help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Luyer, M. D. P.
Right arrow Articles by Miller, V. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Luyer, M. D. P.
Right arrow Articles by Miller, V. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CHOLESTEROL
*ESTROGENIC SUBSTANCES, CONJUGATED
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 8 3629-3634
Copyright © 2001 by The Endocrine Society

Endocrine Care

Prospective Randomized Study of Effects of Unopposed Estrogen Replacement Therapy on Markers of Coagulation and Inflammation in Postmenopausal Women

M. D. P. Luyer, S. Khosla, W. G. Owen and V. M. Miller

Departments of Surgery, Physiology, and Biophysics (M.D.P.L., V.M.M.) and Biochemistry/Molecular Biology (W.G.O.), and Endocrine Research Unit (S.K.), Mayo Clinic and Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. V. M. Miller, Departments of Surgery, Physiology, and Biophysics, Mayo Clinic and Foundation, Rochester, Minnesota 55905.

Abstract

Estrogen replacement therapy decreases the risk of arterial disease while at the same time increases the risk for venous thrombosis. Whether a common mechanism(s) of coagulation and inflammation contributes to both responses is unclear. This study determined simultaneous effects of estrogen replacement therapy on regulators of the direct (extrinsic) pathway for activation of coagulation, coagulation, and the acute phase response. Plasma from 26 postmenopausal women without risk factors for cardiovascular disease was collected before (baseline) and after 3 months of treatment with either conjugated equine estrogen (Premarin, 0.625 mg/d) or placebo. Plasma lipids, tissue factor pathway inhibitor antigen and activity, plasminogen, prothrombin, P-selectin, {alpha}1-protease inhibitor, and C-reactive protein were measured. Estrogen replacement therapy significantly reduced mean concentrations of tissue factor pathway inhibitor (antigen and activity; P < 0.001), which were correlated significantly to decreases in low density lipoprotein (r2 = 0.71). Plasminogen and C-reactive protein increased significantly. Other parameters were unchanged. The results of this prospective study suggest that 3 months of estrogen replacement therapy in healthy postmenopausal women decreases low density lipoprotein with simultaneous decreases in tissue factor pathway inhibitor, a major inhibitor of the extrinsic coagulation pathway, and increases C-reactive protein, a component of the acute phase response. Concomitant changes in these parameters may reduce the risk for arterial disease while altering the threshold for thrombotic events.

OBSERVATIONAL STUDIES indicate that the incidence of coronary artery disease is lower in postmenopausal women using hormone replacement therapy (primary prevention) than in age-matched men or women not using hormone replacement (1, 2, 3). Paradoxically, the incidence of venous thrombosis is increased in postmenopausal women using hormone replacement for primary and secondary prevention of coronary artery disease and in men using estrogen replacement for treatment of prostate cancer and for sex transformation (4, 5, 6, 7). The mechanisms underlying this paradox are unclear. Estrogen increases plasma concentrations of C-reactive protein (8, 9, 10), a marker of the acute phase response associated with inflammation and immunological challenge and a risk factor for cardiovascular disease (11, 12). Inflammation or a proinflammatory state might indirectly contribute to an increased risk of venous thrombosis. For example, leukocytes adhering to venous valves may serve as loci for the formation of thrombi (13). The effects of estrogen/hormone replacement on plasma proteins involved with both thrombosis and fibrinolysis remain equivocal, with increases, decreases, or no effect reported on factors such as fibrinogen or plasminogen (14, 15, 16, 17, 18). Differences in study design, including subject inclusion criteria and type and duration of hormone replacement might account for the varying results (19, 20, 21, 22, 23, 24, 25, 26, 27). Tissue factor pathway inhibitor (TFPI) inactivates the factor VIIa-tissue factor complex and inhibits factor Xa (28). In blood, TFPI is bound to low density lipoproteins (LDLs) (29). Estrogen/progestin oral contraceptives reduce circulating TFPI with no change in LDL in premenopausal women (21).

