title: Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis: A Randomized, Placebo-Controlled Study in Postmenopausal Women Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries. Elevated levels of sE-selectin in post-menopausal females are decreased by hormone replacement therapy to levels observed in pre-menopausal females. Effects of percutaneous estradiol and conjugated estrogens on the level of plasma proteins and triglycerides in postmenopausal women. Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration Effects of hormone replacement therapy in rheumatoid arthritis: a double blind placebo-controlled study. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Estrogen plus progestin and the risk of coronary heart disease. Increased plasma concentrations of TGF-beta1 after hormone replacement therapy. Reduced expression of endothelial cell markers after long-term transdermal hormone replacement therapy in women with coronary artery disease. The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease: results from the estrogen in women with atherosclerosis study. Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women. Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised, placebo-controlled trial. Clinical equivalence of intranasal and oral 17beta-estradiol for postmenopausal symptoms. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Acute Effects of Transdermal 17β-Estradiol on Hemostatic Variables after 24-hour Treatment Randomized Comparison of Intranasal and Transdermal Estradiol A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women. Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.
abstract: Objective —The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C ( APC ) , an important risk factor for venous thrombosis , and levels of related proteins , such as protein S , protein C , and prothrombin . Methods and Results —In a r and omized , double-blind , placebo-controlled study , 152 healthy hysterectomized postmenopausal women received daily either placebo ( n=49 ) , transdermal 17&bgr;-estradiol ( E2 ) 50 & mgr;g ( tE2 group , n=33 ) , oral E2 1 mg ( oE2 group , n=37 ) , or oral E2 1 mg combined with gestodene 25 & mgr;g ( oE2+G group , n=33 ) for 13 28-day treatment cycles , followed by 4 cycles of placebo for each group . Plasma sample s were collected at baseline and in cycles 4 , 13 , and 17 . In cycle 13 , significant increases versus baseline and placebo were found in normalized APC sensitivity ratios ( nAPCsr ) in all treated groups ( tE2 , + 26.9 % ; oE2 , + 102.7 % ; oE2+G , + 69.9 % ) . Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE2 group . In addition , compared with baseline and placebo , after 13 cycles , decreases were observed in total protein S ( tE2 , −4.1 % ; oE2 , −7.9 % ; oE2+G , −5.8 % ) , free protein S ( tE2 , −7.1 % ; oE2 , −8.4 % ; oE2+G , −5.2 % ) , and protein C in the oE2+G group ( −6.4 % ) , but these changes did not explain the increase in nAPCsr . Changes in prothrombin were small and also did not affect the nAPCsr . Conclusions —Increases were observed in resistance to APC , which were more pronounced in the oral treatment groups than in the transdermal group . The increase in resistance to APC was not explained by changes in protein S , protein C , or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy AIMS AND BACKGROUND Coronary endothelial dysfunction improves after acute oestradiol treatment in women with angina and normal coronary angiograms . We sought to analyse whether this effect is also seen in the peripheral circulation and whether it is sustained after a mid-term period of treatment . METHODS We studied 20 women with angina , signs suggestive of myocardial ischaemia and normal coronary angiograms . In five of them , coronary and peripheral endothelial functions were studied at baseline . Brachial artery flow-mediated dilation was reanalysed after 24 h of transdermal oestradiol treatment . In the other 15 women , brachial artery vasoreactivity was studied at baseline and after a 6-week period of treatment with transdermal oestradiol and medroxyprogesterone ( HRT ) or placebo in a double-blinded crossover fashion . RESULTS An abnormal coronary artery response to acetylcholine was observed in all women as well as impaired brachial flow-mediated dilation . Brachial flow-mediated dilation significantly increased after 24 h of oestradiol treatment ( 4.8+/-0.8 % vs 0.06+/-0.6 % , P<0.001 ) . Peripheral flow-mediated dilation also increased after a 6-week period of HRT compared with baseline ( 4.1+/-3 % vs 0.4+/-1 % , P<0.01 ) and placebo treatment ( 4.1+/-3 % vs 0.6+/-1.7 % , P<0.01 ) . CONCLUSION Impaired endothelium-dependent vasodilation exists both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms .  Flow-mediated dilation improves in these women after short and mid-term therapy with transdermal oestradiol irrespective of concomitant progesterone use Observational epidemiological studies have shown that mortality from coronary heart disease is reduced in post-menopausal women by hormone replacement therapy ( HRT ) . The aim of this study was to measure sE-selectin levels in post-menopausal females before and after HRT  and to compare these with pre-menopausal females and aged matched males . Post-menopausal females ( n = 70 ) were given HRT or no treatment to act as a control group . sE-selectin levels were significantly lower in the pre-menopausal ( n = 36 ) when compared with the post-menopausal females ( n = 70 ) ( p = 0.027 ) , whereas no difference between two age matched male groups was found ( n = 40 ) . Oral and transdermal HRT significantly decreased sE-selectin levels ( p<0.0001 and p = 0.0005 respectively ) with no change in the control group . The reduction in the levels of this marker of endothelial activation after HRT , may reflect a decrease in leucocyte/endothelial interaction which may reduce atherosclerotic risk in post-menopausal females Percutaneous administration of estradiol ( E2 ) is a new substitutive treatment for postmenopausal women . In order to compare hepatic action of percutaneous E2 with that of conjugated estrogens , 18 postmenopausal women were allocated at r and om to receive one of these two types of natural estrogens for 21 days . Eight patients ( group I ) received conjugated estrogens orally , 1.25 mg daily . Ten patients ( group II ) were told to apply percutaneous E2 ointment , 5 gm ( i.e. , 3 mg of E2 ) , each evening on the abdominal skin .  E2 , estrone ( E1 ) , follicle-stimulating hormone ( FSH ) , and luteinizing hormone ( LH ) , and several markers of estrogen action were evaluated before and after treatment . Both types of treatment were biologically effective , as indicated by the decrease in plasma gonadotropins and the increase in estrogen levels . However , conjugated estrogens produced a greater increase in E1 than in E2 ; hence , the E2/E1 ratio was 0.57 in group I , whereas it was approximately 1 in group II . Plasma renin substrate increased significantly ( by 180 % ) in group I but not in group II . In the same way , conjugated estrogens produced a modest ( 12 % ) but significant decrease in antithrombin III , whereas there was no variation with percutaneous E2 . Sex steroid-binding protein was the most sensitive parameter for the hepatic action of estrogen , and increased by 18.66 % with percutaneous E2 and by 150 % with conjugated estrogens .  Plasma triglycerides tended to increase in group I and to decrease in group II , but not significantly . Therefore , percutaneous administration of of E2 , in contrast to conjugated estrogens , can produce plasma levels of estrogens closer to those observed in the follicular phase and less alterations in protein synthesis . This lesser toxicity may be explained partially by the route of administration , since with percutaneous administration of E2 , the steroid bypasses the liver BACKGROUND AND OBJECTIVES The incidence of coronary artery disease ( CAD ) is higher in post-menopausal than in pre-menopausal women . Epidemiological studies suggest that hormone replacement therapy ( HRT ) decreases the risk of cardiovascular disease in post-menopausal women .  HRT could modify the cardiovascular risk via several mechanisms , including modifications in the fibrinolytic system and lipoprotein ( a ) levels . Our study was aim ed at investigating some of these modifications . DESIGN AND METHODS In the cross-sectional part of the study we evaluated several components of the fibrinolytic system , coagulation inhibitors and lipid profile in premenopausal ( n=15 ) and post-menopausal women ( n=64 ) with CAD and compared these parameters with those of healthy pre-menopausal ( n=31 ) and post-menopausal women ( n=88 ) . The prospect i ve part of the study analyzed the effect of HRT with transdermal estrogen with or without progestogen in post-menopausal women with CAD . RESULTS Pre- and postmenopausal women with CAD showed significant lower fibrinolytic activity and higher plasminogen activator inhibitor type 1 ( PAI-1 ) levels than their control groups . Lp(a ) levels were higher in premenopausal women with CAD than in healthy premenopausal women . In post-menopausal women with CAD , HRT induced a significant decrease in PAI-1 and Lp(a ) levels . No significant differences were observed in any parameter studied between the groups treated with transdermal estrogen with and without progestogen . INTERPRETATION AND CONCLUSIONS CAD is associated with a decrease in fibrinolytic activity , possibly due to an increase in PAI-1 levels . An increase in fibrinolytic activity and a decrease in PAI-1 and Lp(a ) levels were observed in CAD women receiving transdermal HRT and these changes may have a favorable impact on the risk of new cardiovascular events in post-menopausal CAD women CONTEXT The Heart and Estrogen/progestin Replacement Study ( HERS ) found no overall reduction in risk of coronary heart disease ( CHD ) events among postmenopausal women with CHD . However , in the hormone group , findings did suggest a higher risk of CHD events during the first year , and a decreased risk during years 3 to 5 . OBJECTIVE To determine if the risk reduction observed in the later years of HERS persisted and result ed in an overall reduced risk of CHD events with additional years of follow-up . DESIGN AND SETTING R and omized , blinded , placebo-controlled trial of 4.1 years ' duration ( HERS ) and subsequent unblinded follow-up for 2.7 years ( HERS II ) conducted at outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS ; 2321 women ( 93 % of those surviving ) consented to follow-up in HERS II . INTERVENTION Participants were r and