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The Women’s Health Initiative (WHI) was launched in 1993 to demonstrate that postmenopausal women who receive hormone therapy have a higher risk of coronary heart disease (CHD), bone fractures, and all-cause mortality than women who do not receive hormone therapy. This was when an observational study reported that it was low. Receive hormone therapy. Additionally, hormone therapy is also being used more frequently to prevent cardiovascular disease (CVD) and other chronic diseases in early and late menopausal women. However, no randomized controlled trials (RCTs) have evaluated the benefits or risks of hormone therapy for chronic disease prevention. Additionally, calcium and vitamin D supplementation was thought to reduce bone fractures, and people with certain dietary patterns were thought to have higher rates of breast and colorectal cancer.
Research published in JAMA Network We summarize and evaluate the results of four WHI RCTs and how the WHI applied the data to clinical practice. RCTs evaluate menopausal hormone therapy, calcium and vitamin D supplementation, and dietary modification in postmenopausal women.
The aim of the RCT on menopausal hormone therapy was to establish whether hormone therapy can reduce the primary outcome of CHD compared with placebo. Benefits and risks of conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) versus placebo in women with an in situ uterus and CEE (0.625 mg/day) in women with a uterus in situ. ) Benefits and risks of previous hysterectomy alone versus placebo evaluated for prevention of CHD and other chronic diseases. Both CEE and MPA were chosen for evaluation because they are the most commonly prescribed hormones at the start of the study.
The CEE and MPA cohort RCT included a total of 16,608 women aged 50 to 79 years. After a median follow-up of 5.6 years, the trial was terminated early because the risks outweighed the potential benefits. Of note, researchers observed increases in CHD, stroke, and pulmonary embolism, which outweighed the benefit against colorectal cancer compared to placebo.
Important points
- Hormone therapy findings: The Women’s Health Initiative (WHI) conducted a randomized controlled trial to evaluate the benefits and risks of hormone therapy in postmenopausal women. As a result, combining conjugated equine estrogen (CEE) with medroxyprogesterone acetate (MPA), nor CEE alone, does not reduce the risk of coronary heart disease, stroke, dementia, or other chronic diseases. was shown. However, the combination of CEE and MPA increased the risk of stroke and pulmonary embolism compared to placebo.
- Calcium and vitamin D supplementation: Another arm of the WHI evaluated the effects of calcium and vitamin D supplementation on femoral neck fractures, total fractures, colorectal cancer, and cardiovascular disease in postmenopausal women. This study found no significant reduction in hip fractures or total fractures with the supplement. However, women who took the supplement had a slightly increased risk of kidney stones.
- Diet modification: WHI also investigated whether a low-fat dietary pattern with increased intake of fruits, vegetables, and grains could reduce the risk of breast cancer, colorectal cancer, and even CHD. The results showed that modifying the diet did not significantly reduce the incidence of cancer or CHD. However, over a 20-year follow-up, lower breast cancer mortality rates were observed in the intervention group compared to the usual diet group.
According to the RCT, the results of this study do not support either CEE and MPA, or CEE alone, in preventing CHD, stroke, dementia, or other chronic diseases in postmenopausal women. The researchers observed that young menopausal women had lower absolute risks for most chronic diseases, as well as lower risks associated with hormone therapy during early menopause. Additionally, young menopausal women may significantly improve their quality of life through symptom relief.
CEE and MPA significantly reduced stroke (annualized rate, 0.33% vs. 0.24%, HR, 1.37; 95% CI, 1.07-1.76) and pulmonary embolism (0.18% vs. 0.09%, HR, 1.98) compared with placebo. increased pre-specified secondary outcomes. ; 95% CI, 1.36-2.87), and also non-significantly increased the primary outcome of CHD by approximately 18% (0.41% vs 0.35%; HR, 1.18; 95% CI, 0.95-1.45). All-cause mortality (0.52% vs. 0.53%; HR, 0.97; 95% CI, 0.81-1.16). Additionally, women who had a previous hysterectomy and received CEE had a significantly lower incidence of breast cancer than women who received a placebo (0.28% vs. 0.35%; HR, 0.79; 95% CI, 0.61- 1.02). Additionally, the authors stated that there were no significant differences in colorectal cancer incidence during the intervention or at 13 years of cumulative follow-up.
The WHI Calcium and Vitamin D Supplementation RCT showed that calcium and vitamin D supplementation was superior to placebo in reducing the risk of hip fracture in postmenopausal women who were not selected due to low bone mineral density (BMD). We compared them to see if they were more effective. We also evaluated whether supplement combination therapy reduced the risk of complete fractures and colorectal cancer. A total of 36,282 women were randomly assigned to receive 1000 mg/day of calcium carbonate and 400 IU/day of vitamin D3, or a placebo.
An RCT demonstrated that calcium and vitamin D supplementation did not significantly reduce femoral neck fractures in postmenopausal women compared with placebo. However, evidence to date suggests that bone health is positively affected by calcium and vitamin D supplementation, which promotes preservation of overall hip BMD, particularly in women over 60 years of age who are more likely to have osteoporotic fractures, and Suggested to reduce fractures. Additionally, the combination supplementation regimen did not appear to affect lower arm or wrist fractures, complete fractures, colorectal cancer, CVD, or all-cause mortality. Researchers noted a small but increased risk of kidney stones among women who received this therapy (0.35% vs. 0.30% per year; HR, 1.17; 5 additional cases per 10,000 women).
Finally, a diet modification RCT evaluated whether a low-fat dietary pattern can reduce the risk of invasive breast and colorectal cancer, as well as CHD. According to the researchers, the intervention reduced participants’ total fat intake to 20% of their total energy intake and increased their vegetable and fruit intake and grain intake by at least 5 and 6 servings per day, respectively. The aim was to increase the number of
RCT findings showed that a low-fat dietary pattern with increased intake of vegetables, fruits, and grains did not significantly reduce the incidence of breast and colorectal cancer, or CHD in postmenopausal women . However, at 20 years of follow-up, lower breast cancer mortality was observed in the intervention group compared with the usual diet group (0.037% vs. 0.047%; HR, 0.79; 95% CI, 0.64-0.97 ; 95% CI, 0.64-0.97; P = .02). Additionally, no adverse events or outcomes were reported by participants who received the formula diet. During the first year, researchers observed a small weight loss (1.9 kg) in the modified diet group.
Limitations of this study include the use of the most common hormone therapy formulations (CEE and MPA, and CEE alone) and that other formulations or routes of delivery may show different results. Frequent use of off-study calcium and vitamin D supplements in calcium and vitamin D RCTs. as frequent use of these supplements may have decreased the effectiveness of the intervention. Additionally, the dietary intervention may not be able to achieve the target reduction in total fat to 20% of total calories, which could impact the results. Furthermore, the researchers note that in dietary RCTs, the effects of reducing dietary fat were indistinguishable from the effects of increasing fruit, vegetable, and grain intake.
Results from the WHI RCT evaluating postmenopausal women show that oral CEE and MPA or CEE alone in women who have had a hysterectomy do not prevent CVD or other chronic diseases, and regular supplementation with calcium and vitamin D did not prevent bone fractures, and a modified low-fat diet did not. Increasing intake of fruits, grains, and vegetables did not prevent breast or colorectal cancer. The authors note that the results of this study demonstrate the potential role of low-fat diets in influencing breast cancer mortality and encourage further research to further evaluate this association.
