ABSTRACT
Steroid hormones regulate endometrial expression of matrix metalloproteinases (MMPs) and their inhibitors. Synthetic progestins are widely used in oral contraceptives and for hormone replacement therapy. To assess whether the synthetic progestins norgestimate and its derivative norelgestromin (17-deacetylnorgestimate) modulate the expression of MMPs, Ishikawa endometrial cancer cells were separately treated with 17 beta-estradiol, 17 alpha-hydroxyprogesterone, norgestimate and norelgestromin. Culture supernatants were assayed for MMPs 2, 3 and 9, and for tissue inhibitors of MMPs (TIMP-1 and TIMP-2) by enzyme-linked immunosorbent assays (ELISAs). No marked modulation of MMP-2 and TIMP-2 expression was observed upon incubation of the cells with the synthetic progestins. By ELISA, neither MMP-3 or MMP-9 nor TIMP-1 immunoreactivity was detected. Interestingly, TIMP-2 expression was down-regulated by 17 beta-estradiol and 17 alpha-hydroxyprogesterone.
Subject(s)
Contraceptives, Oral, Combined/pharmacology , Endometrium/drug effects , Matrix Metalloproteinase 2/drug effects , Norgestrel/analogs & derivatives , Norgestrel/pharmacology , Tissue Inhibitor of Metalloproteinase-1/drug effects , Tissue Inhibitor of Metalloproteinase-2/drug effects , 17-alpha-Hydroxyprogesterone/pharmacology , Cell Line, Tumor/drug effects , Contraceptives, Oral, Synthetic/pharmacology , Drug Combinations , Endometrium/cytology , Enzyme-Linked Immunosorbent Assay , Estradiol/pharmacology , Ethisterone/analogs & derivatives , Female , Humans , Matrix Metalloproteinase 2/metabolism , Oximes , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolismABSTRACT
The function and clinical significance of the androgen receptor (AR) in human breast cancer are still not clear. The synthetic progestins, norgestimate and norelgestromin, were designed to minimize the adverse effects such as acne, hirsuitism and metabolic changes observed with older oral contraceptives while maintaining contraceptive effectiveness and cycle control. AR-mediated effects of these synthetic progestins were studied in an in vitro transactivation assay, employing DNA co-transfection of an AR expression vector and luciferase reporter gene construct in the MDA-MB 231 human breast cancer cell line. Testosterone acetate and 5alpha-dihydrotestosterone induced the reporter gene transcription, whereas incubation of the transfected cells with the natural progestin 17alpha-hydroxyprogesterone did not markedly induce luciferase activity. The progestins norgestimate and norelgestromin exerted a very low androgenic activity. Our data suggest that norgestimate and its metabolite norelgestromin possess weak androgen-like properties. The use of these compounds for clinical application may be of great advantage in the treatment of breast cancer as well as hyperandrogenism in women.
