Ethinyl estradiol

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Ethinyl estradiol
Ethinyl estradiol.svg
Systematic (IUPAC) name
Clinical data
Pronunciation /ˌɛθnlˌstrəˈd.əl/
Trade names Numerous
AHFS/ International Drug Names
MedlinePlus a604032
Routes of
Oral, transdermal
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 38–48%[1][2]
Protein binding 97–98% (to albumin;[3] does not bind to SHBG)[4]
Metabolism Liver (CYP3A4)[5]
Biological half-life 10–36 hours[6][1][5]
Excretion Feces: 62%[6]
Urine: 38%[6]
CAS Number 57-63-6 YesY
ATC code G03CA01 (WHO) L02AA03 (WHO)
PubChem CID 5991
DrugBank DB00977 YesY
ChemSpider 5770 YesY
UNII 423D2T571U YesY
KEGG D00554 YesY
Chemical data
Formula C20H24O2
Molar mass 296.403 g/mol

Ethinyl estradiol (EE) (USP) (former brand name Estinyl), or ethinylestradiol (INN, USAN, JAN), also spelled as ethinylœstradiol (BAN), is a synthetic, steroidal estrogen.[7][8][9] It is a derivative of estradiol, the major endogenous estrogen in humans; specifically, EE is 17α-ethynylestradiol.[7] EE is an orally active estrogen used in many formulations of combined oral contraceptives (COCs), and is the most commonly used estrogen for this purpose.[10]

Medical uses[edit]

As Estinyl, EE was formerly used for hormone replacement therapy in menopause and the treatment of female hypogonadism, loss of menstruation, dysmenorrhea, acne, prostate cancer, and breast cancer.[16][11] However, in more recent times, EE is mainly used in COCs. In contraception, due to concerns of unopposed estrogen action and the possible increased risk of endometrial cancer that accompanies this, EE is formulated in combination with progestins. EE is no longer used in menopausal hormone replacement therapy.[12]

The original formulations of combined oral contraceptives contained as much as 150 μg EE.[13] However, it was soon found that EE is associated with incidence of venous thromboembolism and that the risk is dose-dependent.[13] Subsequently, the dosage of EE was greatly reduced, and is now generally between 25 and 35 μg,[13] in some cases less than 20 μg,[13] and not more than 50 μg.[14][15][16] These lower dosages have a significantly reduced risk of venous thromboembolism with no loss of contraceptive effectiveness.[13] According to a bulletin posted by the U.S. FDA, the rate of deep vein thrombosis in women taking COCs containing 20 to 40 μg EE is 4 per 10,000, which is approximately equivalent to the rate of 3 per 10,000 in women not taking a COC.[17] No study has shown a further reduced risk of venous thromboembolism below an EE dosage of 30 or 35 μg.[13]

Side effects[edit]

Side effects of EE are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain.[6]

EE carries a greater risk of blood clot formation and venous thromboembolism than natural estradiol, which has been theorized to be related to different amounts of hepatic metabolism after absorption. The same contraindications and precautions apply for EE as with other estrogens.


EE is an estrogen similarly to natural estrogens like estradiol and conjugated equine estrogens and synthetic estrogens like diethylstilbestrol. It binds to and activates both isoforms of the estrogen receptor, ERα and ERβ, with similar affinity to that of estradiol.[12]


Orally, EE is about 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated equine estrogens.[18] This appears to be true in regards to both modification of hepatic protein synthesis and antigonadotropic activity.[19][20] In contrast, the potencies of EE and natural estrogens are reportedly similar when they are administered intravenously, due to bypassing of first-pass hepatic metabolism.[13] Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.[19]


The oral bioavailability of EE is 38–48%, with a large range of 20% to 65% (mean 45%) due to high inter-individual variability.[6] Although relatively low, the oral bioavailability of EE is considerably higher than that of estradiol (5%).[1][6] EE is metabolized mainly by 2-hydroxylation, primarily by CYP3A4.[6] Hydroxylation of EE at the C4, C6, and C16β positions have also been reported, but appear to contribute to its metabolism to only a small extent.[6] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, presumably owing to steric hindrance of its ethinyl group at C17α.[6] A literature review found that the range of the reported terminal half-life of EE in the literature was 13.1 to 27.0 hours.[1] However, the terminal half-life of EE has also been reported as 36 ± 13 hours[5] Another review reported a terminal half-life of EE of 10–20 hours.[6] Steady-state concentrations are reached after one week of daily administration.[12] Unlike estradiol, which binds with high affinity to sex hormone-binding globulin, EE does not bind to this protein and is instead bound mainly to albumin (97–98%).[3][6]


The first orally active semisynthetic steroidal estrogen, EE (17α-ethynylestradiol), the 17α-ethynyl analogue of estradiol, was synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at Schering AG in Berlin.[21][22][23][24][25] EE was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering as Estinyl.[26] The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.[27]

See also[edit]


