Managing menopause. A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses' Health Study: A Prospective, Observational Study Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies? Remnant-like lipoproteins, hormone therapy, and angiographic and clinical outcomes: the Women's Angiographic Vitamin & Estrogen Trial. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. Evidence-based review of therapies at the menopause. HRT and cardiovascular disease. Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. Women and Menopause: Beliefs, Attitudes, and Behaviors. The North American Menopause Society 1997 Menopause Survey DHEA, important source of sex steroids in men and even more in women. Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults: Synopsis of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Changes in the Use of Postmenopausal Hormone Therapy after the Publication of Clinical Trial Results Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Dietetic guidelines: diet in secondary prevention of cardiovascular disease. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women. Osteoporosis in menopause.
OBJECTIVE To provide up date d guidelines for health care providers on the management of menopause in asymptomatic healthy women as well as in women presenting with vasomotor or urogenital symptoms and on considerations related to cardiovascular disease , breast cancer , urogynaecology , and sexuality . OUTCOMES Lifestyle interventions , prescription medications , and complementary and alternative therapies are presented according to their efficacy in the treatment of menopausal symptoms . Counselling and therapeutic strategies for sexuality concerns in the peri- and postmenopausal years are review ed . Approaches to the identification and evaluation of women at high risk of osteoporosis , along with options for prevention and treatment , are presented in the companion osteoporosis guideline . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library in August and September 2012 with the use of appropriate controlled vocabulary ( e.g. , hormone therapy , menopause , cardiovascular diseases , and sexual function ) and key words ( e.g. , hormone therapy , perimenopause , heart disease , and sexuality ) . Results were restricted to clinical practice guidelines , systematic review s , r and omized control trials/controlled clinical trials , and observational studies . Results were limited to publication date s of 2009 onwards and to material in English or French . Search es were up date d on a regular basis and incorporated in the guideline until January 5 , 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , national and international medical specialty societies , and clinical practice guideline collection Whether to take hormone therapy is one of the most difficult medical decisions that healthy postmenopausal women face . The apparent coronary benefits ( 1 ) of hormone use are an important part of that decision . Although the data appear consistent in suggesting long-term coronary benefits , the Heart and Estrogen/progestin Replacement Study ( 2 ) showed an increased risk for coronary events during the first year of therapy in women with existing heart disease ; we also found such an elevated risk in an examination of secondary prevention in the Nurses ' Health Study ( 3 ) . More recently , a report from the Women 's Health Initiative , an ongoing r and omized clinical trial of hormone therapy for primary prevention of cardiovascular disease , suggested similar findings in healthy women ( National Institutes of Health . Press release ) . However , additional data on short-term effects of hormone use in women without previous cardiovascular disease are sparse . Many further questions also remain . Among them is the cardiovascular effect of daily doses lower than the st and ard 0.625 mg of oral conjugated estrogen . Recent studies suggest that lower doses of hormone therapy provide bone benefits ( 4 ) and , compared with higher doses , might decrease the risk for thromboembolism ( 5 ) and reduce endometrial hyperplasia ( 4 ) . However , few data are currently available on the relation between low-dose estrogen and primary prevention of heart disease and stroke . In an earlier report , we examined the relation between postmenopausal hormone therapy and primary prevention of cardiovascular disease based on 16 years of follow-up from the Nurses ' Health Study ( 6 ) . In the current analysis , we have almost 50 % more follow-up time among women taking daily doses less than 0.625 mg and more than 800 additional cases of cardiovascular disease , allowing more precise assessment of specific associations . Thus , we now report on the relation among  low-dose estrogen , short-term hormone use , and cardiovascular events in 70 533 postmenopausal women with no previous cardiovascular disease who were followed for up to 20 years . We also provide additional information on the effects of estrogen combined with progestin . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about their postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . We up date information with biennial follow-up question naires . Dietary and physical activity question naires were added in 1980 . Cohort follow-up is greater than 90 % . Ascertainment of Hormone Use In 1976 , women were asked about use and duration of hormone therapy after menopause . Beginning in 1978 , we collected information on type of hormones taken , and starting in 1980 , we asked about the dose of oral conjugated estrogen . All information is up date d biennially . Identification of Cardiovascular Disease We identified first occurrences of nonfatal myocardial infa rct ion , fatal coronary disease , and fatal and nonfatal stroke between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion or stroke were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met World Health Organization criteria ( 7 ) ( symptoms plus either elevated levels of cardiac enzymes or diagnostic electrocardiograms ) . Infa rct ions that required hospitalization and were corroborated by interview or letter but for which medical records were unobtainable were included as probable . Infa rct ions of indeterminate age discovered on routine examination were excluded . Nonfatal strokes were confirmed by review of medical records if they were characterized by a typical neurologic deficit , were rapid in onset , lasted at least 24 hours , and met the criteria of the National Survey of Stroke ( 8) . We classified strokes as ischemic ( thrombotic or embolic occlusion of a cerebral artery ) , subarachnoid hemorrhage , or intraparenchymal hemorrhage . We excluded subdural hematomas and strokes caused by infection or neoplasia . Strokes that required hospitalization and were corroborated by letter or interview but for which medical records were unavailable were included as probable . Most deaths were reported by the participants ' families . We search ed the National Death Index to identify deaths among nonrespondents to each 2-year question naire ; mortality follow-up was more than 98 % complete ( 9 ) . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered to be due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . We also included coronary disease listed on the death certificate as the underlying cause without another , more plausible cause , if the nurse was known ( from hospital records , family , or other sources ) to have had coronary disease before death . In no case was the cause listed on the death certificate used as the sole criterion for coronary death . Sudden death within 1 hour of the onset of symptoms in participants with no other plausible cause of death besides coronary disease was also included . Fatal strokes were documented by autopsy or hospital records or if stroke was listed as the underlying cause on the death certificate . The category of major coronary heart disease combines nonfatal myocardial infa rct ion and coronary death ; similarly , total stroke includes nonfatal and fatal cases . The category of combined cardiovascular disease includes major coronary heart disease and stroke . Confirmed and probable cases in each category were analyzed together ( 80 % of major coronary events and 73 % of strokes were confirmed ) . In this and previous analyses ( 6 ) , results for probable cases were similar to those for confirmed cases . The investigators conducted all interviews and record review s without knowledge of participants ' hormone use status . Population for Analysis Women who reported stroke , myocardial infa rct ion , angina , coronary revascularization , or cancer ( except nonmelanoma skin cancer ) on the 1976 question naire were excluded because their disease may have caused them to alter their hormone use . Similarly , women who reported such diagnoses on a subsequent question naire were excluded from further analysis . Thus , at the start of each 2-year interval , the base population included no women reporting these diagnoses . Our own studies ( 6 , 10 ) and other studies ( 11 ) have suggested that hormone therapy may differentially affect incident and fatal strokes ; thus , we separately examined deaths due to stroke . In these analyses , we excluded women with cancer and cardiovascular disease at baseline but did not up date the exclusions because the women who develop cardiovascular disease during follow-up are those most likely to die of stroke . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy  were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) . In this cohort , the women 's reports of age at menopause ( 12 ) and type of menopause ( 13 ) were highly accurate . In 1976 , 21 947 postmenopausal women entered the analysis , and 48 586 women were added during follow-up as they became postmenopausal , for a total of 70 533 participants ; 808 825 person-years of follow-up were accrued from 1976 to 1996 . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the 1976 data and were up date d every 2 years ( for estrogen dose , follow-up began in 1980 ) . For analyses of type of hormone therapy , we assigned the regimen reported on the 1978 question naire to women who reported hormone use in 1976 . Analyses of type of hormone therapy were limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate  , since these were the most common hormone regimens . If no data were available on hormones in a given time period , women were assigned to a missing category for that time period . To maintain the prospect i ve nature of the study , hormone use ( including duration ) during each 2-year period was established from women 's reports at the start of the period ; thus , we probably underestimate duration of use by an average of 1 year . Follow-up for a participant ended at the first diagnosis of cardiovascular disease , death , or 1 June 1996 , whichever came first . The primary analysis is based on incidence rates for which person-months of follow-up were used as the denominator . We used relative risk as the measure of association , defined as the incidence of cardiovascular events among women in various categories of hormone use divided by the incidence among women who never used hormones . We computed age-specific rates by using 5-year categories ( 14 ) and age-adjusted relative risks by using MantelHaenszel rate ratios ( 15 ) with 95 % CIs ( 16 ) . We used pooled logistic regression  across the ten 2-year time periods to adjust simultaneously for potential confounding factors ( 17 ) . In this approach , independent blocks of person-time are pooled for regression analysis , and time-varying covariates are readily accommo date d by assigning successive blocks of person-time to the covariate values at the start of each follow-up cycle . The dependence of the incidence rates on time is modeled nonparametrically with indicator variables . Simulation studies have established the asymptotic equivalence of pooled logistic regression to Cox regression with time-dependent covariates ( 18 ) . The necessary conditions for this equivalence include relatively short time intervals and small probability of the outcome during each interval , both The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of postmenopausal hormone  use in 2763 women ( 1 ) . Unlike previous observational studies , it included only women with previous coronary heart disease , and hormone therapy was exclusively oral conjugated estrogen plus progestin . In HERS , overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups . However , in additional , unplanned analyses , the results of HERS were not uniformly null . A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use ( 1 ) ; in the first year , the rate of major coronary events was 52 % higher in the treatment group . In the second year , rates were equal , but during the final fourth and fifth years , women assigned to hormone therapy had a 33 % lower risk for coronary events . The overall results of HERS and the apparent changes in risk over time were both unexpected . Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events , it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen ( 2 ) . In addition , we were interested in underst and ing how women 's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event . In HERS , duration of hormone therapy before trial entry was necessarily disregarded ( although 23 % of participants had previously taken hormones ) ; thus , it remains unknown how , or whether , to account for hormone use or duration of use before a patient 's initial coronary event . To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens , we investigated the relation between  postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses ' Health Study , a large observational cohort . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 , when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about  postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . Every 2 years , we mail follow-up question naires to the original participants to up date information on risk factors and to identify newly diagnosed cases of major illnesses . The total follow-up for the cohort to date exceeds 92 % . Sample for Analysis For this analysis , we limited the cohort to postmenopausal women who reported a previous myocardial infa rct ion or documented coronary atherosclerosis ( coronary artery bypass graft surgery , percutaneous coronary revascularization , or angiographic evidence of 70 % occlusion of one or more major coronary arteries ) . Such women were identified on the baseline question naire in 1976 ; postmenopausal women who reported one of these conditions on a subsequent follow-up question naire were added to the sample at that time . Women ranged in age from 34 to 73 years at entry into the sample for analysis ; 60 % of women had a natural menopause . These criteria closely parallel those used in HERS ( 1 ) ; however , in HERS , women with hysterectomy were excluded , occlusion was defined as at least 50 % , and participants ranged in age from 44 to 79 years . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy .  Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) ( 3 ) . The women 's reports of age at menopause and type of menopause were highly accurate ( 4 ) . In HERS , women with a history of breast or endometrial cancers were excluded . In the current study , we excluded women who reported stroke or cancer ( except nonmelanoma skin cancer ) on the 1976 baseline question naire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial question naire . This was done to avoid potential bias , in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease . This type of bias could not have occurred in a r and omized trial , such as HERS . Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976 , and 2241 postmenopausal women were added during follow-up as they reported heart disease ; thus , 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996 . Ascertainment of Hormone Use In 1976 , women were asked about current and past use and duration of hormone therapy ;  this information was up date d on each biennial question naire . Beginning in 1978 and on each subsequent question naire , we collected information on type of hormone used . For the period 19761978 , we assigned women to the type of hormone reported on the 1978 question naire . If no data were available on hormone therapy for a given 2-year period , those women were assigned to a missing category for that period . In the HERS trial , women who had taken hormones in the 3 months before their screening visit were excluded ( although 23 % to 24 % of the enrolled participants had previously used hormones ) . Because this study is observational , we could not impose a 3-month washout period ; thus , we could not duplicate that aspect of the HERS protocol . We analyzed duration of hormone use in two different ways . In the main analysis , we performed a HERS replication and used a method similar to that in HERS to calculate duration of use . In HERS , duration of hormone therapy began to accrue at r and omization ( regardless of previous hormone use ) ; r and omization occurred sometime after the participant 's initial coronary disease event . Therefore , in our main analysis , we began accruing duration of hormone use for each participant immediately after her initial coronary disease event ( regardless of hormone use before this event ) . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 4 years . In an alternative analysis , we considered the women 's full experience with hormone therapy ( both before and after the initial coronary disease event ) . Thus , duration of hormone use accumulated continuously from start to termination of therapy . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 6 years . Similar to HERS participants , 29 % of the nurses had taken hormones before their first coronary disease event . Identification of Second Coronary Disease Events Similar to HERS , in our study the category of recurrent major coronary heart disease included nonfatal myocardial infa rct ion and fatal coronary disease that occurred between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met the World Health Organization criteria ( 5 ) ( symptoms , plus either elevated cardiac enzyme levels or diagnostic electrocardiograms ) . Infa rct ions requiring hospitalization and corroborated by interview or letter , but for which medical records were unobtainable , were included as probable . Most deaths were reported by the participants ' families . Every 2 years , we search the National Death Index ( 6 ) to identify deaths among nonrespondents ; follow-up for death remains more than 98 % complete to date . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another , more plausible cause could not be discerned were included as probable cases , since the nurse was known to have had coronary disease before death . The investigators conducted all interviews and medical record review s without knowledge of participants ' hormone use status . In separate analyses , results for probable cases of coronary disease ( 20 % ) were almost identical to those for confirmed cases ( 80 % ) ; thus , we present data from analyses in which confirmed and probable cases are combined . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the baseline data and were up date d every 2 years according to information received on follow-up question naires . Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , as this was the most common hormone regimen . If information on hormone use was missing during a follow-up period , then person-time was assigned to a missing category for that time period . So that the study would be prospect i ve , we established hormone status during each 2-year follow-up period from women 's reports at the start of the time period ; thus , we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis . Follow-up for a participant ended with diagnosis of myocardial infa rct ion , death , or 1 June 1996 , whichever came first . The analysis is based on incidence rates , using person-months of follow-up as the denominator . We used relative risk as the measure of association , defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones CONTEXT The timing of initiation of hormone therapy may influence its effect on  cardiovascular disease .  OBJECTIVE To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began . DESIGN , SETTING , AND PARTICIPANTS Secondary analysis of the Women 's Health Initiative ( WHI ) r and omized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were r and omized to conjugated equine estrogens ( CEE ) or placebo and  16,608 postmenopausal women who had not had a hysterectomy  were r and omized to CEE plus medroxyprogesterone acetate ( CEE + MPA ) or placebo .  Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998 . MAIN OUTCOME MEASURES Statistical test for trend of the effect of hormone therapy on coronary heart disease ( CHD ) and stroke across categories of age and years since menopause in the combined trials . RESULTS In the combined trials , there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [ corrected ] cases of CHD and 239 cases of stroke in the placebo group . For women with less than 10 years since menopause began , the hazard ratio ( HR ) for CHD was 0.76 ( 95 % confidence interval [ CI ] , 0.50 - 1.16 ) ; 10 to 19 years , 1.10 ( 95 % CI , 0.84 - 1.45 ) ; and 20 or more years , 1.28 ( 95 % CI , 1.03 - 1.58 ) ( P for trend = .02 ) . The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years ; for women 10 to 19 years since menopause began , 4 per 10,000 person-years ; and for women 20 or more years from menopause onset , 17 per 10,000 person-years . For the age group of 50 to 59 years , the HR for CHD was 0.93 ( 95 % CI , 0.65 - 1.33 ) and the absolute excess risk was -2 per 10,000 person-years ; 60 to 69 years , 0.98 ( 95 % CI , 0.79 - 1.21 ) and -1 per 10,000 person-years ; and 70 to 79 years , 1.26 ( 95 % CI , 1.00 - 1.59 ) and 19 per 10,000 person-years ( P for trend = .16 ) . Hormone therapy increased the risk of stroke ( HR , 1.32 ; 95 % CI , 1.12 - 1.56 ) . Risk did not vary significantly by age or time since menopause . There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women ( HR of 0.70 for 50 - 59 years ; 1.05 for 60 - 69 years , and 1.14 for 70 - 79 years ; P for trend = .06 ) . CONCLUSIONS Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause , but this trend test did not meet our criterion for statistical significance . A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause . These data should be considered in regard to the short-term treatment of menopausal symptoms . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 Objective To assess the long term risks and benefits of hormone replacement therapy ( combined hormone therapy versus placebo , and oestrogen alone versus combined hormone therapy ) . Design Multicentre , r and omised , placebo controlled , double blind trial . Setting General practice s in UK ( 384 ) , Australia ( 91 ) , and New Zeal and ( 24 ) . Participants Postmenopausal women aged 50 - 69 years at r and omisation . At early closure of the trial , 56 583 had been screened , 8980 entered run-in , and 5692 ( 26 % of target of 22 300 ) started treatment . Interventions Oestrogen only therapy ( conjugated equine oestrogens 0.625 mg orally daily ) or combined hormone therapy ( conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily ) . Ten years of treatment planned . Main outcome measures Primary outcomes : major cardiovascular disease , osteoporotic fractures , and breast cancer . Secondary outcomes : other cancers , death from all causes , venous thromboembolism , cerebrovascular disease , dementia , and quality of life . Results The trial was prematurely closed during recruitment , after a median follow-up of 11.9 months ( interquartile range 7.1 - 19.6 , total 6498 women years ) in those enrolled , after the publication of early results from the women 's health initiative study . The mean age of r and omised women was 62.8 ( SD 4.8 ) years . When combined hormone therapy ( n=2196 ) was compared with placebo ( n=2189 ) , there was a significant increase in the number of major cardiovascular events ( 7 v 0 , P=0.016 ) and venous thromboembolisms ( 22 v 3 , hazard ratio 7.36 ( 95 % CI 2.20 to 24.60 ) ) . There were no statistically significant differences in numbers of breast or other cancers ( 22 v 25 , hazard ratio 0.88 ( 0.49 to 1.56 ) ) , cerebrovascular events ( 14 v 19 , 0.73 ( 0.37 to 1.46 ) ) , fractures ( 40 v 58 , 0.69 ( 0.46 to 1.03 ) ) , and overall deaths ( 8 v 5 , 1.60 ( 0.52 to 4.89 ) ) . Comparison of combined hormone therapy ( n=815 ) versus oestrogen therapy ( n=826 ) outcomes revealed no significant differences . Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause . The results are consistent with the findings of the women 's health initiative study and secondary prevention studies . Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause , when the effect may be different . Trial registration Current Controlled Trials IS RCT N Over the last 40 years , there has been increasing epidemiological evidence that post-menopausal treatment with sex steroids in physiological doses may reduce the relative risk of cardiovascular disease ( CVD ) . These findings have been supported by biological studies showing favourable changes in cardiovascular risk factors with estrogen supplementation . The impact of the so-called ' healthy user ' bias has been eagerly debated , and the results of the first and only r and omized long-term clinical trial of HRT for primary prevention have therefore been long awaited . The dramatic decision to halt the Women 's Health Initiative ( WHI ) study before completion came unexpectedly as the consequence of not only an increased risk of breast cancer but also increased occurrence of cardiovascular events with HRT . Due to the superior design of the study , the results from the WHI study have had an enormous impact on the clinical recommendations of HRT to post-menopausal women , concurrent with a degradation of evidence from observational studies . It is not very likely that other long-term r and omized clinical trials ( RCTs ) will be completed and epidemiology has certainly been disreputed-so is this ' time out ' for HRT studies BACKGROUND Little is known about the impact of post-menopausal hormone therapy on remnant-like particle ( RLP ) concentrations and about the relationship between RLP concentration and angiographic progression of coronary artery disease and clinical events in women . METHODS RLP cholesterol and triglyceride levels were measured at baseline and 3 months after r and omization in 397 post-menopausal women enrolled in The Women 's Angiographic Vitamin & Estrogen ( WAVE ) trial . Correlates of baseline RLP levels and changes in levels with post-menopausal hormone therapy were determined with multiple linear regression . Coronary angiography was performed at baseline and after a mean of 2.9 years . Changes in minimal and average luminal diameter were modeled with multivariate linear regression , clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) with multiple logistic regression . RESULTS The mean subject age was 65 years , 66 % of subjects were white , 18 % of subjects smoked , most subjects were overweight or obese , and 35 % of subjects had diabetes mellitus .  