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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #147973
Title: A-RING REDUCED METABOLITES OF 19-NOR SYNTHETIC PROGESTINS AS SUBTYPE SELECTIVE AGONISTS FOR ER-ALPHA

Author
item LARREA, FERNANDO - INST NATL CIENCIAS MED
item GARCIA-BECERRA, ROCIO - INST NATL CIENCIAS MED
item LEMUS, ANA - UNIV AUTONOMA METRO-IZTAP
item GARCIA, GUSTAVO - UNIV NATL AUTONOMA MEXICO
item PEREZ-PALACIOS, GREGORIO - UNIV NATL AUTONOMA MEXICO
item JACKSON, KATHY - BAYLOR COLLEGE MED
item COLEMAN, KEVIN - BAYLOR COLLEGE MED
item DACE, ROSLYN - BAYLOR COLLEGE MED
item SMITH, CAROLYN - BAYLOR COLLEGE MED
item Cooney, Austin

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/31/2001
Publication Date: 9/1/2001
Citation: Larrea, F., Garcia-Becerra, R., Lemus, A.E., Garcia, G.A., Perez-Palacios, G., Jackson, K.J., Coleman, K.M., Dace, R., Smith, C.L., Cooney, A. 2001. A-ring reduced metabolites of 19-nor synthetic progestins as subtype selective agonists for er-alpha. Endocrinology. 142(9):3791-3799.

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: It has previously been demonstrated that 19-nor contraceptive progestins undergo in vivo and in vitro enzyme-mediated A-ring double bond hydrogenation. Bioconversion of 19-nor progestins to their corresponding tetrahydro derivatives results in the loss of progestational activity and acquisition of estrogenic activities and binding to the estrogen receptor (ER). Herein, we report subtype-selective differences in ligand binding and transcriptional potency of non-phenolic synthetic 19-nor derivatives between the estrogen receptor alpha (ER-alpha) and the estrogen receptor beta (ER-beta). In this study, we have examined both estrogen and progesterone receptor-mediated transcriptional activity of a number of A-ring chemically reduced derivatives of norethisterone (NET) and gestodene (GSD). Double bond hydrogenation decreased the transcriptional potency of NET and GSD through both progesterone receptor (PR) isoforms with a 100 to 1000-fold difference, respectively. In terms of the effects of NET and GSD and their corresponding 5alpha-dihydro (5alpha-NET and 5alpha-GSD), or 3alpha,5alpha-tetrahydro or 3beta,5alpha-tetrahydro derivatives (3alph,5alpha-NET/3alpha,5alpha-GSD and 3beta,5alpha-NET/3beta,5alpha-GSD, respectively) on estrogen mediated transcriptional regulation, the 3beta,5alpha-tetrahydro derivatives of both NET and GSD showed the highest induction when HeLa cells were transiently transfected with an expression vector for ERa. This activity could be inhibited with tamoxifen. These compounds did not activate gene transcription via ER-beta and none of them showed antagonistic activities through either ER subtype. The 3beta,5alpha-tetrahydro derivatives of both NET and GSD were active in other cells in addition to HeLa cells and activated reporter expression through the oxytocin promoter. In summary, two ERa selective agonists have been identified. These compounds, with ERa versus ERb selective agonist activity, may be useful in evaluating the distinct role of these receptors as well as in providing useful insights into ER action.