  1. ^ a b c d Goldzieher JW, Brody SA (1990). "Pharmacokinetics of ethinyl estradiol and mestranol". American Journal of Obstetrics and Gynecology. 163 (6 Pt 2): 2114–9. PMID 2256522. 
  2. ^ Fruzzetti F, Trémollieres F, Bitzer J (2012). "An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest". Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 28 (5): 400–8. doi:10.3109/09513590.2012.662547. PMC 3399636free to read. PMID 22468839. 
  3. ^ a b Facts and Comparisons (Firm); Ovid Technologies, Inc (2005). Drug Facts and Comparisons 2005: Pocket Version. Facts and Comparisons. p. 121. ISBN 978-1-57439-179-4. 
  4. ^ Micromedex (1 January 2003). USP DI 2003: Drug Information for Healthcare Professionals. Thomson Micromedex. pp. 1253,1258,1266. ISBN 978-1-56363-429-1. 
  5. ^ a b c Claude L Hughes; Michael D. Waters (23 March 2016). Translational Toxicology: Defining a New Therapeutic Discipline. Humana Press. pp. 73–. ISBN 978-3-319-27449-2. 
  6. ^ a b c d e f g h i j k Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–27. doi:10.1016/j.contraception.2012.12.011. PMID 23375353. 
  7. ^ a b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 522–. ISBN 978-1-4757-2085-3. 
  8. ^ I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 115–. ISBN 978-94-011-4439-1. 
  9. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 412. ISBN 978-3-88763-075-1. 
  10. ^ Evans G, Sutton EL. Oral contraception. Med Clin North Am. 2015 May;99(3):479-503. PMID 25841596
  11. ^ - Estinyl (ethynyl estradiol)
  12. ^ a b c Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 248,369. ISBN 978-3-642-60107-1. The binding affinity of EE for the estrogen receptor is similar to that of estradiol. [...] During daily intake, the EE levels increase up to a steady state which is reached after about 1 week. 
  13. ^ a b c d e f g Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 388–. ISBN 0-323-03309-1. 
  14. ^ Committee on the Relationship Between Oral Contraceptives and BreastCancer (1 January 1991). Oral Contraceptives and Breast Cancer. National Academies. pp. 143–. 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 [ethinyl estradiol] contents greater than 50 μg. 
  15. ^ Multigenerational Reproductive Toxicology Study of Ethinyl Estradiol (CAS No. 57636) in SpragueDawley Rats (Feed Studies). DIANE Publishing. pp. 27–. ISBN 978-1-4379-4231-6. Oral contraceptive formulations containing greater than 50 ug ethinyl estradiol were removed from the United States market in 1989, and currently marketed formulations generally contain between 20 and 35 μg ethinyl estradiol. 
  16. ^ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1024–. 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. 
  17. ^ Daniel Jeffrey Wallace; Bevra Hahn (2007). Dubois' Lupus Erythematosus. Lippincott Williams & Wilkins. pp. 1252–. ISBN 978-0-7817-9394-0. 
  18. ^ Victor Gomel; Malcolm G. Munro; Timothy C. Rowe (1990). Gynecology: a practical approach. Williams & Wilkins. p. 132,134. ISBN 978-0-683-03631-2. The synthetic estrogen, ethinyl estradiol, more commonly used in oral contraceptives, has a biological activity 100 times that of the native and conjugated substances. 
  19. ^ a b Donna Shoupe (7 November 2007). The Handbook of Contraception: A Guide for Practical Management. Springer Science & Business Media. pp. 23–. ISBN 978-1-59745-150-5. EE has about 100 times the potency of an equivalent weight of conjugated equine estrogen or estrone sulfate for stimulating synthesis of hepatic proteins. [...] EE is about 1.7 times as potent as the same weight of mestranol. 
  20. ^ Nathaniel McConaghy (21 November 2013). Sexual Behavior: Problems and Management. Springer Science & Business Media. pp. 177–. ISBN 978-1-4899-1133-9. Meyer et al. found that ethinyl estradiol was 75 to 100 times more potent than conjugated estrogen on the basis of the doses required to lower testosterone to the adult female range, 0.1 mg of the former and 7.5 to 10 mg of the latter being necessary. 
  21. ^ Inhoffen, H. H.; Hohlweg, W. (1938). "Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17 (New female glandular derivatives active per os: 17α-ethynyl-estradiol and pregnen-in-on-3-ol-17)". Naturwissenschaften. 26 (6): 96. doi:10.1007/BF01681040. 
  22. ^ Maisel, Albert Q. (1965). The Hormone Quest. New York: Random House. OCLC 543168. 
  23. ^ Petrow, Vladimir (December 1970). "The contraceptive progestagens". Chem Rev. 70 (6): 713–26. doi:10.1021/cr60268a004. PMID 4098492. 
  24. ^ Sneader, Walter (2005). "Hormone analogues". Drug discovery : a history. Hoboken, NJ: John Wiley & Sons. pp. 188–225. ISBN 0-471-89980-1. 
  25. ^ Djerassi, Carl (January 2006). "Chemical birth of the pill". American Journal of Obstetrics and Gynecology. 194 (1): 290–8. doi:10.1016/j.ajog.2005.06.010. PMID 16389046. 
  26. ^ FDA (2007). "Approval history: Estinyl (ethinyl estradiol) NDA 005292".  search: Estinyl
  27. ^ FDA (May 5, 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. 

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