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Hormone Replacement Therapy for Cardiovascular Prevention: Hope or Hype?
Shoomena Anil^1 , Vassilios S Vassiliou^1, *
1		Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, UK *Correspondence: v.vassiliou@uea.ac.uk (Vassilios S Vassiliou)
“Nothing in life is to be feared, it is only to be understood.”
— Marie Curie
Introduction
Women, just like men, see an increase in cardiovascular disease (CVD) incidence with age. The peak incidence is observed during the post-menopausal period (Ryczkowska et al, 2022). Comparative analyses of age-matched cohorts indicate a 2.6-fold higher incidence of CVD among post-menopausal women relative to their pre-menopausal counterparts, indicating a protective role of endogenous oestrogen (Kannel et al, 1976). This protective role of oestrogen against CVD has been attributed to multiple mechanisms, including angiogenesis, vasodilation and attenuation of oxidative stress (Ryczkowska et al, 2022). However, the potential of hormone replacement therapy (HRT) to mitigate CVD risk in post-menopausal women remains a subject of ongoing debate.
The Evidence
In the 1990s, HRT was propelled into the spotlight for chronic disease prevention, driven in part by several observational studies supporting HRT for cardiovascular health. This is reflected in prescribing trends, with HRT use in the UK increasing from 18.6% in 1992 to 27.7% in 1998 (Bromley et al, 2004). The observational Nurses’ Health Study found that women beginning HRT near menopause had a significantly reduced risk of CVD (relative risk (RR) = 0.66, 95% confidence interval (CI) 0.54–0.80 for oestrogen alone; RR = 0.72, 95% CI 0.56–0.92 for oestrogen with progestogen), supporting this enthusiasm (Grodstein et al, 2006).

How to cite this article:
Anil S, Vassiliou VS. Hormone
Replacement Therapy for Cardiovascular Prevention: Hope or Hype? Br J Hosp Med. 2025.
https://doi.org/10.12968/hmed.2025.0139
Copyright: © 2025 The Author(s).

However, this early enthusiasm for HRT was dissipated by two landmark randomised controlled trials (RCTs) which questioned the credibility of evidence from observational studies. The Women’s Health Initiative (WHI) and Heart and Es- trogen/Progestin Replacement Study (HERS) evaluated HRT in the primary and secondary prevention of CVD, respectively. The specific HRT regimen used was conjugated equine oestrogens (CEE) and medroxyprogesterone acetate (MPA), a synthetic progestin. In contrast to the observational data, WHI showed a small but significant increase in all cardiovascular events in the HRT cohort, both with CEE + MPA (hazard ratio (HR): 1.13, 95% CI: 1.02–1.25, p = 0.02) and CEE alone (HR: 1.11,	95% CI: 1.01–1.22, p = 0.03). Additionally, WHI showed increases in breast cancer and thromboembolic disease (Manson et al, 2013).
What was responsible for the vastly different outcomes between observational studies and RCTs? Although observational studies are susceptible to confounding and other biases, the discrepancy in findings may be attributable to the study populations. Comparing the characteristics of women between the two study types reveals stark differences in their demographics. Notably, observational study populations consist of women who chose to start HRT for symptomatic relief near or early in menopause. Women in observational studies were therefore younger and closer in proximity to menopause. In the Nurses’ Health Study, which showed protective effects of HRT, women were 30–55 years of age at enrolment and around 80% initiated HRT within 2 years of menopause. This contrasts with the women in RCTs, who were typically >10 years post-menopause and in their 60s. Namely, 67% of WHI participants were aged over 60. The demographic of the WHI cohort, therefore, was not reflective of the typical symptomatic younger women initiating menopausal HRT.
This has led to the suggestion that there is a critical window during which HRT may be cardioprotective. The “timing hypothesis” posits that the cardiovascular risks of HRT correlate with the timing of HRT initiation in relation to the onset of menopause, with the risks of HRT being low in women <10 years from menopause and age <60 years. This is supported by primate models, suggesting that HRT may only afford primary prevention and that oestrogens have a differential effect on vasculature during the early and late stages of atherosclerosis progression (Rosenfeld et al, 2002). In subclinical atherosclerosis, as seen in younger women closer to menopause, oestrogen therapy can improve or reverse vascular disease. However, in established atherosclerotic lesions, seen in older women, oestrogen initiation may lead to plaque instability and rupture and subsequent ischaemic vessel disease (Ouyang et al, 2006). As Marie Curie would put it, understanding this should not lead to a fear of HRT.