As the relationship between coagulation and inflammation is ambiguous, it becomes important to define the effects of unopposed estrogen on both types of markers in women without other risk factors for cardiovascular disease. Therefore, the aim of this study was to measure several factors that have been implicated in both coagulation and inflammation. Tissue factor and TFPI were measured as important regulators of the extrinsic blood coagulation pathway. The prothrombin concentration is a risk factor for venous thrombosis. Plasminogen and plasminogen activator inhibitor-1 (PAI-1) are participants in fibrinolysis. Fibrinogen is a plasma-protein involved in both inflammation and thrombosis. As P-selectin is expressed on both platelets and activated endothelial cells, it can adhere platelets to leukocytes and, therefore, may be involved in activation of both thrombosis and inflammation. C-Reactive protein, a risk factor for arterial disease, and {alpha}1-protease inhibitor were measured as markers of the acute phase response. This study fills an important gap in the literature by reporting the effects of unopposed estrogen on regulators of activation of coagulation and the acute phase response in healthy postmenopausal women in a prospective, randomized trial. A better understanding of the temporal relationships in change among these plasma proteins may provide an insight into how estrogen replacement therapy has opposing effects on the arterial and venous circulation.

Materials and Methods

Subjects

This study was reviewed and approved by the institutional review board of Mayo Clinic (Rochester, MN). Twenty-six healthy postmenopausal women (median age, 68.5 yr; range, 55–80) were enrolled in this study over a period of 18 months (October 1997 to April 1999). Inclusion and exclusion criteria are shown in Table 1Go. Participants were recruited by advertisements and most were residents of Olmsted County, MN. Subjects were randomized into two groups according to a computer-generated table. For 3 months one group received a placebo tablet, and the other group was given a tablet containing conjugated equine estrogen (Premarin; 0.625 mg/d). The study coordinator and investigative team performing the blood collection, and assays were blinded as to the group assignment. Three months was chosen as a treatment period because for this duration concomitant use of progestin is not required. Adequate samples were obtained from 25 of the 26 subjects (13 estrogen-treated and 12 placebo-treated). Participant characteristics are given in Table 2Go.


View this table:
[in this window]
[in a new window]
  		Table 1. Inclusion and exclusion criteria

 

View this table:
[in this window]
[in a new window]
  		Table 2. Participant characteristics

 
Samples

Fasting blood samples were collected at baseline, and after 3 months of treatment blood was collected at the same time of day to avoid diurnal activation in parameters into monoject tubes containing EDTA as anticoagulant (Sherwood Medical, St. Louis, MO). The samples were centrifuged at 3000 x g at 20 C for 15 min. Plasma was separated into aliquots of 5 ml and frozen at -70 C. Samples were thawed and refrozen once in smaller aliquots before starting the analyses. All specimens were treated identically.

Laboratory analyses

C-Reactive protein was measured with a latex particle-enhanced immunoturbidimetric assay on a Hitachi 912 automated analyzer. Reagents for the C-reactive protein assay were obtained from Kamiya Biomedical Co. (Seattle, WA). The assay was linear from 0.01–2.0 mg/dl. Tissue factor and TFPI were measured by ELISA (American Diagnostica, Greenwich CT). A factor Xa inhibition assay was used to measure TFPI activity (American Diagnostica, Greenwich CT). Prothrombin was measured by a kinetic, enzymatic assay (30). A lipid screen was performed by standard enzymatic assays by the Biochemical Genetics Laboratory at Mayo Clinic using selective precipitation and automated enzymatic and colorimetric assays. LDL was calculated using the Friedwald equation. Plasminogen was measured by a chromogenic assay (31). A standard curve was obtained from pooled samples of a normal population. Normal values for women ranged between 65–153%. An ELISA for PAI-1 used a method previously described by Declerck (32). Fibrinogen was measured as clottable protein (33, 34). Fibrinogen concentration was calculated from a standard curve obtained from purified human fibrinogen. Soluble P-selectin fragment was measured by ELISA (R\|[amp ]\|D Systems, Minneapolis, MN). {alpha}1-Protease inhibitor was measured as {alpha}1- antitrypsin by an enzymatic, chromogenic assay in which trypsin was titrated with plasma, and the thrombin substrate was used as an indicator. Blood was diluted 10-fold into Tris-buffered saline, pH 7.8. Ten microliters of a 100-µM solution of trypsin was added. This mixture was incubated for 3 min for the antitrypsin inhibit the trypsin. Twenty-five microliters of this mixture were added to a cuvette containing 1 ml buffer, then 25 µl 1 mM chromogenic substrate were added to the cuvette, and the rate of p-nitroaniline generation was measured. The amount of {alpha}1-protease inhibitor was calculated from percent inhibition of a blank that contained uninhibited trypsin.