RLP cholesterol ( 0.277 + /- 0.254 mmol/L ) and triglyceride ( 0.386 + /- 0.552 mmol/L ) levels corresponded approximately to the 90th percentile in women in the Framingham study . RLP levels did not change significantly with hormone therapy . RLP levels at baseline , changes in RLP levels , and on treatment RLP levels did not relate to angiographic changes or clinical outcomes ( non-fatal myocardial infa rct ion , stroke , or cardiovascular death ) . CONCLUSIONS RLP levels were high among post-menopausal women enrolled in the WAVE study , were not affected by hormone therapy , and did not relate to angiographic progression of coronary artery disease or clinical outcomes BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later . However , the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation ( the hormone-timing hypothesis ) has not been tested . METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause ( < 6 years [ early postmenopause ] or ≥10 years [ late postmenopause ] ) and were r and omly assigned to receive either oral 17β-estradiol ( 1 mg per day , plus progesterone [ 45 mg ] vaginal gel administered sequentially [ i.e. , once daily for 10 days of each 30-day cycle ] for women with a uterus ) or placebo ( plus sequential placebo vaginal gel for women with a uterus ) . The primary outcome was the rate of change in carotid-artery intima-media thickness ( CIMT ) , which was measured every 6 months . Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography ( CT ) , which was performed when participants completed the r and omly assigned regimen . RESULTS After a median of 5 years , the effect of estradiol , with or without progesterone , on CIMT progression differed between the early and late postmenopause strata ( P=0.007 for the interaction ) . Among women who were less than 6 years past menopause at the time of r and omization , the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group ( P=0.008 ) . Among women who were 10 or more years past menopause at the time of r and omization , the rates of CIMT progression in the placebo and estradiol groups were similar ( 0.0088 and 0.0100 mm per year , respectively ; P=0.29 ) . CT measures of coronary-artery calcium , total stenosis , and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum . CONCLUSIONS Oral estradiol therapy was associated with less progression of sub clinical atherosclerosis ( measured as CIMT ) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause . Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum . ( Funded by the National Institute on Aging , National Institutes of Health ; ELITE Clinical Trials.gov number , NCT00114517 . ) Background and Objective The highest level of scientific evidence available for each therapy for menopausal symptoms was sought , for example , systematic review s of r and omised controlled trials ( RCTs ) . Results There is reasonable evidence that some symptoms are modified by lifestyle , for example , cessation of smoking , exercise , reduction of alcohol , diet and alleviation of psychosocial stress . No complementary medicine , for example , phytoestrogens , black cohosh , herbal or homeopathic medicines or complementary therapies , for example , acupuncture , yoga , chiropractic manipulation , reflexology or magnetic devices have a greater effect than the usual placebo effect seen in quality blinded RCTs . Some have potential side-effects . So-called ' bioidentical hormones ' have no evidence -base and potential for harm . None of the above therapies have evidence of efficacy and long-term safety . Selective serotonin and noradrenaline re-uptake inhibitors ameliorate vasomotor symptoms and sometimes menopausal depression better than placebo . The most effective therapy for menopausal ( oestrogen ) deficiency symptoms is oestrogen which is the main component of hormone replacement therapies ( HRT ) . Compared with placebo HRT is highly effective in relieving hot flushes , night sweats , dry vagina and dyspareunia . It also improved joint pains , sexuality and sleeplessness and reduced subsequent fractures in RCTs . The increased risk of oral HRT for thromboembolism is small around menopause , for those without thrombotic risk factors , and is not elevated with non-oral routes . Cardiovascular disease may be reduced when HRT is initiated near menopause . Breast cancer risk increases after several years with the use of oral HRT containing progestogens at an annual rate of 8/10 000 ( < 0.1 % ) . No increase in breast cancer risk was seen with oestrogen-only HRT Hormone replacement therapy ( HRT ) has profound effects on the cardiovascular system , with plausible biological mechanisms explaining both the benefits and harm . Benefits may result from oestrogen action on metabolic risk factors , such as lipids , glucose and insulin metabolism , as well as direct arterial effects , reducing atherogenesis . Harm may arise from inappropriately high starting doses causing transient increases in coagulation activation and adverse vascular remodelling . Observational studies of HRT suggest that there is a beneficial effect on the incidence of coronary heart disease ( CHD ) . Any benefit of HRT seen in r and omized clinical trials appears to be confined to those women within several years of their menopause , and it is clear from the r and omized trials that age at initiation is a crucially important consideration . Women initiating HRT within 10 years of menopause onset may achieve cardiovascular benefit , particularly in terms of primary CHD prevention , whilst avoiding risks of stroke and venous thrombo-embolism 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 The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer 's disease have led to an intense re assessment of gonadal hormone action and the model systems used in basic and clinical science . The power of model systems is their predictive validity for a target population --in this case , menopausal women considering the health benefits and risks of hormone therapy .  Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes : those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function . Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm . This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult . The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues ( Psychoneuroendocrinology 13 : 345 - 357 , 1988 ) , who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause . Observational retrospective and prospect i ve studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention . For the most part , the epidemiological observational data indicate reduction in the risk of Alzheimer 's disease in women who began  estrogen or hormone therapy  at the time of the menopause . In contrast , studies that fall within the second class , hormone intervention in organisms with compromised neurological function -- that is , a treatment paradigm -- exhibit a mixed profile . In a r and omized double-blind clinical trial of  estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer 's disease , estrogen therapy result ed in a modest benefit in the short term ( 2 months ) and adverse progression of disease in the long term ( 12 months ) . In the Women 's Health Initiative Memory Study ( WHIMS ) cohort of women 65 or more years of age , with no indicators of neurological disease but with variable health status , estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer 's disease . These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy , so too do the benefits of estrogen or hormone therapy . If neurons are healthy at the time of estrogen exposure , their response to estrogen is beneficial for both neurological function and survival . In contrast , if neurological health is compromised , estrogen exposure over time exacerbates neurological demise . Based on these and other data , a hypothesis of a healthy cell bias of gonadal hormone action is put forth . The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions BACKGROUND Apparently discrepant findings have been reported by the Women 's Health Initiative ( WHI ) trial compared with observational studies of postmenopausal hormone therapy ( HT ) and coronary heart disease ( CHD ) . METHODS We