Metribolone

Metribolone was never approved for medical use, a situation unlikely to change given its liver toxicity even at low doses. It was studied for the potential treatment of advanced breast cancer in women but development was abandoned.

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

Side effects of metribolone include virilization and hepatotoxicity among others.

Metribolone is an AAS, or an agonist of the AR, with both anabolic and androgenic activity. It is one of the most potent AAS to have ever been synthesized, with 120 to 300 times the oral anabolic potency and 60 to 70 times the androgenic potency of the reference AAS methyltestosterone in castrated male rats, although the same level of potency has not been observed in studies in humans.{{cite book| vauthors = Brueggemeier RW |chapter=Sex Hormones (Male): Analogs and Antagonists | veditors = Meyers RA |title=Encyclopedia of Molecular Cell Biology and Molecular Medicine | volume = 13 | edition = 2nd |year=2006|doi=10.1002/3527600906.mcb.200500066|isbn=3527600906}} In addition to the AR, metribolone has high affinity for the progesterone receptor (PR), and binds to the glucocorticoid receptor (GR) as well.{{cite journal | vauthors = Singh SM, Gauthier S, Labrie F | title = Androgen receptor antagonists (antiandrogens): structure-activity relationships | journal = Current Medicinal Chemistry | volume = 7 | issue = 2 | pages = 211–247 | date = February 2000 | pmid = 10637363 | doi = 10.2174/0929867003375371 }}{{cite journal | vauthors = Ho-Kim MA, Tremblay RR, Dubé JY | title = Binding of methyltrienolone to glucocorticoid receptors in rat muscle cytosol | journal = Endocrinology | volume = 109 | issue = 5 | pages = 1418–1423 | date = November 1981 | pmid = 6975208 | doi = 10.1210/endo-109-5-1418 }} The drug was also identified in 2007 as a potent antimineralocorticoid, with similar affinity for the mineralocorticoid receptor as aldosterone and spironolactone.{{cite journal | vauthors = Takeda AN, Pinon GM, Bens M, Fagart J, Rafestin-Oblin ME, Vandewalle A | title = The synthetic androgen methyltrienolone (r1881) acts as a potent antagonist of the mineralocorticoid receptor | journal = Molecular Pharmacology | volume = 71 | issue = 2 | pages = 473–482 | date = February 2007 | pmid = 17105867 | doi = 10.1124/mol.106.031112 | s2cid = 28647372 }} In addition, metribolone was identified in 2010 as a potent inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) 1 and 2 (IC₅₀ = 0.02 and 0.16 μM, respectively).{{cite book | vauthors = Zheng F | title = Characterization of Enzymes Involved in the Metabolism of Dihydrotestosterone, the Most Potent Natural Androgen | chapter = Methyltrienolone (R1881) is a Potent Inhibitor of 3B-Hydroxysteroid Dehydrogenase (3B-HSD) Activity | pages = 91–103 | type = thesis | year = 2010 | citeseerx = 10.1.1.428.3729 }} On the basis of this finding, it has been said that metribolone should be used very cautiously in scientific research, taking into account 3β-HSD inhibition to avoid erroneous interpretation.

Metribolone has a high potential for hepatotoxicity, similarly to other 17α-alkylated AAS.{{cite journal | vauthors = Krüskemper HL, Noell G | title = Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one) | journal = Steroids | volume = 8 | issue = 1 | pages = 13–24 | date = July 1966 | pmid = 5955468 | doi = 10.1016/0039-128x(66)90114-0 }} However, the hepatotoxic potential of metribolone appears to be exceptionally high, likely in relation to its very high potency and metabolic stability; in a study of treatment with the drug for advanced breast cancer, severe hepatic dysfunction was observed at very low dosages.

{{Relative affinities of nandrolone and related steroids at the androgen receptor}}

Metribolone has very low affinity for human serum sex hormone-binding globulin (SHBG), less than 5% of that of testosterone and less than 1% of that of dihydrotestosterone (DHT).{{cite journal | vauthors = Saartok T, Dahlberg E, Gustafsson JA | title = Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin | journal = Endocrinology | volume = 114 | issue = 6 | pages = 2100–2106 | date = June 1984 | pmid = 6539197 | doi = 10.1210/endo-114-6-2100 }}

{{See also|List of androgens/anabolic steroids}}

Metribolone, also known as 17α-methyltrenbolone, as well as 17α-methyl-δ^9,11-19-nortestosterone or 17α-methylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone). It is the C17α methylated derivative of trenbolone (δ^9,11-19-nortestosterone) and the C9- and C11-dehydrogenated (δ^9,11) analogue of normethandrone (17α-methyl-19-nortestosterone). Other close relatives and derivatives of metribolone include mibolerone (7α,17α-dimethyl-19-nortestosterone) and dimethyltrienolone (RU-2420; 7α,17α-dimethyl-δ^9,11-19-nortestosterone). In addition to AAS, trimethyltrienolone (R2956; 2α,2β,17α-trimethyl-δ^9,11-19-nortestosterone), a highly potent antiandrogen, has been derived from metribolone.{{cite book| vauthors = Phillipps GH | chapter = Structure-Activity Relationships in Steroid Anaesthetics| veditors = James VJ, Pasqualini JR |title=Proceedings of the Fourth International Congress on Hormonal Steroids: Mexico City, September 1974| chapter-url=https://books.google.com/books?id=Iq0aAwAAQBAJ&pg=PA608|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-4566-2|pages=618|quote=R-2956 [41-43], a dimethyl derivative of an extremely potent androgen, R 1881 [44], is a powerful testosterone antagonist with very low androgenic activity.}}{{cite book| vauthors = Harms AF |title=Innovative Approaches in Drug Research: Proceedings of the Third Noordwijkerhout Symposium on Medicinal Chemistry, Held in the Netherlands, September 3-6, 1985|url=https://books.google.com/books?id=PwhtAAAAMAAJ|date=1 January 1986|publisher=Elsevier|isbn=978-0-444-42606-2|quote=At this stage, RU 2956 exerts a competitive effect about 4 times less marked than metribolone may be because the steric hindrance of the dimethyl group in position C-2 interferes with H-bond formation between the C-3 oxygen and the receptor protein, i.e., with the recognition step, and consequently, with the association rate.}}

Metribolone was first described in the literature in 1965. It was studied clinically in the late 1960s and early 1970s, most notably in the treatment of advanced breast cancer. The drug was found to be effective and showed weak androgenicity, but also produced severe signs of hepatotoxicity, and was ultimately never marketed. By the mid-1970s, metribolone was becoming an accepted standard as a ligand and agonist of the AR in scientific research. It remains in wide use for this purpose today. Aside from scientific research, metribolone has also been encountered as an AAS in non-medical contexts, for instance in doping in sports and bodybuilding.

Metribolone is the generic name of metribolone and its {{abbrlink|INN|International Nonproprietary Name}}. It is also known by the name methyltrienolone and its developmental code names R1881, R-1881, RU-1881, and RU1881, and is very commonly referred to by these other names rather than as metribolone in the scientific literature.

Prior to the 2008 Beijing Olympic Games, 11 members of the Greek national weightlifting team and 4 Greek track and field athletes tested positive for metribolone.{{cite web | url = https://www.usatoday.com/sports/olympics/2008-04-04-greek-weightlifters_N.htm | title = Eleven Greek weightlifters test positive; coach suspended | date = 2008-04-04 | publisher = Associated Press / USATODAY.com | access-date = 2009-06-28}}

{{Reflist}}

• {{MeshName|Metribolone}}
• [https://anabolic.org/methyltrienolone/ Methyltrienolone - William Llewellyn's Anabolic.org] {{Webarchive|url=https://web.archive.org/web/20160407084027/http://www.anabolic.org/methyltrienolone/ |date=2016-04-07 }}

{{Navboxes

| title = Pharmacodynamics

| titlestyle = background:#ccccff

| list1 =

{{Androgen receptor modulators}}

{{Glucocorticoid receptor modulators}}

{{Mineralocorticoid receptor modulators}}

{{Progesterone receptor modulators}}

}}

Category:3β-Hydroxysteroid dehydrogenase inhibitors

Category:Tertiary alcohols

Category:Anabolic–androgenic steroids

Category:Antimineralocorticoids

Category:Estranes

Category:Glucocorticoids

Category:Hepatotoxins

Category:Enones

Category:Progestogens

Category:Abandoned drugs