Women taking HT had a significantly decreased incidence of fracture with long-term use .
Research ers found no strong evidence that HT has a clinical ly meaningful impact on the incidence of colorectal cancer .
AUTHORS ' CONCLUSIONS : Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT , provided they do not have specific contraindications .
HT may be unsuitable for some women , including those at increased risk of cardiovascular disease , increased risk of thromboembolic disease ( such as those with obesity or a history of venous thrombosis ) or increased risk of some types of cancer ( such as breast cancer , in women with a uterus ) .
The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented .
HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia , nor for prevention of deterioration of cognitive function in postmenopausal women .
Although HT is considered effective for the prevention of postmenopausal osteoporosis , it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable .
BACKGROUND : Hormone therapy ( HT ) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease , osteoporosis and  dementia in older women .
This is an up date d version of a Cochrane review first published in 2005 .
OBJECTIVES : To assess effects of long-term HT ( at least 1 year 's duration ) on mortality , cardiovascular outcomes , cancer , gallbladder disease , fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment .
Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/progestin Replacement Study
Venous thromboembolism , including thrombosis of the deep veins of the legs and embolism to the pulmonary arteries , is a serious and potentially fatal event . Venous thromboembolism is uncommon in the general population , occurring in about 1 to 4 per 1000 adults annually ( 1 , 2 ) . However , the risk is increased in persons with previous venous thromboembolism ( 3 ) , recent surgical procedures ( 4 , 5 ) , immobilization , fracture of a lower extremity ( 4 , 6 , 7 ) , cancer ( 4 , 6 , 7 ) , and inherited coagulation disorders ( 8 , 9 ) . Use of oral contraceptive pills increases risk for venous thromboembolism ( 1 , 2 ) . This increased risk is thought to be due to estrogen and to be dose related ( 3 , 4 ) . The biological potency of the estrogens generally used in postmenopausal hormone therapy is about one-fourth to one-fifth that of the estrogens in modern oral contraceptives . Until recently , there has been little evidence that low-dose estrogen therapy is associated with increased risk for venous thromboembolism ( 5 - 8 ) . Recent observational studies have suggested that postmenopausal hormone therapy causes a twofold to fourfold increase in risk for idiopathic deep venous thrombosis and pulmonary embolism ( 9 - 13 ) . However , these findings may be biased if women taking estrogen are more likely to be evaluated for nonspecific symptoms suggestive of venous thromboembolism . The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized , blinded , placebo-controlled trial of the effect of daily conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , on the rate of new coronary events in 2763 postmenopausal women with established coronary heart disease ( 14 ) . One of the specified secondary outcomes of this trial was venous thromboembolism . An increased risk for venous thromboembolism among women assigned to hormone therapy was noted by the HERS Data and Safety Monitoring Board . The Board instructed the HERS investigators to inform participants and the scientific community of this risk and to institute measures to reduce risk . At a mean follow-up of 3.3 years , the HERS investigators notified participants to discontinue study medication in situations associated with increased risk for venous thromboembolism , such as surgery , hospitalization , fracture , and cancer , and published a letter noting the increased risk ( 15 ) . This report presents the full analysis of the findings . Methods Participants in HERS were postmenopausal women younger than 80 years of age who had coronary disease ( myocardial infa rct ion , coronary artery bypass surgery , percutaneous coronary revascularization , or angiographic evidence of at least 50 % narrowing of one or more major coronary arteries ) and had not had a hysterectomy . Women were excluded if their coronary event occurred within 6 months of r and omization ; they had used hormone therapy within 3 months of r and omization ; they had a history or baseline findings suggestive of venous thromboembolism , breast cancer , or endometrial cancer ; or they had uncontrolled hypertension , diabetes , or other life-threatening diseases ( 16 ) . The protocol was approved by the institutional review board at each of the 20 HERS clinical centers , and all participants provided written informed consent . Participants were r and omly assigned to take one tablet daily of conjugated equine estrogen , 0.625 mg , plus medroxyprogesterone acetate , 2.5 mg , or placebo that was identical in appearance . R and omization was stratified by clinical center and performed in blocks of 4 . To prevent unblinding of clinical center staff , HERS participants reported breast discomfort and vaginal bleeding directly to gynecology staff , who were located separately from the clinical center staff , did not communicate with clinical center personnel about breast or gynecologic problems , and did not participate in ascertainment of outcomes . Follow-up visits to the clinical centers occurred at 4-month intervals . Coronary events ( nonfatal myocardial infa rct ion and coronary death ) were the primary outcome of the trial ( 14 ) . At each visit , clinic staff asked participants if they had been told by a physician that they had a blood clot in the legs or lungs . Women were also asked whether they had been hospitalized , and records were review ed to determine whether venous thromboembolism had occurred . Women were not routinely asked about symptoms of venous thrombosis , such as lower-extremity edema . Diagnosis of deep venous thrombosis required documentation of thrombosis of the popliteal or more proximal veins of the legs by venography , impedance plethysmography , or sonography . Pulmonary embolism required documentation by a nuclear lung scan that suggested a high probability of pulmonary embolism ( segmental or larger perfusion defect with ventilation mismatch ) or by pulmonary angiography that revealed a constant intraluminal filling defect on multiple films . Suspected venous thromboembolism was adjudicated independently and without knowledge of treatment