Normethandrone

{{Drugbox

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| IUPAC_name = (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

| image = Methylestrenolone.svg

| image_class = skin-invert-image

| width = 225px

| tradename = Metalutin, others

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| routes_of_administration = By mouth

| class = Progestogen; Progestin; Androgen; Anabolic steroid

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| CAS_number_Ref =

| CAS_number = 514-61-4

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| KEGG = C14491

| ATC_prefix = G03

| ATC_suffix = DC31

| PubChem = 5284597

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| ChemSpiderID_Ref =

| ChemSpiderID = 4447645

| UNII = 743F1Z557A

| ChEMBL = 269549

| synonyms = Normetandrone; 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

| C=19 | H=28 | O=2

| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C)O)CCC4=CC(=O)CC[C@H]34

| StdInChI_Ref =

| StdInChI = 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

| StdInChIKey_Ref =

| StdInChIKey = ZXSWTMLNIIZPET-ZOFHRBRSSA-N

}}

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.{{Cite web|url=https://www.medicinescomplete.com/about/|title = Digital Medicines Information Suite | MedicinesComplete}}{{Cite web|url=https://www.drugs.com/international/normethandrone.html|title = Gynomin}} It is taken by mouth.

Side effects of normethandrone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire.{{cite journal| vauthors = Lundberg PO |title=Migraine Prophylaxis with Progestogens|journal=European Journal of Endocrinology|volume=40|issue=4 Suppl|year=1962|pages=S5–S22|issn=0804-4643|doi=10.1530/acta.0.040S0005}} It can also cause liver damage. Normethandrone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. 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). It has some estrogenic activity as well and no other important hormonal activity.{{cite book| vauthors = Heftmann E |title=Steroid Biochemistry|url=https://books.google.com/books?id=gAlrAAAAMAAJ|year=1970|publisher=Academic Press|page=72|isbn=978-0-12-336650-4|quote=Normethandrone (Fig. 49) is a 19-nortestosterone derivative having progestational as well as androgenic and anabolic activity.}}

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

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. It has also been used to treat dysmenorrhea in women.{{cite journal | vauthors = Begni-Calvet D | title = [Two properties of methylestrenolone (17-alpha-methyl-19-nortestosterone): its effectiveness in the treatment of dysmenorrhea, its anabolic action] | journal = Gynécologie Pratique | volume = 10 | pages = 261–272 | year = 1959 | pmid = 13798272 }} Normethandrone has been used successfully to inhibit libido in men with sexual deviance.{{cite journal| vauthors = Servais J |title=A clinical study of cases of psychosexual disturbances in men treated by a libido inhibitor: Methylestrenolone|journal=Archives of Sexual Behavior|volume=2|issue=4|year=1973|pages=387–390|issn=0004-0002|doi=10.1007/BF01541012|s2cid=145090184}} 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.{{cite book| vauthors = Krüskemper HL |title=Anabolic Steroids|url=https://books.google.com/books?id=4xIlBQAAQBAJ&pg=PA10|date=22 October 2013|publisher=Elsevier|isbn=978-1-4832-6504-9|pages=10–}} This is because it is so highly progestogenic in comparison.

{{Androgen replacement therapy formulations and dosages used in women}}

=Available forms=

Normethandrone is marketed in combination with methylestradiol in the form of oral tablets containing 5 mg normethandrone and 0.3 mg methylestradiol.{{cite book|title=Unlisted Drugs|url=https://books.google.com/books?id=BhxtAAAAMAAJ|year=1982|publisher=Pharmaceutical Section, Special Libraries Association.|quote=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.}}{{cite journal | vauthors = Akingba JB, Ayodeji EA | title = Amenorrhea as a leading symptom of choriocarcinoma | journal = The Journal of Obstetrics and Gynaecology of the British Commonwealth | volume = 73 | issue = 1 | pages = 153–155 | date = February 1966 | pmid = 5948541 | doi = 10.1111/j.1471-0528.1966.tb05137.x | s2cid = 38008851 }}

