Document Detail

Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay.
MedLine Citation:
PMID:  18395441     Owner:  NLM     Status:  MEDLINE    
The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17alpha-ethynyl group of each of these progestins produces 17alpha-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.
L McRobb; D J Handelsman; R Kazlauskas; S Wilkinson; M D McLeod; A K Heather
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-02-12
Journal Detail:
Title:  The Journal of steroid biochemistry and molecular biology     Volume:  110     ISSN:  0960-0760     ISO Abbreviation:  J. Steroid Biochem. Mol. Biol.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-06-09     Completed Date:  2008-09-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9015483     Medline TA:  J Steroid Biochem Mol Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  39-47     Citation Subset:  IM    
Heart Research Institute, Sydney, NSW 2050, Australia.
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MeSH Terms
Androgens / chemistry,  metabolism*,  pharmacology
Biological Assay / methods
Dose-Response Relationship, Drug
Ethisterone / chemistry,  metabolism,  pharmacology
Gestrinone / chemistry,  metabolism,  pharmacology
Molecular Structure
Norethindrone / chemistry,  metabolism,  pharmacology
Norgestrel / chemistry,  metabolism,  pharmacology
Norpregnenes / chemistry,  metabolism,  pharmacology
Norprogesterones / chemistry,  metabolism,  pharmacology
Progestins / chemistry,  metabolism*,  pharmacology
Receptors, Androgen / metabolism
Receptors, Progesterone / metabolism
Structure-Activity Relationship
Yeasts / drug effects,  metabolism*
Reg. No./Substance:
0/13-ethyl-17-hydroxy-18,19-dinor-17-pregn-4-en-20-yn-3-one; 0/Androgens; 0/Norpregnenes; 0/Norprogesterones; 0/Progestins; 0/Receptors, Androgen; 0/Receptors, Progesterone; 16320-04-0/Gestrinone; 434-03-7/Ethisterone; 472-54-8/19-norprogesterone; 6533-00-2/Norgestrel; 68-22-4/Norethindrone

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