW 1966 Antiovulatory Activity of Several Synthetic and Natural Estrogens In Robert Benjamin Greenblatt ed Ovulation Stimulation Suppression and Detection Lippincott pp 243 253 Herr F Revesz C Manson AJ Jewell JB 1970 Biological Properties of Estrogen Sulfates Chemical and Biological Aspects of Steroid Conjugation pp 368 408 doi 10 1007 978 3 642 49793 3 8 ISBN 978 3 642 49506 9 Duncan CJ Kistner RW Mansell H October 1956 Suppression of ovulation by trip anisyl chloroethylene TACE Obstetrics and Gynecology 8 4 399 407 PMID 13370006 a b c Shearer RJ Hendry WF Sommerville IF Fergusson JD December 1973 Plasma testosterone an accurate monitor of hormone treatment in prostatic cancer British Journal of Urology 45 6 668 677 doi 10 1111 j 1464 410x 1973 tb12238 x PMID 4359746 a b c Ekback MP 2017 Hirsutism What to do PDF International Journal of Endocrinology and Metabolic Disorders 3 3 doi 10 16966 2380 548X 140 ISSN 2380 548X a b c Nieschlag E Behre HM Nieschlag S 26 July 2012 Testosterone Action Deficiency Substitution Cambridge University Press pp 62 ISBN 978 1 107 01290 5 Coss CC Jones A Parke DN Narayanan R Barrett CM Kearbey JD et al March 2012 Preclinical characterization of a novel diphenyl benzamide selective ERa agonist for hormone therapy in prostate cancer Endocrinology 153 3 1070 1081 doi 10 1210 en 2011 1608 PMID 22294742 Rich P January 2008 Hormonal contraceptives for acne management Cutis 81 1 Suppl 13 18 PMID 18338653 Zimmerman Y Eijkemans MJ Coelingh Bennink HJ Blankenstein MA Fauser BC 2014 The effect of combined oral contraception on testosterone levels in healthy women a systematic review and meta analysis Hum Reprod Update 20 1 76 105 doi 10 1093 humupd dmt038 PMC 3845679 PMID 24082040 Ozcan O den Elzen WP Hillebrand JJ den Heijer M van Loendersloot LL Fischer J et al January 2024 The effect of hormonal contraceptive therapy on clinical laboratory parameters a literature review Clin Chem Lab Med 62 1 18 40 doi 10 1515 cclm 2023 0384 PMID 37419659 S2CID 259361637 Yang LP Plosker GL October 2012 Nomegestrol acetate estradiol in oral contraception Drugs 72 14 1917 1928 doi 10 2165 11208180 000000000 00000 PMID 22950535 S2CID 44335732 a b Jacobi GH Altwein JE Kurth KH Basting R Hohenfellner R June 1980 Treatment of advanced prostatic cancer with parenteral cyproterone acetate a phase III randomised trial British Journal of Urology 52 3 208 215 doi 10 1111 j 1464 410x 1980 tb02961 x PMID 7000222 a b Gunnarsson PO Norlen BJ 1988 Clinical pharmacology of polyestradiol phosphate The Prostate 13 4 299 304 doi 10 1002 pros 2990130405 PMID 3217277 S2CID 33063805 Stahl F Schnorr D Bar CM Frohlich G Dorner G 1989 Suppression of plasma androgen levels with a combination therapy of depot estrogen Turisteron and Dexamethasone in patients with prostatic cancer Experimental and Clinical Endocrinology 94 3 239 243 doi 10 1055 s 0029 1210905 PMID 2630306 S2CID 40497389 a b c Jameson JL De Groot LJ 18 May 2010 Endocrinology E Book Adult and Pediatric Elsevier Health Sciences pp 2282 ISBN 978 1 4557 1126 0 Denis LJ Griffiths K Kaisary AV Murphy GP 1 March 1999 Textbook of Prostate Cancer Pathology Diagnosis and Treatment Pathology Diagnosis and Treatment CRC Press pp 297 ISBN 978 1 85317 422 3 Scott WW Menon M Walsh PC April 1980 Hormonal Therapy of Prostatic Cancer Cancer 45 Suppl 7 1929 1936 doi 10 1002 cncr 1980 45 s7 1929 PMID 29603164 S2CID 4492779 Bingel AS Benoit PS February 1973 Oral contraceptives therapeutics versus adverse reactions with an outlook for the future I Journal of Pharmaceutical Sciences 62 2 179 200 doi 10 1002 jps 2600620202 PMID 4568621 Rietbrock N Staib AH Loew D 11 March 2013 Klinische Pharmakologie Arzneitherapie Springer Verlag pp 426 ISBN 978 3 642 57636 2 Elger W 1972 