TOPLINE

Among postmenopausal women who did not receive prior treatment for high cholesterol, those with unfavorable lipid profiles had an increased risk for coronary heart disease (CHD) when oral menopausal hormone therapy was used, whereas those with favorable profiles did not. Women with low-density lipoprotein (LDL) cholesterol levels ≥ 190 mg/dL taking conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) vs placebo had a higher risk for CHD.

METHODOLOGY

• Researchers conducted a secondary analysis of two randomized trials from the Women’s Health Initiative involving postmenopausal women aged 50-79 years in the US from 1993 to 1998. 
• Participants who had undergone hysterectomy (n = 10,739) were randomly assigned to receive CEE 0.625 mg/d or placebo, whereas those with an intact uterus (n = 16,608) were randomly assigned to receive CEE 0.625 mg/d plus MPA 2.5 mg/d or placebo. The median follow-up durations were 6.8 years and 5.2 years, respectively. 
• Cardiometabolic status was evaluated by lipid profile (LDL cholesterol, high-density lipoprotein [HDL] cholesterol, non-HDL cholesterol, triglyceride levels, and the LDL/HDL ratio), blood pressure, blood glucose levels, and the presence of metabolic syndrome (MetS) using specific criteria. 
• The primary outcome was CHD (nonfatal myocardial infarction or CHD death); the secondary outcomes were stroke, venous thromboembolism, and all-cause mortality. 

TAKEAWAY

• Among women who were not previously treated for hyperlipidemia and received CEE plus MPA, the risk for CHD in those with normal LDL cholesterol levels (< 130 mg/dL) was similar to that in individuals receiving placebo (hazard ratio [HR], 0.59; 95% CI, 0.31-1.10), but for those with LDL levels ≥ 190 mg/dL, the risk for CHD was higher (HR, 2.77; 95% CI, 1.42-5.40; P for trend = .002). 
• In the CEE plus MPA trial, women with higher LDL/HDL ratios had an increased risk for CHD (ratio < 2.5: HR, 0.73; 95% CI, 0.39-1.37 vs ratio ≥ 4: HR, 1.76; 95% CI, 1.08-2.88; P for trend = .008); nonsignificant patterns were observed in the CEE-alone trial. 
• In the first 2 years post-randomization, the overall risk for CHD significantly increased among those in the CEE plus MPA trial (HR, 1.50; 95% CI, 1.06-2.13). 
• Blood pressure, blood glucose levels, triglyceride levels, and the presence of MetS did not modify the risk for CHD due to CEE or CEE plus MPA.

IN PRACTICE

“Measurement of blood lipids could assist with tailoring MHT [menopausal hormone therapy] to the women most likely to benefit,” the authors of the study wrote.

SOURCE

The study was led by Jacques E. Rossouw, MD, of the Division of Public Health Sciences at the Fred Hutchinson Cancer Center in Seattle. It was published online on July 24, 2026, in Obstetrics & Gynecology.

LIMITATIONS

The subgroup analyses were exploratory in nature, and some subgroups had relatively limited data with wide CIs. Given the large number of interactions examined in the study, some statistically significant results might have occurred by chance. The findings were specific to oral CEE and MPA formulations, and the results might not be generalizable to other hormone therapy formulations and alternative routes of delivery.

DISCLOSURES

The Women’s Health Initiative program received funding from the National Heart, Lung, and Blood Institute; National Institutes of Health; and US Department of Health and Human Services through multiple contracts. The active and placebo study pills were donated by Wyeth-Ayerst. The National Heart, Lung, and Blood Institute participated in the design of the parent study. The authors reported having no potential conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.