prospect ively examined the relation of HT to CHD , according to timing of hormone initiation relative to age and time since menopause . Participants were postmenopausal women in the Nurses ' Health Study , with follow-up from 1976 to 2000 . Information on hormone use was ascertained in biennial , mailed question naires . We used proportional hazards models to calculate multivariable adjusted relative risks ( RR ) and 95 % confidence intervals ( CI ) . We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT . RESULTS Women beginning HT near menopause had a significantly reduced risk of CHD ( RR = 0.66 , 95 % CI 0.54 - 0.80 for estrogen alone ; RR = 0.72 , 95 % CI 0.56 - 0.92 for estrogen with progestin ) . In the subgroup of women demographically similar to those in the WHI , we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause ( RR = 0.87 , 95 % CI 0.69 - 1.10 for estrogen alone ; RR = 0.90 , 95 % CI 0.62 - 1.29 for estrogen with progestin ) . Among women who began taking hormones at older ages , we also found no relation between current use of estrogen alone and CHD ( for women aged 60 + years , RR = 1.07 , 95 % CI 0.65 - 1.78 ) , although there was a suggestion of possible reduced risk for combined HT ( RR = 0.65 , 95 % CI 0.31 - 1.38 ) . In sensitivity analyses , we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT . CONCLUSIONS These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk OBJECTIVE The main purpose in organizing this survey was to collect information relevant to The North American Menopause Society 's ( NAMS ) educational mission and to document women 's knowledge of , and attitudes toward , menopause . DESIGN During June-July 1997 , The Gallup Organization conducted 750 telephone interviews with a r and omly selected sample of women 45 - 60 years of age from across the United States . Women were asked about their sources of information on menopause , what changes in health they anticipated as a result of menopause , why they used hormone therapy , and their attitudes toward menopause as a natural or a medical event . RESULTS Women are more likely to believe that depression and irritability are associated with menopause than heart disease , but only a few associate menopause with an increasing vulnerability to either memory loss or Alzheimer 's disease . Relief of physical symptoms of menopause was mentioned as the reason for starting hormone therapy more often than to protect against osteoporosis ( 25 % relative to 15 % ) , or to prevent stroke or a heart attack ( 10 % ) , or to reduce the risk of developing Alzheimer 's disease ( 2 % ) . The single main source of women 's information on menopause was a health professional ( 49 % ) . The majority of women who were already menopausal or experiencing menstrual changes expressed an attitude toward menopause that was either neutral ( 42 % ) or positive ( 36 % ) . CONCLUSIONS Women are divided in their views of menopause , some seeing it as a medical condition requiring medical treatment , whereas others see it as a natural transition to be managed by " natural " means . Providing women with accurate , up-to- date information and enhancing communication between healthcare providers and menopausal women remain the challenges for NAMS A major achievement from 500 million years of evolution is the establishment of a high secretion rate of dehydroepi and rosterone ( DHEA ) by the human adrenal gl and s coupled with the indroduction of menopause which stops secretion of estrogens by the ovary . Cessation of estrogen secretion at menopause eliminates the risks of endometrial hyperplasia and cancer which would result from non-opposed estrogen stimulation during the post-menopausal years . In fact , from the time of menopause , DHEA becomes the exclusive and tissue-specific source of sex steroids for all tissues except the uterus . Intracrinology , a term coined in 1988 , describes the local formation , action and inactivation of sex steroids from the inactive sex steroid precursor DHEA . Over the past 25 years most , if not all , the genes encoding the human steroidogenic and steroid-inactivating enzymes have been cloned and sequenced and their enzymatic activity characterized . The problem with DHEA , however , is that its secretion decreases from the age of 30 years and is already decreased , on average , by 60 % at time of menopause . In addition , there is a large variability in the circulating levels of DHEA with some post-menopausal women having barely detectable serum concentrations of the steroid while others have normal values . Since there is no feedback mechanism controlling DHEA secretion within ' normal ' values , women with low DHEA will remain with such a deficit of sex steroids for their remaining lifetime . Since there is no other significant source of sex steroids after menopause , one can reasonably believe that low DHEA is involved , in association with the aging process , in a series of medical problems classically associated with post-menopause , namely osteoporosis , muscle loss , vaginal atrophy , fat accumulation , hot flashes , skin atrophy , type 2 diabetes , memory loss , cognition loss and possibly Alzheimer 's disease . A recent r and omized , placebo-controlled study has shown that all the signs and symptoms of vaginal atrophy , a classical problem recognized to be due to the hormone deficiency of menopause , can be rapidly improved or corrected by local administration of DHEA without systemic exposure to estrogens . In addition , the four domains of sexual dysfucntion are improved . For the other problems of menopause , although similar large scale , r and omized and placebo-controlled studies usually remain to be performed , the available evidence already strongly suggests that they could be improved , corrected or even prevented by exogenous DHEA . In men , the contribution of adrenal DHEA to the total and rogen pool has been measured at 40 % in 65 - 75-year-old men . Such data stress the necessity of blocking both the testicular and adrenal sources of and rogens in order to achieve optimal benefits in prostate cancer therapy . On the other h and , the comparable decrease in serum DHEA levels observed in both sexes has less consequence in men who continue to receive a practically constant supply of testicular sex steroids during their whole life . In fact , in men , the appearance of hormone-deficiency symptoms common to women is observed at a later age and with a lower degree of severity . Consequently , DHEA replacement has shown much more easily measurable beneficial effects in women . Most importantly , despite the non-scientific and unfortunate availability of DHEA as a food supplement in the United States , a situation that discourages rigorous clinical trials on the crucial physiological and therapeutic role of DHEA , no serious adverse event related to DHEA has ever been reported in the world literature ( thous and s of subjects exposed ) or in the monitoring of adverse events by the FDA ( millions of subjects exposed ) , thus indicating , as expected from its known physiology , the excellent safety profile of DHEA . With today 's knowledge , one can reasonably suggest that DHEA offers the promise of a safe and efficient replacement therapy for the multiple problems related to hormone deficiency after menopause without the risks associated with estrogen-based or any other treatments Atherosclerotic cardiovascular disease ( ASCVD ) is the leading cause of death , decreased quality of life , and medical costs in the United States . Nearly 1 in 3 Americans die of heart disease and stroke ( 1 ) . Most ASCVD is preventable through a healthy lifestyle and effective treatment of cholesterol and blood pressure . The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults from the American College of Cardiology and American Heart Association ( ACC/AHA ) provides an evidence -based approach to reducing ASCVD risk ( 2 ) . Guideline Development Process In 2008 , the National Heart , Lung , and Blood Institute ( NHLBI ) convened the Adult Treatment Panel ( ATP ) IV to up date the 2001 ATP-III cholesterol guidelines using a rigorous systematic process to identify and review r and omized , controlled trials ( RCTs ) with cardiovascular outcomes and meta-analyses of these RCTs . The panel comprised experts and clinicians from the fields of cardiology , epidemiology , primary care , and endocrinology ( 2 ) and received support from the Lifestyle Management and Risk Assessment Work Groups ( 3 , 4 ) . Systematic evidence review s conducted according to principles recommended by the Institute of Medicine ( 5 ) were performed to answer 3 questions relevant to clinical care . Two questions focused on the evidence supporting low-density lipoprotein cholesterol ( LDL-C ) and nonhigh-density lipoprotein cholesterol ( HDL-C ) levels as targets of treatment . One question examined the reduction in ASCVD events