Hormone therapy boosts heart health markers but raises some risks

Women’s Health Initiative study finds CEE and CEE+MPA improve cholesterol and insulin levels but increase triglycerides and clotting factors.

Study: Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the Women’s Health Initiative Hormone Therapy Clinical Trials. Image Credit: Worawee Meepian / Shutterstock.com

A recent study published in Obstetrics and Gynecology assesses hormone therapy (HT)-induced changes in cardiovascular biomarkers during the Women’s Health Initiative (WHI) clinical trials.

The cardiovascular implications of hormone therapy

Several studies have investigated the potential effects of HT on cardiovascular disease (CVD) biomarkers that could influence the future risk of heart attack, stroke, and other cardiovascular events. For example, one trial on conjugated equine estrogens CEE and CEE combined with different progestin regimens reported reduced low-density lipoprotein cholesterol (LDL-C) levels and increased triglycerides levels after three years.

In the WHI trial on CEE plus medroxyprogesterone acetate (MPA), this combination treatment reduced LDL-C, total cholesterol, glucose, and insulin levels from baseline to one year one, whereas high-density lipoprotein cholesterol (HDL-C) and triglyceride levels increased. The CEE alone trial reported similar findings for LDL-C, HDL-C, and triglyceride levels.

Several cross-sectional comparisons at six (CEE) and three years (CEE+MPA) have been conducted among participants without diabetes mellitus. However, there remains a lack of longitudinal analyses studying the effects of HT on CVD while also stratifying these results by age.

About the study

The current study evaluated the effects of CEE+MPA and CEE alone on CVD biomarkers over a period of six years. A total of 27,347 menopausal women between 50 and 79 years of age were randomized by the two double-blinded, placebo-controlled WHI HT trials. Approximately 10% of study participants were randomly selected and grouped into the CEE alone and CEE+MPA trials.

The CEE alone group consisted of 1,188 participants who received 0.625 mg/d CEE or placebo. Comparatively, the CEE+MPA group included 1,508 participants who were administered 0.625 mg/d CEE and continuous 2.5 mg/d MPA or placebo.

Blood samples were collected at baseline and after one, three, and six years. Glucose, HDL-C, LDL-C, total cholesterol, triglycerides, lipoprotein(a), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) were measured. A constant treatment effect across visits was used to quantity overall effects.

Study findings

One year after randomization in the CEE alone group, an 11% reduction in LDL-C levels was observed among women treated with CEE as compared to placebo. This effect was mostly persistent in years three and six.

In the CEE+MPA group, the overall reduction in LDL-C was similar; however, the magnitude of the difference diminished during the follow-up period. Sensitivity analyses yielded similar results.

Among participants randomized to CEE or CEE+MPA, HDL-C and triglyceride levels increased by 13% and 7%, respectively. This led to a slight reduction in cholesterol levels in the CEE alone trial, whereas the reduction in the CEE+MPA trial was more prominent.

Factor VII antigen concentrations rose by 14% and 8% in the CEE and CEE+MPA trials, respectively. This escalation in factor VII antigen levels was most significant at one year until declining thereafter.

CEE+MPA treatment did not increase factor VII coagulant activity, whereas CEE was associated with a 7% increase. In both trials, fibrinogen levels decreased by 4%.

Although the results for most CVD biomarkers were consistent across 10-year age groups, lipoprotein(a) reductions were not observed in the CEE-alone trial as age increased. The reduction in lipoprotein(a) levels was more evident among women self-identifying as Alaska Native, Asian or Pacific Islander, or American Indian.

Across racial and ethnic groups, both trials were associated with broadly consistent patterns. Overall, lipoprotein(a) levels decreased by 15% and 20% in the CEE and CEE+MPA trials, respectively, as compared to placebo.

Similar patterns were observed in subgroups classified by vasomotor symptoms at baseline. Across the baseline hyperlipidemia subgroups, significant effect modification was reported for lipoprotein(a) and insulin levels, which was not consistent between trials.

Statin use during the CEE-alone and CEE+MPA trials increased to 23.3% and 20.7% at year six, respectively, compared to baseline levels of 7.2% and 6.6%.

Conclusions

CEE alone and CEE+MPA are associated with favorable effects on all cardiovascular biomarkers, except triglycerides and factor VII antigen levels, over an extended duration.

Additional research is needed to examine the association between the effect of HT on lipoprotein(a) and genetic differences in specific patient populations. Future studies should also explore whether different progestogen formulations could mitigate the long-term effects of HT on LDL particle size and estrogen on HDL-C.