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The [[elimination half-life]] of mestranol has been reported to be 50&nbsp;minutes.<ref name="RunnebaumRabe2013">{{cite book|author1=Benno Runnebaum|author2=Thomas Rabe|title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}}</ref> The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36&nbsp;hours.<ref name="HughesWaters2016">{{cite book|author1=Claude L Hughes|author2=Michael D. Waters|title=Translational Toxicology: Defining a New Therapeutic Discipline|url=https://books.google.com/books?id=5qPWCwAAQBAJ&pg=PA73|date=23 March 2016|publisher=Humana Press|isbn=978-3-319-27449-2|pages=73–}}</ref><ref name="pmid2256522">{{cite journal | vauthors = Goldzieher JW, Brody SA | title = Pharmacokinetics of ethinyl estradiol and mestranol | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2114–9 | year = 1990 | pmid = 2256522 | doi = 10.1016/0002-9378(90)90550-Q }}</ref><ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–27 | year = 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 | url = }}</ref><ref name="Shellenberger1986">{{cite book|last1=Shellenberger|first1=T. E.|title=Pharmacology of estrogens|year=1986|pages=393–410|doi=10.1007/978-94-009-4145-8_36|journal=The Climacteric in Perspective|isbn=978-94-010-8339-3}}</ref>
The [[elimination half-life]] of mestranol has been reported to be 50&nbsp;minutes.<ref name="RunnebaumRabe2013">{{cite book|author1=Benno Runnebaum|author2=Thomas Rabe|title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie|url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}}</ref> The elimination half-life of the active form of mestranol, ethinylestradiol, is 7 to 36&nbsp;hours.<ref name="HughesWaters2016">{{cite book|author1=Claude L Hughes|author2=Michael D. Waters|title=Translational Toxicology: Defining a New Therapeutic Discipline|url=https://books.google.com/books?id=5qPWCwAAQBAJ&pg=PA73|date=23 March 2016|publisher=Humana Press|isbn=978-3-319-27449-2|pages=73–}}</ref><ref name="pmid2256522">{{cite journal | vauthors = Goldzieher JW, Brody SA | title = Pharmacokinetics of ethinyl estradiol and mestranol | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2114–9 | year = 1990 | pmid = 2256522 | doi = 10.1016/0002-9378(90)90550-Q }}</ref><ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–27 | year = 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 | url = }}</ref><ref name="Shellenberger1986">{{cite book|last1=Shellenberger|first1=T. E.|title=Pharmacology of estrogens|year=1986|pages=393–410|doi=10.1007/978-94-009-4145-8_36|journal=The Climacteric in Perspective|isbn=978-94-010-8339-3}}</ref>


The effective [[ovulation]]-inhibiting dosage of mestranol has been studied.<ref name="pmid4568621">{{cite journal | vauthors = Bingel AS, Benoit PS | title = Oral contraceptives: therapeutics versus adverse reactions, with an outlook for the future I | journal = J Pharm Sci | volume = 62 | issue = 2 | pages = 179–200 | date = February 1973 | pmid = 4568621 | doi = 10.1002/jps.2600620202 | url = }}</ref><ref name="Pincus2013">{{cite book|author=Gregory Pincus|title=The Control of Fertility|url=https://books.google.com/books?id=ehQlBQAAQBAJ&pg=PA222|date=3 September 2013|publisher=Elsevier|isbn=978-1-4832-7088-3|pages=222–}}</ref><ref name="Greenblatt1966">{{cite book|author1=Jorge Martinez-Manautou|author2=Harry W. Rudel|chapter=Antiovulatory Activity of Several Synthetic and Natural Estrogens|pages=243–253|editor=Robert Benjamin Greenblatt|title=Ovulation: Stimulation, Suppression, and Detection|url=https://books.google.com/books?id=le1qAAAAMAAJ|year=1966|publisher=Lippincott}}</ref> It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75&nbsp;μg/day.<ref name="Elger1972">{{cite journal|last1=Elger|first1=Walter|title=Physiology and pharmacology of female reproduction under the aspect of fertility control|volume=67|year=1972|pages=69–168|doi=10.1007/BFb0036328}}</ref>
The effective [[ovulation]]-inhibiting dosage of mestranol has been studied.<ref name="pmid4568621">{{cite journal | vauthors = Bingel AS, Benoit PS | title = Oral contraceptives: therapeutics versus adverse reactions, with an outlook for the future I | journal = J Pharm Sci | volume = 62 | issue = 2 | pages = 179–200 | date = February 1973 | pmid = 4568621 | doi = 10.1002/jps.2600620202 | url = }}</ref><ref name="Pincus2013">{{cite book|author=Gregory Pincus|title=The Control of Fertility|url=https://books.google.com/books?id=ehQlBQAAQBAJ&pg=PA222|date=3 September 2013|publisher=Elsevier|isbn=978-1-4832-7088-3|pages=222–}}</ref><ref name="Greenblatt1966">{{cite book|author1=Jorge Martinez-Manautou|author2=Harry W. Rudel|chapter=Antiovulatory Activity of Several Synthetic and Natural Estrogens|pages=243–253|editor=Robert Benjamin Greenblatt|title=Ovulation: Stimulation, Suppression, and Detection|url=https://books.google.com/books?id=le1qAAAAMAAJ|year=1966|publisher=Lippincott}}</ref> It has been reported to be about 98% effective at inhibiting ovulation at a dosage of 75 or 80&nbsp;μg/day.<ref name="Elger1972">{{cite journal|last1=Elger|first1=Walter|title=Physiology and pharmacology of female reproduction under the aspect of fertility control|volume=67|year=1972|pages=69–168|doi=10.1007/BFb0036328}}</ref><ref name="Greenblatt1966" />