Statistical analyses

The sample size for this study provides 90% power of detection with group changes of 1 SD or greater and 90% power between group differences of 1.4 SD or greater. Statistical analyses included a paired t test to compare changes from baseline to end points within groups. A two-sample t test of the change in estrogen groups vs. the change in placebo groups was performed. This is equivalent to the test for treatment by time interaction from a repeated measure ANOVA. The method of Brown and Forsythe (35) was used to test for equal variance between the estrogen and placebo groups. A method by Pitman (36) was used to test for equal variance between the paired samples of before and after estrogen treatment. The Wilcoxon signed rank test was used for paired comparisons when variances were not equal. Differences in fluctuations of {alpha}1-protease inhibitor were measured (change between baseline and end point) between the placebo and the estrogen-treated group. Statistical significance was accepted at P < 0.05.

Results

Regulators of the direct (extrinsic) pathway for activation of coagulation

Plasma levels of tissue factor were undetectable in most of the samples. Plasma levels of total TFPI and TFPI activity decreased significantly after 3 months of estrogen treatment (Fig. 1Go). Mean concentrations of TFPI in the estrogen group decreased from 54.9 to 38.4 ng/ml. Mean concentrations of TFPI activity in the estrogen group decreased from 56.3 to 43.9 ng/ml. Both the absolute concentration of total TFPI and change from baseline were significantly different between placebo and treated groups after the treatment interval (P < 0.01). LDL also decreased significantly after treatment (Table 3Go). Decreases in TFPI in the estrogen groups correlated with decreases in plasma levels of LDL (r2 = 0.71).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Changes in TFPI antigen concentration and activity in postmenopausal women before (pre) and after (post) treatment with either placebo (upper panel) or Premarin (lower panel) for 3 months. Data are shown as individual values (dots), mean (straight line), median (interrupted line), 5th and 95th percentile (open squares) and SEM (error bars). Results are presented in nanograms per ml. *, Statistically significant difference by t test for paired observations, P < 0.001.

 

View this table:
[in this window]
[in a new window]
  		Table 3. Changes in lipid profile in postmenopausal women treated with placebo or estrogen for 3 months

 
Coagulation and fibrinolytic factors

There were no significant changes in prothrombin and PAI-1 within either the placebo-treated group or the estrogen-treated group (Table 4Go). There was, however, a statistically significant increase in plasminogen from 107–115% with estrogen treatment (Fig. 2Go). No changes were observed in mean plasma levels of fibrinogen and P-selectin (Table 4Go).


View this table:
[in this window]
[in a new window]
  		Table 4. Changes in markers of coagulation and inflammation in postmenopausal women treated with placebo or estrogen for 3 months

 


View larger version (16K):
[in this window]
[in a new window]
  		Figure 2. Changes in plasminogen in postmenopausal women before (pre) and after (post) treatment with either placebo (upper panel) or Premarin (lower panel) for 3 months. Data are shown as individual values (dots), mean (straight line), median (interrupted line), 5th and 95th percentile (open squares), and SEM (error bars). Results are presented as a percentage of plasminogen concentration in a normal population, with normal values for women that range between 65–153%. *, Statistically significant difference by t test for paired observation, P = 0.001.

