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'''Fluoxymesterone''', sold under the brand names '''Halotestin''' and '''Ultandren''' among others, is an [[androgen]] and [[anabolic steroid]] (AAS) which is used in the treatment of [[anemia]] and [[hypogonadism|low androgen levels]] in men, [[delayed puberty]] in boys, and [[breast cancer]] in women.<ref name="Llewellyn2011">{{cite book|author=William Llewellyn|title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT500|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=500–508}}</ref> It is taken [[oral administration|by mouth]].<ref name="Llewellyn2011" />
'''Fluoxymesterone''', sold under the brand names '''Halotestin''' and '''Ultandren''' among others, is an [[androgen]] and [[anabolic steroid]] (AAS) which is used in the treatment of [[hypogonadism|low testosterone levels]] in men, [[delayed puberty]] in boys, [[breast cancer]] in women, and [[anemia]].<ref name="Llewellyn2011">{{cite book|author=William Llewellyn|title=Anabolics|url=https://books.google.com/books?id=afKLA-6wW0oC&pg=PT500|year=2011|publisher=Molecular Nutrition Llc|isbn=978-0-9828280-1-4|pages=500–508}}</ref> It is taken [[oral administration|by mouth]].<ref name="Llewellyn2011" />


<!-- Side effects and mechanism of action -->
<!-- Side effects and mechanism of action -->

Revision as of 03:37, 18 December 2017

Fluoxymesterone
Clinical data
Trade namesHalotestin, Ora-Testryl, Ultandren, others
Other namesAndrofluorene; NSC-12165; 9αあるふぁ-Fluoro-11βべーた-hydroxy-17αあるふぁ-methyltestosterone; 9αあるふぁ-Fluoro-17αあるふぁ-methylandrost-4-en-11βべーた,17βべーた-diol-3-one
AHFS/Drugs.comMonograph
MedlinePlusa682690
Pregnancy
category
  • X
Routes of
administration		By mouth[1]
Drug classAndrogen; Anabolic steroid
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 80%[2]
MetabolismLiver (6βべーた-hydroxylation, 5αあるふぁ- and 5βべーた-reduction, 3αあるふぁ- and 3βべーた-keto-oxidation, 11βべーた-hydroxy-oxidation)[3]
Metabolites• 5αあるふぁ‑Dihydrofluoxymesterone[3]
• 11-Oxofluoxymesterone[3]
Elimination half-life9.2 hours[4][5]
ExcretionUrine (<5% unchanged)[2][3]
Identifiers
  • (8S,9R,10S,11S,13S,14S,17S)-9-fluoro-11,17-dihydroxy-10,13,17-trimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.875 Edit this at Wikidata
Chemical and physical data
FormulaC20H29FO3
Molar mass336.441 g/mol g·mol−1
3D model (JSmol)
  • O=C4\C=C3/[C@]([C@@]2(F)[C@@H](O)C[C@]1([C@@H](CC[C@@]1(O)C)[C@@H]2CC3)C)(C)CC4
  • InChI=1S/C20H29FO3/c1-17-8-6-13(22)10-12(17)4-5-15-14-7-9-19(3,24)18(14,2)11-16(23)20(15,17)21/h10,14-16,23-24H,4-9,11H2,1-3H3/t14-,15-,16-,17-,18-,19-,20-/m0/s1 checkY
  • Key:YLRFCQOZQXIBAB-RBZZARIASA-N checkY
  (verify)

Fluoxymesterone, sold under the brand names Halotestin and Ultandren among others, is an androgen and anabolic steroid (AAS) which is used in the treatment of low testosterone levels in men, delayed puberty in boys, breast cancer in women, and anemia.[1] It is taken by mouth.[1]

Side effects of fluoxymesterone include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire.[1] It can also cause liver damage and cardiovascular side effects like high blood pressure.[1][6][7] The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[1][8] It has strong androgenic effects and moderate anabolic effects, which make it useful for producing masculinization.[1]

Fluoxymesterone was first described in 1956 and was introduced for medical use in 1957.[1][9] In addition to its medical use, fluoxymesterone is used to improve physique and performance.[1] The drug is a controlled substance in many countries and so non-medical use is generally illicit.[1]

Medical uses

Fluoxymesterone is or has been used in the treatment of hypogonadism, delayed puberty, and anemia in males and the treatment of breast cancer in women.[1][10] It is specifically approved in one or more countries for the treatment of hypogonadism in men, delayed puberty in boys, and breast cancer in women.[11] Current prescribing guidelines in the United States list only the treatment of androgen deficiency in males and breast cancer in females as indications.[1]

