Mestranol

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Mestranol
ファイル:Mestranol.svg
ファイル:Mestranol molecule ball.png
Systematic (IUPAC) name
(8R,9S,13S,14S,17R)-17-ethynyl-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-ol
Clinical data
Trade names Enovid, Norinyl, Ortho-Novum, others
AHFS/Drugs.com International Drug Names
MedlinePlus a601050
Pregnancy cat. ?
Legal status ℞ Prescription only
Routes By mouth[1]
Pharmacokinetic data
Half-life Mestranol: 50 min[2]
EE: 7–36 hours[3][4][5][6]
Identifiers
CAS number 72-33-3 YesY
ATC code None
PubChem CID 6291
IUPHAR ligand 7087
DrugBank DB01357
ChemSpider 6054 YesY
UNII B2V233XGE7 YesY
KEGG D00575 YesY
ChEBI CHEBI:6784 YesY
ChEMBL CHEMBL1201151 YesY
Synonyms Ethinylestradiol 3-methyl ether; EEME; EE3ME; CB-8027; L-33355; RS-1044; 17α-Ethynylestradiol 3-methyl ether; 17α-Ethynyl-3-methoxyestra-1,3,5(10)-trien-17β-ol; 3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17β-ol
Chemical data
Formula C21H26O2 
 YesY (what is this?)  (verify)

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.[1][7][8][9] It is formulated in combination with a progestin and is not available alone.[9] It is taken by mouth.[1]

Side effects of mestranol include nausea, breast tension, edema, and breakthrough bleeding among others.[10] It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[11] Mestranol is a prodrug of ethinylestradiol in the body.[11]

Mestranol was discovered in 1956 and was introduced for medical use in 1957.[12][13] It was the estrogen component in the first birth control pill.[12][13] In 1969, mestranol was replaced by ethinylestradiol in most birth control pills, although mestranol continues to be used in a few birth control pills even today.[14][9] Mestranol remains available only in a few countries, including the United States, United Kingdom, Japan, and Chile.[9]

Medical uses

Mestranol was employed as the estrogen component in many of the first oral contraceptives, such as mestranol/noretynodrel (brand name Enovid) and mestranol/norethisterone (brand names Ortho-Novum, Norinyl), and is still in use today.[7][8][9] In addition to its use as an oral contraceptive, mestranol has been used as a component of menopausal hormone therapy for the treatment of menopausal symptoms.[1]

Side effects

See also: Ethinylestradiol § Side effects, and Estrogen (medication) § Side effects

テンプレート:Empty section

Pharmacology

ファイル:Ethinylestradiol.svg
Ethinylestradiol (EE), the active form of mestranol.

Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver (via O-Dealkylation) with a conversion efficiency of 70% (50 μg of mestranol is pharmacokinetically bioequivalent to 35 μg of ethinylestradiol).[15][16][11] It has been found to possess 0.1 to 2.3% of the relative binding affinity of estradiol (100%) for the estrogen receptor, compared to 75 to 190% for ethinylestradiol.[17][18]

The elimination half-life of mestranol has been reported to be 50 minutes.[2] The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36 hours.[3][4][5][6]