 
Markers of inflammation

There was a significant increase in mean plasma concentrations of C-reactive protein in the estrogen-treated group compared with the placebo group after 3 months of treatment (Fig. 3Go). Estrogen treatment increased the mean concentration of C-reactive protein from 1.2 to 3.5 mg/L. In addition to the increase in mean concentration of C-reactive protein in the estrogen group, there was an increase in interindividual variability, which is reflected in a higher SD (P < 0.001). The median before treatment was significantly less than the median after treatment (P = 0.005). No statistically significant changes in mean circulating concentrations {alpha}1-protease inhibitor were observed within the estrogen-treated group (Table 4Go). However, fluctuations in this parameter between baseline and end point were reduced with estrogen treatment (P < 0.02). Furthermore, the variance in the estrogen-treated group was also decreased (P < 0.02). No statistically significant correlations were found between decreased fluctuations of {alpha}1-protease inhibitor and increases in C-reactive protein.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 3. Changes in C-reactive protein in postmenopausal women before (pre) and after (post) treatment with either placebo (upper panel) or Premarin (lower panel) for 3 months. Data are shown as individual values (dots), mean (straight line), median (interrupted line), 5th and 95th percentile (open squares), and SEM (error bars). *, Statistically significant difference by t test for paired observations, P = 0.002. Variance in the data increased significantly after treatment (P < 0.001) by the method of Pitman (36 ). The difference in the median before treatment (0.11) was significantly less than the median after treatment (0.27) by Wilcoxon signed rank test (P = 0.0005).

 
Discussion

Results of this prospective randomized study indicate that treatment with unopposed estrogen in postmenopausal women affects simultaneously components of the extrinsic pathway of coagulation involving production of tissue factor, fibrinolysis, and the inflammatory acute phase response (Fig. 4Go). This conclusion is supported by changes in components associated with each process including decreases in TFPI (antigen and activity), increases in plasminogen, and increases in C-reactive protein. Decreases in TFPI activity reflect the functional importance of decreases in absolute concentrations of TFPI. As expected, tissue factor was not detectable in most of the samples (29). It is likely that decreases in TFPI are associated with and may be secondary to the simultaneous decreases in LDL, as most of the TFPI in plasma is bound to this lipoprotein. Decreases in LDL together with statistically significant changes in high density lipoprotein, cholesterol, and triglycerides are consistent with reported effects of estrogen (37), thus providing proof of treatment efficacy. These results differ from observations of combined estrogen/progestin treatment in premenopausal women, in whom decreases in TFPI were observed with no changes in lipid profile (21). Despite these differences, the similar effects on TFPI by estrogen and combined therapy suggest a common underlying mechanism by which estrogen might shift the threshold for activation of coagulation.



View larger version (22K):
[in this window]
[in a new window]
  		Figure 4. Schematic of possible interactions among coagulation, fibrinolysis, and inflammatory processes and effects of estrogen. {uparrow}, Increase; {downarrow}, decrease; {updownarrow}, increased variability; ?, interactions and modulations by estrogen are unknown.

 
Increases in plasminogen and decreases in PAI-1 are consistent with observations from other studies and indicate that fibrinolysis may be affected by hormone replacement, specifically estrogen replacement (15, 17, 19, 38). The lack of statistical significance in decreases in PAI-1 concentrations may be due to the number of patients in the present study. Plasma samples were collected around the same time of day so as to reduce variability in the circadian concentration of PAI-1 (17).

