Normethandrone

Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women.[1][2][3][4] It is taken by mouth.[5]

Not to be confused with Normethadone or Norethandrolone.
Normethandrone
Clinical data
Trade namesMetalutin, others
Other namesNormetandrone; Methylestrenolone; Methyloestrenolone; Methylnortestosterone; Normethyltestosterone; Normethandrolone; Normethisterone; Methylnandrolone; NMT; 17α-Methyl-19-nortestosterone; 17α-Methylestr-4-en-17β-ol-3-one; P-6051; RU-598; NSC-10039
Routes of
administration		By mouth
Drug classProgestogen; Progestin; Androgen; Anabolic steroid
ATC code
Identifiers
  • (8R,9S,10R,13S,14S,17S)-17-hydroxy-13,17-dimethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.007.440
Chemical and physical data
FormulaC19H28O2
Molar mass288.431 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C)O)CCC4=CC(=O)CC[C@H]34
  • InChI=1S/C19H28O2/c1-18-9-7-15-14-6-4-13(20)11-12(14)3-5-16(15)17(18)8-10-19(18,2)21/h11,14-17,21H,3-10H2,1-2H3/t14-,15+,16+,17-,18-,19-/m0/s1
  • Key:ZXSWTMLNIIZPET-ZOFHRBRSSA-N

Side effects of normethandrone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire.[6] It can also cause liver damage.[7] Normethandrone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[5] It is also a synthetic AAS and hence is an agonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone (DHT).[4][8] It has some estrogenic activity as well and no other important hormonal activity.[9][1][3]

Normethandrone was introduced for medical use by 1957.[10] It is available only in a few countries, including Brazil, Indonesia, and Venezuela, and is available only in combination with methylestradiol or estradiol valerate.[2][1]

Medical uses

Normethandrone is used in combination with an estrogen, either methylestradiol or estradiol valerate, in the treatment of amenorrhea and menopausal symptoms in women.[1][2][11] It has also been used to treat dysmenorrhea in women.[12] Normethandrone has been used successfully to inhibit libido in men with sexual deviance.[13] Although normethandrone can be classified as an AAS and has strong such effects at sufficiently high doses, it is not typically used as such and is instead used medically only as a progestin.[3][1][4] This is because it is so highly progestogenic in comparison.[4]

Androgen replacement therapy formulations and dosages used in women
RouteMedicationMajor brand namesFormDosage
OralTestosterone undecanoateAndriol, JatenzoCapsule40–80 mg 1x/1–2 days
MethyltestosteroneMetandren, EstratestTablet0.5–10 mg/day
FluoxymesteroneHalotestinTablet1–2.5 mg 1x/1–2 days
NormethandroneaGinecosideTablet5 mg/day
TiboloneLivialTablet1.25–2.5 mg/day
Prasterone (DHEA)b–Tablet10–100 mg/day
SublingualMethyltestosteroneMetandrenTablet0.25 mg/day
TransdermalTestosteroneIntrinsaPatch150–300 μg/day
AndroGelGel, cream1–10 mg/day
VaginalPrasterone (DHEA)IntrarosaInsert6.5 mg/day
InjectionTestosterone propionateaTestovironOil solution25 mg 1x/1–2 weeks
Testosterone enanthateDelatestryl, Primodian DepotOil solution25–100 mg 1x/4–6 weeks
Testosterone cypionateDepo-Testosterone, Depo-TestadiolOil solution25–100 mg 1x/4–6 weeks
Testosterone isobutyrateaFemandren M, FolivirinAqueous suspension25–50 mg 1x/4–6 weeks
Mixed testosterone estersClimacteronaOil solution150 mg 1x/4–8 weeks
Omnadren, SustanonOil solution50–100 mg 1x/4–6 weeks
Nandrolone decanoateDeca-DurabolinOil solution25–50 mg 1x/6–12 weeks
Prasterone enanthateaGynodian DepotOil solution200 mg 1x/4–6 weeks
ImplantTestosteroneTestopelPellet50–100 mg 1x/3–6 months
Notes: Premenopausal women produce about 230 ± 70 μg testosterone per day (6.4 ± 2.0 mg testosterone per 4 weeks), with a range of 130 to 330 μg per day (3.6–9.2 mg per 4 weeks). Footnotes: a = Mostly discontinued or unavailable. b = Over-the-counter. Sources: See template.
Androgen/anabolic steroid dosages for breast cancer
RouteMedicationFormDosage
OralMethyltestosteroneTablet30–200 mg/day
FluoxymesteroneTablet10–40 mg 3x/day
CalusteroneTablet40–80 mg 4x/day
NormethandroneTablet40 mg/day
BuccalMethyltestosteroneTablet25–100 mg/day
Injection (IMTooltip intramuscular injection or SCTooltip subcutaneous injection)Testosterone propionateOil solution50–100 mg 3x/week
Testosterone enanthateOil solution200–400 mg 1x/2–4 weeks
Testosterone cypionateOil solution200–400 mg 1x/2–4 weeks
Mixed testosterone estersOil solution250 mg 1x/week
MethandriolAqueous suspension100 mg 3x/week
Androstanolone (DHT)Aqueous suspension300 mg 3x/week
Drostanolone propionateOil solution100 mg 1–3x/week
Metenolone enanthateOil solution400 mg 3x/week
Nandrolone decanoateOil solution50–100 mg 1x/1–3 weeks
Nandrolone phenylpropionateOil solution50–100 mg/week
Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

