Study links menopause hormone therapy to varied heart and blood clot risks

By Hugo Francisco de SouzaReviewed by Danielle Ellis, B.Sc.Dec 3 2024

Research shows oral oestrogen-progestin therapy raises risks of heart disease and blood clots, while tibolone increases risks of stroke and heart attack but not blood clots

In a recent study published in BMJ, researchers evaluated the outcomes of 138 nested trials (between 2007 and 2018) to investigate the impacts of conventional menopausal hormone therapy on cardiovascular disease (CVD) risk.

Their cohort of more than 919,000 women across eight combinations of hormone types and administration routes revealed that up to 43.0% of hormone users experienced adverse cardiovascular events, with ischaemic heart disease (43%) and venous thromboembolic events being the most prevalent.

Tibolone and oral estrogen-progestin therapy were found to be associated with the highest ischaemic heart disease risk. Tibolone contributed substantially to cerebral infarction and myocardial infarction risk.

These findings highlight the relative risks of several conventional menopausal hormone therapies, providing doctors and users with the knowledge required to choose safer

About the study

The present study addresses present knowledge gaps by leveraging a large (N = 919,614) Swedish nationwide cohort (age = 50-58 years) to investigate the relative CVD risk associations of the current systemic menopausal hormone therapy spectrum.

Since different hormone administration methods target differing physiological pathways, this targeted trial research may provide clues into the mechanistic underpinning of hormone-CVD risk associations, allowing clinicians to recommend the safest option from the wide range of available interventions.

Study data was obtained from Statistics Sweden, a composite public health registry of Swedish citizens, which includes demographic, socioeconomic, anthropometric, and medical history datasets. Mortality information and hormone prescriptions were obtained from the Swedish National Board of Health and Welfare and the Anatomical Therapeutical Chemical Codes repository.

The present study comprised 138 nested trials conducted monthly between July 2007 and December 2018, each with a two-year follow-up period. Participants of suitable age without a prior history of sustained hormone use were included in the dataset. In contrast, those reporting significant prior adverse CVD events were excluded for improved outcomes accuracy.

International Classification of Diseases (ICD-10) codes were used to assign CVD events to participants through the course of the study period, with a focus on myocardial infarction (I21, I22), cerebral infarction (I63), and venous thromboembolism (I26, I80, I81, I82).

Cox proportional hazard modeling was used to compute the relative risks of differing hormones and administration routes, both for individual diseases and CVD as a whole.

Study findings

The study revealed that 24,089 of the 919,614 included participants suffered from a CVD event during the study period. Ischaemic heart disease (43.0%; n = 10,360) and venomous thromboembolic events (38.2%; n = 9,196) were the most prevalent, followed by myocardial infarctions (17.9%; n = 4,312) and cerebral infarctions (17.0%; n = 4,098).

Surprisingly, when evaluating CVD risk holistically, no statistically significant differences could be found between initiators (participants taking hormone therapy) and non-initiators. However, when considering specific administration routes or hormone choices, tibolone, and oral estrogen-progestin therapy were found to be associated with substantially higher ischaemic heart disease risk (HR = 1.46 and 1.21, respectively).

Outcomes from differing administration routes were similarly nuanced, with oral continuous estrogen-progestin therapy and sequential therapy significantly increasing venous thromboembolism risk (HR = 1.61 and 2.00, respectively), compared to estrogen-only therapy (HR = 1.57).

Together, these findings help explain the confounding outcomes from previous single-hormone comparisons and highlight how some hormones and administration routes are safer CVD-associated options compared to others.

Conclusions

The present study underscores the differences in CVD risk outcomes following various conventional menopausal hormone therapy administration approaches, further exacerbated by specific hormone choices.

Oral estrogen-progestin therapy was found to substantially increase venous thromboembolism risk, while the hormone tibolone contributed significantly to ischaemic heart disease, and myocardial and cerebral infarction outcomes.

Together, these findings help explain previous discrepancies in research findings and highlight the need for holistic, multifactor evaluations in studies involving complex physiological interactions. The proceeds of these findings will help clinicians and public health agencies recommend the safest therapeutic interventions from the spectrum available, thereby potentially reducing the burden of menopause-associated female CVD prevalence.