The lack of effect of estrogen treatment on fibrinogen concentration observed in the present study is consistent with observations of the larger Postmenopausal Estrogen/Progestin Interventions trial (39). Fibrinogen levels may be independently related to lifestyle and physical characteristics, including age, obesity, smoking, alcohol intake, and high density lipoprotein and LDL cholesterol (40). Although changes in fibrinogen may be a predictor of coronary disease, absolute plasma levels of fibrinogen may not be an independent risk factor. Therefore, when comparing results regarding changes in blood markers for coagulation and inflammation among studies, it becomes important to consider various risk factors of participants, especially smoking, body mass index, age, diabetes, and use of statins or antiinflammatory drugs (4, 39, 40, 41), as well as type and duration of hormone treatment. In the present study participants were nonsmokers with body mass index in the nonobese range. Therefore, the effects of estrogen on the various parameters in the present study can be considered without the confounding influences of these two known risk factors for cardiovascular disease (42).

Increases in C-reactive protein with estrogen treatment are consistent with the results of other studies (8, 9, 10). A significant strength of the present data is that they represent the effects of unopposed estrogen in one dose, which was not the case in other cross-sectional studies, where women on any hormone replacement therapy were included. Therefore, the results of the present study support the speculation from Walsh and co-workers (10) that a rise in C-reactive protein is due to estrogen treatment and are in agreement with results of cardiovascular health studies and Postmenopausal Estrogen/Progestin Interventions trials (8, 43). An additional finding of the present study is the increased interindividual variability of C-reactive protein with estrogen treatment. This increased variability may represent a secondary, rather than direct, effect of estrogen on protein synthesis. Likewise, fluctuations, but not the mean concentrations, of {alpha}1-protease inhibitor decreased with estrogen treatment. Although {alpha}1-protease inhibitor is an indicator of the acute phase response, fluctuations of {alpha}1-protease inhibitor were not directly correlated to the fluctuations of or the rise in C-reactive protein. Nonspecific effects of estrogen on protein synthesis can be ruled out, as prothrombin was not altered by the treatment.

None of the participants in this study reported venous thrombosis during the study period, as would be anticipated from the size of the study group. Although meaningful speculation on underlying thrombogenic mechanisms is not yet plausible, the impact of estrogen therapy on proteins involved in both coagulation and inflammation suggests further investigation of these processes is warranted. There are several limitations of the present study. The number of patients was small, and measurement of changes in plasma proteins represents those of a single time point (3 months of treatment). This can contribute to some differences in results between this study and earlier studies, which looked at similar parameters at different treatment end points. Furthermore, differentiation between simultaneous effects of direct effects of estrogen alone or physiological compensation to alteration in some other parameters is difficult. However, a strength of the present study is that it prospectively defines changes simultaneously in plasma markers of both coagulation and its initiators and inflammation in a defined population with no cardiovascular disease and no cardiovascular risk factors randomized to treatment group.

Acknowledgments

We gratefully acknowledge Mr. Charles Rowland, Department of Biostatistics, for his expert statistical consultation.

Footnotes

This work was supported in part by grants from American Home Products; NHLBI, NIH (HL-51736); and The Netherlands Heart Foundation (to M.D.P.L.).

Abbreviations: LDL, low density lipoprotein; PAI-1, plasminogen activator inhibitor-1; TFPI, tissue factor pathway inhibitor.

Received August 18, 2000.

Accepted April 24, 2001.