Normethandrone is marketed in combination with methylestradiol in the form of oral tablets containing 5 mg normethandrone and 0.3 mg methylestradiol.[11][14]

Side effects
See also: Progestin § Side effects, and Anabolic steroid § Adverse effects

Normethandrone has been associated with symptoms of masculinization and hepatotoxicity.[6][7][15]

Pharmacology

Pharmacodynamics

Normethandrone shows high progestogenic activity.[5] With sublingual administration in women, it has at least 150 times the potency of sublingual progesterone and 50 times the potency of sublingual ethisterone.[5] It also has 10 times the potency of injected progesterone via this route.[5] The oral potency of normethandrone in terms of endometrial transformation is similar to that of norethisterone.[16][17] It has been reported to inhibit ovulation in women.[18]

In addition to its progestogenic activity, normethandrone has anabolic and androgenic activity and can produce effects associated with this activity.[1][4] It has a high ratio of anabolic to androgenic activity.[19] The anabolic potency of normethandrone is similar to that of norethandrolone and is much greater than that of nandrolone or metandienone.[8] It is also greater than that of ethylestrenol.[8] Normethandrone has been found to increase nitrogen retention, a measure of anabolic effect, at a dosage of 30 mg/day.[20] Analogously to nandrolone and norethandrolone, 5α-dihydronormethandrone, the 5α-reduced metabolite of normethandrone, shows reduced affinity for the androgen receptor relative to normethandrone.[21][22] Its affinity for the androgen receptor is specifically about 33 to 60% of that of normethandrone.[21]

Normethandrone has estrogenic activity via aromatization into methylestradiol.[3]

Relative affinities (%) of normethandrone and metabolites
CompoundPRTooltip Progesterone receptorARTooltip Androgen receptorERTooltip Estrogen receptorGRTooltip Glucocorticoid receptorMRTooltip Mineralocorticoid receptorSHBGTooltip Sex hormone-binding globulinCBGTooltip Corticosteroid binding globulin
Normethandrone75–125125–150<11–5<1 ? ?
5α-Dihydronormethandrone15–2550–75 ?<1 ? ? ?
Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PRTooltip progesterone receptor, testosterone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and aldosterone for the MRTooltip mineralocorticoid receptor. Sources: See template.

Pharmacokinetics

Normethandrone is metabolized by aromatase into methylestradiol in small quantities, similarly to methyltestosterone and metandienone.[3][23][24] The metabolites of normethandrone have not been well-studied, but 5α-dihydronormethandrone is a likely metabolite formed by 5α-reductase.[25][26]

The pharmacokinetics of normethandrone have been reviewed.[27]

Chemistry
See also: List of progestogens and List of androgens/anabolic steroids

Normethandrone, also known as 17α-methyl-19-nortestosterone or as 17α-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone; 19-NT). It is specifically the 17α-methyl derivative of nandrolone as well as the 17α-methyl variant of norethandrolone (17α-ethyl-19-NT) and norethisterone (17α-ethynyl-19-NT).[28]

Synthesis

Chemical syntheses of normethandrone have been published.[27]

History

Normethandrone has been marketed for medical use since 1957.[10] The combination of normethandrone and methylestradiol was introduced by at least 1966.[14]

Society and culture

Generic names

Normethandrone has not been assigned an INNTooltip International Nonproprietary Name or other formal name designations.[28][29][2] It is also known as methylestrenolone, methylnortestosterone, normethandrolone, and normethisterone.[28][29][2]

Brand names

Brand names of normethandrone include Batynid, Ginecosid, Ginecoside, Gynomin, Lutenin, Matronal, Mediol, Metalutin, Methalutin, Orgasteron, Orosteron, and Renodiol.[28][29][2][1][30][11]

Availability

Normethandrone is marketed in Brazil, Indonesia, and Venezuela in combination with methylestradiol or estradiol valerate.[2][1]

