Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women: A Randomized Trial

Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest), Lutetia Parisorum, Île-de-France, France
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 09/2003; 23(9):1671-6. DOI: 10.1161/01.ATV.0000087141.05044.1F
Source: PubMed


Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen.
We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17beta-estradiol orally (n=63) or 50 microg 17beta-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio.
Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.

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    • "Spontaneous reports of thrombosis in users of the transdermal patch have raised major public concern about its safety. In contrast to OCs, no gastrointestinal or hepatic first-pass metabolism occurs after transdermal application, and for postmenopausal estrogen therapy it has been suggested that this difference may result in a lower clinical risk of VTE with transdermal estradiol than oral estrogen [12] [13]. So far, no formal studies have been available to investigate whether these spontaneous reports reflect a higher risk of VTE or indeed whether the transdermal contraceptive patch may have a lower risk of VTE than comparable OCs. "
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    ABSTRACT: There is concern that a new transdermal contraceptive patch containing ethinyl estradiol (EE) and the progestin norelgestromin increases the risk for venous thromboembolism (VTE) compared to previously marketed oral contraceptives (OCs). Quantitative information was obtained on the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using OCs, norgestimate (either monophasic or triphasic) and 35 microg EE (norgestimate-35), an OC that has been marketed for over a decade. Nested case-control design based on information from PharMetrics, a US-based company that collects and organizes information on claims paid by managed care plans. The study was nested among all women aged 15 to 44, who started either the contraceptive patch or norgestimate-35 after April 1, 2002. Cases were women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors (idiopathic VTE). Up to four controls were matched to each case by age and calendar time. Odds ratios (ORs) comparing the risk of nonfatal VTE in new users of the two contraceptives and incidence rates of nonfatal VTE for new users of each of the study contraceptives. We identified 68 newly diagnosed, idiopathic cases of VTE in the study population. In the case-control analysis, the OR comparing the contraceptive patch to norgestimate-35 was 0.9 (95% CI 0.5-1.6). The overall incidence rate for VTE was 52.8 per 100,000 women-years (95% CI 35.8-74.9) among users of the contraceptive patch and 41.8 per 100,000 women-years among users of norgestimate-35 (95% CI 29.4-57.6), and the age-adjusted VTE incidence rate ratio (IRR) for current use of the contraceptive patch vs. norgestimate-35 was 1.1 (95% CI 0.7-1.8). The risk of nonfatal VTE for the contraceptive patch is similar to the risk for OCs containing 35 microg ethinylestradiol and norgestimate.
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    • "Oral oestrogen replacement increases the levels of multiple clotting factors and markers of coagulation activation and results in an acquired resistance to activated protein C (Scarabin et al, 1997; Lowe et al, 2001; Oger et al, 2003). In contrast, transdermal HRT has little or no effect on these haemostatic parameters (Scarabin et al, 1997; Lowe et al, 2001; Oger et al, 2003; Post et al, 2003). The thrombotic risk of transdermal (OR 2AE0–2AE1) and oral HRT (OR 2AE1–4AE6) was similar in two case–control studies, although both were limited by the small number of women using the transdermal route (Daly et al, 1996; Perez Gutthann et al, 1997). "
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    ABSTRACT: During their lifetimes, women face several unique situations with an increased risk of venous thromboembolism (VTE). Doctors in a variety of specialties must advise women on the risks of oral contraceptives (OC), hormone replacement or pregnancy. Modern 'low dose' OC are associated with a three to sixfold increased relative risk of VTE. Hormone replacement and selective oestrogen receptor modulators confer a similar two to fourfold increase in thrombotic risk. However, because the baseline incidence of thrombosis is higher in older postmenopausal women, the absolute risk is higher than in younger OC users. The risk of venous thrombosis is six to 10-fold higher during pregnancy than in non-pregnant women of similar age. Thrombophilic disorders increase the thrombotic risk of OC, hormone replacement and pregnancy, especially in women with homozygous or combined defects. This review focuses on recent data estimating the thrombotic risk of hormonal therapies and pregnancy in women with and without other thrombotic risk factors.
    Preview · Article · Sep 2004 · British Journal of Haematology
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