The effective ovulation-inhibiting dosage of mestranol has been studied in women.[19][20][21] It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75 or 80 μg/day.[22][21][23] In another study, the ovulation rate was 15.4% at 50 μg/day, 5.7% at 80 μg/day, and 1.1% at 100 μg/day.[24]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBATooltip Relative binding affinity (%)a REP (%)b
ER ERα ERβ
Estradiol E2 100 100 100
Estradiol 3-sulfate E2S; E2-3S ? 0.02 0.04
Estradiol 3-glucuronide E2-3G ? 0.02 0.09
Estradiol 17β-glucuronide E2-17G ? 0.002 0.0002
Estradiol benzoate EB; Estradiol 3-benzoate 10 1.1 0.52
Estradiol 17β-acetate E2-17A 31–45 24 ?
Estradiol diacetate EDA; Estradiol 3,17β-diacetate ? 0.79 ?
Estradiol propionate EP; Estradiol 17β-propionate 19–26 2.6 ?
Estradiol valerate EV; Estradiol 17β-valerate 2–11 0.04–21 ?
Estradiol cypionate EC; Estradiol 17β-cypionate ?c 4.0 ?
Estradiol palmitate Estradiol 17β-palmitate 0 ? ?
Estradiol stearate Estradiol 17β-stearate 0 ? ?
Estrone E1; 17-Ketoestradiol 11 5.3–38 14
Estrone sulfate E1S; Estrone 3-sulfate 2 0.004 0.002
Estrone glucuronide E1G; Estrone 3-glucuronide ? <0.001 0.0006
Ethinylestradiol EE; 17α-Ethynylestradiol 100 17–150 129
Mestranol EE 3-methyl ether 1 1.3–8.2 0.16
Quinestrol EE 3-cyclopentyl ether ? 0.37 ?

テンプレート:Oral potencies of estrogens

Chemistry

Mestranol, also known as ethinylestradiol 3-methyl ether (EEME) or as 17α-ethynyl-3-methoxyestra-1,3,5(10)-trien-17β-ol, is a synthetic estrane steroid and a derivative of estradiol.[25][26][27] It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a methyl ether at the C3 position.[25][26]

History

In April 1956, noretynodrel was investigated, in Puerto Rico, in the first large-scale clinical trial of a progestogen as an oral contraceptive.[12][13] The trial was conducted in Puerto Rico due to the high birth rate in the country and concerns of moral censure in the United States.[28] It was discovered early into the study that the initial chemical syntheses of noretynodrel had been contaminated with small amounts (1–2%) of the 3-methyl ether of ethinylestradiol (noretynodrel having been synthesized from ethinylestradiol).[12][13] When this impurity was removed, higher rates of breakthrough bleeding occurred.[12][13] As a result, mestranol, that same year (1956),[29] was developed and serendipitously identified as a very potent synthetic estrogen (and eventually as a prodrug of ethinylestradiol), given its name, and added back to the formulation.[12][13] This resulted in Enovid by G. D. Searle & Company, the first oral contraceptive and a combination of 9.85 mg noretynodrel and 150 μg mestranol per pill.[12][13]

Around 1969, mestranol was replaced by ethinylestradiol in most combined oral contraceptives due to widespread panic about the recently uncovered increased risk of venous thromboembolism with estrogen-containing oral contraceptives.[14] The rationale was that ethinylestradiol was approximately twice as potent by weight as mestranol and hence that the dose could be halved, which it was thought might result in a lower incidence of venous thromboembolism.[14] Whether this actually did result in a lower incidence of venous thromboembolism has never been assessed.[14]

Society and culture

Generic names

Mestranol is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name, while mestranolo is its DCITTooltip Denominazione Comune Italiana.[25][26][1][9]

Brand names

Mestranol has been marketed under a variety of brand names, mostly or exclusively in combination with progestins, including Devocin, Enavid, Enovid, Femigen, Mestranol, Norbiogest, Ortho-Novin, Ortho-Novum, Ovastol, and Tranel among others.[7][25][30][26] Today, it continues to be sold in combination with progestins under brand names including Lutedion, Necon, Norinyl, Ortho-Novum, and Sophia.[9]

Availability

Mestranol remains available only in the United States, the United Kingdom, Japan, and Chile.[9] It is only marketed in combination with progestins, such as norethisterone.[9]

Research

Mestranol has been studied as a male contraceptive and was found to be highly effective.[31][32][33][34] At a dosage of 0.45 mg/day, it suppressed gonadotropin levels, reduced sperm count to zero within 4 to 6 weeks, and decreased libido, erectile function, and testicular size.[31][32][34][33] Gynecomastia occurred in all of the men.[31][32][34][33] These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men.[32]

Environmental presence

In 2021, mestranol was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were collectively associated with estrogenic activity in in vitro. [35]

