Ethinylestradiol

Last updated

Ethinylestradiol
Ethinylestradiol.svg
Ethinylestradiol molecule ball.png
Clinical data
Pronunciation /ˌɛθɪnɪlˌɛstrəˈdaɪ.əl/
Trade names Many
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.com International Drug Names
MedlinePlus a604032
Routes of
administration 		• By mouth, Transdermal, Vaginal
Drug class Estrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 38–48% [2] [3] [4]
Protein binding 97–98% (to albumin; [5] is not bound to SHBG Tooltip sex hormone-binding globulin) [6]
Metabolism Liver (primarily CYP3A4) [7]
Metabolites • Ethinylestradiol sulfate [8] [9]
• Others [8] [9]
Elimination half-life 7–36 hours [7] [2] [10] [11]
Excretion Feces: 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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.311 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24O2
Molar mass 296.410 g·mol−1
3D model (JSmol)
Melting point 182 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 Yes check.svgY
  • Key:BFPYWIDHMRZLRN-SLHNCBLASA-N Yes check.svgY
   (verify)

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. [8] [9] 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. [8] [12]

Contents

The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others. [8] 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. [8]

EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. [8] It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways. [8] 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. [8] 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. [8]

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

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. [9] [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

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. [9] 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

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

Dose of ethinylestradiol in birth control pills and risk of venous thromboembolism (VTE)
Ethinylestradiol doseNo. of VTE casesWoman-yearsVTE rateAdjusted RRa
Low (<50 μg)53127,0004.2 in 10,000 woman-years1.0
Intermediate (50 μg)6998,0007.0 in 10,000 woman-years1.5
High (>50 μg)2020,00010.0 in 10,000 woman-years1.7
All142245,0005.8 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

Beneficial and adverse effects of ethinylestradiol-containing birth control pills
Beneficial effects Adverse effects
Disease RR Tooltip Relative risk Disease RR Tooltip 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

VTE is a blood clot in a vein, and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). [8] [51] [52] Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors. [8] [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. [8]

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)
TypeRouteMedications Odds ratio (95% CI Tooltip 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 alone1.02 (0.90–1.15)
Raloxifene alone1.49 (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 alone0.84 (0.73–0.97)
Conjugated estrogens alone1.04 (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

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. [9] However, both EE and diethylstilbestrol nonetheless have highly disproportionate effects on liver protein synthesis, which is thought to be responsible for their cardiovascular toxicity. [8] [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. [9]

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. [9] 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

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

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

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

Estrogens like EE are relatively safe in acute overdose.[ citation needed ]