omly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate ( n = 1380 ) , or placebo ( n = 1383 ) during HERS ; open-label hormone therapy was prescribed at personal physicians ' discretion during HERS II . The proportions with at least 80 % adherence to hormones declined from 81 % ( year 1 ) to 45 % ( year 6 ) in the hormone group , and increased from 0 % ( year 1 ) to 8 % ( year 6 ) in the placebo group . MAIN OUTCOME MEASURES The primary outcome was nonfatal myocardial infa rct ion and CHD death . Secondary cardiovascular events were coronary revascularization , hospitalization for unstable angina or congestive heart failure , nonfatal ventricular arrhythmia , sudden death , stroke or transient ischemic attack , and peripheral arterial disease . RESULTS There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS , HERS II , or overall . The unadjusted relative hazard ( RH ) for CHD events in HERS was 0.99 ( 95 % confidence interval [ CI ] , 0.81 - 1.22 ) ; HERS II , 1.00 ( 95 % CI , 0.77 - 1.29 ) ; and overall , 0.99 ( 0.84 - 1.17 ) . The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups ( RH , 0.97 ; 95 % CI , 0.82 - 1.14 ) , and in analyses restricted to women who were adherent to r and omized treatment assignment ( RH , 0.96 ; 95 % CI , 0.77 - 1.19 ) . CONCLUSIONS Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up . After 6.8 years , hormone therapy did not reduce risk of cardiovascular events in women with CHD . Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD The effects of oral and transdermal administration of estrogen replacement therapy ( ERT ) have been fairly well investigated regarding lipoprotein and carbohydrate metabolism , while the effects of different modes of estrogen administration on the haemostatic system have been less well studied . To delineate and compare the effects of perorally administered conjugated estrogens ( CE ) and transdermally administered estradiol ( E2 ) in doses needed for hormone replacement therapy ( HRT ) on haemostasis parameters , 23 postmenopausal women were engaged in a study with an open cross-over design . The doses compared ( 0.625 mg CE and 50 micrograms E2/24h ) are the lowest which , with few exceptions , eliminate climacteric symptoms . Both CE and E2  increased factor VII : C , factor VII : Ag , and the prothrombin fragment1 + 2 . The increase in factor VII : Ag , however , was significantly higher after treatment with CE . These changes were all towards a state of hypercoagulability . Furthermore , CE decreased plasminogen activator inhibitor ( PAI ) and the thrombin-antithrombin complexes ( TAT ) , as well as antithrombin ( ATIII ) Background — Oral estrogen increases the risk of venous thromboembolism ( VTE ) in postmenopausal women , particularly in those with a prothrombotic mutation .  Transdermal estrogen may be safe with respect to VTE . We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation ( factor V Leiden or prothrombin G20210A mutation ) and VTE risk . Methods and Results — We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France . We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls . Factor V Leiden was associated with a 3.4-fold – increased risk of VTE ( 95 % confidence interval [ CI ] , 2.0 to 5.8 ) , and a prothrombin mutation was associated with a 4.8-fold – increased risk of VTE ( 95 % CI , 2.5 to 9.4 ) . Oral but not transdermal estrogen was associated with an increased risk of VTE ( odds ratio [ OR ] , 4.3 ; 95 % CI , 2.6 to 7.2 ; and OR , 1.2 ; 95 % CI , 0.8 to 1.7 , respectively ) . After adjustment for potential confounding factors , the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold – increased risk of VTE compared with nonusers without mutation ( 95 % CI , 6.9 to 95.0 ) . However , the risk for women with prothrombotic mutation  using transdermal estrogen was similar to that of women with a mutation who were not using estrogen ( OR , 4.4 ; 95 % CI , 2.0 to 9.9 ; and OR , 4.1 ; 95 % CI , 2.3 to 7.4 , respectively ) . Conclusions — In contrast to oral estrogen , transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation . The safety of transdermal estrogen has to be confirmed in r and omized trials AIMS --To study the effects of ovarian hormone replacement therapy ( HRT ) on bone mineral density and disease activity in postmenopausal women with rheumatoid arthritis ( RA ) . METHOD --A placebo controlled double-blind study was carried out on 62 patients with RA , 22 on placebo and 40 on HRT ( transdermal oestradiol patches twice weekly for 48 weeks plus norithisterone tablets when clinical ly indicated ) . Bone mineral density of spine , hip and wrist was measured at 0 and 48 weeks and clinical and laboratory measures of general well-being and disease activity at 0 , 12 , 24 and 48 weeks . RESULTS --Thirteen of 22 ( 59 % ) of placebo and 31 of 40 ( 78 % ) of the HRT group completed 48 weeks in the study . At entry ,  bone mineral density ( BMD ) values in the lumbar spine and femoral neck were similar to those in age and sex matched controls in both treatment groups , whereas at the distal radius , BMD was significantly reduced to approximately 50 % of control values ( both p < 0.001 from controls ) . In the HRT group , spine BMD increased significantly by a median of + 0.94 % at 48 weeks ( p = 0.024 ) , but did not change significantly in the placebo group . BMD at the femoral neck and distal radius did not change in either group . In the HRT group , there was significant improvement in well being as assessed by the Nottingham Health Care Profile ( p < 0.01 ) and in the articular index ( p < 0.05 ) . There were no significant changes in ESR or CRP in either group . CONCLUSION --Transdermal HRT was well tolerated , increased well being , reduced articular index and increased lumbar spine bone density over a one year period in postmenopausal women with RA . Although no laboratory evidence was found of a disease modifying effect , the symptomatic benefits and improvements in bone density indicate that HRT may be a valuable adjunct to conventional antirheumatic therapy in RA BACKGROUND Results of observational studies suggest that hormone replacement therapy ( HRT ) could reduce the risk of coronary heart disease ( CHD ) , but those of r and omised trials do not indicate a lower risk in women who use oestrogen plus progestagen .  The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infa rct ion . METHODS The study was a r and omised , blinded , placebo controlled , secondary prevention trial of postmenopausal women , age 50 - 69 years ( n=1017 ) who had survived a first myocardial infa rct ion . Individuals were recruited from 35 hospitals in Engl and and Wales . Women received either one tablet of oestradiol valerate ( 2 mg ; n=513 ) or placebo ( n=504 ) , daily for 2 years . Primary outcomes were reinfa rct ion or cardiac death , and all-cause mortality . Analyses were by intention-to-treat . Secondary outcomes were uterine bleeding , endometrial cancer , stroke or other embolic events , and fractures . FINDINGS Frequency of reinfa rct ion or cardiac death did not differ between treatment groups at 24 months ( rate ratio 0.99 , 95 % CI 0.70 - 1.41 , p=0.97 ) . Similarly , the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant ( 0.79 , 0.50 - 1.27 , p=0.34 ) . The relative risk of any death ( 0.56 , 0.23 - 1.33 ) and cardiac death ( 0.33 , 0.11 - 1.01 ) was lowest at 3 months post-recruitment . INTERPRETATION Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infa rct ion BACKGROUND Recent r and omized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease ( CHD ) . In this report , we provide the final results with regard to estrogen plus progestin and CHD from the Women 's Health Initiative ( WHI ) . METHODS The WHI included a r and omized primary -prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line . Participants were r and omly assigned to receive conjugated equine estrogens ( 0.625 mg per day ) plus medroxyprogesterone acetate ( 2.5 mg per day ) or placebo . The primary efficacy outcome of the trial was CHD ( nonfatal myocardial infa rct ion or death due to CHD ) . RESULTS After a mean follow-up of 5.2 years ( planned duration , 8.5 years ) , the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits . Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 ( nominal 95 percent confidence interval , 1.00 to 1.54 ; 95 percent confidence interval after adjustment for sequential monitoring , 0.97 to 1.60 ) . The elevation in risk was most apparent at one year ( hazard ratio , 1.81 [ 95 percent confidence interval , 1.09 to 3.01 ] ) . Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy , higher base-line levels of C-reactive protein , other biomarkers , and other clinical characteristics did not significantly modify the treatment-related risk of CHD . CONCLUSIONS Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women , especially during the first year after the initiation of hormone use . This treatment should not be prescribed for the prevention of cardiovascular disease OBJECTIVES AND DESIGN Hormone replacement therapy ( HRT ) in postmenopausal women may reduce the cardiovascular risk . A dominant protective role of transforming growth factor beta ( TGF-beta1 ) on coronary arteries has been proposed . Lp(a ) lipoprotein may block the activation of latent TGF-beta1 . Given this background , we examined the effects of HRT on TGF-beta1 and Lp(a ) lipoprotein in 99 postmenopausal women . The women had angiographically documented coronary heart disease ( CHD ) and were r and omized to either sequential transdermal 17beta-oestradiol for 14 weeks and then medroxyprogesterone ( MPA ) for 14 days ( HRT ) or to a control group ( C ) . RESULTS Serum levels of TGF-beta1 were increased in the HRT group compared with the C group after 3 months ' treatment and this effect was sustained after 12 months . There was a significant reduction in Lp(a ) lipoprotein serum levels after 3 months ' treatment in the HRT group compared with the C group . However , after 12 months , no significant difference in changes in Lp(a ) lipoprotein serum levels was detected between the two groups . CONCLUSION The novel observation that transdermal 17beta-oestradiol in postmenopausal women increases levels of TGF-beta1 and lowers the concentration of Lp(a ) lipoprotein suggests yet another possible mechanism for the cardioprotective effect of HRT . Whereas combination therapy of oestradiol and MPA preserves the beneficial effect on TGF-beta1 , it reduces the unopposed oestradiol effects on Lp(a ) lipoprotein The effects of 12 months hormone replacement therapy ( HRT ) on biochemical markers associated with endothelial function were studied in 98 postmenopausal women with CAD , who were r and omized to transdermal HRT or a control group .  