Cholesterol modifies oral hormone heart risk

Baseline cholesterol levels helped identify women at higher heart risk from oral menopausal hormone therapy.
*Secondary subgroup analysis of randomized trials; Level 2 (OCEBM).

Citation

Rossouw JE, Aragaki AK, Manson JE, et al. Influence of Cardiometabolic Status on Cardiovascular Effects of Oral Menopausal Hormone Therapy. Obstet Gynecol. 2026;00:1-11. doi:10.1097/AOG.0000000000006381

Background

Oral menopausal hormone therapy can relieve hot flashes but may raise heart and clotting risks. This study asked whether common risk factors identify safer or higher-risk candidates.

Patients

27,347 postmenopausal women aged 50-79 years in two Women’s Health Initiative trials. Prior hormone users completed a 3-month washout; women were grouped by uterus status.

Intervention

Conjugated equine estrogens alone after hysterectomy, or combined with medroxyprogesterone acetate with an intact uterus.

Control

Matching placebo.

Outcome

Primary: coronary heart disease, defined as nonfatal heart attack or heart-related death. Secondary: stroke, blood clots, and death from any cause.

Follow-up Period

Median 6.8 years for estrogen alone; 5.2 years for combined therapy.

Results

Finding Effect
Combined therapy in untreated high low-density cholesterol, 190 mg/dL or higher Heart disease risk more than doubled: hazard ratio 2.77 (95% confidence interval, 1.42-5.40)
Combined therapy in untreated high non-high-density cholesterol, 220 mg/dL or higher Hazard ratio 2.15 (95% confidence interval, 1.18-3.92)
Combined therapy with high low-density to high-density cholesterol ratio, 4 or higher Hazard ratio 1.76 (95% confidence interval, 1.08-2.88)
First 2 years of combined therapy Overall heart disease risk increased: hazard ratio 1.50 (95% confidence interval, 1.06-2.13)

Hazard ratio: relative event rate over time. Confidence interval: range of plausible values.

Blood pressure, blood sugar, triglycerides, and metabolic syndrome did not meaningfully change hormone-related heart risk. Analyses used intention-to-treat. Placebo represented no hormone therapy.

Limitations

Subgroup analyses were exploratory, with many comparisons and some wide uncertainty. About half of biomarker values were imputed. Findings apply only to oral conjugated equine estrogens with or without medroxyprogesterone acetate.

Funding

U.S. NIH funded; Wyeth Ayerst donated pills; no reported conflicts.

Clinical Application

Check and treat cholesterol before oral menopausal hormone therapy; avoid combined oral therapy in untreated markedly elevated low-density cholesterol.