Physiology and pharmacology of female reproduction under the aspect of fertility control Reviews of Physiology Biochemistry and Experimental Pharmacology Volume 67 Ergebnisse der Physiologie Reviews of Physiology Vol 67 pp 69 168 doi 10 1007 BFb0036328 ISBN 3 540 05959 8 PMID 4574573 Bastianelli C Farris M Rosato E Brosens I Benagiano G November 2018 Pharmacodynamics of combined estrogen progestin oral contraceptives 3 Inhibition of ovulation Expert Review of Clinical Pharmacology 11 11 1085 1098 doi 10 1080 17512433 2018 1536544 PMID 30325245 S2CID 53246678 Martinez Manautou J Rudel HW 1966 Antiovulatory Activity of Several Synthetic and Natural Estrogens In Greenblatt RB ed Ovulation Stimulation Suppression and Detection Lippincott pp 243 253 ISBN 978 0 397 59010 0 Herr F Revesz C Manson AJ Jewell JB 1970 Biological Properties of Estrogen Sulfates Chemical and Biological Aspects of Steroid Conjugation pp 368 408 doi 10 1007 978 3 642 49793 3 8 ISBN 978 3 642 49506 9 Goldzieher JW Pena A Chenault CB Woutersz TB July 1975 Comparative studies of the ethynyl estrogens used in oral contraceptives II Antiovulatory potency American Journal of Obstetrics and Gynecology 122 5 619 624 doi 10 1016 0002 9378 75 90061 7 PMID 1146927 a b c Margioris AN Chrousos GP 20 April 2001 Adrenal Disorders Springer Science amp Business Media pp 84 ISBN 978 1 59259 101 5 a b c Polderman KH Gooren LJ van der Veen EA October 1995 Effects of gonadal androgens and oestrogens on adrenal androgen levels Clinical Endocrinology 43 4 415 421 doi 10 1111 j 1365 2265 1995 tb02611 x PMID 7586614 S2CID 6815423 Tremollieres F February 2012 Oral combined contraception is there any difference between ethinyl estradiol and estradiol Oral combined contraception is there any difference between ethinyl estradiol and estradiol Gynecologie Obstetrique amp Fertilite in French 40 2 109 115 doi 10 1016 j gyobfe 2011 10 009 PMID 22244780 a b c Lobo RA 5 June 2007 Treatment of the Postmenopausal Woman Basic and Clinical Aspects Academic Press pp 177 770 771 ISBN 978 0 08 055309 2 Shoupe D 10 February 2011 Contraception John Wiley amp Sons pp 79 ISBN 978 1 4443 4263 5 Sitruk Ware R Nath A June 2011 Metabolic effects of contraceptive steroids Reviews in Endocrine amp Metabolic Disorders 12 2 63 75 doi 10 1007 s11154 011 9182 4 PMID 21538049 S2CID 23760705 a b c Boyd RA Zegarac EA Eldon MA January 2003 The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate ethinyl estradiol tablets intended for continuous hormone replacement therapy Journal of Clinical Pharmacology 43 1 52 58 doi 10 1177 0091270002239706 PMID 12520628 S2CID 27729272 a b Dodick D Silberstein SD 2016 Migraine Oxford University Press pp 272 ISBN 978 0 19 979361 7 a b c Orme ML Back DJ Breckenridge AM 1983 Clinical pharmacokinetics of oral contraceptive steroids Clinical Pharmacokinetics 8 2 95 136 doi 10 2165 00003088 198308020 00001 PMID 6342899 S2CID 43298472 a b Notelovitz M van Keep PA 6 December 2012 The Climacteric in Perspective Proceedings of the Fourth International Congress on the Menopause held at Lake Buena Vista Florida October 28 November 2 1984 Springer Science amp Business Media pp 395 ISBN 978 94 009 4145 8 Pugeat MM Dunn JF Nisula BC July 1981 Transport of steroid hormones interaction of 70 drugs with testosterone binding globulin and corticosteroid binding globulin in human plasma The Journal of Clinical Endocrinology and Metabolism 53 1 69 75 doi 10 1210 jcem 53 1 69 PMID 7195405 Backeljauw P Klein K March 2019 Sex hormone replacement therapy for individuals with Turner syndrome American Journal of Medical Genetics Part C Seminars in Medical Genetics 181 1 13 17 doi 10 1002 ajmg c 31685 PMID 30809949 S2CID 73487051 a b c d Mattison DR Karyakina N Goodman M LaKind