title: Investigating the anti-mineralocorticoid properties of synthetic progestins used in hormone therapy.
abstract: A more detailed understanding of the affinities and efficacies for transcriptional regulation by the synthetic progestins medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A) via the mineralocorticoid receptor (MR) is required, to better understand their relative risk profiles. Both MPA and NET-A bind to the MR, although with about 100-fold lower affinities than that of Prog. MPA and NET-A exhibit no agonist activity, but NET-A, unlike MPA, has similar antagonistic efficacy to Prog on the endogenous mineralocorticoid/glucocorticoid response element (MRE/GRE)-containing genes, α-glycolytic protein or orosomucoid-1 (Orm-1) and plasminogen activator inhibitor-1 (PAI-1). This study is the first to show that NET-A, but not MPA, can dissociate between transrepression and transactivation via the MR. Given the relatively low affinity and potency of MPA and NET-A for the MR, our results suggest that these progestins are unlikeley to exert significant effects via the MR at doses used in hormonal therapy. However, considering their relative free concentrations compared to endogenous hormones, the possibility that NET-A may exhibit significant MR antagonist activity, with some possible cardiovascular protective benefits, should not be excluded.
authors.affiliation: Department of Biochemistry, University of Stellenbosch, 7600 Stellenbosch, South Africa.
authors.forename: Donita
authors.initials: D
authors.lastname: Africander
authors.forename: Renate
authors.initials: R
authors.lastname: Louw
authors.forename: Janet P
authors.initials: JP
authors.lastname: Hapgood
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077563:Norethindrone Acetate; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003280:Contraceptives, Oral, Synthetic; D009961:Orosomucoid; D017395:Plasminogen Activator Inhibitor 1; D018161:Receptors, Mineralocorticoid; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D008156:Luciferases; D009640:Norethindrone