How does menopausal hormone replacement therapy (HRT) affect cardiac disease risk?

Updated: Sep 13, 2021
  • Author: Nicole K Banks, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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The incidence of cardiac disease is heightened in postmenopausal women. This finding has been linked to a causative pathogenic role of ovarian hormone deficiency.

When the concept of HT was initially introduced, it was believed that replacing ovarian hormones would reduce the observed increase in the risk of cardiovascular disease. However, this expected result has not been unequivocally demonstrated in various trials over the years.

The WHI study revealed an increased annual risk of heart attacks of 7 per 10,000 women who took combined therapy as opposed to women who took estrogen alone, in whom no significant difference was noted. Subsequent re-analysis showed similar results for breast cancer, demonstrating no increased risk in the fifth decade, though the risk rose with advancing age.

Two important clinical trials have been conducted to examine the relationship between cardiac disease and HT: the Postmenopausal Estrogen/Progestogen Interventions Trial (PEPI) and the Heart and Estrogen-Progestogen Replacement Study (HERS).

PEPI investigators looked at the effect of estrogen alone and combination therapies on bone mass and key risk factors for heart disease. They found generally positive results, including a reduction in low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol by both types of therapy.

HERS researchers tested whether estrogen plus progestogen would prevent a second heart attack or other coronary event in a secondary prevention study. They found no reduction in risk with such hormone therapy over 4 years. In fact, treatment increased the women’s risk for having a heart attack during the first year of hormone use. The risk declined thereafter. In the HERS follow-up study, participants were monitored for about 3 more years. This study showed no lasting decrease in heart disease from estrogen plus progestogen.

The widely discordant results might have been due to a few important factors that govern the effect of HT on the participant's cardiovascular status. These factors are as follows:

  • Time to the start of HT after menopause

  • Associations related to estrogen and progestogen

  • Body mass of postmenopausal women

  • Underlying risk factors for cardiac disease

After menopause, the cardioprotective effect of estrogen is lost, but the detrimental procoagulant effects persist. If HT is started early in postmenopausal women, the cardiac endothelium is still responsive to estrogens, and the procoagulant effects may be buffered. On the contrary, in elderly postmenopausal women, HT may not show a similar benefit. In these women, ovarian hormones have either no effect or a detrimental effect because of the predominance of the procoagulant effects over the vasoprotective effects.

Women who already had a low risk of dying from coronary heart disease by virtue of their lean body mass have the greatest decrease in risk with estrogen use, as compared with women whose body mass index is >30 kg/m2.

A meta-analysis found strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events, has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events. [16, 17]

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