References

  1. ↑ 以下の位置に戻る: 1.0 1.1 1.2 1.3 1.4 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 177–. ISBN 978-94-011-4439-1.
  2. ↑ 以下の位置に戻る: 2.0 2.1 Runnebaum B, Rabe T (17 April 2013). Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie. Springer-Verlag. pp. 88–. ISBN 978-3-662-07635-4.
  3. ↑ 以下の位置に戻る: 3.0 3.1 Hughes CL, Waters MD (23 March 2016). Translational Toxicology: Defining a New Therapeutic Discipline. Humana Press. pp. 73–. ISBN 978-3-319-27449-2.
  4. ↑ 以下の位置に戻る: 4.0 4.1 Goldzieher JW, Brody SA (December 1990). "Pharmacokinetics of ethinyl estradiol and mestranol". American Journal of Obstetrics and Gynecology. 163 (6 Pt 2): 2114–2119. doi:10.1016/0002-9378(90)90550-Q. PMID 2256522.
  5. ↑ 以下の位置に戻る: 5.0 5.1 Stanczyk FZ, Archer DF, Bhavnani BR (June 2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. PMID 23375353.
  6. ↑ 以下の位置に戻る: 6.0 6.1 Shellenberger TE (1986). "Pharmacology of estrogens". The Climacteric in Perspective. Springer. pp. 393–410. doi:10.1007/978-94-009-4145-8_36. ISBN 978-94-010-8339-3.
  7. ↑ 以下の位置に戻る: 7.0 7.1 7.2 Marks L (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 75–. ISBN 978-0-300-16791-7.
  8. ↑ 以下の位置に戻る: 8.0 8.1 Blum RW (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
  9. ↑ 以下の位置に戻る: 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 "Mestranol and norethindrone Uses, Side Effects & Warnings". Archived from the original on 2017-12-01. Retrieved 2017-11-24.
  10. ↑ Wittlinger H (1980). "Clinical Effects of Estrogens". Functional Morphologic Changes in Female Sex Organs Induced by Exogenous Hormones. Springer. pp. 67–71. doi:10.1007/978-3-642-67568-3_10. ISBN 978-3-642-67570-6.
  11. ↑ 以下の位置に戻る: 11.0 11.1 11.2 Shoupe D (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 is about 1.7 times as potent as the same weight of mestranol.
  12. ↑ 以下の位置に戻る: 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Sneader W (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 202–. ISBN 978-0-471-89979-2.
  13. ↑ 以下の位置に戻る: 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Lentz GM, Lobo RA, Gershenson DM, Katz VL (2012). Comprehensive Gynecology. Elsevier Health Sciences. pp. 224–. ISBN 978-0-323-06986-1.
  14. ↑ 以下の位置に戻る: 14.0 14.1 14.2 14.3 Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 224–. ISBN 978-0-08-093292-7.
  15. ↑ Faigle JW, Schenkel L (1998). "Pharmacokinetics of estrogens and progestogens". In Fraser IS, Whitehead MI, Jansen R, Lobo RA (eds.). Estrogens and Progestogens in Clinical Practice. London: Churchill Livingstone. pp. 273–294. ISBN 0-443-04706-5.
  16. ↑ Falcone T, Hurd WW (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 388–. ISBN 978-0-323-03309-1.
  17. ↑ Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, et al. (March 2000). "The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands". Toxicological Sciences. 54 (1): 138–153. doi:10.1093/toxsci/54.1.138. PMID 10746941.
  18. ↑ Ruenitz PC (2010). "Female Sex Hormones, Contraceptives, And Fertility Drugs". Burger's Medicinal Chemistry and Drug Discovery. Wiley. pp. 219–264. doi:10.1002/0471266949.bmc054. ISBN 978-0-471-26694-5.
  19. ↑ Bingel AS, Benoit PS (February 1973). "Oral contraceptives: therapeutics versus adverse reactions, with an outlook for the future I". Journal of Pharmaceutical Sciences. 62 (2): 179–200. doi:10.1002/jps.2600620202. PMID 4568621.
