{{Short description|Chemical compound}} {{Distinguish|Testolone|Trenbolone}} {{Drugbox | Verifiedfields = correct | Watchedfields = correct | verifiedrevid = 470612783 | IUPAC_name = (7''R'',8''R'',9''S'',10''R'',13''S'',14''S'',17''S'')-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1''H''-cyclopenta[''a'']phenanthren-3-one | image = Trestolone structure.svg | image_class = skin-invert-image | width = 225px
<!--Clinical data--> | tradename = | pregnancy_category = | legal_status = | routes_of_administration = Subcutaneous implant, intramuscular injection (as trestolone acetate) | class = Androgen; Anabolic steroid; Progestogen; Antigonadotropin
<!--Identifiers--> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 3764-87-2 | ATC_prefix = None | ATC_suffix = | PubChem = 9838899 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB05830 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 8014619 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 40P3287I94 | synonyms = MENT; MENTR; RU-27333; 7α-Methylnandrolone; 7α-Methyl-19-nortestosterone; 7α-Methylestr-4-en-17β-ol-3-one
<!--Chemical data--> | C=19 | H=28 | O=2 | SMILES = O=C4\C=C2/[C@@H]([C@H]1CC[C@@]3([C@@H](O)CC[C@H]3[C@@H]1[C@H](C)C2)C)CC4 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C19H28O2/c1-11-9-12-10-13(20)3-4-14(12)15-7-8-19(2)16(18(11)15)5-6-17(19)21/h10-11,14-18,21H,3-9H2,1-2H3/t11-,14+,15-,16+,17+,18-,19+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = YSGQGNQWBLYHPE-CFUSNLFHSA-N }} <!-- Definition and medical uses --> '''Trestolone''', also known as '''7α-methyl-19-nortestosterone''' ('''MENT'''), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in androgen replacement therapy for low testosterone levels in men but has never been marketed for medical use.<ref name="Elks2014">{{cite book|author=J. Elks|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–}}</ref><ref name="AdisInsight">{{cite web |url=https://adisinsight.springer.com/drugs/800016155 |title = 7-alpha-methyl-19-nortestosterone - AdisInsight}}</ref><ref name="pmid23063338">{{cite journal | vauthors = Nieschlag E, Kumar N, Sitruk-Ware R | title = 7α-methyl-19-nortestosterone (MENTR): the population council's contribution to research on male contraception and treatment of hypogonadism | journal = Contraception | volume = 87 | issue = 3 | pages = 288–95 | year = 2013 | pmid = 23063338 | doi = 10.1016/j.contraception.2012.08.036 }}</ref><ref name="pmid8489761" /><ref name="pmid22612692">{{cite journal | vauthors = Corona G, Rastrelli G, Vignozzi L, Maggi M | title = Emerging medication for the treatment of male hypogonadism | journal = Expert Opin Emerg Drugs | volume = 17 | issue = 2 | pages = 239–59 | year = 2012 | pmid = 22612692 | doi = 10.1517/14728214.2012.683411 | s2cid = 22068249 }}</ref> It is given as an implant that is placed into fat.<ref name="pmid23063338" /> As trestolone acetate, an androgen ester and prodrug of trestolone, the medication can also be given by injection into muscle.<ref name="Elks2014" /><ref name="pmid22612692" />
<!-- Side effects and mechanism --> Side effects Trestolone is an AAS, and hence is an agonist of the androgen receptor, the biological target of androgens like testosterone.<ref name="pmid23063338" /><ref name="pmid22065861" /> It is also a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.<ref name="pmid23063338" /><ref name="pmid22065861" /> Due to its androgenic and progestogenic activity, trestolone has antigonadotropic effects.<ref name="pmid23063338" /><ref name="pmid22065861" /> These effects result in reversible suppression of sperm production and are responsible for the contraceptive effects of trestolone in men.<ref name="pmid23063338" />
<!-- History, society, and culture --> Trestolone was first described in 1963.<ref name="pmid13931986" /> Subsequently, it was not studied again until 1990.<ref name="pmid2363352" /> Development of trestolone for potential clinical use started by 1993 and continued thereafter.<ref name="pmid8489761" /><ref name="pmid8146434" /> No additional development appears to have been conducted since 2013.<ref name="pmid23063338" /> The medication was developed by the Population Council, a non-profit, non-governmental organization dedicated to reproductive health.<ref name="pmid23063338" /><ref name="PopulationCouncil">[http://www.popcouncil.org/research/ment-subdermal-implants-for-men MENT] {{Webarchive|url=https://web.archive.org/web/20171230103528/http://www.popcouncil.org/research/ment-subdermal-implants-for-men |date=2017-12-30 }} – project information from the Population Council</ref>
