Ethinylestradiol

Source: Wikipedia, the free encyclopedia.

Ethinylestradiol
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
JSmol)
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 checkY
  • Key:BFPYWIDHMRZLRN-SLHNCBLASA-N checkY
  (verify)

Ethinylestradiol (EE) is an

gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.[7][12]

The general

liver damage, and cancer of the uterus.[7]

EE is an

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

There are many uses for EE. It is most commonly used as

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

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

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.

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

EE should be avoided in individuals with a history of or known susceptibility to

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

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

hepatic tumors, active hepatitis, and familial defects in biliary excretion.[44]

Side effects

Dose of ethinylestradiol in
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.

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 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
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

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

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.

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]

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)
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,

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

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

At the lower dosages that are now used in birth control pills, EE has been associated rarely with

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

See also: Estrogen (medication) § Overdose

Estrogens like EE are relatively safe in acute

overdose.[citation needed
]

Interactions

EE is metabolized by certain

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]

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

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

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)
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
CBG
Tooltip 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
CBG
Tooltip Corticosteroid-binding globulin. Sources: See template.
Relative oral potencies of estrogens
Estrogen
HF
Tooltip 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
CBG
Tooltip Corticosteroid-binding globulin
AGT
Tooltip 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
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

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

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 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

EE has marked effects on

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%.

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%.

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

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

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

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
affinity
 1 × 1010 M-1 2–5 × 1011 M-1
Nuclear retention 6–8 hours 24 hours
Elimination half-life
 90 minutes 7 hours
17β-HSD
Tooltip 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

Absorption

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

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

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

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

Due to high first-pass metabolism in the

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

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.

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

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

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

17α-alkylated androgens/anabolic steroids like methyltestosterone
(17α-methyltestosterone).

Analogues

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

A number of

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

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.

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]

References

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  37. ISBN 978-3-7692-2114-5
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    .
  47. ^
    PMID 1983923
    .
  48. PMID 23904209
    .
  49. ISBN 978-1-4832-7064-7
    .
  50. ISBN 978-3-642-60107-1
    .
  51. ^
    ISBN 978-0-08-092150-1
    .
  52. ^
    ISBN 978-1-119-03909-9
    .
  53. ^
    PMID 27793376
    .
  54. ^
    PMID 23384743
    .
  55. PMID 32431379
    .
  56. ^
    ISBN 978-0-323-03309-1
    .
  57. PMID 28376481
    .
  58. ISBN 978-0-7817-1750-2
    . Low-dose COCs contain <50 μg of estrogen and are the primary choice for oral contraception. COCs containing ≥50 μg of estrogen should no longer be routinely used for contraception. [...] The estrogen component of COCs can cause breast fullness and tenderness.
  59. 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 μg.
  60. 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 μg ethinyl estradiol.
  61. PMID 27678035
    .
  62. PMID 23904209
    .
  63. ^
    PMID 12047300
    .
  64. S2CID 20803995
    .
  65. PMID 18692609
    .
  66. ^
    ISBN 978-3-319-53298-1
    .
  67. PMID 16915215
    .
  68. PMID 22011208
    .
  69. ^
    S2CID 32650111
    .
  70. ^
    S2CID 21510744
    .
  71. ^
    PMID 3817605
    .
  72. ^
    S2CID 34563641.[dead link
    ]
  73. ^
    PMID 24932461
    .
  74. ^
    ISBN 978-1-60795-014-1
    .
  75. ^
    PMID 28667081
    .
  76. ISBN 978-0-306-48240-3
    .
  77. ^
    ISBN 978-0-470-98697-4
    .
  78. ^
    ISSN 0171-2004
    .
  79. ISBN 978-3-527-32363-0
    .
  80. ^
    S2CID 73398961
    .
  81. PMID 30020636
    .
  82. ^
    S2CID 7932937
    .
  83. S2CID 128359413
    .
  84. S2CID 260318275
    .
  85. ^
    ISBN 978-1-4757-1767-9
    .
  86. ISBN 978-1-4613-0867-6
    .
  87. ^
    PMID 17517636
    .
  88. ^
    S2CID 32669410
    .
  89. S2CID 86245855
    .
  90. ^
    S2CID 71784426
    .
  91. PMID 16554039
    .
  92. PMID 21321128
    .
  93. PMID 26023144
    .
  94. PMID 20403194
    .
  95. PMID 21844907
    . Further research showed that the therapeutic effect of ethynylestradiol in established EAE was mediated via GPER, but not via ERα, and possibly involved production of the anti-inflammatory cytokine Il‑10.115
  96. PMID 24530924
    . In addition, the therapeutic effect of ethinyl estradiol in established disease was demonstrated to require expression of GPER but not ERα, and was associated with the production of the anti-inflammatory cytokine IL-10 (Yates et al., 2010).
  97. PMID 23841731
    .
  98. ISBN 978-0-7817-3762-3
    .
  99. ISBN 978-1-904798-74-3
    .
  100. ^
    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.
  101. ^
    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.
  102. 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.
  103. 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.
  104. ^
    PMID 6291391
    .
  105. PMID 2215269
    .
  106. PMID 559617
    .
  107. ISBN 978-3-642-75101-1
    .
  108. ISBN 978-3-11-024568-4
    .
  109. ISBN 978-3-662-00942-0
    .
  110. ISBN 978-94-009-8195-9
    .
  111. ISBN 978-3-11-150424-7
    .
  112. PMID 779393
    .
  113. ISSN 0001-6349
    .
  114. ISSN 0172-777X
    .
  115. PMID 29603164
    .
  116. PMID 29756046
    .
  117. PMID 15432047
    .
  118. PMID 14902290
    .
  119. 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.
  120. ISBN 978-3-642-57636-2
    .
  121. ^ 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.
  122. ISBN 978-3-642-49506-9
    .
  123. PMID 13370006
    .
  124. ^
    PMID 4359746
    .
  125. ^
    ISSN 2380-548X
    .
  126. ^
    ISBN 978-1-107-01290-5
    .
  127. PMID 22294742
    .
  128. PMID 18338653
    .
  129. PMID 24082040
    .
  130. S2CID 259361637
    .
  131. S2CID 44335732
    .
  132. ^
    PMID 7000222
    .
  133. ^
    S2CID 33063805
    .
  134. S2CID 40497389
    .
  135. ^
    ISBN 978-1-4557-1126-0
    .
  136. ISBN 978-1-85317-422-3
    .
  137. S2CID 4492779
    .
  138. PMID 4568621
    .
  139. ISBN 978-3-642-57636-2
    .
  140. PMID 4574573
    .
  141. S2CID 53246678
    .
  142. ISBN 978-0-397-59010-0
    .
  143. ISBN 978-3-642-49506-9
    .
  144. PMID 1146927
    .
  145. ^
    ISBN 978-1-59259-101-5
    .
  146. ^
    S2CID 6815423
    .
  147. PMID 22244780
    .
  148. ^
    ISBN 978-0-08-055309-2
    .
  149. ISBN 978-1-4443-4263-5
    .
  150. S2CID 23760705
    .
  151. ^
    S2CID 27729272
    .
  152. ^
    ISBN 978-0-19-979361-7
    .
  153. ^
    S2CID 43298472
    .
  154. ^
    ISBN 978-94-009-4145-8
    .
  155. PMID 7195405
    .
  156. S2CID 73487051
    .
  157. ^
    S2CID 11212469
    .
  158. ^
    ISBN 978-3-88763-075-1
    .
  159. S2CID 46648877
    .
  160. OCLC 543168
    .
  161. PMID 4098492
    .
  162. ISBN 978-0-471-89980-8
    .
  163. PMID 16389046
    .
  164. ^ 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.
  165. PMID 13359169
    .
  166. ISBN 978-0-387-90087-2
    .
  167. ISBN 978-3-642-99942-0
    .
  168. ^ a b c d e f g "Ethinylestradiol - Drugs.com".
  169. ISBN 978-94-011-4439-1
    .
  170. ISBN 978-0-88416-175-2
    . Ethinyl Estradiol [Estinyl, Feminone, Lynoral, Novestrol, Palonyl]
  171. ISBN 978-0-930530-02-0
    . ETHINYL ESTRADIOL U.S.P. (Esteed®, Estinyl®, Lynoral®, Menolyn®, Novestrol®, Palonyl®, Spanestrin®, Ylestrol®)

Further reading
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