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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #148539
Title: THE INTRINSIC TRANSCRIPTIONAL ESTROGENIC ACTIVITY OF A NON-PHENOLIC DERIVATIVE OF LEVONORGESTREL IS MEDIATED VIA THE ESTROGEN RECEPTOR-ALPHA

Author
item GARCIA-BECERRA, ROCIO - INST NATL CIENCIAS MED N
item BORJA-CACHO, ELIZABETH - INST NATL CIENCIAS MED
item Cooney, Austin
item JACKSON, KATHY - BAYLOR COLLEGE MED
item LEMUS, ANA - UNIV AUTONOMA METRO-IZTAP
item PEREZ-PALACIOS, GREGORIO - UNIV NATL AUTONOMA MEX
item LARREA, FERNANDO - INST NATL CIENCIAS MED

Submitted to: The Journal of Steroid Biochemistry and Molecular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2002
Publication Date: 11/1/2002
Citation: Garcia-Becerra, R., Borja-Cacho, E., Cooney, A., Jackson, K.J., Lemus, A.E., Perez-Palacios, G., Larrea, F. 2002. The intrinsic transcriptional estrogenic activity of a non-phenolic derivative of levonorgestrel is mediated via the estrogen receptor-alpha. The Journal of Steroid Biochemistry and Molecular Biology. 82(4-5):333-341.

Interpretive Summary: This is a peer reviewed article describing the analysis of by-products of a contraceptive pill that are produced in the body. The pill targets the progesterone receptor but the by-products do not but instead target the estrogen receptor.

Technical Abstract: 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 biotransformation 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 ERa and ERb subtypes were investigated. Transactivation assays were performed in HeLa cells transfected with expression vectors for ERa and ERb 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 (3a,5a- and 3b,5a-LNG) showed significantly lower PR-mediated transcriptional activities through both isoforms when compared with progesterone (P4) and LNG. In contrast, the 3b,5a-tetrahydro derivative resulted in a significant activation of estrogen-dependent gene transcription. This effect was selectively confined to the ERa since little if any activity could be observed with the ERb 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 ERa recognition.