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Oral Conjugated Equine Estrogen Increases Plasma Von Willebrand Factor in Postmenopausal Women Leroy E

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Oral Conjugated Equine Estrogen Increases Plasma Von Willebrand Factor in Postmenopausal Women Leroy E View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by 40,Elsevier No. 11,- Publisher 2002 Connector © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)02565-2 Oral Conjugated Equine Estrogen Increases Plasma von Willebrand Factor in Postmenopausal Women LeRoy E. Rabbani, MD, FACC, Nicole A. Seminario, Robert R. Sciacca, ENGSCD, Hong Jun Chen, MD, Elsa-Grace V. Giardina, MD, FACC New York, New York OBJECTIVES We sought to test whether one month of daily oral conjugated equine estrogen (CEE) or transdermal estradiol alters hemostatic factors in postmenopausal subjects. BACKGROUND Estrogen replacement therapy and hormonal replacement therapy (HRT) effect an early increase in cardiovascular events in postmenopausal women. Circulating plasma von Wille- brand factor (vWF) antigen is a marker of generalized endothelial dysfunction and atherothrombosis. METHODS Thirty-eight healthy postmenopausal women (average 59 Ϯ 7 years) were randomized to receive daily oral CEE, 0.625 mg (n ϭ 21); transdermal estradiol, 0.1 mg/day (n ϭ 7); or oral placebo (n ϭ 10) for one month. Blood samples were collected at baseline and after two weeks and four weeks of therapy for measurement of circulating plasma hormones, lipid concen- trations, and hemostatic factors. RESULTS Oral CEE decreased total cholesterol (p Ͻ 0.01) and low-density lipoprotein cholesterol (p Ͻ 0.01), although it increased both triglycerides (p Ͻ 0.05) and high-density lipoprotein cholesterol (p Ͻ 0.01). Transdermal estradiol had no significant effect on lipids. Plasminogen activator inhibitor-1 antigen declined in both oral CEE and transdermal estradiol users, but did not achieve statistical significance. Fibrin D-dimer antigen did not vary significantly in any group. However, oral CEE users had a significant increase in vWF from baseline to four weeks (p Ͻ 0.03) and a decrease in tissue-type plasminogen activator antigen from baseline to four weeks (p Ͻ 0.004), which was significantly different from the change observed in the transdermal estradiol group (p Ͻ 0.05). CONCLUSIONS These data suggest that the oral CEE-mediated increase in plasma vWF may have clinical relevance given the early atherothrombotic effects of HRT in postmenopausal women. (J Am Coll Cardiol 2002;40:1991–9) © 2002 by the American College of Cardiology Foundation Cardiovascular disease is the leading cause of mortality for protective effects of HRT. The secondary prevention trial— women in the U.S. (1,2). The role of hormone replacement the Heart and Estrogen/progestin Replacement Study therapy (HRT) with estrogen and progesterone for primary (HERS)—examined 2,763 subjects with proven coronary and secondary prevention of coronary artery disease in artery disease and randomized them to conjugated equine- women remains controversial. Observational studies have estrogen (CEE) with medroxyprogesterone acetate (MPA) demonstrated that women who had used estrogen- or placebo (16). Over a four-year period, there was no replacement therapy (ERT) with or without progestins (i.e., difference in the number of secondary cardiovascular events HRT) during the menopausal years had a lower incidence of and adverse events from peripheral vascular disease between cardiovascular events, as compared with untreated women the HRT-treated subjects and the placebo-treated subjects (3,4). Indeed, several potential mechanisms attributed to (16). The group receiving HRT experienced a 50% higher ERT or HRT had been considered to account for a cardiac event rate during the first year (absolute excess of beneficial effect. For example, oral exogenous estrogen 1.4%) and a lower rate from the third year onward. The increases the level of high-density lipoprotein (HDL) cho- investigators considered that the results might be attribut- lesterol and decreases the concentration of low-density able to dual effects, such as an immediate prothrombotic, lipoprotein (LDL). Moreover, several studies have sug- proarrhythmic, or proischemic effect that was later out- gested that ERT or HRT exerts a profibrinolytic effect by weighed by slower progression of atherosclerosis. In further reducing plasminogen activator inhibitor-1 (PAI-1), the support of the lack of a benefit from HERS, the Estrogen endogenous inhibitor of tissue-type plasminogen activator Replacement and Atherosclerosis (ERA) trial demonstrated (t-PA) and urokinase plasminogen activator (5–15). that three years of treatment with either CEE or CEE with However, recent studies have cast doubt on the cardio- MPA did not slow the rate of angiographic coronary artery disease progression, compared with placebo, in 309 post- From the Cardiology Division and Center for Women’s Health, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New menopausal women with established coronary artery disease York. This study was supported in part by Grant HL-07406 from the Department of (17). Health and Human Services; Grant