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A-Ring Reduced Metabolites of 19-nor Synthetic Progestins as Subtype Selective Agonists for ER

Department of Reproductive Biology (F.L., R.G.-B.), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico 14000; Department of Reproductive Biology (A.E.L.), Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico 09340; Facultad de Química (G.A.G.), Universidad Nacional Autónoma de México, Mexico City, Mexico 04510; School of Medicine (G.P.-P.), Universidad Nacional Autónoma de México, Mexico City General Hospital, Mexico 06726; and Department of Molecular and Cellular Biology (K.J.J., K.M.C., R.D., C.L.S., A.J.C.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Fernando Larrea, M.D., Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Quiroga No. 15, México D. F., C. P. 14000, México. E-mail: larrea{at}conacyt.mx

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 ER. Herein, we report subtype-selective differences in ligand binding and transcriptional potency of nonphenolic synthetic 19-nor derivatives between ER and ERß. In this study, we have examined both ER- and PR-mediated transcriptional activity of a number of A-ring chemically reduced derivatives of norethisterone and Gestodene. Double bond hydrogenation decreased the transcriptional potency of norethisterone and Gestodene through both PR isoforms with a 100- to 1,000-fold difference, respectively. In terms of the effects of norethisterone and Gestodene and their corresponding 5-dihydro (5-norethisterone and 5-Gestodene), or 3,5-tetrahydro or 3ß,5-tetrahydro derivatives (3,5-norethisterone/3,5-Gestodene and 3ß,5-norethisterone/3ß,5-Gestodene, respectively) on estrogen-mediated transcriptional regulation, the 3ß,5-tetrahydro derivatives of both norethisterone and Gestodene showed the highest induction when HeLa cells were transiently transfected with an expression vector for ER. This activity could be inhibited with tamoxifen. These compounds did not activate gene transcription via ERß, and none of them showed antagonistic activities through either ER subtype. The 3ß,5-tetrahydro derivatives of both norethisterone and Gestodene were active in other cells in addition to HeLa cells and activated reporter expression through the oxytocin promoter. In summary, two ER selective agonists have been identified. These compounds, with ER vs. ERß selective agonist activity, may be useful in evaluating the distinct role of these receptors as well as in providing useful insights into ER action.

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