and adverse effects for each cholesterol-lowering drug class . The panel synthesized the evidence from these 3 review s as well as from Lifestyle Management and Risk Assessment Work Groups review s ( 3 , 4 ) that addressed 5 additional critical questions . Systematic electronic search es of relevant data bases of the peer- review ed English- language literature published from 1 January 1995 through 1 December 2009 for each critical question were conducted by an NHLBI-selected independent contractor and focused on RCTs and systematic review s and meta-analyses of RCTs assessed as fair to good quality . In addition , RCTs with ASCVD outcomes that included coronary heart disease , stroke , and cardiovascular deaths published after that date were eligible for consideration through July 2013 . Evidence tables were constructed , and the strength of evidence was rated according to the NHLBI ( Table 1 of the Supplement ) . Recommendations were grade d according to criteria from the NHLBI ( Table 2 of the Supplement ) and ACC/AHA ( Table 3 of the Supplement ) . Because of the inherent differences in grading systems and the clinical questions driving the recommendations , alignment between the NHLBI and ACC/AHA formats was imperfect . A complete description of the methods used and results of the evidence review are provided in the guideline ( 2 ) and the NHLBI evidence report ( www.nhlbi.nih.gov/ guidelines /cholesterol/ser/index.htm ) . Supplement . NHLBI and ACC/AHA Criteria for Rating Strength of Evidence To help clinicians estimate ASCVD risk , the risk assessment working group developed the Pooled Cohort Equations using data from 5 NHLBI-sponsored longitudinal , population -based cohorts of African American and non-Hispanic white men and women to estimate risk for a first myocardial infa rct ion , coronary heart disease death , or fatal or nonfatal stroke on the basis of age , sex , race , smoking status , total cholesterol level , HDL-C level , systolic blood pressure , antihypertensive therapy , and diabetes ( 4 , 6 ) . These equations significantly advance ASCVD risk estimation by providing sex- and race-specific estimates and including stroke as an outcome . The earlier Framingham equations calculated only coronary heart disease risk for non-Hispanic whites . The draft recommendations were review ed by 23 experts and representatives of federal agencies identified by the NHLBI . In September 2013 , the recommendations developed by the panel were transitioned to the ACC/AHA and had additional review by 4 experts nominated by the ACC Foundation and the AHA . The governing bodies of the ACC and AHA approved the guideline , which also received endorsement from the American Association of Cardiovascular and Pulmonary Rehabilitation , American Pharmacists Association , American Society for Preventive Cardiology , Association of Black Cardiologists , Preventive Cardiovascular Nurses Association , and WomenHeart : The National Coalition for Women with Heart Disease . Recommendations The guideline focuses on treatment of blood cholesterol to reduce ASCVD risk in adults . Major recommendations are summarized here and in Table 1 . The guideline report provides a complete listing of recommendations and supporting evidence behind each recommendation ( 2 ) . Table 1 . Major Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults * 1 . Encourage Adherence to a Healthy Lifestyle A healthy lifestyle is the foundation for cardiovascular health . The panel endorsed the 2013 ACC/AHA Lifestyle Management Guideline ( 3 ) for a diet that is low in saturated fat , trans fat , and sodium ; emphasizes vegetables , fruits , whole grains , low-fat dairy products , poultry , fish , legumes , nontropical vegetable oils , and nuts ; and limits sweets , sugar-sweetened beverages , and red meats and engage in regular aerobic physical activity . Adults also should maintain a healthy body weight , avoid smoking , and control hypertension and diabetes when present . 2 . Statin Therapy Is Recommended for Adults in Groups Demonstrated to Benefit Strong RCT evidence shows that reduction in ASCVD events from statin therapy exceeds adverse events for 4 patient groups : those with clinical ASCVD ( acute coronary syndromes , myocardial infa rct ion , stable angina , coronary or other arterial revascularization , stroke , transient ischemic attack , or peripheral arterial disease of atherosclerotic origin ) when  statins are used for secondary prevention , and those with LDL-C levels 190 mg/dL ; those aged 40 to 75 years with diabetes and LDL-C levels 70 to 189 mg/dL ; and those aged 40 to 75 years without diabetes and with a 10-year ASCVD risk 7.5 % when statins are used for primary prevention . Moderate evidence supports consideration of statin therapy for primary prevention in individuals with a 10-year ASCVD risk of 5 % to < 7.5 % . Routine initiation of statin therapy is not recommended in adults with New York Heart Association heart failure class II to IV or those receiving maintenance hemodialysis . R and omized , controlled trials in these groups showed no reduction in ASCVD . 3 . Statins have an Acceptable Margin of Safety When Used in Properly Selected Individuals and Appropriately Monitored Strong RCT evidence supports safety of statins when they are used as directed in conjunction with regular follow-up assessment s in properly selected patients . Adjustment of statin intensity is recommended in individuals older than 75 years with a history of statin intolerance or other characteristics ( 2 ) or those receiving drug therapy that may increase statin adverse events . Routine monitoring of hepatic aminotransferase level or creatine kinase level is not recommended unless clinical ly indicated by symptoms suggesting hepatotoxicity or myopathy . Given the potential for decreasing ASCVD events and death , the relationship of muscle and other symptoms to statin treatment must be confirmed . Therefore , eliciting a history of muscle symptoms before statin initiation and carefully monitoring symptoms during statin discontinuation and rechallenge is recommended . Severe myopathy , rhabdomyolysis , and possibly hemorrhagic stroke are rare complications of statin therapy . Although statin therapy modestly increases the risk for type 2 diabetes , ASCVD risk reduction outweighs the excess risk for diabetes for high-intensity statins in secondary prevention or for 10-year ASCVD risk 7.5 % . Similarly , ASCVD risk reduction outweighs the excess risk for diabetes for moderate-intensity statin therapy in adults with a 10-year ASCVD risk 5 % . 4 . Engage in a ClinicianPatient Discussion Before Initiating Statin Therapy , Especially for Primary Prevention in Patients With Lower ASCVD Risk Decisions to initiate statin therapy in primary prevention should be based on clinical judgment and preferences of informed patients . In adults without clinical ASCVD or diabetes whose LDL-C level is < 190 mg/dL , calculating the estimated 10-year ASCVD risk should be the start of the clinicianpatient discussion and should not automatically lead to statin initiation . As the absolute risk for ASCVD events decreases , so does the net benefit of the intervention . Therefore , discussion of the potential for ASCVD event reduction , adverse effects , drugdrug interactions , and patient preferences is especially important for lower-risk primary prevention . The discussion provides the opportunity to encourage healthy lifestyle habits and control other risk factors . Additional factors may be considered when a risk-based decision is uncertain , including LDL-C levels 160 mg/dL , family history of premature ASCVD , elevated  lifetime ASCVD risk  , high-sensitivity C-reactive protein level 2.0 mg/L ,  coronary artery calcification score  > 300 Agatston units , and anklebrachial index < 0.9 . After age 75 years , comorbid conditions , anticipated longevity , safety considerations , and patient preferences should play a large role in decision making . 