Subsequent secondary age-stratified analysis of the WHI data provides support to the timing hypothesis, with data showing a decrease in all-cause mortality and myocardial infarction in women 50–59 years old, but increased risk in women >70 years old (Manson et al, 2013). The Early versus Late Intervention Trial with Estradiol (ELITE) trial was designed to specifically test the timing hypothesis. Oral oestradiol therapy was associated with reduced progression of subclin- ical atherosclerosis relative to placebo when initiated in women within 6 years of menopause, but not later (≥10 years). However, carotid intima-media thickness (CIMT), a measure of subclinical, asymptomatic atherosclerosis, was used as a surrogate marker of CVD. ELITE also failed to show a significant effect on cardiac computed tomography (CT) measures of atherosclerosis (Hodis et al, 2016). Therefore, the clinical translation of the implication of these results in terms of morbidity and mortality is brought into question.
HRT for Cardiovascular Protection: Mind the Gap
Accumulating data implies that HRT is protective against atherosclerosis if initiated early in menopause, but may be harmful if administered as secondary prevention to women with established plaque disease. However, crucial questions remain unanswered. What formulations and doses of HRT confer maximal cardiovascular protection? Are hard endpoints of myocardial infarction, heart failure and/or allcause mortality reduced with timely HRT? Does oral versus transdermal oestrogen differentially affect cardiovascular risk?
Future trials need to address these gaps in our knowledge and there should be a focus on at-risk groups with established cardiovascular risk factors, such as patients with diabetes, hypertension and obesity. Until this gap is addressed, what we can emphasize to our patients is that if they are close in proximity to menopause and have symptoms which could benefit from HRT, then they should not fear cardiovascular risks, as the observational studies support a benefit, and the RCTs have not addressed this specific scenario.
onclusion
Whilst the observational studies and RCTs do not agree with regard to the effect on cardiovascular risk, the different populations used between them likely explain the discordance. Whilst there is no evidence to support HRT for cardiovascular risk reduction in all patients, symptomatic patients starting HRT early in menopause are likely to be the ones who could benefit most.
Key Points
•		Post-menopausal women have an accelerated risk of CVD compared with their pre-menopausal counterparts, presenting a critical time period in which early intervention strategies should be implemented to reduce the risk of CVD.
•		Animal, clinical and human studies indicate that risk outweighs benefit when HRT is initiated ≥10 years after menopause. However, in younger women, more representative of actual HRT use patterns, there remains uncertainty regarding the use of HRT as a cardioprotective therapy.
•		For medical professionals, evidence emphasizes early identification of at- risk women, individualized HRT recommendations balancing risks and benefits, and promoting cardioprotective strategies like diet, exercise, and pharmacotherapy.
•		Future research, including RCTs on the scale of the WHI, should validate HRT use by formulation, route and duration of therapy, across ethnic groups and in women with established risk factors for cardiovascular disease. Outcomes measured should be hard clinical endpoints that directly translate to morbidity and mortality.
•		We propose that symptomatic patients who may benefit from HRT should consider this, especially if started near or early in menopause, as at this time it may have some beneficial cardiovascular effects.
Availability of Data and Materials
Not applicable.
Author Contributions
Both authors made substantial contributions to the conception and design of this manuscript. SA wrote the first draft. VV revised the manuscript critically for important intellectual content. Both authors approved the final version of the manuscript. Both authors agreed to be accountable for all aspects of the work.
Ethics Approval and Consent to Participate
Not applicable.
Acknowledgement
Not applicable.
Funding
This research received no external funding.
Conflict of Interest
The authors declare no conflict of interest.
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British Journal of Hospital Medicine | 2025 | https://doi.org/10.12968/hmed.2025.0139