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==Medical uses== Trestolone is an experimental medication and is not currently approved for medical use.<ref name="AdisInsight" /><ref name="pmid23063338" /> It has been under development for potential use as a male hormonal contraceptive and in androgen replacement therapy for low testosterone levels.<ref name="AdisInsight" /><ref name="pmid23063338" /><ref name="pmid8489761" /><ref name="pmid8146434" /><ref name="pmid22612692" /> The medication has been studied and developed for use as a subcutaneous implant.<ref name="pmid23063338" /> An androgen ester and prodrug of trestolone, trestolone acetate, has also been developed, for use via intramuscular injection.<ref name="Elks2014" /><ref name="pmid22612692" />
==Side effects== {{See also|Anabolic steroid#Adverse effects}}
Trestolone may cause sexual dysfunction (e.g., decreased sex drive, reduced erectile function) and decreased bone mineral density due to estrogen deficiency.<ref name="pmid22612692" /><ref name="pmid23063338" /><ref name="pmid12788888">{{cite journal | vauthors = Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K | title = Evidence for tissue selectivity of the synthetic androgen 7 alpha-methyl-19-nortestosterone in hypogonadal men | journal = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 6 | pages = 2784–93 | date = June 2003 | pmid = 12788888 | doi = 10.1210/jc.2002-021960 | doi-access = free }}</ref>
==Pharmacology==
===Pharmacodynamics=== As an AAS, trestolone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and dihydrotestosterone (DHT).<ref name="pmid8489761" /><ref name="pmid23063338" /> Trestolone is not a substrate for 5α-reductase and hence is not potentiated or inactivated in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland.<ref name="pmid20599615">{{cite journal | vauthors = Attardi BJ, Hild SA, Koduri S, Pham T, Pessaint L, Engbring J, Till B, Gropp D, Semon A, Reel JR | title = The potent synthetic androgens, dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone, do not require 5α-reduction to exert their maximal androgenic effects | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 122 | issue = 4 | pages = 212–8 | date = October 2010 | pmid = 20599615 | pmc = 2949447 | doi = 10.1016/j.jsbmb.2010.06.009 }}</ref> As such, it has a high ratio of anabolic to androgenic activity, similarly to other nandrolone derivatives.<ref name="pmid8489761" /><ref name="pmid23063338" /> Trestolone is a substrate for aromatase and hence produces the estrogen 7α-methylestradiol as a metabolite.<ref name="pmid22065861">{{cite journal | vauthors = García-Becerra R, Ordaz-Rosado D, Noé G, Chávez B, Cooney AJ, Larrea F | title = Comparison of 7α-methyl-19-nortestosterone effectiveness alone or combined with progestins on androgen receptor mediated-transactivation | journal = Reproduction | volume = 143 | issue = 2 | pages = 211–9 | year = 2012 | pmid = 22065861 | doi = 10.1530/REP-11-0171 | doi-access = free }}</ref><ref name="pmid18555683">{{cite journal | vauthors = Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR | title = Dimethandrolone (7,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 3–5 | pages = 214–22 | date = June 2008 | pmid = 18555683 | pmc = 2575079 | doi = 10.1016/j.jsbmb.2007.11.009 }}</ref> However, trestolone has only weak estrogenic activity and an amount that would appear to be insufficient for replacement purposes, as evidenced by decreased bone mineral density in men treated with it for hypogonadism.<ref name="pmid22612692" /><ref name="pmid23063338" /> Trestolone also has potent progestogenic activity.<ref name="pmid22065861" /><ref name="pmid23063338" /> Both the androgenic and progestogenic activity of trestolone are thought to be involved in its antigonadotropic activity.<ref name="pmid22065861" /><ref name="pmid23063338" />