Side effects

See also: Anabolic steroid § Adverse effects

Side effects that have been associated with fluoxymesterone include acne, edema, seborrhea/seborrheic dermatitis, alopecia, hirsutism, voice deepening, virilization in general, flushing, gynecomastia, breast pain, menstrual disturbances, hypogonadism, testicular atrophy, clitoral enlargement, penile enlargement, priapism, increased aggressiveness, prostate enlargement, cardiovascular toxicity, and hepatotoxicity, among others.[1][12]

Pharmacology

Pharmacodynamics

As an AAS, fluoxymesterone is an agonist of the androgen receptor (AR), similarly to androgens like testosterone and DHT.[1][13] It is a substrate for 5αあるふぁ-reductase like testosterone, and so is potentiated in so-called "androgenic" tissues like the skin, hair follicles, and prostate gland via transformation into 5αあるふぁ-dihydrofluoxymesterone.[1][13][3] As such, fluoxymesterone has a relatively poor ratio of anabolic to androgenic activity similarly to testosterone and methyltestosterone.[1][13]

Fluoxymesterone has been reported to be non-aromatizable due to steric hindrance by its C11βべーた hydroxyl group,[14] and hence is not considered to have a propensity for producing estrogenic effects such as gynecomastia or fluid retention.[1][15] However, paradoxically, a case report of severe fluoxymesterone-induced gynecomastia exists, and gynecomastia associated with fluoxymesterone has also been reported in other publications, although this may not be due to estrogenic activity.[16] Fluoxymesterone is thought to possess little or no progestogenic activity.[1][13]

Because of the presence of its 17αあるふぁ-methyl group, the metabolism of fluoxymesterone is impeded, resulting in it being orally active, although also hepatotoxic.[1][13]

11βべーた-HSD inhibition

Fluoxymesterone has been found to act as a potent inhibitor of 11βべーた-hydroxysteroid dehydrogenase type 2 (11βべーた-HSD2) (IC50Tooltip Half-maximal inhibitory concentration = 60–630 nM), with a potency comparable to that of the 11βべーた-HSD2 inhibitor glycyrrhetinic acid.[6][7] This action of fluoxymesterone is unique among AAS and is likely related to its 11βべーた-hydroxyl group.[6] 11βべーた-HSD2 is responsible for the inactivation of the glucocorticoids cortisol and corticosterone (into cortisone and 11-dehydrocorticosterone, respectively).[6][7] Inhibition of 11βべーた-HSD2 by fluoxymesterone may result in mineralocorticoid receptor overactivation and associated side effects such as hypertension and fluid retention, and has been hypothesized to be involved in the cardiovascular and other adverse effects of fluoxymesterone.[6][7]

Glucocorticoid activity

Unlike other AAS, fluoxymesterone has structural features in common with corticosteroids, including its C9αあるふぁ fluoro and C11βべーた hydroxyl groups.[17] In relation to this, it has weak (micromolar) but potentially clinically significant affinity for the glucocorticoid receptor.[18]

Pharmacokinetics

Fluoxymesterone has approximately 80% oral bioavailability, unlike testosterone, as the C17αあるふぁ methyl group of fluoxymesterone inhibits first-pass metabolism.[2][1] Fluoxymesterone is metabolized in the liver, mainly by 6βべーた-hydroxylation, 5αあるふぁ- and 5βべーた-reduction, 3αあるふぁ- and 3βべーた-keto-oxidation, and 11βべーた-hydroxy-oxidation.[3] Its known active metabolites include 5αあるふぁ-dihydrofluoxymesterone and 11-oxofluoxymesterone.[3][6][19][20] Fluoxymesterone has an elimination half-life of approximately 9.2 hours, which is long relative to that of testosterone.[4] The drug is eliminated in the urine, with less than 5% excreted unchanged.[2][3]

Chemistry

See also: List of androgens/anabolic steroids

Fluoxymesterone is an androstane steroid and a 17αあるふぁ-alkylated derivative of testosterone (androst-4-en-17βべーた-ol-3-one), and is also known as 9αあるふぁ-fluoro-11βべーた-hydroxy-17αあるふぁ-methyltestosterone or as 9αあるふぁ-fluoro-17αあるふぁ-methylandrost-4-en-11βべーた,17βべーた-diol-3-one.[21][22] It is testosterone with a fluorine atom at the C9αあるふぁ position, a hydroxyl group at the C11βべーた position, and a methyl group at the C17αあるふぁ position.[21][22]

