Hormone Therapy, Vitamin Supplementation in Postmenopausal Women Did Not Decrease Risk of Cancer, Chronic Disease


Study investigators also found that dietary modifications were not associated in improving risks of certain chronic diseases and cancers.

Woman at a doctor's appointment -- Image credit: fizkes | stock.adobe.com

Image credit: fizkes | stock.adobe.com

The origination of the Women’s Health Initiative (WHI) in 1993 occurred when observational studies had reported that postmenopausal women who underwent hormone therapy experienced lower risks of coronary heart disease (CHD), bone fractures, and all-cause mortality compared with those who did not undergo hormone therapy. Additionally, hormone therapy was also being used more frequently to prevent cardiovascular (CVD) and other chronic diseases for both women in early and late menopause; however, no randomized controlled trials (RCTs) assessed the benefits or risks of hormone therapy for chronic disease prevention. Further, supplementation with calcium plus vitamin D were believed to reduce fractures and those with certain dietary patterns were believed to experience higher rates of breast and colorectal cancer.

A study published in JAMA Network summarizes and evaluates the results of 4 WHI RCTs as well as how WHI has applied the data to clinical practice. The RCTs assess menopausal hormone therapy, calcium and vitamin D supplementation, and dietary modifications in postmenopausal women.

For the menopausal hormone therapy RCTs, the objective was to establish whether hormone therapy can reduce the primary outcome of CHD compared with placebo. The benefits and risks of conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) versus placebo among women with uterus in situ, and CEE (0.625 mg/d) alone versus placebo among women with prior hysterectomy were evaluated for prevention of CHD and other chronic diseases. Both CEE and MPA were selected for evaluation because the regimens are the most commonly prescribed hormones at the start of the trial.

The CEE plus 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 ended early because of the risks outweighing the potential benefits. Notably, the investigators observed an increase in CHD, stroke, and pulmonary embolism, which was more prominent than the benefits for colorectal cancer compared with placebo.

Key Takeaways

  1. Hormone Therapy Findings: The Women's Health Initiative (WHI) conducted randomized controlled trials to assess the benefits and risks of hormone therapy in postmenopausal women. Results showed that neither conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) nor CEE alone reduced the risk of coronary heart disease, stroke, dementia, or other chronic diseases. However, CEE plus MPA increased the risk of stroke and pulmonary embolism compared to placebo.
  2. Supplementation With Calcium and Vitamin D: Another arm of the WHI evaluated calcium plus vitamin D supplementation's effect on hip fractures, total fractures, colorectal cancer, and cardiovascular disease in postmenopausal women. The study found no significant reduction in hip fractures or total fractures with supplementation. However, there was a small increase in the risk of kidney stones among women who received the supplementation regimen.
  3. Dietary Modification: The WHI also examined whether a low-fat dietary pattern with increased fruit, vegetable, and grain intake could reduce the risk of breast and colorectal cancer, as well as CHD. Results indicated no significant decrease in cancer or CHD incidence with the modified diet; however, at a 20-year follow-up, a lower incidence of breast cancer mortality was observed in the intervention group compared to the usual diet group.

According to the RCT, the findings do not support either CEE plus MPA or CEE alone for preventing CHD, stroke, dementia, or other chronic diseases in women post-menopause. The investigators observed that younger menopausal women presented low absolute risks of most of the chronic diseases, with low hormone therapy-related risks in early menopause. Additionally, younger menopausal women potentially developed significant quality-of-life benefits from symptom relief.

CEE plus MPA, compared with placebo, increased the prespecified secondary outcomes of 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; 95% CI, 1.36-2.87), and it 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) with no significant effect on all-cause mortality (0.52% vs 0.53%; HR, 0.97; 95% CI, 0.81-1.16). Further, women with a prior hysterectomy who received CEE experienced non-significantly lower rates of breast cancer than those who received placebo (0.28% vs 0.35%; HR, 0.79; 95% CI, 0.61-1.02). Additionally, the authors noted no significant differences in rates of colorectal cancer during the intervention or at a 13-year cumulative follow-up.

The WHI calcium and vitamin D supplementation RCT evaluated whether calcium plus vitamin D supplementation compared with placebo was more effective in lowering the risk of hip fracture in postmenopausal women who were not selected for low bone mineral density (BMD). Additionally, it also assessed whether the combined supplementation regimen lowered the risk of total fractures and colorectal cancer. A total of 36,282 women were randomly assigned to receive 1000 mg/d of calcium carbonate with 400 IU/d of vitamin D3, or placebo.

The RCT demonstrated that, compared with placebo, calcium with vitamin D supplementation did not significantly reduce hip fractures in postmenopausal women; however, prior evidence suggests that bone health is positively affected by calcium and vitamin D supplementation, notably boosting preservation of total hip BMD and reducing hip fractures in women aged 60 years and older who are likely to have osteoporotic fracture. Further, the combined supplementation regimen did not appear to effect lower arm or wrist fracture, total fracture, colorectal cancer, CVD, or total mortality. The investigators noted that there was an increase in the risk of kidney stones among women who received this regimen, although it was somewhat small (0.35% vs 0.30% annually; HR, 1.17; 5 extra cases per 10,000 women/year).

Lastly, the dietary modification RCT assessed whether a low-fat dietary pattern can reduce the risk of invasive breast cancer or colorectal cancer, as well as CHD. The intervention, according to investigators, intended to reduce participants’ total fat consumption to 20% of total energy intake, as well as increase vegetable plus fruit intake and grain intake to at least 5 and 6 servings per day, respectively.

The RCT findings indicated that a low-fat dietary pattern with an increased intake of vegetables, fruit, and grains did not significantly decrease the incidence of breast and colorectal cancer, or CHD in postmenopausal women; however, at a 20-year follow-up, a lower incidence of 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; P = .02). Additionally, no adverse events or outcomes were reported by participants who received the adjusted diet. At year 1, the investigators observed a small loss in weight (1.9 kg) in the adjusted diet group.

Limitations of the study include the use of the most common hormone therapy formulations—CEE plus MPA, and CEE alone—with other formulations or routes of delivery potentially demonstrating different results; the frequent use of non-study calcium and vitamin D supplements in the calcium plus vitamin D RCT, as the frequent use of these supplements may have decreased the effects of the intervention; and the dietary intervention not achieving the targeted total fat reduction to 20% of total calories, potentially influencing the results. Additionally, the investigators note that the effects of reducing dietary fat could not be distinguished from the effects of increasing fruit, vegetable, and grain intake in the diet RCT.

According to the WHI RCT findings evaluating postmenopausal women, oral CEE plus MPA or CEE alone did not prevent CVD or other chronic diseases in women who received hysterectomies, routine supplementation with calcium plus vitamin D did not prevent fractures, and an adjusted low-fat diet with increased fruit, grain, and vegetable intake did not prevent breast cancer or colorectal cancer. The authors note that the findings indicated a potential role of a low-fat diet influencing breast cancer mortality and urge further research to further assess this association.

Manson, JE, Crandall, CJ, Rossouw, JE, et al. The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA. Published online May 01, 2024. doi:10.1001/jama.2024.6542
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