References
  1. "Digital Medicines Information Suite | MedicinesComplete".
  2. "Gynomin".
  3. Friedl KE (1990). "Reappraisal of the health risks associated with the use of high doses of oral and injectable androgenic steroids". NIDA Research Monograph. 102: 142–177. PMID 1964199.
  4. Krüskemper HL (22 October 2013). Anabolic Steroids. Elsevier. pp. 10–. ISBN 978-1-4832-6504-9.
  5. Ferin J (August 1956). "A new substance with progestational activity; comparative assays in ovariectomized women; clinical results". Acta Endocrinologica. 22 (4): 303–317. doi:10.1530/acta.0.0220303. PMID 13354223.
  6. Lundberg PO (1962). "Migraine Prophylaxis with Progestogens". European Journal of Endocrinology. 40 (4 Suppl): S5–S22. doi:10.1530/acta.0.040S0005. ISSN 0804-4643.
  7. Delorimier AA, Gordan GS, Lowe RC, Carbone JV (August 1965). "Methyltestosterone, Related Steroids, and Liver Function". Archives of Internal Medicine. 116 (2): 289–294. doi:10.1001/archinte.1965.03870020129023. PMID 14315662.
  8. Brueggemeier RW (2006). "Sex Hormones (Male): Analogs and Antagonists". Encyclopedia of Molecular Cell Biology and Molecular Medicine. p. 42. doi:10.1002/3527600906.mcb.200500066. ISBN 3527600906.
  9. Heftmann E (1970). Steroid Biochemistry. Academic Press. p. 72. ISBN 9780123366504. Normethandrone (Fig. 49) is a 19-nortestosterone derivative having progestational as well as androgenic and anabolic activity.
  10. Official Gazette of the United States Patent Office. U.S. Patent Office. 1957.
  11. Unlisted Drugs. Pharmaceutical Section, Special Libraries Association. 1982. Batynid. C. Each dragee contains: normethandrone, 5 mg.; and methylestradiol, 0.3 mg. E. (Formerly) Gynaekosid. M. Boehringer Biochemia, Florence. A. Estrogenic; Rx of secondary amenorrhea. R. Notiz Med Farm 32;295, Nov-Dec 81.
  12. Begni-Calvet D (1959). "[Two properties of methylestrenolone (17-alpha-methyl-19-nortestosterone): its effectiveness in the treatment of dysmenorrhea, its anabolic action]". Gynecologie Pratique. 10: 261–272. PMID 13798272.
  13. Servais J (1973). "A clinical study of cases of psychosexual disturbances in men treated by a libido inhibitor: Methylestrenolone". Archives of Sexual Behavior. 2 (4): 387–390. doi:10.1007/BF01541012. ISSN 0004-0002. S2CID 145090184.
  14. Akingba JB, Ayodeji EA (February 1966). "Amenorrhea as a leading symptom of choriocarcinoma". The Journal of Obstetrics and Gynaecology of the British Commonwealth. 73 (1): 153–155. doi:10.1111/j.1471-0528.1966.tb05137.x. PMID 5948541. S2CID 38008851.
  15. Feldman EB, Carter AC (June 1960). "Endocrinologic and metabolic effects of 17 alpha-methyl-19-nortestosterone in women". The Journal of Clinical Endocrinology and Metabolism. 20 (6): 842–857. doi:10.1210/jcem-20-6-842. PMID 13822027.
  16. Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In Horský J, Presl J (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN 978-94-009-8195-9.
  17. Boschann HW (July 1958). "Observations of the role of progestational agents in human gynecologic disorders and pregnancy complications". Annals of the New York Academy of Sciences. 71 (5): 727–752. Bibcode:1958NYASA..71..727B. doi:10.1111/j.1749-6632.1958.tb46803.x. PMID 13583829.
  18. Camerino B, Sala G (1960). "Anabolic steroids". Fortschritte der Arzneimittelforschung. Progress in Drug Research. Progres des Recherches Pharmaceutiques. 2: 71–134. doi:10.1007/978-3-0348-7038-2_2. ISBN 978-3-0348-7040-5. PMID 14448579.
  19. Kochakian CD (6 December 2012). Anabolic-Androgenic Steroids. Springer Science & Business Media. pp. 379–. ISBN 978-3-642-66353-6.
  20. Dorfman RI (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 68–. ISBN 978-1-4832-7300-6.
  21. Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". Journal of Steroid Biochemistry. 27 (1–3): 255–269. doi:10.1016/0022-4731(87)90317-7. PMID 3695484.
  22. Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E (December 2001). "Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone". Human Reproduction. 16 (12): 2570–2577. doi:10.1093/humrep/16.12.2570. PMID 11726576.
  23. Thieme D, Hemmersbach P (18 December 2009). Doping in Sports. Springer Science & Business Media. pp. 470–. ISBN 978-3-540-79088-4.
  24. Llewellyn W (2011). Anabolics. Molecular Nutrition Llc. pp. 444–454, 533. ISBN 978-0-9828280-1-4.
  25. Fragkaki AG, Angelis YS, Tsantili-Kakoulidou A, Koupparis M, Georgakopoulos C (May 2009). "Schemes of metabolic patterns of anabolic androgenic steroids for the estimation of metabolites of designer steroids in human urine". The Journal of Steroid Biochemistry and Molecular Biology. 115 (1–2): 44–61. doi:10.1016/j.jsbmb.2009.02.016. PMID 19429460. S2CID 10051396.
  26. Schjølberg TH (2013). In Vitro Synthesis of Metabolites of three Anabolic Androgenic Steroids, by Human Liver Microsomes (Master's thesis thesis). Institutt for Bioteknologi.
  27. Die Gestagene. Springer-Verlag. 27 November 2013. pp. 12–13, 282. ISBN 978-3-642-99941-3.
  28. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 888–. ISBN 978-1-4757-2085-3.
  29. Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 202–. ISBN 978-94-011-4439-1.
  30. Negwer M, Scharnow HG (2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. p. 1831. ISBN 978-3-527-30247-5.
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