Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat.
Oral contraceptives (OC) and postmenopausal hormone therapy (HT) modulate plasma levels of proteins that regulate blood coagulation. It remains unclear whether the progestin component contributes to these changes. The present study was designed to determine whether progestins modulate two essential plasma anticoagulants, antithrombin (AT) and tissue factor pathway inhibitor (TFPI), in an animal model. Ovariectomized rats were treated orally with three progestins, norethindrone acetate (NETA), trimegestone (TMG), or drospirenone (DSP), either alone or combined with 17alpha-ethyinylestradiol (EE). Plasma AT levels were unchanged. However, TFPI activity was reduced by EE alone (10-100 microg/kg/day) in a dose-dependent manner; NETA (3 or 10 mg/kg/day) reduced TFPI by approximately 40 or approximately 80%, respectively, while TMG and DSP had no effect. NETA and EE effects were blocked by co-administration of ICI-182,780, an estrogen receptor antagonist, suggesting that both responses were likely estrogen receptor-mediated. Reduced TFPI after NETA or EE treatment was not accompanied by changes in TFPI mRNA levels in tissues that express TFPI, but there was a positive correlation between plasma TFPI and total cholesterol. Sex hormone effects on TFPI in this model and as reported in women may help to shift the coagulation balance to a more prothrombotic state. Progestins such as TMG and DSP that lack estrogenic activity could potentially have an improved clinical profile.
Shirk
Rebecca A
RA
Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. shirkr@wyeth.com
Zhang
Zhiming
Z
Winneker
Richard C
RC
D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D002784:Cholesterol / Q000097:blood; D004967:Estrogens / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism*; D023421:Models, Animal; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077563:Norethindrone Acetate; D009641:Norethynodrel / Q000031:analogs & derivatives* / Q000494:pharmacology; D010052:Ovariectomy; D011372:Progestins / Q000494:pharmacology*; D011397:Promegestone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000736:Androstenes; D000991:Antithrombins; D004967:Estrogens; D008074:Lipoproteins; D011372:Progestins; C051928:lipoprotein-associated coagulation inhibitor; C002029:17alpha-ethynylestr-5(10)-ene-3alpha,17beta-diol; D004997:Ethinyl Estradiol; C050319:trimegestone; D009641:Norethynodrel; D002784:Cholesterol; D000077563:Norethindrone Acetate; D011397:Promegestone; C035144:drospirenone; D009640:Norethindrone