Synthesis

Step one: The first step in the synthesis of fluoxymesterone is the microbiological oxidation of commercially available androstenedione (1.11) by Actinomyces; this introduces a hydroxyl group to the 11αあるふぁ-position (1.12), which is then oxidised to a ketone using Jones’ reagent, yielding the 3,11,17-triketone, adrenosterone (1.13). Pyrrolidine then reacts to form an enamine (1.14) by reaction with the 3αあるふぁ-keto group, protecting it from alkylation in a subsequent step. The regioselectivity of pyrrolidine for reaction at the 3αあるふぁ-position occurs inherently in the structure of adrenosterone, due to the position of the sterically bulky methyl groups. In subsequent steps, alkylation of the 17-keto group (1.14) using Grignard reagent, addition of hydride at the 11-position (1.15) and regeneration of the protected 3-keto group yields the starting material (1.16) for the final steps of the fluoxymesterone synthesis. This involves more standard synthetic transformations.

Scheme showing the full synthesis of fluoxymesterone from andrestenedione

Step two: The 11αあるふぁ-hydroxyl of the starting material (1.16) is sulfonylated by p-toluenesulfonyl chloride; addition of trimethylamine (base) deprotonates the 11αあるふぁ-carbon, yielding an (E2) elimination of tosylate (pka - 5) to give olefin (1.17). Stereospecificity of reaction between olefin and hypobromous acid (HOBr) in base, N-bromosuccinimide (NBS), is determined by the formation of a bromonium intermediate; the electrophilic bromonium cation approaches the ring’s less sterically hindered αあるふぁ-face and is attacked by the πぱい-electron density of the alkene. The hydroxide ion then attacks from above the ring (βべーた-face) at the 11-carbon, resulting in a structure (1.18) by the stereospecific addition of hydroxyl and bromine across the double bond. Addition of sodium hydroxide results in deprotonation of the 11αあるふぁ-hydroxyl, and the subsequent structure undergoes an intramolecular SN2 epoxy ring formation. The epoxy ring of the βべーた-epoxide (1.19) is protonated to give an oxironium ion intermediate. In a concerted process, fluoride attacks the ring’s αあるふぁ-face from below, as one of the two oxygen-carbon bonds is broken on the opposite face; hence regenerating the 11αあるふぁ-hydroxyl trans to the fluorine substituent. The resulting structure (1.20) is the androgenic steroid, fluoxymesterone.

Detection in body fluids

Detection of halotestin and other such illegal anabolic steroids in sports is achieved by GS-MS identification of urinary excreted anabolic steroids and their metabolites. In a test for halotestin, a dry residue obtained from a urine sample is dissolved in dimethylformamide and a sulfur trioxide-pyridine complex and is heated with 1% potassium carbonate solution. Halotestin and many of its metabolites contain two polar hydroxyl groups, leading to intermolecular hydrogen bonding that increases their boiling point and reduces volatility. In order to attain a gaseous sample for GC-MS, the products of hydrolysis are extracted, dissolved in methanol and derivatised to form volatile trimethylsilyl (TMS) esters by adding N-methyl-N-trimethylsilyl-trifluoroacetamide (MSTFA) and trimethylsilylimidazole (TMSImi).[23]

History

Fluoxymesterone was first described in 1956 and was introduced for medical use in the United States in 1957.[1][9] Over time the use of fluoxymesterone has become increasingly controversial and limited.[1]

Society and culture

Generic names

Fluoxymesterone is the generic name of the drug and its INNTooltip International Nonproprietary Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name, while fluoxymestérone is its DCFTooltip Dénomination Commune Française.[21][22][24][25]

Brand names

Brand names of fluoxymesterone include Android-F, Androxy, Halotestin, Ora-Testryl, and Ultandren among others.[21][22][24][25]

Availability

United States

See also: List of androgens/anabolic steroids available in the United States

Fluoxymesterone is one of the few AAS that remains available for medical use in the United States.[26] The others (as of November 2017) are testosterone, testosterone cypionate, testosterone enanthate, testosterone undecanoate, methyltestosterone, nandrolone decanoate, oxandrolone, and oxymetholone.[26]

Other countries

Availability of fluoxymesterone aside from the United States remains scarce, but it is marketed in some other countries, such as Mexico, Moldova, and Taiwan.[1][25]

