Noretynodrel

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Noretynodrel
Noretynodrel.svg
Noretinodrel3D.png
Clinical data
Trade names Enovid, Enovid-E, Enovid-E 21, Enavid (all with mestranol)
ATC code
Identifiers
Synonyms NSC-15432
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.000.620
Chemical and physical data
Formula C20H26O2
Molar mass 298.419 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Noretynodrel (INN), or norethynodrel (USAN, BAN), also known as 17α-ethynyl-19-nor-5(10)-testosterone or as 5(10)-norethisterone, is a steroidal progestin of the 19-nortestosterone group and an isomer of norethisterone.[1] Noretynodrel was introduced in 1957 in Enovid, a combination formulation of noretynodrel and mestranol, for the treatment of gynecological and menstrual disorders.[2] A few years later, in May 1960, Enovid was also approved as the first oral contraceptive.[2][3]

Noretynodrel, unlike most progestins but similarly to etynodiol diacetate, has some estrogenic activity.[4] It has little or no androgenic activity.[2][4][5] The drug is a relatively weak progestogen, with only about one-tenth of the progestogenic activity of norethisterone, and in relation to this fact, is no longer used in oral contraceptives.[6]

Pharmacology[edit]

Noretynodrel is very closely related to norethisterone and tibolone, which are the Δ4-isomer and the 7α-methyl derivative of noretynodrel, respectively.[7][8] Noretynodrel is metabolized in a very similar manner to tibolone, whereas the metabolism of norethisterone differs.[7] Both noretynodrel and tibolone are transformed into 3α- and 3β-hydroxylated metabolites and a Δ4-isomer metabolite (in the case of noretynodrel, this being norethisterone), whereas norethisterone is not 3α- or 3β-hydroxylated (and of course does not form a Δ4-isomer metabolite).[7][8] The major metabolites of noretynodrel are 3α-hydroxynoretynodrel and to a lesser extent 3β-hydroxynoretynodrel, formed by 3α- and 3β-hydroxysteroid dehydrogenases (AKR1C14), while the Δ4-isomer norethisterone is a minor metabolite formed in small amounts.[7] Tibolone is considered to be a prodrug into both its 3α- and 3β-hydroxylated and Δ4-isomerized metabolites.[7] Noretynodrel is also thought to be a prodrug, as it is rapidly metabolized and cleared from circulation (within 30 minutes)[9] and shows very weak relative affinity for the progesterone receptor (PR), although noretynodrel appears to form norethisterone in only minor quantities.[7][10]

Progestogenic activity[edit]

In terms of the PR, noretynodrel possesses only about 6% to 19% of the affinity of norethisterone for the PRA, whereas the affinity of the two drugs for the PRB is similar (noretynodrel possesses 94% of the affinity of norethisterone for the PRB).[8] Tibolone and the Δ4-isomer metabolite of tibolone have similar affinity for the PRs as noretynodrel and norethisterone, respectively, whereas the 3α- and 3β-hydroxylated metabolites of tibolone are virtually devoid of affinity for the PR.[8] Since the structurally related anabolic-androgenic steroid trestolone (7α-methyl-19-nortestosterone) is known to be a potent progestogen,[11] suggesting that a 7α-methyl substitution does not interfere with progestogenic activity, 3α- and 3β-hydroxynoretynodrel likely are devoid of affinity for the PR similarly to the 3α- and 3β-hydroxylated metabolites of tibolone.[8]

Androgenic activity[edit]

Relative to norethisterone, noretynodrel has 45% to 81% reduced affinity for the androgen receptor (AR).[8] In contrast to norethisterone (which is mildly androgenic), noretynodrel is said to have no or only very weak androgenic activity.[2] In accordance, no androgenic effects (such as hirsutism, clitoral enlargement, or voice changes) have been observed with noretynodrel even when used in large dosages (e.g., 60 mg/day) for prolonged periods of time (9–12 months) in the treatment of women with endometriosis.[12] Additionally, noretynodrel has not been found to virilize female fetuses, in contrast to many other testosterone-derived progestins including ethisterone, norethisterone, and norethisterone acetate.[13] However, according to Korn (1961), at least one case of pseudohermaphroditism (virilized genitalia) has been observed that may have been due to noretynodrel.[14] The Δ4-isomer metabolite of tibolone shows dramatically and disproportionately increased affinity for the AR relative to norethisterone and noretynodrel (5.7- to 18.5-fold greater than that of norethisterone), indicating that the 7α-methyl group of tibolone markedly increases its androgenic activity and is responsible for the greater androgenic effects of tibolone relative to noretynodrel.[8]