Side effects

{{See also|Progestin#Side effects|Anabolic steroid#Adverse effects}}

Normethandrone has been associated with symptoms of masculinization and hepatotoxicity.{{cite journal | vauthors = Delorimier AA, Gordan GS, Lowe RC, Carbone JV | title = Methyltestosterone, Related Steroids, and Liver Function | journal = Archives of Internal Medicine | volume = 116 | issue = 2 | pages = 289–294 | date = August 1965 | pmid = 14315662 | doi = 10.1001/archinte.1965.03870020129023 }}{{cite journal | vauthors = Feldman EB, Carter AC | title = Endocrinologic and metabolic effects of 17 alpha-methyl-19-nortestosterone in women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 20 | issue = 6 | pages = 842–857 | date = June 1960 | pmid = 13822027 | doi = 10.1210/jcem-20-6-842 }}

Pharmacology

=Pharmacodynamics=

Normethandrone shows high progestogenic activity.{{cite journal | vauthors = Ferin J | title = A new substance with progestational activity; comparative assays in ovariectomized women; clinical results | journal = Acta Endocrinologica | volume = 22 | issue = 4 | pages = 303–317 | date = August 1956 | pmid = 13354223 | doi = 10.1530/acta.0.0220303 }} With sublingual administration in women, it has at least 150 times the potency of sublingual progesterone and 50 times the potency of sublingual ethisterone. It also has 10 times the potency of injected progesterone via this route. The oral potency of normethandrone in terms of endometrial transformation is similar to that of norethisterone.{{cite book| vauthors = Horský J, Presl J |chapter=Hormonal Treatment of Disorders of the Menstrual Cycle|pages=309–332|doi=10.1007/978-94-009-8195-9_11| veditors = Horský J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|series=Developments in Obstetrics and Gynecology |chapter-url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA145|date=1981|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9}}{{cite journal | vauthors = Boschann HW | title = Observations of the role of progestational agents in human gynecologic disorders and pregnancy complications | journal = Annals of the New York Academy of Sciences | volume = 71 | issue = 5 | pages = 727–752 | date = July 1958 | pmid = 13583829 | doi = 10.1111/j.1749-6632.1958.tb54649.x | bibcode = 1958NYASA..71..727B }} It has been reported to inhibit ovulation in women.{{cite book | vauthors = Camerino B, Sala G | chapter = Anabolic Steroids | title = Fortschritte der Arzneimittelforschung / Progress in Drug Research / Progrès des recherches pharmaceutiques | series = Fortschritte der Arzneimittelforschung. Progress in Drug Research. Progres des Recherches Pharmaceutiques | veditors= Jucker E | volume = 2 | pages = 71–134 | year = 1960 | pmid = 14448579 | doi = 10.1007/978-3-0348-7038-2_2 | isbn = 978-3-0348-7040-5 }}

In addition to its progestogenic activity, normethandrone has anabolic and androgenic activity and can produce effects associated with this activity. It has a high ratio of anabolic to androgenic activity.{{cite book| vauthors = Kochakian CD |title=Anabolic-Androgenic Steroids|url=https://books.google.com/books?id=3-LrCAAAQBAJ&pg=PA379|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-66353-6|pages=379–}} The anabolic potency of normethandrone is similar to that of norethandrolone and is much greater than that of nandrolone or metandienone.{{cite book| vauthors = Brueggemeier RW |title=Encyclopedia of Molecular Cell Biology and Molecular Medicine|chapter=Sex Hormones (Male): Analogs and Antagonists |year=2006 |doi= 10.1002/3527600906.mcb.200500066 |page=42|publisher=Wiley-VCH Verlag GmbH & Co. KGaA |isbn=3-527-60090-6}} It is also greater than that of ethylestrenol. Normethandrone has been found to increase nitrogen retention, a measure of anabolic effect, at a dosage of 30 mg/day.{{cite book| vauthors = Dorfman RI |title=Steroidal Activity in Experimental Animals and Man|url=https://books.google.com/books?id=uizgBAAAQBAJ&pg=PA68|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7300-6|pages=68–}} Analogously to nandrolone and norethandrolone, 5α-dihydronormethandrone, the 5α-reduced metabolite of normethandrone, shows reduced affinity for the androgen receptor relative to normethandrone.{{cite journal | vauthors = Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP | title = Towards the mapping of the progesterone and androgen receptors | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 1–3 | pages = 255–269 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}{{cite journal | vauthors = Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E | title = Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone | journal = Human Reproduction | volume = 16 | issue = 12 | pages = 2570–2577 | date = December 2001 | pmid = 11726576 | doi = 10.1093/humrep/16.12.2570 | doi-access = }} Its affinity for the androgen receptor is specifically about 33 to 60% of that of normethandrone.

Normethandrone has estrogenic activity via aromatization into methylestradiol.

=Pharmacokinetics=

Normethandrone is metabolized by aromatase into methylestradiol in small quantities, similarly to methyltestosterone and metandienone.{{cite journal | vauthors = Friedl KE | title = Reappraisal of the health risks associated with the use of high doses of oral and injectable androgenic steroids | journal = NIDA Research Monograph | volume = 102 | pages = 142–177 | year = 1990 | pmid = 1964199 }}{{cite book| vauthors = Thieme D, Hemmersbach P |title=Doping in Sports|url=https://books.google.com/books?id=R-hIC-caIn8C&pg=PA470|date=18 December 2009|publisher=Springer Science & Business Media|isbn=978-3-540-79088-4|pages=470–}}{{cite book| vauthors = Llewellyn W |title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT444|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=444–454, 533}} The metabolites of normethandrone have not been well-studied, but 5α-dihydronormethandrone is a likely metabolite formed by 5α-reductase.{{cite journal | vauthors = Fragkaki AG, Angelis YS, Tsantili-Kakoulidou A, Koupparis M, Georgakopoulos C | title = Schemes of metabolic patterns of anabolic androgenic steroids for the estimation of metabolites of designer steroids in human urine | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 115 | issue = 1–2 | pages = 44–61 | date = May 2009 | pmid = 19429460 | doi = 10.1016/j.jsbmb.2009.02.016 | s2cid = 10051396 }}{{cite thesis | vauthors = Schjølberg TH | date = 2013 | title = In Vitro Synthesis of Metabolites of three Anabolic Androgenic Steroids, by Human Liver Microsomes | degree = Master's thesis | publisher = Institutt for Bioteknologi | url = https://brage.bibsys.no/xmlui/handle/11250/246018 | access-date = 2018-03-25 | archive-date = 2018-03-26 | archive-url = https://web.archive.org/web/20180326001355/https://brage.bibsys.no/xmlui/handle/11250/246018 | url-status = dead }}

The pharmacokinetics of normethandrone have been reviewed.

Chemistry

{{See also|List of progestogens|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).{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA888|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=888–}}

=Synthesis=

Chemical syntheses of normethandrone have been published.{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA12|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=12–13,282}}

History

Normethandrone has been marketed for medical use since 1957.{{cite book |title=Official Gazette of the United States Patent Office|url=https://archive.org/details/officialgazette720unit|year=1957|publisher=U.S. Patent Office.}} The combination of normethandrone and methylestradiol was introduced by at least 1966.

Society and culture

=Generic names=

Normethandrone has not been assigned an {{abbrlink|INN|International Nonproprietary Name}} or other formal name designations.{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA202|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=202–}} It is also known as methylestrenolone, methylnortestosterone, normethandrolone, and normethisterone.

=Brand names=

Brand names of normethandrone include Batynid, Ginecosid, Ginecoside, Gynomin, Lutenin, Matronal, Mediol, Metalutin, Methalutin, Orgasteron, Orosteron, and Renodiol.{{cite book| vauthors = Negwer M, Scharnow HG |title=Organic-chemical drugs and their synonyms: (an international survey)|url=https://books.google.com/books?id=zmpqAAAAMAAJ|year=2001|publisher=Wiley-VCH|isbn=978-3-527-30247-5|page=1831}}