Interactions

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

Pharmacodynamics

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. [9] 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)aAction
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
Estrone E1; 17-Ketoestradiol16.39 (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-E212.65 (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-E24.03.04.919Estrogen
Alfatradiol 17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol1.013 ? ?Metabolite
2-Hydroxyestradiol 2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol 2-MeO-E20.0027–2.01.0 ? ?Metabolite
4-Hydroxyestradiol 4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol 4-MeO-E22.01.0 ? ?Metabolite
2-Hydroxyestrone 2-OH-E12.0–4.00.2–0.4 ? ?Metabolite
2-Methoxyestrone 2-MeO-E1<0.001–<1<1 ? ?Metabolite
4-Hydroxyestrone 4-OH-E11.0–2.01.0 ? ?Metabolite
4-Methoxyestrone 4-MeO-E1<1<1 ? ?Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol2.0–6.535 ? ?Metabolite
2-Hydroxyestriol 2-OH-E32.01.0 ? ?Metabolite
4-Methoxyestriol 4-MeO-E31.01.0 ? ?Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate<1<1 ? ?Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate0.0004 ? ? ?Metabolite
Estradiol 3-glucuronide E2-3G0.0079 ? ? ?Metabolite
Estradiol 17β-glucuronide E2-17G0.0015 ? ? ?Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S0.0001 ? ? ?Metabolite
Estrone sulfate E1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate10 ? ? ?Estrogen
Estradiol 17β-benzoate E2-17B11.332.6 ? ?Estrogen
Estrone methyl ether Estrone 3-methyl ether0.145 ? ? ?Estrogen
ent-Estradiol 1-Estradiol1.31–12.349.44–80.07 ? ?Estrogen
Equilin 7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin 6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone 8,9-Dehydroestrone19320.520.57Estrogen
EthinylestradiolEE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
Mestranol EE 3-methyl ether ?2.5 ? ?Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol 17α-Methyl-17β-estradiol7044 ? ?Estrogen
Diethylstilbestrol DES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
Hexestrol Dihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
Dienestrol Dehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2) –114 ? ? ?Estrogen
Chlorotrianisene TACE1.74 ?15.30 ?Estrogen
Triphenylethylene TPE0.074 ? ? ?Estrogen
Triphenylbromoethylene TPBE2.69 ? ? ?Estrogen
Tamoxifen ICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ?7.14–20.315.4SERM
Clomifene MRL-4125 (19.2–37.2)120.91.2SERM
Cyclofenil F-6066; Sexovid151–152243 ? ?SERM
Nafoxidine U-11,000A30.9–44160.30.8SERM
Raloxifene –41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
Arzoxifene LY-353,381 ? ?0.179 ?SERM
Lasofoxifene CP-336,15610.2–16619.00.229 ?SERM
Ormeloxifene Centchroman ? ?0.313 ?SERM
Levormeloxifene 6720-CDRI; NNC-460,0201.551.88 ? ?SERM
Ospemifene Deaminohydroxytoremifene0.82–2.630.59–1.22 ? ?SERM
Bazedoxifene – ? ?0.053 ?SERM
Etacstil GW-56384.3011.5 ? ?SERM
ICI-164,384 –63.5 (3.70–97.7)1660.20.08Antiestrogen
Fulvestrant ICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
Propylpyrazoletriol PPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE2 16α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol30.22.30 ? ?ERα agonist
Methylpiperidinopyrazole MPP110.05 ? ?ERα antagonist
Diarylpropionitrile DPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
Prinaberel ERB-041; WAY-202,0410.2767–72 ? ?ERβ agonist
ERB-196 WAY-202,196 ?180 ? ?ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ?2.680.19ERβ agonist
SERBA-2 – ? ?14.51.54ERβ agonist
Coumestrol –9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein –0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol –0.2–0.2870.85 (0.10–2.85) ? ?Xenoestrogen
Daidzein –0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A –0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
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-PN4.4 ? ? ?Xenoestrogen
Quercetin –<0.001–0.010.002–0.040 ? ?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-Zearalanol48–111 ? ? ?Xenoestrogen
Taleranol β-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
Zearalenone ZEN7.68 (2.04–28)9.45 (2.43–31.5) ? ?Xenoestrogen
Zearalanone ZAN0.51 ? ? ?Xenoestrogen
Bisphenol A BPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
Endosulfan EDS<0.001–<0.01<0.01 ? ?Xenoestrogen
Kepone Chlordecone0.0069–0.2 ? ? ?Xenoestrogen
o,p'-DDT –0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT –0.03 ? ? ?Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13 ? ?Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT1.2–1.7 ? ? ?Xenoestrogen
Testosterone T; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
Dihydrotestosterone DHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone 19-Nortestosterone; 19-NT0.010.2376553Androgen
Dehydroepiandrosterone DHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-Androstenediol A5; Androstenediol6173.60.9Androgen
4-Androstenediol –0.50.62319Androgen
4-Androstenedione A4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol 3α-Adiol0.070.326048Androgen
3β-Androstanediol 3β-Adiol3762Androgen
Androstanedione 5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione 5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone 17α-Methyltestosterone<0.0001 ? ? ?Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol4.0<0.07 ? ?Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol505.6 ? ?Estrogen
Progesterone P4; 4-Pregnenedione<0.001–0.6<0.001–0.010 ? ?Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel 5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone 7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?Progestogen
Δ4-Tibolone 7α-Methylnorethisterone0.069–<0.10.027–<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 (%)
ER Tooltip Estrogen receptor AR Tooltip Androgen receptor PR Tooltip Progesterone receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Estradiol 1007.92.60.60.138.7–12<0.1
Estradiol benzoate  ? ? ? ? ?<0.1–0.16<0.1
Estradiol valerate 2 ? ? ? ? ? ?
Estrone 11–35<1<1<1<12.7<0.1
Estrone sulfate 22 ? ? ? ? ?
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 ? ?
Ethinylestradiol100–1121–315–251–3<10.18<0.1
Mestranol 1 ? ? ? ?<0.1<0.1
Methylestradiol 671–33–251–3<1 ? ?
Moxestrol 12<0.10.83.2<0.1<0.2<0.1
Diethylstilbestrol  ? ? ? ? ?<0.1<0.1
Notes: Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, testosterone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: See template.
Relative oral potencies of estrogens
Estrogen HF Tooltip Hot flashes VE Tooltip Vaginal epithelium UCa Tooltip Urinary calcium FSH Tooltip Follicle-stimulating hormone LH Tooltip Luteinizing hormone HDL Tooltip High-density lipoprotein-C Tooltip Cholesterol SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid-binding globulin AGT Tooltip AngiotensinogenLiver
Estradiol 1.01.01.01.01.01.01.01.01.01.0
Estrone  ? ? ?0.30.3 ? ? ? ? ?
Estriol 0.30.30.10.30.30.2 ? ? ?0.67
Estrone sulfate  ?0.90.90.8–0.90.90.50.90.5–0.71.4–1.50.56–1.7
Conjugated estrogens 1.21.52.01.1–1.31.01.53.0–3.21.3–1.55.01.3–4.5
Equilin sulfate  ? ?1.0 ? ?6.07.56.07.5 ?
Ethinylestradiol12015040060–150100400500–600500–6003502.9–5.0
Diethylstilbestrol  ? ? ?2.9–3.4 ? ?26–2825–37205.7–7.5
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 UCa Tooltip urinary calcium. FSH = Suppression of FSH Tooltip follicle-stimulating hormone levels. LH = Suppression of LH Tooltip 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]
CompoundDosage for specific uses (mg usually) [lower-alpha 1]
ETD [lower-alpha 2] EPD [lower-alpha 2] MSD [lower-alpha 2] MSD [lower-alpha 3] OID [lower-alpha 3] TSD [lower-alpha 3]
Estradiol (non-micronized) 30≥120–3001206--
Estradiol (micronized) 6–1260–8014–421–2>5>8
Estradiol valerate 6–1260–8014–421–2->8
Estradiol benzoate -60–140----
Estriol ≥20120–150 [lower-alpha 4] 28–1261–6>5-
Estriol succinate -140–150 [lower-alpha 4] 28–1262–6--
Estrone sulfate 1260422--
Conjugated estrogens 5–1260–808.4–250.625–1.25>3.757.5
Ethinylestradiol200 μg1–2280 μg20–40 μg100 μg100 μg
Mestranol 300 μg1.5–3.0300–600 μg25–30 μg>80 μg-
Quinestrol 300 μg2–4500 μg25–50 μg--
Methylestradiol -2----
Diethylstilbestrol 2.520–30110.5–2.0>53
DES dipropionate -15–30----
Dienestrol 530–40420.5–4.0--
Dienestrol diacetate 3–530–60----
Hexestrol -70–110----
Chlorotrianisene ->100-->48-
Methallenestril -400----
Sources and footnotes:
  1. ↑ Dosages are given in milligrams unless otherwise noted.
  2. 1 2 3 Dosed every 2 to 3 weeks
  3. 1 2 3 Dosed daily
  4. 1 2 In divided doses, 3x/day; irregular and atypical proliferation.