Estrogenic activity[edit]

Whereas norethisterone has virtually no affinity for the estrogen receptors (ERs), noretynodrel shows some, albeit very weak affinity for both the ERα and the ERβ (in terms of relative binding affinity, 0.7% and 0.22% of that of estradiol, respectively).[8][15] The estrogenic activity of 3α- and 3β-hydroxynoretynodrel has never been assessed.[7] However, while tibolone shows similar affinity for the ERs as noretynodrel, the 3α- and 3β-hydroxylated metabolites of tibolone have several-fold increased affinity for the ERs.[7][8] As such, the 3α- and 3β-hydroxylated metabolites of noretynodrel may also show increased estrogenic activity, and this may account for the known estrogenic effects of noretynodrel.[7][8] The Δ4-isomer of tibolone, similarly to norethisterone, is virtually devoid of affinity for the ERs.[8] Neither tibolone nor its metabolites are aromatized, whereas trestolone is readily aromatized similarly to testosterone and 19-nortestosterone, and for these reasons, it is unlikely that noretynodrel or its metabolites are aromatized either.[16] As such, aromatization likely does not play a role in the estrogenic activity of tibolone or noretynodrel.[16] However, controversy on this matter exists, and other researchers have suggested that tibolone and noretynodrel may be aromatized in small amounts to highly potent estrogens (ethinylestradiol and its 7α-methyl derivative, respectively).[17][18]

Relative to other 19-nortestosterone progestins, noretynodrel is said to possess much stronger estrogenic activity.[9]

Chemistry[edit]

Noretynodrel is an estrane (C18) steroid and is also known chemically as 17α-ethynyl-δ5(10)-19-nortestosterone or as 17α-ethynylestr-5(10)-en-17β-ol-3-one. It is a derivative of testosterone that has been ethynylated at the C17α position, demethylated at the C19 position, and dehydrogenated (i.e., has a double bond) between the C5 and C10 positions. As such, noretynodrel is also a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone). In addition, it is an isomer of norethisterone (17α-ethynyl-19-nortestosterone) in which the C4 double bond has been replaced with a double bond between the C5 and C10 positions. For this reason, noretynodrel is also known as 5(10)-norethisterone. Few other 19-nortestosterone progestins share the C5(10) double bond of noretynodrel, but an example of one that does is tibolone, the 7α-methyl derivative of noretynodrel (i.e., 7α-methylnoretynodrel).

History[edit]

Noretynodrel was first synthesized by Frank B. Colton of G. D. Searle & Company in 1952, and this was preceded by the synthesis of norethisterone by Luis E. Miramontes and Carl Djerassi of Syntex in 1951.[2] In 1957, both noretynodrel and norethisterone were approved in the United States for the treatment of menstrual disorders.[19] In 1960, noretynodrel, in combination with mestranol (as Enovid), was introduced in the United States as the first oral contraceptive, and the combination of norethisterone and mestranol followed in 1963 as the second oral contraceptive to be introduced.[19] In 1988, Enovid, along with other oral contraceptives containing high doses of estrogen, was discontinued.[20][21]

Society and culture[edit]

Availability[edit]

Noretynodrel is no longer available in any formulation in the U.S.,[22] nor does it appear to still be marketed in any other country.[23][24]

References[edit]

