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 To assess the effect of  combined hormone replacement therapy ( HRT )  on health related quality of life . Design R and omised placebo controlled double blind trial . Setting General practice s in United Kingdom ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 at r and omisation ; 3721 women with a uterus were r and omised to combined oestrogen and progestogen  ( n=1862 ) or placebo  ( n=1859 ) . Data on health related quality of life at one year were available from 1043 and 1087 women , respectively . Interventions Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year . Main outcome measures Health related quality of life and psychological wellbeing as measured by the women ’s health question naire . Changes in emotional and physical menopausal symptoms as measured by a symptoms question naire and depression by the Centre for Epidemiological Studies depression scale ( CES-D ) . Overall health related quality of life and overall quality of life as measured by the European quality of life instrument ( EuroQol ) and visual analogue scale , respectively . Results After one year small but significant improvements were observed in three of nine components of the women ’s health question naire for those taking combined HRT compared with those taking placebo :  vasomotor symptoms ( P<0.001 ) , sexual functioning ( P<0.001 ) , and sleep problems ( P<0.001 ) . Significantly fewer women in the combined HRT group reported hot flushes ( P<0.001 ) , night sweats ( P<0.001 ) , aching joints and muscles ( P=0.001 ) , insomnia ( P<0.001 ) , and vaginal dryness ( P<0.001 ) than in the placebo group , but greater proportions reported breast tenderness ( P<0.001 ) or vaginal discharge ( P<0.001 ) . Hot flushes were experienced in the combined HRT and placebo groups by 30 % and 29 % at trial entry and 9 % and 25 % at one year , respectively . No significant differences in other menopausal symptoms , depression , or overall quality of life were observed at one year . Conclusions Combined HRT started many years after the menopause can improve health related quality of life . Trial registration IS RCT N 63718836 Gene expression analysis of healthy postmenopausal women in a prospect i ve clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy ( HT ) with natural versus synthetic estrogens .  Two 28-day cycles of daily estradiol ( E2 ) gel 1.5 mg and oral micronized progesterone ( P ) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation ( Ki-67 MIB-1 positive cells ) at the cell level nor at the mRNA level ( MKI-67 gene ) . A borderline significant beneficial reduction in anti-apoptotic protein bcl-2 , favouring apoptosis , was also seen followed by a slight numeric decrease of its mRNA . By contrast , two 28-day cycles of daily oral conjugated equine estrogens ( CEE ) 0.625 mg and oral medroxyprogesterone acetate ( MPA ) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level , and significantly enhanced mammographic breast density , an important risk factor for breast cancer . In addition , CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional , synthetic therapy The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered The efficacy of estrogen replacement therapy ( ERT ) for mood disturbances associated with menopause has yet to be firmly established . The objective of this study was to investigate the efficacy of ERT for improving mood and anxiety of non-depressive postmenopausal women . This double-blind , r and omized , placebo-controlled study involved two treatment groups : one receiving conjugated equine estrogens ( CEEs ; 0.625 mg/day ) and the other placebo , for six cycles of 28 days each . Subjects were hysterectomized , healthy , non-depressive ( according to Schedule for Affective Disorders and Schizophrenia , Life Time Version [ SADS-L ] ) women .  Depressive and anxiety symptoms were assessed with the Beck Depression Inventory ( BDI ) , and the Hamilton Anxiety Scale ( HAMA ) , respectively . The Profile of Mood States ( POMS ) and other scales were used to characterize symptoms . In both groups , BDI scores were significantly lower at cycles 1 , 2 , 3 , and 6 , compared with baseline assessment s ( p < 0.01 ) . Anxiety scores for both groups significantly improved from cycle 3 to study endpoint . The only significant difference favoring the active group occurred at cycle 1 . POMS scores were significantly improved at the end of cycles 1 , 2 , 3 and 6 among treated subjects and at the end of cycles 2 , 3 , and 6 among placebo subjects . ERT is not associated with improvements in mood or anxiety symptoms in non-depressive , hysterectomized , postmenopausal women Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease . However , inconclusive results have been reported with respect to the risk of stroke , and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen .  There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis , and the impact of the route of estrogen administration on hemostasis has not been well documented . Therefore , we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables . Forty-five healthy postmenopausal women , aged 45 to 64 years , were assigned r and omly to one of the three following groups : cyclic oral or transdermal estradiol , both combined with progesterone , or no hormonal treatment .  Hemostatic variables were assayed at baseline and after a 6-month period . Pairwise differences in the mean change between the three groups were compared using nonparametric tests . Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide ( F1 + 2 ) and decreased mean antithrombin activity compared with no treatment . Differences in fragment F1 + 2 levels between active treatments were significant . The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen ( t-PA ) concentration and plasminogen activator inhibitor ( PAI-1 ) activity and a significant rise in global fibrinolytic capacity ( GFC ) compared with the two other groups . A transdermal estrogen regimen had no significant effect on PAI-1 , t-PA , and GFC levels . There were no significant changes in mean values of fibrinogen , factor VII , von Willebr and factor , protein C , fibrin D-dimer , and plasminogen between and within the three groups . We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential , whereas opposed transdermal estrogen appears without any substantial effects on hemostasis . Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen  , they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women , especially to those at high risk of thrombotic disease The present article prospect ively examines the effect of change in menopause status on depression , while controlling for prior depression . This is a longitudinal follow-up of previous cross-sectional analyses reported by McKinlay , McKinlay , and Brambilla who examined the relative contribution of menopause to depression . The data derive from the Massachusetts Women 's Health Study , a 5-year longitudinal study of a cohort of 2565 women aged 45 to 55 years at baseline ( 1981 to 1982 ) . Results show that prior depression is the variable most predictive of subsequent depression , as measured by the Center for Epidemiologic Studies -Depression ( CES-D ) scale . Onset of natural menopause was not associated with increased risk of depression . Experiencing a long perimenopausal period ( at least 27 months ) , however , was associated with increased risk of depression . The association between a long perimenopause and depression appeared to be explained by increased menopausal symptoms rather than by the menopause status itself . The observed increase in depression during a lengthy perimenopause appears to be transitory The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest . In a pilot r and omised placebo controlled cross-over study , we aim ed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age . Nineteen cognitively normal women , without clinical depression whom had undergone a hysterectomy in the past were recruited . Women were r and omised to receive either transdermal estradiol 50 microg/24 h ( Femseven ) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks . Cognition was assessed every 6 weeks by the cognitive drug research ( CDR ) computerised assessment which recorded both accuracy and speed in the following cognitive tests ; simple reaction time , choice reaction time , digit vigilance , visual tracking , spatial working memory , immediate and delayed word recall and delayed face and picture recall . Depressive symptoms were measured using the brief assessment scale depression card ( BASDEC ) depression rating scale at baseline , 12 and 24 weeks . Participants had a mean age of 71 , IQ of 115 and MMSE of 29 .  Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use . All other tests were unaltered by estradiol . Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests . However , the results do support the concept that depressive symptoms may be reduced by estradiol , and not simply due to the relief of climacteric symptoms CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , 
    Output:
    
agent
This moderate to large effect size , showing lower ratings of depressed mood in treated patients compared with controls , implicated HRT as a potential treatment of or prophylactic for depression in menopausal women .