A significant reduction in the levels of von Willebr and factor in the HRT-group compared to controls was seen after 3 months , maintained after 12 months ( p < 0.001 ) . Significant reduction in the HRT-group compared to controls was also seen in VCAM-1 after 3 months , sustained after 12 months ( p = 0.013 and p = 0.045 , respectively ) , and E-selectin was reduced by about 20 % after 3 months on HRT , the reduction being statistically significant after 12 months ( p < 0.001 ) . Significantly reduced levels of ICAM-1 were also seen after 12 months ( p = 0.048 ) . No effects could be observed on tPA-antigen or thrombomodulin . The reduction in procoagulant and proinflammatory markers of endothelial function after long-term transdermal HRT could indicate a beneficial effect on the endothelium and thus a potentially modulating effect on the progression of atherosclerosis in women with CAD Data on the effect of hormone replacement therapy on hemostasis are inconsistent , and there are few data in women with coronary artery disease . In a single-center , open , r and omized study , 118 postmenopausal women with angiographically verified coronary artery disease were r and omized to hormone replacement therapy , given as long-cycle transdermal 17-beta-estradiol ( 50 microg/24 hour ) for 3 months with sequential medroxy-progesterone acetate for 14 days , or to a control group receiving no therapy .  Hemostatic parameters were measured at baseline and after 3 and 12 months of therapy . The coagulation inhibitors antithrombin , protein C , and protein S , but not tissue factor pathway inhibitor , decreased significantly from baseline in the hormone replacement therapy group at both 3 and 12 months as compared with the control group . The absolute decreases within the hormone replacement therapy group were 3 to 10 % . No significant differences between the two treatment groups were observed for the coagulation products prothrombin fragment 1 + 2 or thrombin-antithrombin complex or for D-dimer , although there were significant decreases in the levels within the hormone replacement therapy group . Levels of fibrinogen , activated factor VII , and factor VII antigen were not significantly influenced by hormone replacement therapy treatment . Similarly , nonsignificant changes were detected for the fibrinolytic parameters tissue plasminogen activator activity , tissue plasminogen activator antigen , and global fibrinolytic activity , but plasminogen activator inhibitor type 1 was significantly lower in the hormone replacement therapy group due to a question able increase in the levels in the control group . In conclusion , treatment with transdermal estradiol combined with long-cycle progestins was associated with no net activation of coagulation despite reduced levels of coagulation inhibitors 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 Willebr and factor ( vWF ) antigen is a marker of generalized endothelial dysfunction and atherothrombosis . METHODS Thirty-eight healthy postmenopausal women ( average 59 + /- 7 years ) were r and omized to receive daily oral CEE , 0.625 mg ( n = 21 ) ; transdermal estradiol , 0.1 mg/day ( n = 7 ) ; or oral placebo ( n = 10 ) for one month . Blood sample s were collected at baseline and after two weeks and four weeks of therapy for measurement of circulating plasma hormones , lipid concentrations , and hemostatic factors . RESULTS Oral CEE decreased total cholesterol ( p < 0.01 ) and low-density lipoprotein cholesterol ( p < 0.01 ) , although it increased both triglycerides ( p < 0.05 ) and high-density lipoprotein cholesterol ( p < 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 < 0.03 ) and a decrease in tissue-type plasminogen activator antigen from baseline to four weeks ( p < 0.004 ) , which was significantly different from the change observed in the transdermal estradiol group ( p < 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 OBJECTIVE To establish levels of plasma endothelin-1 in postmenopausal women with increased CV risk as compared with healthy premenopausal women and to measure the effects of different forms of estrogen replacement on plasma endothelin-1 . DESIGN Prospect i ve r and omized study . SETTING University of Southern California Medical Center . PATIENT(S ) We studied 18 postmenopausal women ( mean age 53.4 + /- 4.9 years ) with total cholesterol levels > 240 mg/dL divided into those with and without hypertension as well as in 10 healthy premenopausal women . INTERVENTION(S ) The postmenopausal women were r and omized to receive oral estrone sulfate , transdermal E2 , or placebo for 30 days . MAIN OUTCOME MEASURE(S ) We measured the endothelin-1 levels and total cholesterol  at baseline and after 30 days of estrogen treatment . RESULT ( S ) In the postmenopausal women , endothelin-1 was higher ( 4.58 + /- 0.46 pg/mL ) compared with premenopausal levels ( 2.80 + /- 0.46 pg/mL ) . In hypertensive postmenopausal women , endothelin-1 was 5.56 + /- 0.44 pg/mL. After estrogen , plasma endothelin-1 values decreased from 5.38 + /- 0.66 to 4.82 + /- 0.9 pg/mL with oral estrone sulfate , 4.84 + /- 0.25 to 4.54 + /- 0.49 pg/mL with transdermal