  1. ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 886–. ISBN 978-1-4757-2085-3. 
  2. ^ a b c d e Lara Marks (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 74–75. ISBN 0-300-16791-1. 
  3. ^ Mannfred A. Hollinger (19 October 2007). Introduction to Pharmacology, Third Edition. CRC Press. pp. 160–. ISBN 978-1-4200-4742-4. 
  4. ^ a b Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 36–. ISBN 978-3-642-73790-9. 
  5. ^ Ethel Sloane (2002). Biology of Women. Cengage Learning. pp. 426–. ISBN 0-7668-1142-5. 
  6. ^ David A. Williams; William O. Foye; Thomas L. Lemke (January 2002). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 700–. ISBN 978-0-683-30737-5. 
  7. ^ a b c d e f g h i Jin Y, Duan L, Chen M, Penning TM, Kloosterboer HJ (2012). "Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily". J. Steroid Biochem. Mol. Biol. 129 (3-5): 139–44. doi:10.1016/j.jsbmb.2011.12.002. PMC 3303946Freely accessible. PMID 22210085. 
  8. ^ a b c d e f g h i j k de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ (2003). "Receptor profiling and endocrine interactions of tibolone". Steroids. 68 (1): 21–30. doi:10.1016/s0039-128x(02)00112-5. PMID 12475720. 
  9. ^ a b Hammerstein J (1990). "Prodrugs: advantage or disadvantage?". Am. J. Obstet. Gynecol. 163 (6 Pt 2): 2198–203. PMID 2256526. 
  10. ^ Stanczyk, Frank Z. (Sep 2002). "Pharmacokinetics and Potency of Progestins used for Hormone Replacement Therapy and Contraception". Reviews in Endocrine and Metabolic Disorders. 3 (3): 211–224. doi:10.1023/A:1020072325818. ISSN 1389-9155. PMID 12215716. Although there is no convincing evidence for the in vivo transformation of norethynodrel to norethindrone, data from receptor-binding tests and bioassays suggest that norethynodrel is also a prodrug. 
  11. ^ Beri, Ripla; Kumar, Narender; Savage, T.; Benalcazar, L.; Sundaram, Kalyan (1998). "Estrogenic and progestational activity of 7α-methyl-19-nortestosterone, a synthetic androgen". The Journal of Steroid Biochemistry and Molecular Biology. 67 (3): 275–283. doi:10.1016/S0960-0760(98)00114-9. ISSN 0960-0760. 
  12. ^ Kistner RW (1964). "Steroid compounds with progestational activity". Postgrad Med. 35: 225–32. doi:10.1080/00325481.1964.11695038. PMID 14129897. This difference is important clinically since no androgenic effects (hirsutism, enlarged clitoris, voice change) have been reported even with large dosages of norethynodrel (60 mg. daily) continued from 9 to 12 months in patients with endometriosis. 
  13. ^ Simpson, Joe Leigh; Kaufman, Raymond H. (1998). "Fetal effects of estrogens, progestogens and diethylstilbestrol". In Fraser, Ian S. Estrogens and Progestogens in Clinical Practice (3rd ed.). London: Churchill Livingstone. pp. 533–53. ISBN 0-443-04706-5. 
  14. ^ KORN GW (1961). "The use of norethynodrel (enovid) in clinical practice". Can Med Assoc J. 84: 584–7. PMC 1939348Freely accessible. PMID 13753182. Pseudohermaphroditism should not be a problem in these patients as it appears that norethynodrel does not possess androgenic properties, but it is believed that Wilkins has now found one such case in a patient who has been on norethynodrel therapy. 
  15. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584. 
  16. ^ a b de Gooyer, Marcel E.; Oppers-Tiemissen, Hendrika M.; Leysen, Dirk; Verheul, Herman A.M.; Kloosterboer, Helenius J. (2003). "Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE):". Steroids. 68 (3): 235–243. doi:10.1016/S0039-128X(02)00184-8. ISSN 0039-128X. 
  17. ^ Kuhl, H.; Wiegratz, I. (2009). "Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?". Climacteric. 10 (4): 344–353. doi:10.1080/13697130701380434. ISSN 1369-7137. 
  18. ^ "Tibolone is not aromatized in postmenopausal women". Climacteric. 11 (2): 175–176. 2009. doi:10.1080/13697130701752087. ISSN 1369-7137. 
  19. ^ a b Enrique Ravina (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 190–. ISBN 978-3-527-32669-3. 
  20. ^ Reuters News Service (1988-04-15). "Searle, 2 others to stop making high-estrogen pill". St. Louis Post-Dispatch. pp. 7D. Retrieved 2009-08-29. 
  21. ^ "High-estrogen 'pill' going off market". San Jose Mercury News. 1988-04-15. Retrieved 2009-08-29. 
  22. ^ "Drugs@FDA: FDA Approved Drug Products" (HTML). United States Food and Drug Administration. Retrieved 27 November 2016. 
  23. ^ https://www.drugs.com/international/noretynodrel.html
  24. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 1–. ISBN 978-3-88763-075-1.