The intrinsic transcriptional estrogenic activity of a non-phenolic derivative of levonorgestrel is mediated via the estrogen receptor-α

• Published in: The Journal of steroid biochemistry and molecular biology 2002-11, Vol.82 (4), p.333-341
• Main Authors: Garcı́a-Becerra, Rocio, Borja-Cacho, Elizabeth, Cooney, Austin J., Jackson, Kathy J., Lemus, Ana E., Pérez-Palacios, Gregorio, Larrea, Fernando
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase; Bacterial Proteins; Biological and medical sciences; Contraceptive Agents, Female - pharmacology; Estrogen effects; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen receptors; Estrogens - pharmacology; Gene Expression Regulation - drug effects; Genital system. Reproduction; HeLa Cells; Humans; Levonorgestrel; Levonorgestrel - analogs & derivatives; Levonorgestrel - pharmacology; Medical sciences; Pharmacology. Drug treatments; Plasmids; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, Progesterone - genetics; Serine Endopeptidases; Synthetic progestins; Transcription regulation; Transcription, Genetic - drug effects; Transcriptional Activation; Transfection
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(02)00192-9

Levonorgestrel (LNG), a 19-nor-testosterone derivative, is widely used in contraceptive formulations. This compound does not bind to the estrogen receptor (ER), but it shows estrogen-like effects under in vivo and in vitro conditions. The estrogenicity of LNG may be attributed to its bio-transformation into non-phenolic metabolites. In this study, the ability of A-ring reduced LNG metabolites to activate transcription via an estrogenic mechanism of action, including differences between ERα and ERβ subtypes, were investigated. Transactivation assays were performed in HeLa cells transfected with expression vectors for ERα and ERβ and an estrogen-responsive reporter gene. Cells were also transfected with expression vectors for both progesterone receptor (PR) isoforms (A or B). As expected, the tetrahydro derivatives of LNG (3α,5α- and 3β,5α-LNG) showed significantly lower PR-mediated transcriptional activities through both isoforms when compared with progesterone (P 4) and LNG. In contrast, the 3β,5α-tetrahydro derivative resulted in a significant activation of estrogen-dependent gene transcription. This effect was selectively confined to the ERα, since little if any activity could be observed with the ERβ and no antagonistic activities were demonstrated. This study provides structural and molecular clues for the well documented in vitro and in vivo intrinsic estrogenicity of 19-nor-testosterone-derived progestins and ligand requirements for ERα recognition.