human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    