  20. ↑ Pincus G (3 September 2013). The Control of Fertility. Elsevier. pp. 222–. ISBN 978-1-4832-7088-3.
  21. ↑ 以下の位置に戻る: 21.0 21.1 Martinez-Manautou J, Rudel HW (1966). "Antiovulatory Activity of Several Synthetic and Natural Estrogens". In Greenblatt BR (ed.). Ovulation: Stimulation, Suppression, and Detection. Lippincott. pp. 243–253. ISBN 978-0-397-59010-0.
  22. ↑ Elger W (1972). "Physiology and pharmacology of female reproduction under the aspect of fertility control". Reviews of Physiology Biochemistry and Experimental Pharmacology, Volume 67. Ergebnisse der Physiologie Reviews of Physiology. Vol. 67. pp. 69–168. doi:10.1007/BFb0036328. ISBN 3-540-05959-8. PMID 4574573.
  23. ↑ Herr F, Revesz C, Manson AJ, Jewell JB (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. Springer. pp. 368–408. doi:10.1007/978-3-642-49793-3_8 (inactive 2024-11-02). ISBN 978-3-642-49506-9.{{cite book}}: CS1 maint: DOI inactive as of 11月 2024 (link)
  24. ↑ Goldzieher JW, Pena A, Chenault CB, Woutersz TB (July 1975). "Comparative studies of the ethynyl estrogens used in oral contraceptives. II. Antiovulatory potency". American Journal of Obstetrics and Gynecology. 122 (5): 619–624. doi:10.1016/0002-9378(75)90061-7. PMID 1146927.
  25. ↑ 以下の位置に戻る: 25.0 25.1 25.2 25.3 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 775–. ISBN 978-1-4757-2085-3.
  26. ↑ 以下の位置に戻る: 26.0 26.1 26.2 26.3 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 656–. ISBN 978-3-88763-075-1.
  27. ↑ Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-96158-8.
  28. ↑ Filshie M, Guillebaud J (22 October 2013). Contraception: Science and Practice. Elsevier Science. pp. 12–. ISBN 978-1-4831-6366-6.
  29. ↑ Billingsley FS (February 1969). "Lactation suppression utilizing norethynodrel with mestranol". The Journal of the Florida Medical Association. 56 (2): 95–97. PMID 4884828.
  30. ↑ Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. 22 October 2013. pp. 2109–. ISBN 978-0-8155-1856-3.
  31. ↑ 以下の位置に戻る: 31.0 31.1 31.2 Dorfman RI (1980). "Pharmacology of estrogens-general". Pharmacology & Therapeutics. 9 (1): 107–119. doi:10.1016/0163-7258(80)90018-2. PMID 6771777.
  32. ↑ 以下の位置に戻る: 32.0 32.1 32.2 32.3 Jackson H (November 1975). "Progress towards a male oral contraceptive". Clinics in Endocrinology and Metabolism. 4 (3): 643–663. doi:10.1016/S0300-595X(75)80051-X. PMID 776453.
  33. ↑ 以下の位置に戻る: 33.0 33.1 33.2 Oettel M (1999). "Estrogens and Antiestrogens in the Male". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Handbook of Experimental Pharmacology. Vol. 135 / 2. Springer Science & Business Media. pp. 505–571. doi:10.1007/978-3-642-60107-1_25. ISBN 978-3-642-60107-1. ISSN 0171-2004.
  34. ↑ 以下の位置に戻る: 34.0 34.1 34.2 Heller CG, Moore DJ, Paulsen CA, Nelson WO, Laidlaw WM (December 1959). "Effects of progesterone and synthetic progestins on the reproductive physiology of normal men". Federation Proceedings. 18: 1057–1065. PMID 14400846.
  35. ↑ Black GP, He G, Denison MS, Young TM (May 2021). "Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge". Environmental Science & Technology. 55 (10): 6729–6739. Bibcode:2021EnST...55.6729B. doi:10.1021/acs.est.0c07846. PMC 8378343. PMID 33909413.
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