RR-00645 from the Research Resources The von Willebrand factor (vWF) has recently been Administration, Bethesda, Maryland; and a grant from Linda and Peter Nisselson. Manuscript received May 2, 2002; revised manuscript received July 1, 2002, proposed as a marker of generalized endothelial dysfunc- accepted August 19, 2002. tion, and as such, may contribute to the development of 1992 Rabbani et al. JACC Vol. 40, No. 11, 2002 Oral Estrogen Increases vWF December 4, 2002:1991–9 four weeks of therapy. At enrollment, each had a history and Abbreviations and Acronyms physical examination. Venous blood samples were collected CEE ϭ conjugated equine estrogen during each visit. At baseline and after four weeks, blood CRP ϭ C-reactive protein was collected for a complete blood count, chemical- ϭ ERT estrogen replacement therapy metabolic profile—including electrolytes, hepatic and renal HDL ϭ high-density lipoprotein cholesterol HRT ϭ hormone replacement therapy function, total cholesterol, LDL cholesterol, HDL choles- LDL ϭ low-density lipoprotein cholesterol terol, triglycerides, estradiol, follicle-stimulating hormone, MPA ϭ medroxyprogesterone acetate progesterone, luteinizing hormone—and urinalysis, as well ϭ PAI-1 plasminogen activator inhibitor-1 as t-PA antigen, PAI-1 antigen, fibrin D-dimer, vWF ϭ t-PA tissue-type plasminogen activator antigen, and fibrinogen. After two weeks, blood was also vWF ϭ von Willebrand factor collected for hormonal and hemostatic factors to assess patient compliance. Subjects were entered into a randomized, double-blind, atherothrombotic disease (18,19). vWF is synthesized by placebo-controlled trial using one of two forms of hormonal the endothelium and megakaryocytes, and increased con- replacement: oral CEE (Premarin), 0.625 mg/day, or trans- centrations of vWF have been found in patients with dermal estrogen (Climara), 0.1 mg/day. Because concurrent peripheral vascular disease, cerebral vascular disease, and progestins given in conjunction with CEE may offset coronary artery disease (20–22). In addition, patients with estrogenic effects, we elected to treat subjects with estrogen known disease are at greater risk of cardiovascular mortality monotherapy. Subjects were randomized by means of a if they have high concentrations of vWF (21–25). The random table to three groups in a ratio of 2:1:1, as to Hoorn study of 631 patients demonstrated that increased whether they received oral CEE, transdermal estrogen, or vWF is independently associated with cardiovascular and oral placebo, respectively. The rationale for the randomiza- all-cause mortality in both diabetic and nondiabetic patients tion scheme, which favored oral administration, was the (26). consideration that the majority of women prescribed post- We hypothesized that the early effects of treatment with menopausal ERT use CEE. oral CEE in postmenopausal women might increase mark- There were 55 subjects enrolled: 48 were randomized, ers associated with endothelial dysfunction, such as vWF. and 38 completed the trial. Three subjects randomized to Therefore, we conducted a short-term study and measured oral CEE did not complete the study because of stomach the concentrations of vWF, lipids, and other hemostatic upset (n ϭ 1) or noncompliance (n ϭ 2). Three subjects factors in postmenopausal subjects receiving daily oral CEE randomized to transdermal estrogen did not complete the versus transdermal estradiol or placebo for one month. In study because of vaginal bleeding (n ϭ 1), noncompliance this study, we demonstrate that one-month treatment with (n ϭ 1), and elective withdrawal (n ϭ 1). Four randomized oral CEE, but not transdermal estradiol, significantly in- to placebo did not complete the study because of migraine creases vWF, thereby potentially increasing the likelihood headache (n ϭ 1), noncompliance (n ϭ 1), a hormone of cardiovascular events. concentration that did not meet entry criteria for menopause ϭ METHODS (n 1), and generalized discomfort following medication (n ϭ 1). Thirty-eight postmenopausal subjects completed The Institutional Review Board of the Columbia– the study. The subjects (average age 59 Ϯ 7 years) received Presbyterian Medical Center approved the protocol, and daily oral CEE, 0.625 mg (n ϭ 21); transdermal estradiol, written, informed consent was obtained from each subject, 0.1 mg/day (n ϭ 7); or oral placebo (n ϭ 10) for one month. in accordance with institutional guidelines. Subjects who Plasma samples were collected before and after treatment were postmenopausal for at least one year participated. in the morning, at the same time of the day for each visit. Menopausal status was confirmed by measures of the Blood samples were drawn at rest from a large antecubital estradiol concentration (Ͻ50 pg/ml) and follicle- vein into 0.1 mol/liter trisodium citrate tubes for analysis of stimulating hormone (Ͼ20 mU/ml), consistent with meno- t-PA antigen, PAI-1 antigen, fibrin D-dimer antigen, and pause. No subject was currently taking or had previously vWF. The tubes were immediately centrifuged and spun at taken ERT within the past year. Exclusion criteria included 3,000g for 20 min at 4°C.
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