One can generalize from the studies review ed here only with great caution , but there is little evidence to support the use of estradiol to improve mood in nondepressed patients ( not surprisingly ) and some evidence to support the antidepressant efficacy of estradiol in perimenopausal but not postmenopausal women
***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 To assess the effect of  combined hormone replacement therapy ( HRT )  on health related quality of life . Design R and omised placebo controlled double blind trial . Setting General practice s in United Kingdom ( 384 ) , Australia ( 94 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 at r and omisation ; 3721 women with a uterus were r and omised to combined oestrogen and progestogen  ( n=1862 ) or placebo  ( n=1859 ) . Data on health related quality of life at one year were available from 1043 and 1087 women , respectively . Interventions Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year . Main outcome measures Health related quality of life and psychological wellbeing as measured by the women ’s health question naire . Changes in emotional and physical menopausal symptoms as measured by a symptoms question naire and depression by the Centre for Epidemiological Studies depression scale ( CES-D ) . Overall health related quality of life and overall quality of life as measured by the European quality of life instrument ( EuroQol ) and visual analogue scale , respectively . Results After one year small but significant improvements were observed in three of nine components of the women ’s health question naire for those taking combined HRT compared with those taking placebo :  vasomotor symptoms ( P<0.001 ) , sexual functioning ( P<0.001 ) , and sleep problems ( P<0.001 ) . Significantly fewer women in the combined HRT group reported hot flushes ( P<0.001 ) , night sweats ( P<0.001 ) , aching joints and muscles ( P=0.001 ) , insomnia ( P<0.001 ) , and vaginal dryness ( P<0.001 ) than in the placebo group , but greater proportions reported breast tenderness ( P<0.001 ) or vaginal discharge ( P<0.001 ) . Hot flushes were experienced in the combined HRT and placebo groups by 30 % and 29 % at trial entry and 9 % and 25 % at one year , respectively . No significant differences in other menopausal symptoms , depression , or overall quality of life were observed at one year . Conclusions Combined HRT started many years after the menopause can improve health related quality of life . Trial registration IS RCT N 63718836 Gene expression analysis of healthy postmenopausal women in a prospect i ve clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy ( HT ) with natural versus synthetic estrogens .  Two 28-day cycles of daily estradiol ( E2 ) gel 1.5 mg and oral micronized progesterone ( P ) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation ( Ki-67 MIB-1 positive cells ) at the cell level nor at the mRNA level ( MKI-67 gene ) . A borderline significant beneficial reduction in anti-apoptotic protein bcl-2 , favouring apoptosis , was also seen followed by a slight numeric decrease of its mRNA . By contrast , two 28-day cycles of daily oral conjugated equine estrogens ( CEE ) 0.625 mg and oral medroxyprogesterone acetate ( MPA ) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level , and significantly enhanced mammographic breast density , an important risk factor for breast cancer . In addition , CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional , synthetic therapy The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered The efficacy of estrogen replacement therapy ( ERT ) for mood disturbances associated with menopause has yet to be firmly established . The objective of this study was to investigate the efficacy of ERT for improving mood and anxiety of non-depressive postmenopausal women . This double-blind , r and omized , placebo-controlled study involved two treatment groups : one receiving conjugated equine estrogens ( CEEs ; 0.625 mg/day ) and the other placebo , for six cycles of 28 days each . Subjects were hysterectomized , healthy , non-depressive ( according to Schedule for Affective Disorders and Schizophrenia , Life Time Version [ SADS-L ] ) women .  Depressive and anxiety symptoms were assessed with the Beck Depression Inventory ( BDI ) , and the Hamilton Anxiety Scale ( HAMA ) , respectively . The Profile of Mood States ( POMS ) and other scales were used to characterize symptoms . In both groups , BDI scores were significantly lower at cycles 1 , 2 , 3 , and 6 , compared with baseline assessment s ( p < 0.01 ) . Anxiety scores for both groups significantly improved from cycle 3 to study endpoint . The only significant difference favoring the active group occurred at cycle 1 . POMS scores were significantly improved at the end of cycles 1 , 2 , 3 and 6 among treated subjects and at the end of cycles 2 , 3 , and 6 among placebo subjects . ERT is not associated with improvements in mood or anxiety symptoms in non-depressive , hysterectomized , postmenopausal women Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease . However , inconclusive results have been reported with respect to the risk of stroke , and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen .  There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis , and the impact of the route of estrogen administration on hemostasis has not been well documented . Therefore , we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables . Forty-five healthy postmenopausal women , aged 45 to 64 years , were assigned r and omly to one of the three following groups : cyclic oral or transdermal estradiol , both combined with progesterone , or no hormonal treatment .  Hemostatic variables were assayed at baseline and after a 6-month period . Pairwise differences in the mean change between the three groups were compared using nonparametric tests . Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide ( F1 + 2 ) and decreased mean antithrombin activity compared with no treatment . Differences in fragment F1 + 2 levels between active treatments were significant . The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen ( t-PA ) concentration and plasminogen activator inhibitor ( PAI-1 ) activity and a significant rise in global fibrinolytic capacity ( GFC ) compared with the two other groups . A transdermal estrogen regimen had no significant effect on PAI-1 , t-PA , and GFC levels . There were no significant changes in mean values of fibrinogen , factor VII , von Willebr and factor , protein C , fibrin D-dimer , and plasminogen between and within the three groups . We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential , whereas opposed transdermal estrogen appears without any substantial effects on hemostasis . Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen  , they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women , especially to those at high risk of thrombotic disease The present article prospect ively examines the effect of change in menopause status on depression , while controlling for prior depression . This is a longitudinal follow-up of previous cross-sectional analyses reported by McKinlay , McKinlay , and Brambilla who examined the relative contribution of menopause to depression . The data derive from the Massachusetts Women 's Health Study , a 5-year longitudinal study of a cohort of 2565 women aged 45 to 55 years at baseline ( 1981 to 1982 ) . Results show that prior depression is the variable most predictive of subsequent depression , as measured by the Center for Epidemiologic Studies -Depression ( CES-D ) scale . Onset of natural menopause was not associated with increased risk of depression . Experiencing a long perimenopausal period ( at least 27 months ) , however , was associated with increased risk of depression . The association between a long perimenopause and depression appeared to be explained by increased menopausal symptoms rather than by the menopause status itself . The observed increase in depression during a lengthy perimenopause appears to be transitory The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest . In a pilot r and omised placebo controlled cross-over study , we aim ed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age . Nineteen cognitively normal women , without clinical depression whom had undergone a hysterectomy in the past were recruited . Women were r and omised to receive either transdermal estradiol 50 microg/24 h ( Femseven ) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks . Cognition was assessed every 6 weeks by the cognitive drug research ( CDR ) computerised assessment which recorded both accuracy and speed in the following cognitive tests ; simple reaction time , choice reaction time , digit vigilance , visual tracking , spatial working memory , immediate and delayed word recall and delayed face and picture recall . Depressive symptoms were measured using the brief assessment scale depression card ( BASDEC ) depression rating scale at baseline , 12 and 24 weeks . Participants had a mean age of 71 , IQ of 115 and MMSE of 29 .  Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use . All other tests were unaltered by estradiol . Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests . However , the results do support the concept that depressive symptoms may be reduced by estradiol , and not simply due to the relief of climacteric symptoms CONTEXT Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions , particularly memory . OBJECTIVE The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women . DESIGN This study was a r and omized , double-blind , placebo-controlled clinical trial . SETTING Participants were women from 14 of 40 clinical centers of the Women 's Health Initiative ( WHI ) . PARTICIPANTS Postmenopausal women ( 1416 ) aged 65 yr and older , free of probable dementia , and enrolled in WHI and the WHI Memory Study ( WHIMS ) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr , were studied . INTERVENTION Intervention was conjugated equine estrogen ( CEE ; 0.625 mg ) with 2.5 mg medroxyprogesterone acetate ( MPA ) in one daily tablet ( CEE + MPA ) or placebo . MAIN OUTCOME MEASURES Annual rates of change in specific cognitive functions and affect , adjusted for time since r and omization , were measured . RESULTS CEE + MPA had a negative impact on verbal memory ( P < or= 0.01 ) and a trend to a positive impact on figural memory ( P = 0.012 ) over time compared with placebo , but other cognitive domains were not affected . Both effects on memory were evident only after long-term therapy . CEE + MPA did not significantly influence positive affect , 
    Output:
    