Antiandrogenic and antigonadotropic effects

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

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. [8] [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). [9] [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. [9] 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. [9] 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. [9] However, investigation revealed that the progestin was the more important component responsible for the suppression in testosterone levels. [9] In accordance, the progestin component of COCs is primarily responsible for inhibition of ovulation in women. [9] 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. [9] 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. [9] [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. [9] [145] [146] This may additionally contribute to suppression of androgen levels by estrogens. [9] [145] [146]

Effects on liver protein synthesis

EE has marked effects on liver protein synthesis, even at low dosages and regardless of route of administration. [9] [8] These effects are mediated by its estrogenic activity. [9] [8] 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. [9] [8] 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. [9] At doses above 20 µg/day, the incremental effects of EE on liver protein synthesis become continuously smaller. [9]

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%. [9] Androgens decrease hepatic SHBG production, and have been found to oppose the effects of EE on SHBG levels. [9] This is of particular relevance when it is considered that many progestins used in COCs have varying degrees of weak androgenic activity. [9] 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%. [9] 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%. [9] As such, the type and dosage of progestin contained in COCs potently moderates the effects of EE on SHBG levels. [9]

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%. [9] 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. [9] COCs may increase CBG levels by 100 to 150%. [9] 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%. [9] Progestins that are progesterone derivatives do not affect TBG levels, while progestins with androgenic activity may decrease TBG levels. [9] 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%. [9]

Differences from estradiol

Changes in levels of estrogen-sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women. 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. Levels of estrogen-sensitive proteins with oral estradiol valerate and ethinylestradiol in postmenopausal women.png
Changes in levels of estrogen-sensitive proteins after treatment with oral estradiol or oral ethinylestradiol in postmenopausal women. FSH is a pituitary protein and represents general/systemic estrogenic effect, while SHBG and PZP Tooltip pregnancy zone protein are hepatic proteins and represent liver estrogenic effect.
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 ug/day oral ethinylestradiol; 3) orchiectomy only. SHBG levels with polyestradiol phosphate, ethinylestradiol, and orchiectomy.png
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.

