Comparative evaluation of androgen and progesterone receptor transcription selectivity indices of 19-nortestosterone-derived progestins.

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.

Citation

Rocio García-Becerra, Austin J Cooney, Elizabeth Borja-Cacho, Ana E Lemus, Gregorio Pérez-Palacios, Fernando Larrea. Comparative evaluation of androgen and progesterone receptor transcription selectivity indices of 19-nortestosterone-derived progestins. The Journal of steroid biochemistry and molecular biology. 2004 Jun;91(1-2):21-7

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PMID: 15261304

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