5 . Use the Newly Developed Pooled Cohort Equations for Estimating 10-Year ASCVD Risk The Pooled Cohort Equations are currently the best available method for estimating 10-year ASCVD risk to guide statin initiation ( 4 , 6 ) . Application of the inclusion and exclusion criteria from RCTs is cumbersome and results in underidentifying high-risk and overidentifying low-risk individuals for statin treatment . The Pooled Cohort Equations were developed using recent data from 5 NHLBI-sponsored , longitudinal , population -based cohorts of African American and white men and women ( ARIC [ The postmenopausal hormone therapy ( PHT ) component of the Women ’s Health Initiative ( WHI ) is composed of two r and omized , placebo-controlled , double-blind trials in postmenopausal women aged 50 to 79 years at initial screening , testing the effects of estrogen alone ( E-alone ) and estrogen plus progestin ( E P ) on coronary heart disease ( CHD ) as the primary outcome , hip and other fractures and colorectal cancer as secondary outcomes , and pulmonary embolism , breast and endometrial cancers as potential risks . The design and rationale of the PHT trials , including general eligibility and exclusion criteria and considerations regarding sample size and statistical power , have been described previously ( 1 ) . Postmenopausal hormones have been initiated in menopausal women for the treatment of vasomotor symptoms , mood disturbances , vaginal dryness , and prevention of rapid bone loss for several decades . Despite a paucity of data on effects of initiating hormone use in older women , postmenopausal hormones have also been promoted for the prevention of CHD , osteoporotic fractures , and other diseases that occur years after menopause ( 2 ) . It is generally recommended ( 2 ) that women with a uterus be prescribed a combination of estrogen and progestin to prevent Context Since 1998 , 2 large trials have drastically changed the evidence for the preventive health benefits of postmenopausal hormone replacement therapy .  However , changes in practice often lag behind changes in evidence . Contribution Among mammography recipients in San Francisco , California , the use of  hormone replacement therapy decreased 1 % per quarter after publication of the Heart and Estrogen/progestin Replacement Study and 18 % per quarter after publication of results from the Women 's Health Initiative ( WHI ) . Reduction in use was unrelated to a woman 's age , hysterectomy status , or race or ethnicity . Implication s The WHI result ed in more dramatic changes in practice than are often associated with changes in evidence . The vigorous media coverage of the WHI may have contributed to rapid changes in practice . The Editors In 1995 , approximately 38 % of postmenopausal women in the United States were taking hormone therapy  ( 1 ) . At that time , several observational studies had suggested that hormone therapy offered women some protection against coronary heart disease and osteoporosis ( 2 - 5 ) . A decision analysis published in 1997 concluded that the benefits of hormone therapy outweighed its risks for nearly all women ( 6 ) . More recently , the results from 2 large r and omized clinical trials , the Heart and Estrogen/progestin Replacement Study ( HERS ) ( 7 ) and the Women 's Health Initiative ( WHI ) , have been published ( 8) . These clinical trials demonstrated that the risks associated with hormone therapy outweigh the benefits for women taking continuous estrogen and progestin regimens . As a result of these trial results , the U.S. Food and Drug Administration required new warning labels for all estrogen products ( 9 ) , and the U.S. Preventive Services Task Force revised its assessment of hormone therapy to recommend against the routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women ( 10 ) . It is important to underst and whether this new scientific evidence is changing the use of hormone therapy . Of note , the results of the WHI were widely disseminated . Despite this publicity , differential access to new information , varied interpretations of study findings , and individual perceptions of menopausal symptoms and hormone side effects may have result ed in different patterns of use . An underst and ing of how use is changing over time provides important information about the dissemination of clinical trial results to women . We design ed our analysis to examine whether the use of hormone therapy  has changed among postmenopausal women as a result of the publication of the results from HERS and the WHI . We were also interested in examining whether patterns of use differ by patient characteristics . Because HERS examined the outcomes of older women , we hypothesized that there would be earlier and more substantial declines in hormone therapy use among this group . We also expected that there would be variation in use by race or ethnicity because white women may have better access to new information ( 11 ) . Finally , because the WHI study results were specific to women taking continuous estrogen plus progestin , we hypothesized that hormone use would be more stable among women who had had hysterectomies because such women typically take only estrogen and may believe that the findings do not apply to them . Methods Sample The San Francisco Mammography Registry is a population -based registry of women undergoing mammography in San Francisco , California . It is 1 of 7 registries participating in the National Cancer Institute Breast Cancer Surveillance Consortium ( 12 ) . This registry began to prospect ively collect patient data and mammography results in 1995 and currently captures about 90 % of mammography examinations performed in San Francisco . Data from 11 mammography facilities are included in this analysis . Women were eligible for this analysis if they were between the ages of 50 to 74 years , were postmenopausal , did not report a personal history of breast cancer , and underwent screening or diagnostic mammography between January 1997 and 19 May 2003 . Women 55 years of age and older were assumed to be menopausal . Women 50 to 54 years of age were considered to be menopausal if both ovaries had been removed or if they reported that their periods had stopped permanently . For women who had mammography more than once in any calendar year , we included only the first instance of mammography in that year to prevent overrepresentation of women undergoing an evaluation of an abnormal mammogram because this experience may influence use of hormone therapy . Our final sample included 15 1862 mammograms received by 71 219 women . Data At the facilities that participate in the San Francisco Mammography Registry , each woman completes a brief , scannable question naire at the time of mammography . This question naire collects information about current use of hormone therapy  and several personal characteristics , including race or ethnicity ( categorized as white , African American , Latina , Chinese , Filipina , other Asian , other ) , family history of breast cancer ( including mother , sisters , and daughters ) , history of childbirth , whether the woman had undergone a hysterectomy , menopausal status , history of breast biopsy ( including fine-needle aspiration , core biopsy , and surgical biopsy ) . Information about age at the time of mammography , date of mammography , and ZIP code of residence is reported by the facility . Data from the year 2000 U.S. Census was used to assign median income for each woman 's ZIP code of residence as a proxy for socioeconomic status . Variables Our outcome variable for this analysis was the current use of hormone therapy . Date of mammography  was represented as a linear term . Binary variables were created for the publication date s of HERS ( before 19 August 1998 vs. that date or later ) and the publication of the principal findings from the WHI ( before 17 July 2002 vs. that date or later ) . Other independent variables examined were age at the time of mammography  , race or ethnicity , median income of the ZIP code of residence , history of childbirth , family history of breast cancer , history of breast biopsy , and previous hysterectomy . Statistical Analysis Because some of the women in this sample had more than 1 mammogram represented in this data set , which spanned a 7-year period , we conducted a repeated- measures logistic regression to adjust the variance estimates for clustering of hormone therapy use over time for individual women and for the clustering of women within mammography facilities ( 13 ) . Generalized estimating equations were implemented by using the SUDAAN statistical package , version 8.0.0 ( Research Triangle Institute , Research Triangle Park , North Carolina ) assuming an exchangeable correlation matrix . These models included a linear term indicating quarter from January 1997 to the first quarter of 2003 to control for temporal trends ( the last quarter included mammograms through 19 May 2003 ) , the variables specified above to indicate the date s of publication of HERS and the WHI , and an interaction term between each of these publication indicators and the time ( in quarters ) following each of these publications to measure changes in use after the publication of these clinical trials . These models also controlled for the individual characteristics described earlier ( that is , age , race or ethnicity , history of childbirth , family history of breast cancer , history of breast biopsy , previous hysterectomy , median income for the ZIP code of residence ) . To specifically test our hypotheses about differential changes in the use of hormone therapy  for subgroups of women on the basis of age , hysterectomy status , and race or ethnicity , we examined interaction terms to test for effect modification . For the main effects , a P value less than 0.05 was