JS September 2014 Pharmaco and toxicokinetics of selected exogenous and endogenous estrogens a review of the data and identification of knowledge gaps Critical Reviews in Toxicology 44 8 696 724 doi 10 3109 10408444 2014 930813 PMID 25099693 S2CID 11212469 a b c d e f g h i j k Index Nominum 2000 International Drug Directory Taylor amp Francis January 2000 p 412 ISBN 978 3 88763 075 1 Inhoffen HH Hohlweg W 1938 Neue per os wirksame weibliche Keimdrusenhormon Derivate 17 Aethinyl oestradiol und Pregnen in on 3 ol 17 New female glandular derivatives active per os 17a ethynyl estradiol and pregnen in on 3 ol 17 Naturwissenschaften 26 6 96 Bibcode 1938NW 26 96I doi 10 1007 BF01681040 S2CID 46648877 Maisel AQ 1965 The Hormone Quest New York Random House OCLC 543168 Petrow V December 1970 The contraceptive progestagens Chemical Reviews 70 6 713 726 doi 10 1021 cr60268a004 PMID 4098492 Sneader W 2005 Hormone analogues Drug discovery a history Hoboken NJ John Wiley amp Sons pp 188 225 ISBN 978 0 471 89980 8 Djerassi C January 2006 Chemical birth of the pill 1992 American Journal of Obstetrics and Gynecology 194 1 290 298 doi 10 1016 j ajog 2005 06 010 PMID 16389046 U S Food and Drug Administration FDA 5 May 2004 Schering Corp et al Withdrawal of Approval of 92 New Drug Applications and 49 Abbreviated New Drug Applications Notice PDF Federal Register 69 87 25124 30 Cantor EB September 1956 A survey of estrogens Postgraduate Medicine 20 3 224 231 doi 10 1080 00325481 1956 11691266 PMID 13359169 Beller FK Knorr K Lauritzen C Wynn RM 1974 Family Planning Gynecology pp 189 213 doi 10 1007 978 1 4615 7128 5 17 ISBN 978 0 387 90087 2 Haller J 1968 Die antikonzeptionelle Therapie Die Gestagene pp 1125 1178 doi 10 1007 978 3 642 99941 3 8 ISBN 978 3 642 99942 0 a b c d e f g Ethinylestradiol Drugs com Morton IK Hall JM 6 December 2012 Concise Dictionary of Pharmacological Agents Properties and Synonyms Springer Science amp Business Media pp 115 ISBN 978 94 011 4439 1 American Medical Association Dept of Drugs Council on Drugs American Medical Association American Society for Clinical Pharmacology and Therapeutics 1 February 1977 Estrogens Progestagens Oral Contraceptives and Ovulatory Agents AMA drug evaluations Publishing Sciences Group pp 540 572 ISBN 978 0 88416 175 2 Ethinyl Estradiol Estinyl Feminone Lynoral Novestrol Palonyl American Society of Hospital Pharmacists Committee on Pharmacy and Pharmaceuticals 1983 American Hospital Formulary Service A Two volume Collection of Drug Monographs and Other Information American Society of Hospital Pharmacists ISBN 978 0 930530 02 0 ETHINYL ESTRADIOL U S P Esteed Estinyl Lynoral Menolyn Novestrol Palonyl Spanestrin Ylestrol Further reading editOettel M Schillinger E 6 December 2012 Estrogens and Antiestrogens II Pharmacology and Clinical Application of Estrogens and Antiestrogen Springer Science amp Business Media pp 4 10 15 165 247 248 276 291 363 408 424 514 540 543 581 ISBN 978 3 642 60107 1 Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 Stanczyk FZ Archer DF Bhavnani BR June 2013 Ethinyl estradiol and 17b estradiol in combined oral contraceptives pharmacokinetics pharmacodynamics and risk assessment Contraception 87 6 706 727 doi 10 1016 j contraception 2012 12 011 PMID 23375353 Mattison DR Karyakina N Goodman M LaKind JS September 2014 Pharmaco and toxicokinetics of selected exogenous and endogenous estrogens a review of the data and identification of knowledge gaps Critical Reviews in Toxicology 44 8 696 724 doi 10 3109 10408444 2014 930813 PMID 25099693 S2CID 11212469 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Ethinylestradiol amp oldid 1215479073, wikipedia, wiki, book, books, library,

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