References

  1. Oparil S 1999 Hormones and vasoprotection. Hypertension 33:170–176[Abstract/Free Full Text]
  2. Barrett-Connor E, Wenger NK, Grady D, et al. 1998 Hormone and nonhormone therapy for the maintenance of postmenopausal health: the need for randomized controlled trials of estrogen and Raloxifene. J Women Health 7:839–847[Medline]
  3. Stampfer MJ, Colditz GA, Willett WC 1991 Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N Engl J Med 325:756–762[Abstract]
  4. Hulley S, Grady D, Bush T, et al. 1998 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613[Abstract/Free Full Text]
  5. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S 1996 Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 348:977–980[CrossRef][Medline]
  6. van Kesteren PJM, Asscheman H, Megens JAJ, Gooren LJG 1997 Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 47:337–342[CrossRef][Medline]
  7. Chang A, Yeap B, Davis T, et al. 1996 Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. J Clin Oncol 14:2250–2257[Abstract]
  8. Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP 1999 Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 19:893–899[Abstract/Free Full Text]
  9. Ridker PM, Hennekens CH, Nader R, Buring JE, Manson JE 1999 Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 100:713–716[Abstract/Free Full Text]
  10. Walsh BW, Paul S, Wild RA, et al. 2000 The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 85:214–218[Abstract/Free Full Text]
  11. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH 1997 Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979[Abstract/Free Full Text]
  12. Gabay C, Kushner I 1999 Mechanisms of disease: acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454[Free Full Text]
  13. Stewart GJ 1993 Neutrophils and deep venous thrombosis. Haemostasis 23:127–140
  14. Frohlich M, Schunkert H, Hense H-W, et al. 1998 Effects of hormone replacement therapies on fibrinogen and plasma viscosity in postmenopausal women. Br J Haematol 100:577–581[CrossRef][Medline]
  15. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M 1997 Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women: a randomized controlled trial. Arterioscler Thromb Vasc Biol 17:3071–3078[Abstract/Free Full Text]
  16. Walsh BW, Kuller LH, Wild RA, et al. 1998 Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279:1445–1451[Abstract/Free Full Text]
  17. Katz RJ, Hsia J, Walker P, Jacobs H, Kessler C 1996 Effects of hormone replacement therapy on the circadian pattern of atherothrombotic risk factors. Am J Cardiol 78:876–880[CrossRef][Medline]
  18. Kon Koh K, Horne III MK, Csako G, Waclawiw MA, Cannon RO, III 1999 Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women. Am J Cardiol 83:466–469[CrossRef][Medline]
  19. Conard J, Gompel A, Pelissier C, Mirabel C, Basdevant A 1997 Fibrinogen and plasminogen modifications during oral estradiol replacement therapy. Fertil Steril 68:449–453[CrossRef][Medline]
  20. Rosenson RS, Tangney CS, Mosca LJ 1998 Hormone replacement therapy improves cardiovascular risk by lowering plasma viscosity in postmenopausal women. Arterioscler Thromb Vasc Biol 18:1902–1905[Abstract/Free Full Text]
  21. Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG 1999 Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 60:175–180[CrossRef][Medline]
  22. Lip GYH, Blann AD, Jones AF, Beevers DG 1997 Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. Am Heart J 134:764–771[CrossRef][Medline]
  23. Lindoff C, Peterson F, Lecander I, Martinsson G, Astedt B 1996 Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas 24:43–50[CrossRef][Medline]
  24. Grodstein F, Stampfer MJ, Goldhaber SZ, et al. 1996 Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 348:983–987[CrossRef][Medline]
  25. Gebara OC, Mittleman MA, Sutherland P, et al. 1995 Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 91:1952–1958[Abstract/Free Full Text]
  26. Saleh AA, Dorey LG, Dombrowski MP, et al. 1993 Thrombosis and hormone replacement therapy in postmenopausal women. Am J Obstet Gynecol 169:1554–1557[Medline]
  27. Bonduki CE, Lourenco DM, Baracat E, et al. 1998 Effect of estrogen-progestin hormonal replacement therapy on plasma antithrombin III of postmenopausal women. Acta Obstet Gynecol Scand 77:330–333[CrossRef][Medline]
  28. Rao LVM, Rapaport SI 1987 Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 69:645–651[Abstract/Free Full Text]
  29. Sandset PM, Abildgaard U 1991 Extrinsic pathway inhibitor: the key to feedback control of blood coagulation initiated by tissue thromboplastin. Haemostasis 21:219–239[Medline]
  30. Bergstrom K, Egberg N 1978 Determination of vitamin K sensitive coagulation factors in plasma. Studies on three methods using synthetic chromogenic substrates. Thromb Res 12:531–547[CrossRef][Medline]
