title: Tibolone and its metabolites enhance tissue factor and PAI-1 expression in human endometrial stromal cells: Evidence of progestogenic effects.
abstract: Tibolone is a highly effective postmenopausal hormone treatment that has its biological activity dependent on metabolism to 3alpha- and 3beta-OH tibolone, which bind solely to the estrogen receptor. Despite the high levels of estrogen receptor-binding metabolites in the circulation, the endometrium becomes atrophic, suggesting inactivation of the estrogen response in this tissue which may be due to the progestogenic activity of tibolone and the Delta-4 tibolone metabolite. We evaluated the effects of tibolone and its metabolites on tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) expression in human endometrial stromal cells (HESCs). Since TF and PAI-1 exhibit long-term in vivo and in vitro up-regulation by progestin they serve as endpoints for assessing chronic effects of progestin exposure. Confluent HESCs were primed in serum-containing medium with vehicle control, 10(-8)mol/L estradiol, 10(-7)mol/L medroxyprogesterone acetate, or 10(-8) to 10(-6)mol/L tibolone or its metabolites, then switched to a defined medium with corresponding vehicle or steroids. After 24h, ELISAs indicated that the progestin elevated TF (6.2-fold +/-3.0; p<0.05) and PAI-1 (eight-fold +/-2.1; p<0.05) levels, whereas the cells were refractory to estradiol exposure. Tibolone and Delta-4 tibolone (10(-8) to 10(-6)mol/L) were as effective as 10(-7)mol/L medroxyprogesterone acetate in enhancing TF and PAI-1 output (p<0.05). Unexpectedly, at the higher concentrations 3alpha- and 3beta-OH tibolone also elevated TF and PAI-1 expression (p<0.05). Western blotting confirmed the ELISA results. Our findings suggest that HESCs metabolize 3alpha- and 3beta-OH tibolone to tibolone and subsequently to Delta-4 tibolone, which can both stimulate the progesterone receptor. Since TF and PAI-1 promote hemostasis by complementary mechanisms, our findings account for the reduced occurrence of abnormal uterine bleeding associated with tibolone therapy.
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8063, USA. frederick.schatz@yale.edu
authors: Frederick
authors: F
authors: Schatz
authors: Edward
authors: E
authors: Kuczynski
authors: Helenius J
authors: HJ
authors: Kloosterboer
authors: Lynn
authors: L
authors: Buchwalder
authors: Caroline
authors: C
authors: Tang
authors: Graciela
authors: G
authors: Krikun
authors: Charles J
authors: CJ
authors: Lockwood
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009652:Norpregnenes / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011372:Progestins / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis*; D014592:Uterine Hemorrhage / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D009652:Norpregnenes; D017395:Plasminogen Activator Inhibitor 1; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C051321:SERPINE1 protein, human; D013925:Thromboplastin; C027385:tibolone