{| class="wikitable center mw-collapsible mw-collapsed" style="width:550px; text-align:left; margin-left:auto; margin-right:auto; border:none;" |+ class="nowrap" | Relative affinities (%) of trestolone and related steroids<ref name="pmid3695484">{{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 = J. Steroid Biochem. | volume = 27 | issue = 1–3 | pages = 255–69 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}</ref><ref name="pmid7382482">{{cite journal | vauthors = Delettré J, Mornon JP, Lepicard G, Ojasoo T, Raynaud JP | title = Steroid flexibility and receptor specificity | journal = J. Steroid Biochem. | volume = 13 | issue = 1 | pages = 45–59 | date = January 1980 | pmid = 7382482 | doi = 10.1016/0022-4731(80)90112-0 }}</ref><ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | title = Steroid hormone receptors and pharmacology | journal = J. Steroid Biochem. | volume = 12 | pages = 143–57 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref><ref name="pmid8136304">{{cite journal | vauthors = Ojasoo T, Raynaud JP, Doé JC | title = Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data | journal = J. Steroid Biochem. Mol. Biol. | volume = 48 | issue = 1 | pages = 31–46 | date = January 1994 | pmid = 8136304 | doi = 10.1016/0960-0760(94)90248-8 | s2cid = 21336380 }}</ref><ref name="RaynaudOjasoo1979">{{cite book| vauthors = Raynaud J, Ojasoo T, Bouton M, Philibert D |chapter=Receptor Binding as a Tool in the Development of New Bioactive Steroids | title = Drug Design: Medicinal Chemistry: A Series of Monographs | volume = 8 |year=1979 |pages=[https://archive.org/details/drugdesign0004unse/page/169 169–214]|publisher=New York, Academic Press |doi=10.1016/B978-0-12-060308-4.50010-X |chapter-url=https://books.google.com/books?id=bhAlBQAAQBAJ&pg=PA169|isbn=9780120603084 |url=https://archive.org/details/drugdesign0004unse/page/169}}</ref> |- ! Compound || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|AR|Androgen receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}} || {{abbrlink|SHBG|Sex hormone-binding globulin}} || {{abbrlink|CBG|Corticosteroid binding globulin}} |- | Nandrolone || 20 || 154–155 || <0.1 || 0.5 || 1.6 || 1 || ? |- | Trestolone || 50–75 || 100–125 || ? || <1 || ? || ? || ? |- | 7α-Methylestradiol || 1–3 || 15–25 || 101 || <1 || <1 || ? || ? |- class="sortbottom" | colspan="9" style="width: 1px;" | Values are percentages (%). Reference ligands (100%) were progesterone for the {{abbrlink|PR|progesterone receptor}}, testosterone for the {{abbrlink|AR|androgen receptor}}, {{abbr|E2|estradiol}} for the {{abbrlink|ER|estrogen receptor}}, {{abbrlink|DEXA|dexamethasone}} for the {{abbrlink|GR|glucocorticoid receptor}}, aldosterone for the {{abbrlink|MR|mineralocorticoid receptor}}, {{abbrlink|DHT|dihydrotestosterone}} for {{abbrlink|SHBG|sex hormone-binding globulin}}, and cortisol for {{abbrlink|CBG|Corticosteroid-binding globulin}}. |}
====Mechanism of action==== Spermatozoa are produced in the testes of males in a process called spermatogenesis. In order to render a man infertile, a hormone-based male contraceptive method must stop spermatogenesis by interrupting the release of gonadotropins from the pituitary gland. Even in low concentrations, trestolone is a potent inhibitor of the release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH).<ref name="pmid8489761" /><ref name="pmid23063338" /> In order for spermatogenesis to occur in the testes, both FSH and testosterone must be present. By inhibiting release of FSH, trestolone creates an endocrine environment in which conditions for spermatogenesis are not ideal.<ref name="pmid8489761" /><ref name="pmid23063338" /> Manufacture of sperm is further impaired by the suppression of LH, which in turn drastically curtails the production of testosterone.<ref name="pmid8489761" /><ref name="pmid23063338" /> Sufficient regular doses of trestolone cause severe oligozoospermia or azoospermia, and therefore infertility, in most men.<ref name="pmid8489761" /><ref name="pmid23063338" /> Trestolone-induced infertility has been found to be quickly reversible upon discontinuation.<ref name="pmid8489761" /><ref name="pmid23063338" />