assignment by two physicians at the HERS Coordinating Center , located at the University of California , San Francisco ; disagreements were resolved by consensus . Persons who analyzed data were also blinded to participants ' treatment status . Data were collected on events that occurred during the trial that might be predictors of venous thromboembolism , including fractures , nonfatal myocardial infa rct ion , congestive heart failure , stroke , and transient ischemic attack ( 16 ) . Venous thromboembolism was classified as idiopathic in women who did not have concomitant cancer , nonfatal myocardial infa rct ion , congestive heart failure , or stroke and did not have a fracture , inpatient surgery , or hospitalization in the 3 months before the venous thromboembolic event . In the primary analysis , an unadjusted Cox proportional-hazards model for time to first event was used to compare the rate of venous thromboembolism among women assigned to  hormone therapy with the rate among women assigned to placebo . The primary analysis was intention-to-treat ; participants were categorized according to treatment assignment regardless of compliance . Participants who were lost to follow-up ( 33 women in the hormone therapy group and 36 in the placebo group ) were censored at the last date at which they were known to be alive without venous thromboembolism ; vital status was known for all women at the end of the trial . We also performed an as-treated analysis , in which inclusion in the risk sets was limited to women in both treatment groups whose average compliance with therapy during the trial ( measured by pill count ) was at least 80 % . Relative hazards were also estimated by year since r and omization ( women with events in earlier years were censored ) , and continuous trend in the log relative hazard was examined in a companion model . We repeated the main analyses separately for idiopathic and nonidiopathic venous thromboembolism . Potential risk factors for venous thromboembolism were first examined by using univariate proportional hazards models adjusted for treatment assignment . In these models , postr and omization events and medication use were represented by time-dependent indicators , which reverted to zero 90 days after fracture , surgery , or hospitalization or when therapy was discontinued . Variables associated with venous thromboembolism for which the associated P value was less than 0.2 in univariate analyses were considered for inclusion in multivariate models and retained in the model if the P value remained less than 0.2 . Statistical analyses were performed by using SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Results The 20 HERS centers enrolled 2763 women between February 1993 and September 1994 ; of these , 1380 were assigned to the hormone therapy group and 1383 to the placebo group . Participants ranged in age from 44 to 79 years ( mean age [ SD ] , 67 7 years ) . At baseline , the treatment groups did not differ significantly ( Table 1 ) . Table 1 . Baseline Characteristics of HERS Participants At the end of the first year , 82 % of women in the hormone therapy group and 91 % in the placebo group reported taking study medication ; by the end of the third year , these proportions had decreased to 75 % and 81 % , respectively . Cumulative incidence curves for all venous thromboembolic events ( deep venous thrombosis and pulmonary embolism ) are shown in the Figure . During 10 985 woman-years of follow-up , 47 women experienced a  venous thromboembolic event : 34 in the hormone-treated group ( 6.2 per 1000 woman-years ) and 13 in the placebo group ( 2.3 per 1000 woman-years ) ( relative hazard , 2.7 [ 95 % CI , 1.4 to 5.0 ] [ P = 0.003 ] ; excess risk , 3.9 per 1000 woman-years [ CI , 1.4 to 6.4 per 1000 woman-years ] ; number needed to treat for harm , 256 [ CI , 157 to 692 ] ) . The relative hazard of venous thromboembolism did not differ significantly among the 20 clinical centers . Figure . Kaplan-Meier estimates of the cumulative incidence of venous thromboembolic events ( top ) , deep venous thrombosis ( middle ) , and pulmonary embolism ( bottom ) . More women in the hormone therapy group than in the placebo group experienced deep venous thrombosis ( 25 compared with 9 ; relative hazard , 2.8 [ CI , 1.3 to 6.0 ] ; P = 0.008 ) and pulmonary embolism ( 11 compared with 4 ; relative hazard , 2.8 [ CI , 0.9 to 8.7 ] ; P = 0.08 ) ( Table 2 ) . Two women , both in the hormone therapy group , died of pulmonary embolism . The relative hazard was increased for idiopathic ( relative hazard , 3.1 [ CI , 0.8 to 11.3 ] ) and nonidiopathic venous thromboembolic events ( relative hazard , 2.5 [ CI , 1.2 to 5.3 ] ) . The overall results were unchanged in an as-treated analysis that was limited to women who reported taking more than 80 % of their assigned study medication ( relative hazard , 3.2 [ CI , 1.5 to 6.9 ] ; P = 0.003 ) . Table 2 . Venous Thrombolic Events by Treatment Group and Year of R and omization Table 2 shows relative hazards for venous thromboembolism by year since r and omization . The number of episodes of pulmonary
Women taking HT had a significantly decreased incidence of fracture with long-term use .
Research ers found no strong evidence that HT has a clinical ly meaningful impact on the incidence of colorectal cancer .
AUTHORS ' CONCLUSIONS : Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT , provided they do not have specific contraindications .
HT may be unsuitable for some women , including those at increased risk of cardiovascular disease , increased risk of thromboembolic disease ( such as those with obesity or a history of venous thrombosis ) or increased risk of some types of cancer ( such as breast cancer , in women with a uterus ) .
The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented .
HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia , nor for prevention of deterioration of cognitive function in postmenopausal women .
Although HT is considered effective for the prevention of postmenopausal osteoporosis , it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable .
BACKGROUND : Hormone therapy ( HT ) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease , osteoporosis and  dementia in older women .
This is an up date d version of a Cochrane review first published in 2005 .
OBJECTIVES : To assess effects of long-term HT ( at least 1 year 's duration ) on mortality , cardiovascular outcomes , cancer , gallbladder disease , fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment .