Women’s Health Initiative (WHI)-National Institutes of Health sponsored clinical and large observational studies addressing the most common causes of death and disability in postmenopausal women-cardiovascular disease, cancer and osteoporosis.

The Women’s Health Initiative, contains data on more than nearly 90,000 postmenopausal women.

In the Women’s Health Initiative women with an intact uterus received conjugated equine estrogens (CEE) 0.625 mg/day plus medroxyprogesterone acetate (MPA) 2.5 mg/day or women with previous hysterectomy received CEE 0.625 mg/day only.

In the WHI study a total of 27,347 postmenopausal women age 50-79 were role in the latest analysis follow-up for a median of 13 years through September 2010 was completed.

The WHI randomized trial of CEE found there was a significantly reduced incidence of poor prognosis ER positive, PR negative breast cancers in postmenopausal women with prior hysterectomy.

Coronary artery disease, stroke and venous thromboembolic disease increased in postmenopausal women on estrogen and progestin.

WHI suggested increase risk of coronary heart disease and stroke among patients to start hormone therapy after the age of 60 years, with a greater risk after the age of 70 years, and no significant increase in risk among those starting therapy before the age of 60 years or within within 10 years after the onset of menopause.

Women’s Health Initiative (WHI) reported a hazard ratio for coronary artery disease of 0.95 in the trial of conjugated equine estrogens and an hazard ratio of 1.24 in the trial of conjugated equine estrogens plus medroxyprogesterone acetate.

Health-related outcomes associated with HRT include coronary heart disease (CHD), breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.

Both trials were stopped due to increased risk of breast cancer with the CEE plus MPA regimen and increased risk of stroke with CEE only group.

The risk of breast cancer in women who have had a first-degree relative with breast cancer is twice as high as that in other women: in the WHI trial relative risk of breast cancer associated with combine hormone therapy was similar regardless of family history of breast cancer

In the CEE plus MPA trial post-intervention and follow-up, the increased breast cancer risk persisted, along with other chronic disease risks.

In a long-term follow-up of two randomized trials, prior randomized use of CEE alone compared with placebo among women with previous hysterectomy was significantly associated with lower breast cancer incidence and lower breast cancer in mortality.

In the above studies, women randomized to CEE plus MPA compared with placebo, among women with an intact uterus it was a significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality (Chlebpwski RT).

In a metaanalysis involving 1100 women with a BRCA mutation and intact breasts who underwent risk reduction bilateral salpingooophorectomy before the onset of natural menopause, no excess risk was found to be associated with the use of hormone therapy beyond baseline increasing the risk of breast cancer for carriers of mutated BRAC1BRCA2.

Women in the trial who had 4-5 years of combination therapy at a higher risk of breast cancer than those assigned to placebo.

In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer.

The colorectal cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones.

There was no increase in risk seen at seven years among women in the trial who took estrogen alone or after 13 years of follow up, prospective observational data showing increased risk of breast cancer by four years among women who received any post menopausal estrogen therapy except vaginal estrogen.

In the CEE only trial, younger women, aged 50–59 years, had a more favorable risk-to-benefit ratio than older women, indicating the impact of age on health outcomes with HRT.

In older women, a higher risk of CHD was also demonstrated.

Both combination therapy and estrogen alone decrease the risk of hip fracture by approximately 33%, while combination therapy reduce the risk of colorectal cancer.

No increased risk of ovarian cancer with hormone therapy occurred.

During an 18 year follow up no significant increase in overall mortality or mortality related to cardiovascular disease or cancer was found to be associated with systemic hormone therapy.

Both regimens were associated with an increased risk of stroke, venous thrombosis, and gallbladder disease.

The Woman’s Health Initative clinical trial identified no increased risk of heart disease in women randomized to receive estrogen or estrogen-progestogen therapy who were younger than 60 years or within 10 years of menopause onset.

Results confirm that HRT should not be used for chronic disease prevention.

The Women’s Health Initiative trial showed that estrogen-progestin replacement had no cardioprotective effect and may have produced harm, increasing the risk of coronary disease, stroke, venous thromboembolism, and breast cancer.

The risk of VTE was twice as high among women in the WHI trial who received oral combination therapy as it was among those assigned placebo.

Long-term follow up of the WHI participants, however, has found no difference in all-cause, cardiovascular, or cancer mortality with HRT.

Fewer cases of diabetes were reported in WHI trials among women who received estrogen alone in those receiving estrogen combined with progesterone than among those who were assigned to placebo.

May effectively treat menopausal vasomotor symptoms, such as hot flashes: but must must weigh the chronic disease risks and strongly consider alternative therapies.

Women’s Health Initiative (WHI) involved a total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.

Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102).

Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429).

The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up.

Results: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo with a hazard ratio of 1.18, and 206 vs 155, respectively, for invasive breast cancer with HR, 1.24.

Other risks included increased stroke, pulmonary embolism, dementia for women aged ≥65 years, gallbladder disease, and urinary incontinence.

Benefits included decreased hip fractures, diabetes, and vasomotor symptoms.

While most risks and benefits diminished post therapy, although some elevation in breast cancer risk persisted during cumulative follow-up with 434 cases for CEE plus MPA vs 323 for placebo, a hazard ratio of1.28.

The risks and benefits during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo a HR, 0.94 and 104 vs 135, respectively, for invasive breast cancer a HR, 0.79 and cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed for a HR, 0.79.

Neither regimen affected all-cause mortality.

For CEE alone, younger women, aged 50-59 years, had more favorable results for all-cause mortality, and myocardial infarction.

Incontinence was increase in the WHI trial with administration of oral systemic conjugated estrogens.

Absolute risks of adverse events per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years.

WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Womens’s Health Initiative (WHI) revealed increased risk of breast cancer, cardiovascular disease, stroke, and thromboembolic events in women taking conjugated equine estrogen and medroxyprogesterone acetate compared with placebo.

Conjugated equine estrogens in healthy postmenopausal women aged 50-79 increased the risk of stroke, decreased the risk of fractures and does not significantly effect the incidence of coronary heart disease or overall mortality.

Breast cancer was increased, but colorectal cancer, hip fracture and other fractures were reduced in postmenopausal women treated with estrogens and progestin.

Effects of conjugated equine estrogen plus medroxyprogesterone in 16,608 postmenopausal women revealed that the incidence of non-small cell lung cancer and mortality during 5.6 years of intervention and 2.4 years of additional follow-up revealed: no significant difference in lung cancer incidence compared to placebo, but mortality after a lung cancer diagnosis was significantly higher in patients receiving combined hormone therapy .

In the above study women in the hormone therapy group were 60% more likely to die from lung cancer during the follow-up period then were women in the placebo group.

In the above study women taking hormone therapy and who were current smokers had a high risk of dying from lung cancer with the mortality rate after diagnosis of 3.4% among smokers compared to 2.3% among smokers in the placebo group.

Movement toward lower doses of estrogen and estrogen/progesterone indicated that low-dose and standard dose therapies has similar benefits.

Women’s Health Initiative (WHI) study indicated that antidepressant therapy maybe detrimental with respect to stroke and total mortality in a large cohort of postmenopausal women.

Proton pump inhibitors associated with incresed rate of rate of spine, lower arm and total fractures demonstrated in the Women’s Health Study (Gray SL et al).

In a prospective analysis of 161,806 postmenopausal women age 50-79 years without history of hip fracture, part of the Women’s Health Initiative (WHI) Observational Study and Clinical Trials with a mean follow-up of 7.8 years: use of PPI’s was not associated with hip fractures but was modestly associated with spine, forearm, wrist, and total fractures (Gray SL et al).

In a randomized controlled study a low-fat diet did not reduce the risk of colorectal cancer in postmenopausal women during an 8 year study.

Estrogen plus progesterone increases risk of myocardial infarction and stroke despite beneficial reduction in cholesterol levels.

Incidence of breast cancer has been falling since 2002 in the U.S. since this study: with reductions in incidence primarily in ER+ breast cancer , among women age 50 years or loder and in areas where prevalence of hormonal therapy use was high.

The estrogen only arm participants all had a hysterectomy and therefore differed from the estrogen progesterone group.

With estrogen alone thromboembolic risk increased, but the risk of heart disease and breast cancer subsided.

Movement toward lower doses of estrogen and estrogen/progesterone indicated that low-dose and standard dose therapies has similar benefits.

The average age of participants was 63 years of age.

Low risk women treated with 600 IU of vitamin E had no benefits in prevention of cardiovascular events or death.

In a randomized controlled study a low-fat diet did not reduce the risk of colorectal cancer in postmenopausal women during an 8 year study.

Trial of conjugated equine estrogens plus medroxyprogesterone acetate found the group receiving combination hormonal therapy was associated with a decreased risk of breast compared to placebo treated patients during the initial 2 years of the study, but the incidence increased over the course of 5.6 years intervention period.

Trial of conjugated equine estrogens plus medroxyprogesterone acetate was stopped when health risk exceeded the benefits of combined hormone therapy: it was associated with increased in risk of breast cancer and when use of the combination decreased after the study the incidence of breast cancer also dropped rapidly.

Incidence of breast cancer was higher in the hormone therapy group with more advanced and larger cancers than in control groups.

The frequency of abnormal mammograms and breast biopsies was higher in the combined hormonal group compared to placebo treated group.

In 133,855 postmenopausal women with 3411 loop diuretic users and 130,444 non loop diuretic users there was no difference in the drug use and risk of falls, fractures or bone mineral density changes.

Among women who enrolled in this study around the time of their menopause, hormone therapy with both estrogen and progestin did not increase the risk of cardiovascular disease and may have reduced it slightly.

Most women enrolled in the study were passed menopause, with an average age of 63 years, negative effects of hormone therapy, which increased with more elapsed time after menopause, exceeded any small benefits that might have been experienced by younger women.

Other negative effects of hormone therapy were demonstrated in this study included increased risk of stroke and pulmonary embolism.

The only long-term benefit of hormone therapy in this study was reduction in the osteoporotic fractures.

Breast cancer rates increased among women receiving hormone therapy was about the same as the deleterious effect on cardiovascular health.

The absolute risk of breast cancer was approximately 0.5% over the course of the study.

An 11 year follow-up found that hormone therapy increases the frequency of breast cancer and that the breast cancers are on average more advanced and may be larger, with no evidence that the lesions have favorable prognostic features, such as estrogen receptor positivity or lacking HER2 gene amplification (Chlebowski RT et al).

At 11 years there was strong evidence that the rate of breast cancer death was increased by hormone therapy.

Approximately 1.3 additional deaths from breast cancer per 10,000 person-years of follow-up have occurred among women who received hormone therapy in this study.

The use of multivitamins did not reduce the risk of cancer including colorectal cancer (Newhouser ML et al).

Women’s Health Initiative study indicated a 31% lower risk of invasive breast cancer among bisphosphonate users.

The Women’s Health Initiative Estrogen Alone trial was stopped after a mean of 7.1 years and it involved women with prior hysterectomy randomly assigned to conjugated equine estrogens vs. placebo: equine estrogens was associated with a higher risk of stroke, a lower risk of hip fracture, and a similar risk of coronary artery disease as women who received placebo.

In the above study with a mean follow-up of 10.7 years and in median use of conjugated equine estrogens of 5.9 years: was not associated with a change in coronary artery disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer or mortality, but was associated with a decreased risk of breast cancer (Lacroix AZ et al).

For estrogen alone there was a significant reduction of breast cancer incidence, and the reduction persisted throughout the early post-intervention phase but was lost during the late postoperative intervention phase.

In the estrogen and progesterone trial, the high of breast cancer risk was seen during intervention followed by a substantial drop in risk the early post-intervention phase, but a high of breast cancer risk remained during the late post-intervention phase.

In the estrogen alone trial the lower breast cancer risk seen during intervention was sustained in the early post-intervention phase but not during the late post-intervention phase.

The Women’s Health Initiative observational study of 90,014 postmenopausal women showed diet quality based on a Mediterranean diet with emphasis on consumption of fruits, vegetables, fish, nuts, legumes, whole grains and intake of monosaturated fat, as well as avoidance of red and processed meats was associated with a lower risk for hip fractures (Haring B et al).

Updated analyses have revealed hormonal therapy is appropriate and safe for symptom relief in younger, recently menopausal women without contraindications, and the risks identified in the WHI trials apply primarily to women who initiate hormonal therapy after age 60 years and more than a decade after menopause.

18 year follow up data from WHI revealed no difference in the long term all-cause and cause-specific mortality and women treated with hormonal therapy versus placebo.

Women’s Health Initiative analysis into the impact of increased sedentary behavior on heart failure risk in older women.

The Women’s Health Initiative, contains data on more than nearly 90,000 postmenopausal women.

Women spending 9.5 hours or more sitting or lying down each day had a 42% higher risk of being hospitalized with heart failure than women who spent 6.5 hours or less engaged in sedentary behavior.

The mean reported time spent engaging in sedentary behavior per day was 7 hours.

11% of patients reported no recreational physical activity.

When controlling for age, race-ethnicity, education, income, smoking, alcohol, menopausal hormone therapy, and hysterectomy status, results of the analysis indicated heart failure risk increased across incrementals of total sedentary behavior- 6.6-9.5 hours: HR, 1.15; More than 9.5 hours: HR, 1.42; sitting time 4.6-8.5 hours: HR, 1.14, More than 8.5 hours: HR, 1.54.

Associations with sedentary behavior exposures did not differ based on age, race-ethnicity, BMI, physical activity, physical functioning, diabetes, hypertension, or coronary heart disease.

People with more daily sedentary time are more likely to develop chronic health conditions such as diabetes, high blood pressure, heart attack, stroke and premature death from heart disease and other causes.

Since the termination of the randomized treatment phase of these trials, many studies have been done of the early post intervention phase and a late post intervention phase.

In the CEE alone study there was a lower breast cancer risk through the intervention and early post intervention phase, although the risk reduction was not observed in the late post intervention phase.

These late studies showed that CE plus MPA was associated with an increased breast cancer risk in the early post intervention phase and late post intervention phase.

Previous survival analyses show that women in the CEE Group who developed breast cancer after the receipt of estrogen had significantly reduced breast cancer specific mortality and all-cause mortality, which contrasted with the large observance observational studies demonstrating both combination hormone therapy and unopposed estrogen therapy were associated with significantly higher risk of breast cancer mortality.

The significantly increased risk of breast cancer among women who were receives CEE plus MPA compared to those who receive placebo, but there was no statistically significant difference in breast cancer mortality.

The use of CEE alone versus placebo what is associated with a lower risk of estrogen receptor positive, progesterone receptor negative breast cancer and HER2 negative breast cancer.

There were no significant associations between the use of CEE plus MPA in tumor subtype.

The 20 year study of treatment groups in a large randomized clinical trial has not been able to isolate the of influence of exposure to hormone therapy and subsequent late outcomes: suboptimal adherence to treatment with 54% discontinuing CEE and 42% discontinuing CEE plus MPA during the trial.

The breast cancer specific mortality decrease among patients who received CE is modest, with for breast cancer related deaths presented for 10,000 person-years

The WHI dietary modification study looked at the effects of dietary fat and 48,835 patients assigned to a low-fat dietary pattern or usual diet with the end point of primary breast cancer incidence: there was no statistical significant difference in breast cancer incidence, but they were statistically significant decrease incidence of breast cancer mortality.

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