E2 , and did not change after placebo 4.76 + /- 0.71 to 4.81 + /- 0.46 pg/mL. In evaluating hypertensive women alone with estrogen therapy , plasma endothelin-1 showed the greatest decrement from 5.39 + /- 0.49 to 4.4 + /- 0.59 pg/mL ( 18.4 % ) . The decrease in endothelin-1 with estrogen , which was statistically significant for the entire group , did appear to be influenced by the route of administration . Baseline plasma endothelin-1 levels were correlated positively to plasma cholesterol levels with a correlation coefficient of 0.632 . CONCLUSION ( S ) These data provide another potential mechanism explaining the cardioprotective effects of hormone replacement therapy To investigate the effect of  postmenopausal oral and transdermal hormone therapy  on plasma levels of C-reactive protein ( CRP ) , we performed a r and omised , double-blind , double-dummy , placebo-controlled , 15-month study . One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo ( n = 49 ) , or transdermal 17beta-oestradiol ( E(2 ) ) 50 micro g ( tE(2 ) group , n = 33 ) , or oral E(2 ) 1 mg ( oE(2 ) group , n = 37 ) , or oral E(2 ) 1 mg combined with gestodene 25 micro g ( oE(2 ) + G group , n = 33 ) for thirteen 28-day treatment cycles , followed by four cycles placebo for each group . Data were collected at baseline and in cycles 4 , 13 and 17 . In cycle 13 , CRP was significantly increased in the oE(2 ) group compared to placebo ( P = 0.004 ) . The median percentage change from baseline versus placebo was + 75 % ( P < 0.001 ) . In cycle 17 , significantly lower values were observed in the oE(2 ) group compared to cycle 13 and to the placebo group ( -49 % , P < 0.001 ) . There were no significant changes versus placebo in the other groups . In conclusion , oral E(2 ) significantly increased CRP levels . This change was larger than the increase found during oral E(2 ) + G. Transdermal E(2 ) did not affect CRP levels OBJECTIVE The aim of this study was to demonstrate clinical equivalence between a novel intranasal estradiol formulation and a reference oral drug . STUDY DESIGN In this multinational , double-blind , parallel-group study 659 postmenopausal women with moderate to severe postmenopausal symptoms were r and omly assigned to receive either 300 microg/d intranasal 17beta-estradiol ( S21400 ) or 2 mg/d oral micronized estradiol , plus the appropriate placebo , for 24 weeks . All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle . Adjustment of intranasal dosage was permitted from week 14 on . The primary efficacy criterion was the Kupperman index at week 14 , with a predefined limit of equivalence of 4 . RESULTS Kupperman index scores improved similarly in the 2 groups , from 28.4 + /- 6.2 to 10.0 + /- 8.6 ( mean + /- SD ) for S21400 and from 28.1 + /- 6.0 to 8.9 + /- 8.0 for oral therapy , with a difference between groups at week 14 of 1.1 + /- 0.6 ( 90 % confidence interval , 0 . 0 to 2.2 ) . This was below the predefined equivalence limit of + 4 for statistical noninferiority ( P < .001 ) . The daily number and intensity of hot flushes decreased similarly in the two treatment groups . Withdrawal bleeding was 20 % less frequent with intranasal therapy ( 90 % confidence interval , 12.5 to 27.6 ) . Severe mastalgia was less frequent in the S21400 group ( 1.0 % ) than in the group with oral therapy ( 5.2 % ; P < .01 ) . Triglyceride and angiotensinogen levels increased significantly with oral therapy but not with S21400 . The same number of patients required dose adaptation in the 2 groups ( approximately 20 % ) . CONCLUSION Intranasal administration of 300 microg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms , with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue The aim of this study was to investigate the acute effects of transdermal 17β-estradiol ( Estraderm ® ) on plasma levels of coagulatory and fibrinolytic factors in postmenopausal normotensive and hypertensive women . Eleven normotensive and 13 hypertensive women were included in this placebo-controlled crossover study . In a r and omized order each subject was treated with a patch of 100 yig 17β-estradiol or placebo for 24 hours . Serum levels of tissue type plasminogen activator ( tPA ) activity , plasminogen activator inhibitor I ( PAI-1 ) activity , tPA antigen , PAI-I antigen , FVII , FX , and fibrinogen were assayed after both treatments . There was no significant difference in serum levels of hemostatic variables after treatment with estrogen compared to levels after placebo treatment in either of the groups . Nor was there any measurable difference when comparing hypertensive and normotensive subjects Objective To compare the efficacy and patient acceptability of intranasal versus transdermal 17β-estradiol ( E2 ) delivery systems for postmenopausal symptoms . Methods Postmenopausal women were r and omly assigned to intranasal 17β-E2  , 300 μg daily ( n = 176 )  or transdermal 17β-E2 ( delivering 50 μg/day ) , two patches per week ( n = 185 ) for 12 weeks , followed by a 4-week period with the alternate treatment . Efficacy was compared between groups using the Kupperman Index and vasomotor symptoms at week 12 . Patient acceptability was compared by patient choice of administration route and by question naire at week 16 . Results Intranasal and transdermal therapy produced significant