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      Inhibitory effect of ethinylestradiol on coagulation factors in rats

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      Experimental Animals
      Japanese Association for Laboratory Animal Science
      coagulation, estrogens, male rat

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          Abstract

          Epidemiological and experimental data have indicated the beneficial and adverse effects of estrogenic replacement therapy. In the present study, we explored the effect of ethinylestradiol (EE) and 17β-estradiol (E 2) on screening tests, prothrombin time (PT) and activated partial thromboplastin time (APTT), as well as the activity of coagulation factors (FVII, FX, FXI, and FXII) in male Wistar rats. Animals were injected subcutaneously during three consecutive days with EE or E 2 (1, 3, 10, and 30 mg/kg) and propylene glycol (0.3 ml; vehicle, V). EE produced significant increments ( P<0.05) on PT (8, 13, 15, and 10%) and APTT (32, 35, and 28%), whereas E 2 did not show any effect. EE diminished the activity of factors VII (−10, −13, and −10%) and X (−10, −9, −15, and −14%; P<0.05), and E 2 (1 mg/kg) produced a modest increment (8%; P<0.05) on FX only. E 2 (10 mg/kg) showed a diminution of 9% ( P<0.05), while EE did not produce any response on factor XII. EE diminished (−15, −14, −19, and −17%) but E 2 augmented (10, 14, 24, and 24%) factor XI activity ( P<0.05). Our findings suggest that EE and E 2 produce different effects on coagulation and that EE seems to act across an inhibitory mechanism of coagulation factor activity in the present experimental model.

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          Most cited references21

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          The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies.

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            Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study.

            Combined oral contraceptives (OC) are known to increase the risk of venous thromboembolism. The aim of this randomized, cycle-controlled, cross-over study in 28 healthy volunteers was to assess potential differences between the effects of an OC containing 150 microg levonorgestrel (as representative of the so-called second generation OC) and an OC containing 150 microg desogestrel (as representative of the third generation OC) in combination with 30 microg ethinylestradiol on several coagulation factors and markers of thrombin formation. All participants used each OC for two cycles, and were switched to the other OC after a washout period of two menstrual cycles. The plasma concentrations of factors II, VII, X, and fibrinogen significantly increased during use of both the levonorgestrel- and desogestrel-containing OC's. The plasma concentrations of factor VIII increased, and of factor V decreased, changes which only reached statistical significance during the use of the desogestrel-containing OC. During exposure to the desogestrel-containing OC, as compared with the levonorgestrel-containing OC, both factor VII and factor II showed a greater increase (FVII: 32% and 12% respectively; p <0.0001; FII: 16% and 12% respectively; p = 0.048), whereas factor V showed a greater decrease (-11% and -3% respectively; p = 0.010). Only one of the markers for ongoing coagulation (prothrombin fragment 1+2) showed a significant increase during OC use, whereas concentrations of thrombin-antithrombin complexes and soluble fibrin remained unchanged. For these markers, there was no difference between the tested OC's. We conclude that there are differences between the effects of levonorgestrel and desogestrel-containing OC's on some coagulation factors. Whether these changes provide a biological explanation for the reported differences in venous thromboembolic risk is as yet unclear. The real challenge now becomes to define a pattern of changes in the various systems which, if affected simultaneously, may tip the hemostatic balance towards a prethrombotic state and may lead to overt clinical venous thromboembolism.
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              17α-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor α.

               Oral estrogen use is associated with changes in plasma levels of many coagulation proteins.  To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation.  Ovariectomized female mice were used to study the impact of oral 17α-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) α and ERβ.  Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-γ, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and α(2) -antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ERα-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ERβ-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5-5 h after EE administration, suggesting a short chain of events leading to its final effects.  Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ERα. © 2010 International Society on Thrombosis and Haemostasis.
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                Author and article information

                Journal
                Exp Anim
                Exp. Anim
                EXPANIM
                Experimental Animals
                Japanese Association for Laboratory Animal Science
                1341-1357
                1881-7122
                9 November 2016
                2017
                : 66
                : 2
                : 107-113
                Affiliations
                Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Z.P. 04510, México
                Author notes
                Address corresponding: R. Jaimez, Laboratorio de Estrógenos y Hemostasia, Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM)
                Article
                16-0084
                10.1538/expanim.16-0084
                5411297
                27829580
                a41c7f16-d9fd-4723-b27f-3cca4603332d
                ©2017 Japanese Association for Laboratory Animal Science

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: http://creativecommons.org/licenses/by-nc-nd/4.0/ )

                History
                : 29 September 2016
                : 21 October 2016
                Categories
                Original

                coagulation,estrogens,male rat
                coagulation, estrogens, male rat

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