{{Oral potencies of estrogens}}
{{Oral potencies of estrogens}}

Revision as of 22:26, 1 December 2019

Mestranol
Clinical data
Trade namesEnovid, Norinyl, Ortho-Novum, others
Other namesEthinylestradiol 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-17α-ol
AHFS/Drugs.comInternational Drug Names
MedlinePlusa601050
Routes of
administration		By mouth[1]
Drug classEstrogen; Estrogen ether
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolitesEthinylestradiol
Elimination half-lifeMestranol: 50 min[2]
EE: 7–36 hours[3][4][5][6]
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.707 Edit this at Wikidata
Chemical and physical data
FormulaC21H26O2
Molar mass310.437 g/mol g·mol−1
3D model (JSmol)
  • O(c1cc4c(cc1)[C@H]3CC[C@]2([C@@H](CC[C@]2(C#C)O)[C@@H]3CC4)C)C
  • InChI=1S/C21H26O2/c1-4-21(22)12-10-19-18-7-5-14-13-15(23-3)6-8-16(14)17(18)9-11-20(19,21)2/h1,6,8,13,17-19,22H,5,7,9-12H2,2-3H3/t17-,18-,19+,20+,21+/m1/s1 checkY
  • Key:IMSSROKUHAOUJS-MJCUULBUSA-N checkY
  (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

Pharmacology

Ethinylestradiol (EE), the active form of mestranol.

Mestranol is a biologically inactive prodrug of ethinylestradiol to which it is demethylated in the liver with a conversion efficiency of 70% (50 μg of mestranol is pharmacokinetically bioequivalent to 35 μg of ethinylestradiol, or ethinylestradiol being about 1.7 times as orally potent by weight as mestranol).[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.[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]

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. ^ [23][24][25][26][27][28] [29][30][31][32] [33][34][35][36][37][38][21][39][40]
  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.

Chemistry

See also: List of estrogens and List of estrogen esters § Ethers of steroidal estrogens

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.[41][42][43] It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a methyl ether at the C3 position.[41][42]

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.[44] 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),[45] 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.[41][42][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][41][46][42] 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.[47][48][49][50] 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.[47][48][50][49] Gynecomastia occurred in all of the men.[47][48][50][49] These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men.[48]

References

  1. ^ a b c d e I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 177–. ISBN 978-94-011-4439-1.
  2. ^ a b Benno Runnebaum; Thomas Rabe (17 April 2013). Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie. Springer-Verlag. pp. 88–. ISBN 978-3-662-07635-4.
  3. ^ a b 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.
  4. ^ a b Goldzieher JW, Brody SA (1990). "Pharmacokinetics of ethinyl estradiol and mestranol". American Journal of Obstetrics and Gynecology. 163 (6 Pt 2): 2114–9. doi:10.1016/0002-9378(90)90550-Q. PMID 2256522.
  5. ^ a b 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.
  6. ^ a b Shellenberger, T. E. (1986). Pharmacology of estrogens. pp. 393–410. doi:10.1007/978-94-009-4145-8_36. ISBN 978-94-010-8339-3. {{cite book}}: |journal= ignored (help)
  7. ^ a b c Lara Marks (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 75–. ISBN 978-0-300-16791-7.
  8. ^ a b Robert W. Blum (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
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  11. ^ a b c 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 is about 1.7 times as potent as the same weight of mestranol.
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  37. ^ Kottmeier HL (1947). "Ueber blutungen in der menopause: Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung: Part I". Acta Obstetricia et Gynecologica Scandinavica. 27 (s6): 1–121. doi:10.3109/00016344709154486. ISSN 0001-6349. There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
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  40. ^ Duncan CJ, Kistner RW, Mansell H (October 1956). "Suppression of ovulation by trip-anisyl chloroethylene (TACE)". Obstetrics and Gynecology. 8 (4): 399–407. PMID 13370006.
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