This page uses content from Wikipedia and is licensed under CC BY-SA.

Mestranol

Mestranol
Mestranol.svg
Mestranol molecule ball.png
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
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)
  (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

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 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]

Oral potencies of estrogens

Estrogen Type Class ETD
(mg/14 days)
EPD
(mg/14 days)
EPD
(mg/day)
MSD
(mg/14 days)
MSD
(mg/day)
TSD
(mg/day)
Estradiol (micronized) Bioidentical Steroidal ? 60–80 4.3 14–28 1.0–2.0 >8
Estradiol valerate Bioidentical Steroidal 6–10 60–80 4.3 14–28 1.0–2.0 >8
Estriol Bioidentical Steroidal 20a 120–150b 10.0–10.7b 28–84 1.0–6.0 ?
Estriol succinate Bioidentical Steroidal ? 140–150b 10.0–10.7b 28–84 2.0–6.0 ?
Conjugated estrogens Natural Steroidal 5–12 60–80 4.3 8.4–17.5 0.625–1.25 7.5
Ethinylestradiol Synthetic Steroidal 0.2 1.0–2.0 0.071–0.11 0.28 0.02–0.04 0.1
Mestranol Synthetic Steroidal 0.3 1.5–3.0 0.11–0.13 0.3–0.5 0.025 ?
Quinestrol Synthetic Steroidal 0.3 2.0–4.0 0.14–0.29 ? 0.025–0.05 ?
Methylestradiol Synthetic Steroidal ? 2.0 ? ? ? ?
Diethylstilbestrol Synthetic Nonsteroidal 2.5 20–30 1.4–2.1 ? 0.5–2.0 3
Diethylstilbestrol dipropionate Synthetic Nonsteroidal ? 15–30 1.1–1.4 ? ? ?
Dienestrol Synthetic Nonsteroidal ? 30 ? ? 0.5–4.0 ?
Dienestrol diacetate Synthetic Nonsteroidal 3–5 30–60 2.9–4.3 ? ? ?
Hexestrol Synthetic Nonsteroidal ? 70–110 ? ? ? ?
Hexestrol diacetate Synthetic Nonsteroidal ? 45 ? ? ? ?
Chlorotrianisene Synthetic Nonsteroidal ? >100 ? ? ? ?
Methallenestril Synthetic Nonsteroidal ? 400 ? ? ? ?
Note: The OID of EE is 0.1 mg/day. Footnotes: a = Very variable, often higher. b = In divided doses, 3x/day; irregular and atypical proliferation. Sources: See template.

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.[24][25][26] It is specifically a derivative of ethinylestradiol (17α-ethynylestradiol) with a methyl ether at the C3 position.[24][25]

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.[27] 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),[28] 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 INN, USAN, USP, BAN, DCF, and JAN, while mestranolo is its DCIT.[24][25][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][24][29][25] 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.[30][31][32][33] 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.[30][31][33][32] Gynecomastia occurred in all of the men.[30][31][33][32] These findings contributed to the conclusion that estrogens would be unacceptable as contraceptives for men.[31]

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. The Climacteric in Perspective. pp. 393–410. doi:10.1007/978-94-009-4145-8_36. ISBN 978-94-010-8339-3.
  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.
  9. ^ a b c d e f g h i [www.drugs.com]
  10. ^ Wittlinger, H. (1980). "Clinical Effects of Estrogens": 67–71. doi:10.1007/978-3-642-67568-3_10. Cite journal requires |journal= (help)
  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.
  12. ^ a b c d e f g Walter Sneader (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 202–. ISBN 978-0-471-89979-2.
  13. ^ a b c d e f g Gretchen M. Lentz; Rogerio A. Lobo; David M. Gershenson; Vern L. Katz (2012). Comprehensive Gynecology. Elsevier Health Sciences. pp. 224–. ISBN 0-323-06986-X.
  14. ^ a b c d Jeffrey K. Aronson (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 224–. ISBN 978-0-08-093292-7.
  15. ^ Faigle, Johann W.; Schenkel, Lotte (1998). "Pharmacokinetics of estrogens and progestogens". In in Fraser; Ian S. (eds.). Estrogens and Progestogens in Clinical Practice. London: Churchill Livingstone. pp. 273–294. ISBN 0-443-04706-5.
  16. ^ Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 388–. ISBN 0-323-03309-1.
  17. ^ Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM (March 2000). "The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands". Toxicol. Sci. 54 (1): 138–53. doi:10.1093/toxsci/54.1.138. PMID 10746941.
  18. ^ Ruenitz, Peter C. (2010). "Female Sex Hormones, Contraceptives, And Fertility Drugs". doi:10.1002/0471266949.bmc054. Cite journal requires |journal= (help)
  19. ^ Bingel AS, Benoit PS (February 1973). "Oral contraceptives: therapeutics versus adverse reactions, with an outlook for the future I". J Pharm Sci. 62 (2): 179–200. doi:10.1002/jps.2600620202. PMID 4568621.
  20. ^ Gregory Pincus (3 September 2013). The Control of Fertility. Elsevier. pp. 222–. ISBN 978-1-4832-7088-3.
  21. ^ a b Jorge Martinez-Manautou; Harry W. Rudel (1966). "Antiovulatory Activity of Several Synthetic and Natural Estrogens". In Robert Benjamin Greenblatt (ed.). Ovulation: Stimulation, Suppression, and Detection. Lippincott. pp. 243–253.
  22. ^ Elger, Walter (1972). "Physiology and pharmacology of female reproduction under the aspect of fertility control". 67: 69–168. doi:10.1007/BFb0036328. Cite journal requires |journal= (help)
  23. ^ Herr, F.; Revesz, C.; Manson, A. J.; Jewell, J. B. (1970). "Biological Properties of Estrogen Sulfates": 368–408. doi:10.1007/978-3-642-49793-3_8. Cite journal requires |journal= (help)
  24. ^ a b c d J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 775–. ISBN 978-1-4757-2085-3.
  25. ^ a b c d Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 656–. ISBN 978-3-88763-075-1.
  26. ^ A. Labhart (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-96158-8.
  27. ^ Marcus Filshie; John Guillebaud (22 October 2013). Contraception: Science and Practice. Elsevier Science. pp. 12–. ISBN 978-1-4831-6366-6.
  28. ^ Billingsley FS (1969). "Lactation suppression utilizing norethynodrel with mestranol". J Fla Med Assoc. 56 (2): 95–7. PMID 4884828.
  29. ^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 2109–. ISBN 978-0-8155-1856-3.
  30. ^ a b c Dorfman RI (1980). "Pharmacology of estrogens-general". Pharmacol. Ther. 9 (1): 107–19. doi:10.1016/0163-7258(80)90018-2. PMID 6771777.
  31. ^ a b c d Jackson H (November 1975). "Progress towards a male oral contraceptive". Clin Endocrinol Metab. 4 (3): 643–63. doi:10.1016/S0300-595X(75)80051-X. PMID 776453.
  32. ^ a b c Oettel, M (1999). "Estrogens and Antiestrogens in the Male". In Michael Oettel; Ekkehard Schillinger (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. 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.
  33. ^ a b c 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". Fed. Proc. 18: 1057–65. PMID 14400846.