EE shows strong and disproportionate effects on liver protein synthesis relative to estradiol. [8] 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). [8] 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. [8] [148] [11] This is the mechanism of the disproportionately strong effects of EE on hepatic protein production, [8] [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. [8] 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. [8] 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] [9] However, the potency of EE on liver protein synthesis is in any case reduced with parenteral administration. [9] 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. [9] 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. [9] 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. [8]

Comparison of estradiol and ethinylestradiol
Parameters Estradiol Ethinylestradiol
ER Tooltip Estrogen receptor affinity 1 × 1010 M-12–5 × 1011 M-1
Nuclear retention6–8 hours24 hours
Elimination half-life 90 minutes7 hours
Substrate for 17β-HSD Tooltip 17β-hydroxysteroid dehydrogenase?YesNo
Bound to SHBG Tooltip Sex hormone-binding globulin?YesNo
Relative oral liver potency 1~500–1,500
Relative oral pituitary potency1200
Sources: [70]

Pharmacokinetics

Absorption

EE levels while fasting or with a high-fat meal following ingestion of tablets containing a single oral dose of 20 ug EE and 2 mg norethisterone acetate in women. Ethinylestradiol levels following a single 20 ug oral dose of ethinylestradiol in women.png
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.

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. [8] Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached; [8] [151] steady-state is reached after one week of daily administration. [9] 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. [8] 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] [8] In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels. [8] [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] [8]

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. [9] 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. [9] It has been suggested that this phenomenon could represent a "protection mechanism" of males against environmental estrogen exposure. [9]

Distribution

The plasma protein binding of EE is 97 to 98%, and it is bound almost exclusively to albumin. [5] [8] [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

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. [8] 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. [8] [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. [8] 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. [8] EE is also not metabolized into estradiol. [156]

Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens. [8] 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. [8] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α. [10] [8] The ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters. [8] 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. [7]

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. [8] 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. [8] [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. [8] [157] The contribution of enterohepatic recirculation to total circulating EE levels appears to be 12 to 20% or less, and is not observed consistently. [9] [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. [8] 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

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

Chemistry

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

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] [9] The former three are prodrugs of EE, while the latter one is not. [9] 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

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

Generic names

Ethinylestradiol is the English generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip 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 BAN Tooltip 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 USP Tooltip United States Pharmacopeia name. [168] [158] The generic name of EE in French and its DCF Tooltip Dénomination Commune Française are éthinylestradiol, in Spanish is etinilestradiol, in Italian and its DCIT Tooltip 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

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

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

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Mestranol</span> Chemical compound

Mestranol, sold under the brand names Enovid, Norinyl, and Ortho-Novum among others, is an estrogen medication which has been used in birth control pills, menopausal hormone therapy, and the treatment of menstrual disorders. It is formulated in combination with a progestin and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Drospirenone/ethinylestradiol/levomefolic acid</span> Pharmaceutical combination

Drospirenone/ethinylestradiol/levomefolic acid (EE/DRSP/LMF), sold under the brand name Beyaz among others, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestogen, antimineralocorticoid, and antiandrogen, and levomefolic acid (LMF), a form of vitamin B9, which is used as a birth control pill to prevent pregnancy in women. The formulation contains folate as the calcium salt of levomefolic acid to lower the risk of complications such as fetal neural tube defects should the medication fail as a form of birth control. EE/DRSP/LMF was approved for use by the US Food and Drug Administration (FDA) in September 2010.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">Ethinylestradiol sulfonate</span> Estrogenic drug

Ethinylestradiol sulfonate (EES), sold under the brand names Deposiston and Turisteron among others, is an estrogen medication which has been used in birth control pills for women and in the treatment of prostate cancer in men. It has also been investigated in the treatment of breast cancer in women. The medication was combined with norethisterone acetate in birth control pills. EES is taken by mouth once per week.

Combined birth control pills that contain natural estradiol or an estradiol ester include:

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

<span class="mw-page-title-main">Estetrol (medication)</span> Estrogen medication

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

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