title: Tibolone exerts progestational inhibition of matrix metalloproteinase expression in human endometrial stromal cells.
abstract: Tibolone and its metabolites were evaluated on matrix metalloproteinase (MMP) expression in human endometrial stromal cells (HESCs) under the hypothesis that these steroids would act as progestins on MMP-1, -2, and -3 expression. After 7 days of priming and 24h experimental incubation of confluent cultured HESCs, 10(-7) M medroxyprogesterone acetate (P) reduced MMP-1 to 49+/-34% (p<0.05) and MMP-3 to 33+/-22% of basal levels (mean+/-S.E.M., p<0.05, n=5). Although HESCs were unaffected by 10(-8) M estradiol (E), E+P reduced MMP-1 and MMP-3 levels an additional 2.5-fold from P alone. Tibolone and Delta-4 tibolone were equivalent to E+P in inhibiting MMP-1 and MMP-3 output, whereas 10(-6)M of 3alpha-OH or 3beta-OH tibolone was required to elicit significant inhibition of both MMPs (p<0.05). By contrast, none of the treatments affected HESC-secreted MMP-2 output. The ELISA results were confirmed by Western blotting and by substrate gel zymography. Quantitative RT-PCR demonstrated corresponding changes in MMP-1 and MMP-3 mRNA levels. Inhibition of MMP-1 and MMP-3 expression by tibolone and Delta-4 tibolone is consistent with the metabolism of tibolone to Delta-4 tibolone, and subsequent binding of Delta-4 tibolone to the progesterone receptor. Since 3alpha-OH and 3beta-OH tibolone bind exclusively to the estrogen receptor, their inhibition of MMP-1 and MMP-3 suggests metabolism by HESCs to Delta-4 tibolone. These observations help to explain the paradox that the endometrium becomes atrophic after tibolone administration despite the persistence in the circulation of 3alpha-OH and 3beta-OH tibolone, but not tibolone or Delta-4 tibolone.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street Room 334 FMB, PO Box 208063, New Haven, CT 06520-8063, USA. frederick.schatz@yale.edu
authors.forename: Frederick
authors.initials: F
authors.lastname: Schatz
authors.forename: Edward
authors.initials: E
authors.lastname: Kuczynski
authors.forename: Lenus
authors.initials: L
authors.lastname: Kloosterbooer
authors.forename: Graciela
authors.initials: G
authors.lastname: Krikun
authors.forename: Lynn F
authors.initials: LF
authors.lastname: Buchwalder
authors.forename: Mizanur
authors.initials: M
authors.lastname: Rahman
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
mesh_terms: D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009652:Norpregnenes / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D009652:Norpregnenes; D011372:Progestins; D020782:Matrix Metalloproteinases; C027385:tibolone