Fluoxymesterone was first described in 1956 and was introduced for medical use in 1957.[1][11] 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][12] 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.[13] Current prescribing guidelines in the United States list only the treatment of androgen deficiency in males and breast cancer in females as indications.[1]
Fluoxymesterone is less effective in inducing masculinization than testosterone, but is useful for maintaining established masculinization in adults.[14]
Notes: Men produce about 3 to 11 mg of testosterone per day (mean 7 mg/day in young men). Footnotes:a = Never marketed. b = No longer used and/or no longer marketed. Sources: See template.
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.
Fluoxymesterone has been reported to be non-aromatizable due to steric hindrance by its C11β hydroxyl group,[18] and hence is not considered to have a propensity for producing estrogenic effects such as gynecomastia or fluid retention.[1][19] 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.[20] Fluoxymesterone is thought to possess little or no progestogenic activity.[1][17]
Because of the presence of its 17α-methyl group, the metabolism of fluoxymesterone is impeded, resulting in it being orally active, although also hepatotoxic.[1][17]
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-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-keto group, protecting it from alkylation in a subsequent step. The regioselectivity of pyrrolidine for reaction at the 3α-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-hydroxyl of the starting material (1.16) is sulfonylated by p-toluenesulfonyl chloride; addition of trimethylamine (base) deprotonates the 11α-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-face and is attacked by the π-electron density of the alkene. The hydroxide ion then attacks from above the ring (β-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-hydroxyl, and the subsequent structure undergoes an intramolecular SN2 epoxy ring formation. The epoxy ring of the β-epoxide (1.19) is protonated to give an oxironium ion intermediate. In a concerted process, fluoride attacks the ring's α-face from below, as one of the two oxygen-carbon bonds is broken on the opposite face; hence regenerating the 11α-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).[27]
History
Fluoxymesterone was first described in 1956 and was introduced for medical use in the United States in 1957.[1][11] 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.[25][26][28][29]
Brand names
Brand names of fluoxymesterone include Android-F, Androxy, Halotestin, Ora-Testryl, and Ultandren among others.[25][26][28][29]
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][29]
^ abcdefghKammerer 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. doi:10.1016/0022-4731(90)90185-u. PMID2214783.
^Saartok T, Dahlberg E, Gustafsson JA (1984). "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". Endocrinology. 114 (6): 2100–6. doi:10.1210/endo-114-6-2100. PMID6539197.
^Gordan GS (1976). "Cancer in Man". In Kochakian CD (ed.). Anabolic-Androgenic Steroids. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology. Springer. pp. 499–513. doi:10.1007/978-3-642-66353-6_16. ISBN978-3-642-66355-0.