reductions in the Kupperman Index and in the occurrence of hot flushes and night sweats at week 12 . Alleviation of climacteric symptoms was statistically equivalent in the two treatment groups ( P < .001 ) . The difference between groups in the Kupperman Index score of −0.5 ± 0.9 ( 95 % confidence interval −2.3 , 1.3 ) was within the predetermined interval of equivalence . Both therapies were well tolerated with similar adverse event rates , except for moderate and severe mastalgia which was significantly less frequent with intranasal E2 ( 7.2 % ) than with the patch ( 15.5 % , P = .02 ) . Sixty-six percent of patients chose to continue the intranasal therapy and 34 % the transdermal therapy ( P < .001 ) . Satisfaction was greater with intranasal therapy at week 16 ( P < .001 ) . Conclusion Intranasal and transdermal estrogen delivery systems had equivalent efficacy and similar safety profiles . Intranasal therapy was the patients ' choice for long-term treatment Objective To assess the possible benefit of hormone replacement therapy ( HRT ) in the secondary prevention of ischaemic heart disease CONTEXT Despite decades of use and considerable research , the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain . OBJECTIVE To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled disease prevention trial ( the estrogen-alone component of the Women 's Health Initiative [ WHI ] ) conducted in 40 US clinical centers beginning in 1993 . Enrolled were 10 739 postmenopausal women , aged 50 - 79 years , with prior hysterectomy , including 23 % of minority race/ethnicity . INTERVENTION Women were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen ( CEE ) or placebo . MAIN OUTCOME MEASURES The primary outcome was coronary heart disease ( CHD ) incidence ( nonfatal myocardial infa rct ion or CHD death ) . Invasive breast cancer incidence was the primary safety outcome . A global index of risks and benefits , including these primary outcomes plus stroke , pulmonary embolism ( PE ) , colorectal cancer , hip fracture , and deaths from other causes , was used for summarizing overall effects . RESULTS In February 2004 , after review ing data through November 30 , 2003 , the National Institutes of Health ( NIH ) decided to end the intervention phase of the trial early . Estimated hazard ratios ( HRs ) ( 95 % confidence intervals [ CIs ] ) for CEE vs placebo for the major clinical outcomes available through February 29 , 2004 ( average follow-up 6.8 years ) , were : CHD , 0.91 ( 0.75 - 1.12 ) with 376 cases ; breast cancer , 0.77 ( 0.59 - 1.01 ) with 218 cases ; stroke , 1.39 ( 1.10 - 1.77 ) with 276 cases ; PE , 1.34 ( 0.87 - 2.06 ) with 85 cases ; colorectal cancer , 1.08 ( 0.75 - 1.55 ) with 119 cases ; and hip fracture , 0.61 ( 0.41 - 0.91 ) with 102 cases . Corresponding results for composite outcomes were : total cardiovascular disease , 1.12 ( 1.01 - 1.24 ) ; total cancer , 0.93 ( 0.81 - 1.07 ) ; total fractures , 0.70 ( 0.63 - 0.79 ) ; total mortality , 1.04 ( 0.88 - 1.22 ) , and the global index , 1.01 ( 0.91 - 1.12 ) . For the outcomes significantly affected by CEE , there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years . The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years . CONCLUSIONS The use of CEE increases the risk of stroke , decreases the risk of hip fracture , and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years . A possible reduction in breast cancer risk requires further investigation . The burden of incident disease events was equivalent in the CEE and placebo groups , indicating no overall benefit . Thus , CEE should not be recommended for chronic disease prevention in postmenopausal women BACKGROUND There is increasing use of hormone replacement therapy ( HRT ) by post-menopausal women . Observational epidemiological studies have shown reductions in cardiovascular risk factors in  HRT users in the USA , but no r and omized controlled trials of HRT have been carried out in the primary practice setting . Previous studies of cardiovascular risk factors have shown a variety of responses according to type of progestagen and oral or topical administration . None has examined the effect of route using an identical progestagen . OBJECTIVES Our aim was to establish differences , if any , in alteration in cardiovascular risk factors with HRT in post-menopausal women according to route of administration of HRT , oral , transdermal and implant , using first oestrogen alone then oestrogen plus norethisterone , or testosterone for implant . METHODS Subjects were recruited by letter of invitation to women aged 50 - 65 years from lists in general practice s local to the Charing Cross Hospital Lipid Clinic in West London . Their menopausal status was confirmed and they were r and omized to one of three treatment groups or acted as controls . They attended for three visits ; at baseline , HRT was initiated as oestrogen alone , oral or transdermal . At the 3-month visit , HRT with the progestagen , norethisterone , was given cyclically , continuously or transdermally until the final visit at 6 months . A separate group of women from the menopause clinic at Chelsea and Westminster Hospital were studied on oestrogen implant then on implanted oestrogen and testosterone . The outcome measures studied were the separate effects of