When LH release is inhibited, the amount of testosterone made in the testes declines dramatically.<ref name="pmid8489761" /><ref name="pmid23063338" /> As a result of trestolone's gonadotropin-suppressing qualities, levels of serum testosterone fall sharply in men treated with sufficient amounts of the medication.<ref name="pmid8489761" /><ref name="pmid23063338" /> Testosterone is the main hormone responsible for maintenance of male secondary sex characteristics. Normally, an inadequate testosterone level causes undesirable effects such as fatigue, loss of skeletal muscle mass, reduced libido, and weight gain. However, the androgenic and anabolic properties of trestolone largely ameliorate this {{nowrap|problem<ref name="pmid8489761" /><ref name="pmid23063338" />{{hsp}}{{mdash}}}}{{tsp}}essentially, trestolone replaces testosterone's role as the primary male hormone in the body.<ref name="pmid8489761" /><ref name="pmid23063338" />
===Pharmacokinetics=== The pharmacokinetic properties of trestolone, such as poor oral bioavailability and short elimination half-life, make it unsuitable for oral administration or long-term intramuscular injection.<ref name="pmid16497801">{{cite journal | vauthors = Attardi BJ, Hild SA, Reel JR | title = Dimethandrolone undecanoate: a new potent orally active androgen with progestational activity | journal = Endocrinology | volume = 147 | issue = 6 | pages = 3016–26 | date = June 2006 | pmid = 16497801 | doi = 10.1210/en.2005-1524 | quote = The pharmacokinetic properties of MENT make it unsuitable for once-daily oral treatment or long-term injection; thus, administration by sc implant or by patch or gel is required (27). MENT showed a more rapid metabolic clearance rate than T in men and monkeys, probably due in part to its failure to bind SHBG (28). In monkeys, MENT acetate in subdermal implants was 10 times as potent as T in suppression of gonadotropin secretion and anabolic effects, but was only twice as potent in stimulating prostate growth (29).| doi-access = free }}</ref><ref name="pmid9194649">{{cite journal | vauthors = Suvisaari J, Sundaram K, Noé G, Kumar N, Aguillaume C, Tsong YY, Lähteenmäki P, Bardin CW | title = Pharmacokinetics and pharmacodynamics of 7alpha-methyl-19-nortestosterone after intramuscular administration in healthy men | journal = Hum. Reprod. | volume = 12 | issue = 5 | pages = 967–73 | date = May 1997 | pmid = 9194649 | doi = 10.1093/humrep/12.5.967| doi-access = free }}</ref> As such, trestolone must be administered parenterally via a different and more practical route such as subcutaneous implant, transdermal patch, or topical gel.<ref name="pmid16497801" /> Trestolone acetate, a prodrug of trestolone, can be administered via intramuscular injection.<ref name="pmid22612692" />
==Chemistry== {{See also|List of androgens/anabolic steroids}}
Trestolone, also known as 7α-methyl-19-nortestosterone (MENT) or as 7α-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of nandrolone (19-nortestosterone).<ref name="Elks2014" /> It is a modification of nandrolone with a methyl group at the C7α position.<ref name="Elks2014" /> Closely related AAS include 7α-methyl-19-norandrostenedione (MENT dione, trestione) (an androgen prohormone of trestolone) and dimethandrolone (7α,11β-dimethyl-19-nortestosterone) (the C11β methylated derivative of trestolone), as well as mibolerone (7α,17α-dimethyl-19-nortestosterone) and dimethyltrienolone (7α,17α-dimethyl-δ<sup>9,11</sup>-19-nortestosterone).<ref name="Elks2014" /> The progestin tibolone (7α-methyl-17α-ethynyl-δ<sup>5(10)</sup>-19-nortestosterone) is also closely related to trestolone.<ref name="Elks2014" /> ===Synthesis & Applications=== The chemical synthesis of trestolone is reported:<ref>J. Stoelwinder, M. Ostendorf, & Van P.A.M. Buggenum, WO2003059931 (to Akzo Nobel NV).</ref><ref>Marc Willuhn, et al. US20040010138 (to Bayer Pharma AG).</ref><ref>Joyce F. Grunwell & Harvey D. Benson, US4000273 (1976 to Richardson Vicks Inc).</ref>
Trestolone is an intermediate used in the synthesis of mibolerone, tibolone & isotibolone. If it is oxidized to mentabolan, this in-turn can be used to synthesize almestrone, a compound with manifold steroid synthesis applications.
==History== Trestolone was first described in 1963.<ref name="pmid13931986">{{cite journal | vauthors = Lyster SC, Duncan GW | title = Anabolic, androgenic and myotropic activities of derivatives of 7alpha-methyl-19-nortestosterone | journal = Acta Endocrinol. | volume = 43 | issue = 3| pages = 399–411 | date = July 1963 | pmid = 13931986 | doi = 10.1530/acta.0.0430399}}</ref> However, it was not subsequently studied again until 1990.<ref name="pmid2363352">{{cite journal | vauthors = Ma JB, Li ZS | title = [Synthesis of 4-substituted 17 beta-hydroxy-7 alpha-methyl-4-estren-3-one and their 17-acetates as antifertility compounds] | language = zh | journal = Yao Xue Xue Bao | volume = 25 | issue = 1 | pages = 18–23 | date = 1990 | pmid = 2363352 }}</ref><ref name="pmid2278844">{{cite journal | vauthors = Kumar N, Didolkar AK, Ladd A, Thau R, Monder C, Bardin CW, Sundaram K | title = Radioimmunoassay of 7 alpha-methyl-19-nortestosterone and investigation of its pharmacokinetics in animals | journal = J. Steroid Biochem. Mol. Biol. | volume = 37 | issue = 4 | pages = 587–91 | date = November 1990 | pmid = 2278844 | doi = 10.1016/0960-0760(90)90405-a| s2cid = 37597215 }}</ref> Development of trestolone for potential use in male hormonal contraception and androgen replacement therapy was started by 1993, and continued thereafter.<ref name="pmid8489761">{{cite journal | vauthors = Sundaram K, Kumar N, Bardin CW | title = 7 alpha-methyl-nortestosterone (MENT): the optimal androgen for male contraception | journal = Ann. Med. | volume = 25 | issue = 2 | pages = 199–205 | date = April 1993 | pmid = 8489761 | doi = 10.3109/07853899309164168}}</ref><ref name="pmid8146434">{{cite journal | vauthors = Sundaram K, Kumar N, Bardin CW | title = 7 alpha-Methyl-19-nortestosterone: an ideal androgen for replacement therapy | journal = Recent Prog. Horm. Res. | volume = 49 | pages = 373–6 | date = 1994 | pmid = 8146434 | doi = 10.1016/b978-0-12-571149-4.50027-1| isbn = 9780125711494 }}</ref><ref name="pmid23063338" /> No additional development appears to have been conducted since 2013.<ref name="pmid23063338" /> Trestolone was developed by the Population Council, a non-profit, non-governmental organization dedicated to reproductive health.<ref name="pmid23063338" /><ref name="PopulationCouncil" />
==Society and culture==
===Generic names=== ''Trestolone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}.<ref name="Elks2014" /> It is also commonly known as ''7α-methyl-19-nortestosterone'' (''MENT'').<ref name="Elks2014" /><ref name="AdisInsight" /><ref name="pmid23063338" />
==References== {{Reflist}}
{{Androgen receptor modulators}} {{Estrogen receptor modulators}} {{Progesterone receptor modulators}}
Category:Abandoned drugs Category:Secondary alcohols Category:Androgens Category:Antigonadotropins Category:Contraception for males Category:Estranes Category:Experimental methods of birth control Category:Hormonal contraception Category:Cyclic ketones Category:Progestogens Category:Synthetic estrogens Category:Hydroxy ketones