considered statistically significant , and for the interaction terms , a P value less than 0.01 was considered to be statistically significant . The likelihood ratio test compared the null model with the fitted model . Role of the Funding Source This work was supported by a National Cancer Institutefunded Breast Cancer Surveillance Consortium agreement . The funding source did not participate in the design , conduct , or reporting of this analysis or in the decision to su bmi t the manuscript for publication . Results The Table shows the characteristics of the sample for each of the study years . Over the time period of the study , the median age decreased from 61 years to 59 years . The racial and ethnic composition of the sample also changed somewhat across the study years . Fewer women undergoing mammography  in 2003 reported a history of childbirth ( 71.7 % vs. 75.2 % ) or hysterectomy than did women undergoing mammography in 1997 . Conversely , more women reported a family history of breast cancer ( 17.1 % vs. 11.8 % ) or a personal history of a previous breast biopsy or aspiration . The average number of mammograms obtained for each woman in our sample across the 7-year study period was 2.1 ( range , 1 to 7 ) . Table . Description of the Sample ( 151 862 Mammograms ) The Figure shows the unadjusted rates of current hormone therapy use by month for all of the women in the sample . Among menopausal women who had received mammography , we estimated that the average proportion reporting the current use of hormone therapy  was 41 % in 1997 . In 1997 , hormone use was highest among white women ( 52.6 % ) and lowest among African-American women ( 34.1 % ) , Latina women ( 33.9 % ) , Chinese women ( 32.2 % ) , and Filipina women ( 29.6 % ) . In 1997 , hormone use was higher among younger women than older women ( 48.7 % vs. 28.7 % ; P < 0.001 ) and among women who had had a hysterectomy compared with women who had not had a hysterectomy ( 60.0 % vs. 36.4 % ; P < 0.001 ) . Figure . Rates of hormone therapy use among postmenopausal women , 1997 to 2003 HERS WHI The adjusted multivariate model estimates that before the publication of HERS , the use of hormone Visceral fat ( VF ) increases with the menopause and is an independent predictor of the metabolic syndrome , diabetes , and cardiovascular disease ( CVD ) in women . Little is known about how hormonal changes during the menopausal transition are related to the increase in VF . We aim ed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors . The Study of Women 's Health Across the Nation ( SWAN ) is a longitudinal , community-based study . This report uses baseline data from a population -based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)-assessed VF  in women at different stages of the menopausal transition . Included are 359 women ( 47.2 % black ) , aged 42 - 60 years , who were r and omly selected from a complete community census in which a 72 % participation rate was achieved . In multivariate models , bioavailable testosterone was associated with VF independent of age , race , percent total body fat , and other cardiovascular risk factors . Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone-binding globulin ( SHBG ) . As bioavailable testosterone was associated with VF even after adjusting for insulin resistance , this suggests that it plays an important role in regional fat distribution . Our findings may have direct implication s in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk AIM To produce dietetic guidelines summarizing the systematic review evidence on dietary advice for secondary prevention of cardiovascular disease . METHODS The Cochrane Library , MEDLINE and EMBASE were comprehensively search ed for systematic review s on aspects of diet and heart health . Review s were included if they search ed systematic ally for r and omised controlled trials relating to diet and secondary prevention of cardiovascular disease . Two members of the UK Heart Health and Thoracic Dietitians Group critically appraised each review . The quality and results of each review were discussed and summarized in a whole group meeting . The guidelines were trialled in seven dietetic departments and modified where necessary . RESULTS Providing evidence -based dietary information ( including increasing omega-3 fat plus fruit and vegetable intake ) to all people after myocardial infa rct ion will save more lives than concentrating dietary advice on those in need of weight loss or lipid lowering . The practice of prioritizing dietetic time to those with raised lipids is out of date since the advent of statin therapy . CONCLUSION There is good systematic review evidence that dietary advice to those with cardiovascular disease can reduce mortality and morbidity as well as modify risk factors .  Dietary advice that does this most effectively should be prioritized BACKGROUND Whether menopausal hormone therapy ( MHT ) protects against cardiovascular disease ( CVD )  remains unclear . OBJECTIVE To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause . DESIGN R and omized , controlled trial . ( Clinical Trials.gov : NCT00154180 ) . SETTING Nine U.S. academic centers . PARTICIPANTS Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium ( CAC ) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days . INTERVENTION Oral conjugated equine estrogens ( o-CEE ) , 0.45 mg/d , or transdermal 17β-estradiol ( t-E2 ) , 50 mcg/d , each with 200 mg of oral progesterone for 12 days per month , or placebo for 48 months . MEASUREMENTS Primary end point was annual change in carotid artery intima-media thickness ( CIMT ) . Secondary end points included changes in markers of CVD risk . RESULTS Of 727 r and omly assigned women , 89.3 % had at least 1 follow-up CIMT and 79.8 % had CIMT at 48 months . Mean CIMT increases of 0.007 mm/y were similar across groups . The percentages of participants in whom CAC score increased did not differ significantly across groups . No changes in blood pressure were observed with o-CEE or t-E2 . Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone-binding globulin but not interleukin-6 increased with o-CEE . Insulin resistance decreased with t-E2 . Serious adverse events did not differ by treatment . LIMITATION Power to compare clinical events was insufficient . CONCLUSION Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk . PRIMARY FUNDING SOURCE Aurora Foundation 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 OBJECTIVE To provide guidelines for the health care provider on the prevention , diagnosis , and clinical management of postmenopausal osteoporosis . OUTCOMES Strategies for identifying and evaluating high-risk individuals , the use of bone mineral density ( BMD ) and bone turnover markers in assessing diagnosis and response to management , and recommendations regarding nutrition , physical activity , and the selection of pharmacologic therapy to prevent and manage osteoporosis . EVIDENCE Published literature was retrieved through search es of PubMed and The Cochrane Library on August 30 and September 18 , 2012 , respectively . The strategy included the use of appropriate controlled vocabulary ( e.g. , oteoporosis , bone density , menopause ) and key words ( e.g. , bone health , bone loss , BMD ) . Results were restricted to systematic review s , practice guidelines , r and omized and controlled clinical trials , and observational studies published in English or French . The search was limited to the publication years 2009 and following , and up date s were incorporated into the guideline to March 2013 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , clinical practice guideline collection s , clinical trial registries , and national and international medical specialty societies
We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality , cardiovascular death , non-fatal myocardial infa rct ion , angina , or revascularisation .
There was no strong evidence of effect on risk of stroke in this group .
Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall , for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events
BACKGROUND Evidence from systematic review s of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women , however the results of r and omised controlled trials ( RCTs ) have had mixed results .
This is an up date d version of a Cochrane review published in 2013 .
OBJECTIVES To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women , and whether there are differential effects between use in primary or secondary prevention .
Secondary aims were to undertake exploratory analyses to ( i ) assess the impact of time since menopause that treatment was commenced ( ≥ 10 years versus < 10 years ) , and where these data were not available , use age of trial participants at baseline as a proxy ( ≥ 60 years of age versus < 60 years of age ) ; and ( ii ) assess the effects of length of time on treatment .