the four regimes as compared with controls on lipoproteins , glucose , insulin , fibrinogen , factor VII and E-selectin , together with weight , waist : hip ratio and blood pressure . RESULTS The continuous combined oestrogen-progestagen therapy had similar effects on cardiovascular risk factors as oestrogen with cyclical progestagen . All regimes lowered low-density lipoprotein cholesterol , the oral route being more potent than the parenteral ; the effect of transdermal HRT was similar to the implant . Lp(a ) was reduced only with the oral route . Reductions in factor VII and E-selectin were observed in both the oral and transdermal routes . There was no increase in body mass index , waist : hip ratio , blood pressure or glucose and insulin levels with any of the HRT regimes used . Systolic blood pressure was reduced with the transdermal route . CONCLUSIONS This study supports the evidence that oestrogen-progestagen HRT , both oral and transdermal , although attenuating some of the benefit of oestrogen alone on fibrinogen and high-density lipoprotein , significantly reduces cardiovascular risk factors , which should diminish post-menopausal risk of coronary disease Low levels of insulin-like growth factor binding protein-1 ( IGFBP-1 ) have recently been associated with several risk factors for cardiovascular disease . The effects of estrogen replacement therapy ( ERT ) on plasma IGFBP-1 levels are , however , unclear . A double-blind , placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women r and omized into two groups : oral estradiol ( E2 ) valerate , 2 mg/day ( n = 35 ) and transdermal E2 gel , 1 mg/day ( n=38 ) . Plasma IGFBP-1 , insulin-like growth factor-I ( IGF-I ) and lipoprotein(a ) ( Lp(a ) ) were determined at baseline , 3 and 6 months . The groups were similar for age and BMI . The baseline levels of estrone ( E1 ) , E2 , IGFBP-1 , IGF-I and Lp(a ) did not differ between the groups . During treatment , serum estradiol concentrations increased in both groups . During oral ERT , IGFBP-1 levels increased by 104 % ( P<0.001 ) , whereas IGF-I levels decreased by 13 % ( mean , P<0.05 ) . IGF-I and IGFBP-1 levels remained unchanged in the transdermal group . Lp(a ) levels decreased by 23 % ( median , P<0.001 ) in the oral group , but were unaffected by transdermal therapy . The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a ) ( r = -0.40 , P<0.05 , Spearman correlation ) . In conclusion , oral ERT seems to enhance plasma levels of IGFBP-1 , which may be one reason for the reduced Lp(a ) levels We compared the effects of oral estradiol ( 2 mg ) , transdermal estradiol ( 50 microg ) , and placebo on measures of coagulation , fibrinolysis , inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment . Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations . Oral therapy increased the plasma concentrations of factor VII antigen ( FVIIag ) and activated factor VII ( FVIIa ) , and the plasma concentration of the prothrombin activation marker prothrombin fragment 1 + 2 ( F1 + 2 ) . Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 ( PAI-1 ) antigen and tissue-type plasminogen activator ( tPA ) antigen concentrations and PAI-1 activity , and increased D-dimer concentrations , suggesting increased fibrinolysis . The concentration of soluble E-selectin decreased and serum C-reactive protein ( CRP ) increased significantly in the oral but not in the transdermal or placebo groups . In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein ( LDL ) cholesterol , apolipoprotein B and lipoprotein ( a ) concentrations decreased while high-density-lipoprotein ( HDL ) cholesterol , apolipoprotein AI and apolipoprotein All concentrations increased significantly . LDL particle size remained unchanged . In summary , oral estradiol increased markers of fibrinolytic activity , decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins . In contrast to these beneficial effects , oral estradiol changed markers of coagulation towards hypercoagulability , and increased serum CRP concentrations .  Transdermal estradiol or placebo had no effects on any of these parameters . These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed
target: For non-oral HT , decreases in lipoprotein(a ) , cell adhesion molecules , and factor VII generally were significant , resistance to activated protein C ( APCr ) was slightly increased , and other markers including CRP and homocysteine did not change .
  Compared with oral HT , changes in CRP and APCr were smaller , changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller , whereas changes in other factors including lipoprotein(a ) and homocysteine did not differ .
  ( S ) Potentially unfavorable changes seen with oral HT on two important markers , CRP and APCr , are substantially smaller with non-oral HT .
  Non-oral HT has minor effects on the other cardiovascular risk markers studied .
  Therefore , compared with oral HT , non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk
background: OBJECTIVE To review the effects of non-oral administration of postmenopausal hormone therapy ( HT ) on risk markers for atherosclerotic and venous thromboembolic disease .
  Non-oral postmenopausal HT appears not to increase venous thromboembolic risk , whereas the effect on coronary heart disease risk is less clear .