Legal status

Fluoxymesterone, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act.[27]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 500–508. ISBN 978-0-9828280-1-4.
  2. ^ a b c d Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1360–. ISBN 978-1-60913-345-0.
  3. ^ a b c d e f g h Kammerer RC, Merdink JL, Jagels M, Catlin DH, Hui KK (1990). "Testing for fluoxymesterone (Halotestin) administration to man: identification of urinary metabolites by gas chromatography-mass spectrometry". J. Steroid Biochem. 36 (6): 659–66. PMID 2214783.
  4. ^ a b Seth Roberts (2009). Anabolic Pharmacology.
  5. ^ Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1279–. ISBN 978-0-7817-6879-5.
  6. ^ a b c d e f Fürstenberger C, Vuorinen A, Da Cunha T, Kratschmar DV, Saugy M, Schuster D, Odermatt A (2012). "The anabolic androgenic steroid fluoxymesterone inhibits 11βべーた-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation". Toxicol. Sci. 126 (2): 353–61. doi:10.1093/toxsci/kfs022. PMID 22273746.
  7. ^ a b c d Joseph JF, Parr MK (2015). "Synthetic androgens as designer supplements". Curr Neuropharmacol. 13 (1): 89–100. doi:10.2174/1570159X13666141210224756. PMC 4462045. PMID 26074745.
  8. ^ Kicman AT (2008). "Pharmacology of anabolic steroids". Br. J. Pharmacol. 154 (3): 502–21. doi:10.1038/bjp.2008.165. PMC 2439524. PMID 18500378.
  9. ^ a b William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1676–. ISBN 978-0-8155-1856-3.
  10. ^ Susan M. Ford; Sally S. Roach (7 October 2013). Roach's Introductory Clinical Pharmacology. Lippincott Williams & Wilkins. pp. 502–. ISBN 978-1-4698-3214-2.
  11. ^ http://adisinsight.springer.com/drugs/800012288
  12. ^ Jerome Z. Litt; Neil Shear (17 December 2014). Litt's Drug Eruptions and Reactions Manual, 19th Edition. CRC Press. pp. 177–. ISBN 978-1-84214-599-9.
  13. ^ a b c d e Kicman, A T (2008). "Pharmacology of anabolic steroids". British Journal of Pharmacology. 154 (3): 502–521. doi:10.1038/bjp.2008.165. PMC 2439524. PMID 18500378.
  14. ^ Attardi BJ, Pham TC, Radler LC, Burgenson J, Hild SA, Reel JR (2008). "Dimethandrolone (7alpha,11beta-dimethyl-19-nortestosterone) and 11beta-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase". J. Steroid Biochem. Mol. Biol. 110 (3–5): 214–22. doi:10.1016/j.jsbmb.2007.11.009. PMC 2575079. PMID 18555683.
  15. ^ Norman T. Adler; Donald Pfaff; Robert W. Goy (6 December 2012). Reproduction. Springer Science & Business Media. pp. 630–. ISBN 978-1-4684-4832-0.
  16. ^ Lo TE, Andal ZC, Lantion-Ang FL (2015). "Fluoxymesterone-induced gynaecomastia in a patient with childhood aplastic anaemia". BMJ Case Rep. 2015: bcr2014207474. doi:10.1136/bcr-2014-207474. PMC 4434366. PMID 25948845.
  17. ^ Kirschbaum J (27 October 1978). Profiles of Drug Substances, Excipients and Related Methodology. Academic Press. pp. 253–. ISBN 978-0-08-086102-9.
  18. ^ Mayer M, Rosen F (1975). "Interaction of anabolic steroids with glucocorticoid receptor sites in rat muscle cytosol". Am. J. Physiol. 229 (5): 1381–6. PMID 173192.
  19. ^ Gordan, G. S. (1976). "Cancer in Man": 499–513. doi:10.1007/978-3-642-66353-6_16. {{cite journal}}: Cite journal requires |journal= (help)
  20. ^ Charles D. Kochakian (6 December 2012). Anabolic-Androgenic Steroids. Springer Science & Business Media. pp. 504–. ISBN 978-3-642-66353-6.
  21. ^ a b c d J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 568–. ISBN 978-1-4757-2085-3.
  22. ^ a b c d Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 461. ISBN 978-3-88763-075-1.
  23. ^ Schänzer, Willi; Opfermann, Georg; Donike, Manfred (1992-11-01). "17-Epimerization of 17αあるふぁ-methyl anabolic steroids in humans: metabolism and synthesis of 17αあるふぁ-hydroxy-17βべーた-methyl steroids". Steroids. 57 (11): 537–550. doi:10.1016/0039-128X(92)90023-3.
  24. ^ a b I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 123–. ISBN 978-94-011-4439-1.
  25. ^ a b c https://www.drugs.com/international/Fluoxymesterone.html
  26. ^ a b "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 17 December 2016.
  27. ^ Steven B. Karch, MD, FFFLM (21 December 2006). Drug Abuse Handbook, Second Edition. CRC Press. pp. 30–. ISBN 978-1-4200-0346-8.{{cite book}}: CS1 maint: multiple names: authors list (link)

Further reading


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