title: Comparative evaluation of androgen and progesterone receptor transcription selectivity indices of 19-nortestosterone-derived progestins.
abstract: Synthetic 19-nortestosterone-derived progestins show affinity for the androgen receptor (AR) and retain varying degrees of androgenic activity. In this study, AR- and progesterone receptor (PR)-dependent transcriptional activation induced by norethisterone (NET), levonorgestrel (LNG) and gestodene (GSD), and their 5alpha-reduced derivatives, including limited trypsin digestion of AR in the presence of natural and synthetic progestins were investigated. The results confirmed the progestogenic activity of the three 19-nortestosterone derivatives, which decreases after reduction of the 4-ene-double bound. These compounds were able to activate AR-dependent reporter gene expression, LNG and GSD being the stronger activators. 5alpha-Reduction of LNG and GSD did not change their androgenic transcriptional activity; however, the activation of AR by 5alpha-NET was four-fold higher than NET. The highest selectivity transcriptional index, as a measure of progestogenicity versus androgenicity, was obtained for NET. The 5alpha-reduced derivatives had values significantly lower than those of their parent compounds. Non-reduced and 5alpha-reduced 19-nortestosterone progestins induced virtually identical proteolysis fragmentation patterns of the AR to those observed with DHT.
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Quiroga No. 15, México City 14000, Mexico.
authors.forename: Rocio
authors.initials: R
authors.lastname: García-Becerra
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Cooney
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Borja-Cacho
authors.forename: Ana E
authors.initials: AE
authors.lastname: Lemus
authors.forename: Gregorio
authors.initials: G
authors.lastname: Pérez-Palacios
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
mesh_terms: D000728:Androgens / Q000494:pharmacology; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D016912:Levonorgestrel / Q000494:pharmacology; D008024:Ligands; D009277:Nandrolone / Q000378:metabolism*; D009640:Norethindrone / Q000494:pharmacology; D009652:Norpregnenes / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011372:Progestins / Q000378:metabolism*; D014176:Protein Biosynthesis; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology
chemical_list: D000728:Androgens; D003280:Contraceptives, Oral, Synthetic; D008024:Ligands; D009652:Norpregnenes; D011372:Progestins; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; C033273:Gestodene; D016912:Levonorgestrel; D009277:Nandrolone; D014357:Trypsin; D009640:Norethindrone