  31. Friberger P, Eriksson E, Gustavsson S, Claeson G 1978 Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 7:138–145[Medline]
  32. Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I 1988 Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 71:220–225[Abstract/Free Full Text]
  33. Morrison PR 1947 Preparation and properties of serum and plasma proteins. XV. Some factors influencing the quantitative determination of fibrinogen. J Am Chem Soc 69:2723–2731[CrossRef]
  34. Mann FD, Shonyo ES, Mann FC 1951 Effect of removal of the liver on blood coagulation. Am J Physiol 164:111–116
  35. Brown MB, Forsythe AB 1974 Robust tests for the equality of variances. J Am Stat Assoc 69:364–367[CrossRef]
  36. Pitman EG 1939 A note on normal correlation. Biometrika 31:9–12[Free Full Text]
  37. Takkanen MJ 1996 The menopause and hormone replacement therapy: lipids, lipoproteins, coagulation and fibrinolytic factors. Maturitas 23:209–216[CrossRef][Medline]
  38. Kon Koh K, Mincemoyer R, Bui MN, et al. 1997 Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 336:683–690[Abstract/Free Full Text]
  39. The Writing Group for the PEPI Trial. 1995 Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 273:199–208[Abstract/Free Full Text]
  40. Stefanick ML, Legault C, Tracy RP, et al. 1995 Distribution and correlates of plasma fibrinogen in middle-aged women: initial findings of the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Arterioscler Thromb Vasc Biol 15:2085–2093[Abstract/Free Full Text]
  41. Grady D, Wenger NK, Herrington D, et al. 2000 Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study. Ann Intern Med 132:689–696[Abstract/Free Full Text]
  42. Tracy RP, Psaty BM, Macy E, et al. 1997 Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in elderly subjects. Arterioscler Thromb Vasc Biol 17:2167–2176[Abstract/Free Full Text]
  43. Cushman M, Legault C, Barrett-Connor E, et al. 1999 Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 100:717–722[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J EndocrinolHome page
I. C Villar, A. J Hobbs, and A. Ahluwalia
Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor
J. Endocrinol., June 1, 2008; 197(3): 447 - 462.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Jayachandran, A. Sanzo, W. G. Owen, and V. M. Miller
Estrogenic regulation of tissue factor and tissue factor pathway inhibitor in platelets
Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1908 - H1916.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
E. Nikander, M. Metsa-Heikkila, A. Tiitinen, and O. Ylikorkala
Evidence of a Lack of Effect of a Phytoestrogen Regimen on the Levels of C-Reactive Protein, E-Selectin, and Nitrate in Postmenopausal Women
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5180 - 5185.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
M. Yilmazer, V. Fenkci, S. Fenkci, O. Aktepe, M. Sonmezer, and G. Kurtay
Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post-menopausal women
Hum. Reprod., July 1, 2003; 18(7): 1531 - 1535.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Davison and S. R. Davis
New Markers for Cardiovascular Disease Risk in Women: Impact of Endogenous Estrogen Status and Exogenous Postmenopausal Hormone Therapy
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2470 - 2478.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
L. E. Rabbani, N. A. Seminario, R. R. Sciacca, H. J. Chen, and E.-G. V. Giardina
Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women
J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1991 - 1999.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
E.M. Bladbjerg, S.O. Skouby, L.F. Andersen, and J. Jespersen
Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor
Hum. Reprod., December 1, 2002; 17(12): 3235 - 3241.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Jayachandran and V. M. Miller
Ovariectomy upregulates expression of estrogen receptors, NOS, and HSPs in porcine platelets
Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H220 - H226.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
D. A. Lewis, M. P. Bracamonte, K. S. Rud, and V. M. Miller
Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Effects of sex and ovariectomy on responses to platelets in porcine femoral veins
J Appl Physiol, December 1, 2001; 91(6): 2823 - 2830.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Luyer, M. D. P.
Right arrow Articles by Miller, V. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Luyer, M. D. P.
Right arrow Articles by Miller, V. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CHOLESTEROL
*ESTROGENIC SUBSTANCES, CONJUGATED

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals