For decades, scientists and doctors have debated an important question: Does menopausal hormone therapy protect the heart, increase cardiovascular risks, or produce a mixture of benefits and harms?
Hormone therapy can significantly improve symptoms such as hot flashes, night sweats, and menopause-related sleep disturbances. However, its effects on cardiovascular health are more complicated.
A major analysis of the Women’s Health Initiative (WHI), published in Obstetrics & Gynecology in 2025, provides new insight into this question.
Led by cardiologist Matthew Nudy, MD, and colleagues, the research found that certain forms of oral hormone therapy improved several blood markers associated with cardiovascular health, including LDL cholesterol, lipoprotein(a), and insulin resistance.
However, the treatments also increased triglycerides, and earlier Women’s Health Initiative findings showed that favorable cholesterol changes do not necessarily translate into fewer heart attacks or strokes.
The research highlights an essential distinction: Improving cardiovascular biomarkers is not the same as proving that a treatment prevents cardiovascular disease.
Understanding this difference can help women make informed decisions about managing menopause symptoms while considering their long-term health.
Original research: Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the Women’s Health Initiative Hormone Therapy Clinical Trials.
What Is the Women’s Health Initiative?
The Women’s Health Initiative is one of the largest and most influential research programs investigating the health of postmenopausal women.
Launched in the 1990s with support from the US National Institutes of Health, the program enrolled more than 160,000 women across its clinical trials and observational study.
Its research has examined cardiovascular disease, cancer, osteoporosis, menopause treatments, and other major health concerns associated with aging.
The hormone therapy component included two large randomized, placebo-controlled trials involving 27,347 women.
Researchers tested two different treatments.
Estrogen-Only Hormone Therapy
This trial studied conjugated equine estrogens (CEE), given at 0.625 milligrams daily.
It included women who had previously undergone a hysterectomy, meaning their uterus had been removed.
Estrogen Plus Progestin Hormone Therapy
The second trial examined conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA).
Participants received 0.625 milligrams of CEE and 2.5 milligrams of MPA daily.
This trial included women with an intact uterus.
The distinction matters because systemic estrogen without adequate progestogen protection can increase the risk of endometrial cancer in women who still have a uterus.
The original WHI trials were designed to evaluate clinical outcomes, including coronary heart disease, rather than simply changes in laboratory measurements.
The Women’s Health Initiative official website provides additional information about the program and its continuing research.
What Did the 2025 Hormone Therapy Study Investigate?
The 2025 analysis revisited data collected during the WHI hormone therapy trials to investigate how cardiovascular biomarkers changed over time.
Researchers analyzed blood samples from 2,696 participants:
- 1,188 women from the estrogen-only trial.
- 1,508 women from the estrogen-plus-progestin trial.
Blood samples were collected before treatment and at approximately 1, 3, and 6 years after randomization.
The team examined several cardiovascular and metabolic biomarkers, including LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol, lipoprotein(a), blood glucose, insulin, and insulin resistance.
LDL cholesterol was the primary outcome.
Because participants were originally randomly assigned to hormone therapy or placebo, the researchers could compare how the treatments affected these measurements.
However, this was a secondary analysis of a subset of participants, not a newly conducted clinical trial.
The findings were published in April 2025 in Obstetrics & Gynecology, following online publication on February 27, 2025.
The full research article is available through PubMed Central.
Key Findings: How Hormone Therapy Affected Cardiovascular Biomarkers
The study found several differences between women assigned to hormone therapy and those receiving placebo.
Some of these changes are generally considered favorable, while others raise concerns.
1. LDL Cholesterol Decreased by Approximately 11–12%
LDL cholesterol is commonly called “bad cholesterol” because elevated levels contribute to atherosclerosis.
Atherosclerosis occurs when cholesterol-rich deposits build up in artery walls, potentially increasing the risk of heart attacks and strokes.
In the WHI analysis, the researchers found that:
- Estrogen-only therapy reduced LDL cholesterol by approximately 11% compared with placebo.
- Estrogen-plus-progestin therapy reduced LDL cholesterol by approximately 12% compared with placebo.
These differences were statistically significant.
In many settings, reducing LDL cholesterol is an important strategy for lowering cardiovascular risk.
However, hormone therapy affects other biological pathways, including blood clotting and inflammation.
Therefore, an improvement in LDL cholesterol does not automatically mean that hormone therapy reduces cardiovascular events.
2. HDL Cholesterol Increased
HDL cholesterol is often described as “good cholesterol” because HDL particles participate in transporting cholesterol from tissues toward the liver.
The researchers found that HDL cholesterol increased by approximately:
- 13% with estrogen-only therapy.
- 7% with estrogen-plus-progestin therapy.
The larger increase in the estrogen-only group suggests that adding medroxyprogesterone acetate may influence some of estrogen’s effects on cholesterol metabolism.
However, higher HDL cholesterol does not necessarily guarantee better cardiovascular outcomes.
HDL function, overall lipid balance, inflammation, and other cardiovascular risk factors also matter.
3. Lipoprotein(a) Levels Decreased
Lipoprotein(a), commonly abbreviated as Lp(a), is a cholesterol-containing particle associated with inherited cardiovascular risk.
Elevated Lp(a) levels can increase the risk of atherosclerotic cardiovascular disease and certain forms of aortic valve disease.
Unlike ordinary LDL cholesterol, Lp(a) concentrations are strongly influenced by genetics and often remain relatively stable throughout adulthood.
The WHI analysis found that:
- Estrogen-only therapy lowered Lp(a) by approximately 15%.
- Estrogen-plus-progestin therapy lowered Lp(a) by approximately 20%.
These findings suggest that the studied oral hormone formulations can influence Lp(a) concentrations.
However, the study did not prove that lowering Lp(a) through hormone therapy reduces heart attacks or other cardiovascular events.
4. Insulin Resistance Markers Improved
Insulin helps regulate blood glucose by allowing cells to absorb and use glucose for energy.
Insulin resistance occurs when cells respond less effectively to insulin, so the body produces more of the hormone to maintain normal blood sugar levels.
Insulin resistance is associated with conditions such as type 2 diabetes and metabolic syndrome, both of which influence cardiovascular health.
Researchers used the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) to assess changes in insulin resistance.
They found that HOMA-IR was approximately:
- 14% lower in the estrogen-only group.
- 8% lower in the estrogen-plus-progestin group.
These results suggest favorable effects on this metabolic marker.
Nevertheless, a reduction in HOMA-IR does not mean fewer cases of diabetes or cardiovascular disease.
5. Triglycerides Increased
Not all of the findings were favorable.
Triglycerides are fats circulating in the bloodstream that the body uses for energy storage and metabolism.
Persistently elevated triglyceride levels can be associated with metabolic abnormalities and cardiovascular risk.
The study reported triglyceride increases of approximately:
- 13% with estrogen-only therapy.
- 7% with estrogen-plus-progestin therapy.
This is an important finding because oral estrogen passes through the liver before entering the wider circulation.
This process can influence lipoprotein production and metabolism, triglycerides, and other substances involved in cardiovascular health.
Consequently, hormone therapy may improve some blood markers while worsening others.
Summary of the Study’s Findings
| Cardiovascular marker | Estrogen only | Estrogen + progestin |
| LDL cholesterol | 11% lower | 12% lower |
| HDL cholesterol | 13% higher | 7% higher |
| Lipoprotein(a) | 15% lower | 20% lower |
| Insulin resistance (HOMA-IR) | 14% lower | 8% lower |
| Triglycerides | 13% higher | 7% higher |
Values represent approximate overall differences compared with placebo during the treatment period, rather than guaranteed changes for individual patients.
Source: Nudy et al., 2025, Obstetrics & Gynecology.
Do Better Cholesterol Levels Mean a Lower Risk of Heart Disease?
This is one of the most important questions raised by the research.
Although the WHI analysis reported improvements in several cardiovascular biomarkers, the original hormone therapy trials did not show an overall benefit for coronary heart disease from the regimens studied.
The estrogen-plus-progestin trial raised concerns about coronary events, stroke, blood clots, and other outcomes.
The estrogen-only trial also found an increased risk of stroke, despite producing some favorable changes in cholesterol measurements.
These differences are not necessarily contradictory.
Cardiovascular disease is influenced by numerous interacting processes, including cholesterol metabolism, blood vessel health, inflammation, clotting activity, blood pressure, and existing arterial plaques.
A treatment may improve one risk factor while negatively affecting another.
For example, oral hormone therapy can influence coagulation proteins and inflammatory markers through its effects on the liver.
The 2025 research also observed changes in some coagulation-related biomarkers, including factor VII antigen.
These effects may help explain why improvements in cholesterol levels do not automatically produce better clinical cardiovascular outcomes.
For this reason, systemic menopausal hormone therapy should not be prescribed solely to prevent heart attacks, strokes, or cardiovascular disease.
This distinction is also reflected in the American College of Obstetricians and Gynecologists’ patient guidance.
Why Age and Timing of Hormone Therapy Matter
The cardiovascular risk of hormone therapy is not identical for every woman.
A major factor is the age at which treatment begins and how long it has been since menopause.
This has led researchers to investigate the menopause hormone therapy “timing hypothesis.”
The hypothesis proposes that starting treatment near menopause may have different cardiovascular effects from starting it many years later, when age-related vascular changes may be more advanced.
Women Younger Than 60 or Within 10 Years of Menopause
For otherwise healthy women younger than 60, or within approximately 10 years of menopause onset, the balance of benefits and risks may be favorable when hormone therapy is used to treat bothersome menopausal symptoms.
The 2022 position statement of The Menopause Society emphasized this individualized approach.
It also noted that the treatment’s safety depends on factors such as dose, formulation, route, duration, and whether a progestogen is required.
Women Older Than 60 or More Than 10 Years Past Menopause
Beginning systemic hormone therapy later may carry a less favorable benefit-risk balance.
This is partly because the absolute risks of coronary heart disease, stroke, blood clots, and other complications generally rise with age.
However, these age and timing thresholds do not guarantee safety or harm.
Individual medical history and cardiovascular risk remain essential.
Women who are already using hormone therapy should not assume they must automatically discontinue treatment upon reaching age 60 or 65.
Instead, continued treatment requires periodic medical evaluation.
Source: The 2022 Hormone Therapy Position Statement of The North American Menopause Society.
Oral Hormone Therapy vs. Patches: Does the Delivery Method Matter?
The 2025 WHI analysis focused on two oral hormone therapy formulations.
Its results should not automatically be applied to estrogen patches, gels, sprays, or other preparations.
Oral estrogen passes through the liver before circulating throughout the body.
This first-pass effect can influence triglycerides, clotting factors, and inflammatory proteins.
Transdermal estrogen, delivered through the skin, largely avoids this initial liver exposure.
Some research and clinical guidance suggest that transdermal estrogen may be associated with a lower risk of venous blood clots than oral estrogen.
However, direct randomized comparisons assessing major cardiovascular events remain limited.
Therefore, patches should not be described as completely risk-free or proven to prevent heart disease.
The choice between oral and transdermal therapy depends on a woman’s symptoms, risk factors, preferences, and clinical history.
For women who still have a uterus, systemic estrogen also generally requires an appropriate progestogen regimen to protect the uterine lining.
A Major 2026 Update: FDA Changes Hormone Therapy Warning Labels
An important development followed the publication of the original 2025 study.
On February 12, 2026, the US Food and Drug Administration announced that it had approved labeling changes for six menopausal hormone therapy products.
The changes removed statements about cardiovascular disease, breast cancer, and probable dementia from the prominent boxed warning for these products.
The decision followed an FDA reassessment of the available evidence and the benefits and risks of hormone therapy.
However, removing information from a boxed warning does not mean the risks have disappeared.
The agency explained that cardiovascular and breast cancer risk information remains in other sections of systemic hormone therapy labeling.
The FDA also retained the boxed warning about endometrial cancer for systemic estrogen-only products.
This regulatory change should not be interpreted as evidence that hormone therapy is now approved for preventing cardiovascular disease.
Instead, it reflects an evolving approach to communicating treatment risks and benefits.
The FDA has also emphasized considerations around initiating systemic hormone therapy for moderate to severe menopausal symptoms in women younger than 60 or within 10 years of menopause.
Patients should review the current prescribing information for their specific product with a qualified healthcare professional.
Source: FDA — Approves Labeling Changes to Menopausal Hormone Therapy Products, February 12, 2026.
Who May Benefit From Menopausal Hormone Therapy?
Hormone therapy remains an effective treatment for several menopausal symptoms, particularly moderate to severe hot flashes and night sweats.
Systemic therapy may also help some women with associated sleep disruption and can prevent bone loss.
For women experiencing primarily vaginal dryness, discomfort, or certain urinary symptoms, local vaginal estrogen or other targeted treatments may be appropriate.
However, systemic hormone therapy is not suitable for everyone.
Factors that may make treatment inappropriate include a history of certain cancers, unexplained vaginal bleeding, blood clots, stroke, heart attack, or serious liver disease.
A healthcare professional must consider these and other individual circumstances.
For many healthy women with bothersome symptoms near menopause, hormone therapy may provide meaningful improvements in quality of life.
The purpose of treatment, however, is generally to address menopausal symptoms and selected related indications—not to serve as a substitute for established cardiovascular prevention strategies.
What Should Women Discuss With Their Doctor Before Starting Hormone Therapy?
A treatment decision should consider both symptom relief and potential health risks.
Useful topics include:
- Age and the number of years since menopause began.
- The severity of hot flashes, night sweats, and sleep disturbances.
- Personal or family history of cardiovascular disease, stroke, or blood clots.
- Blood pressure, cholesterol, diabetes, and smoking history.
- History of breast cancer, endometrial cancer, or abnormal uterine bleeding.
- Whether oral or transdermal therapy would be more appropriate.
- Whether a progestogen is needed.
- Alternatives if systemic hormone therapy is contraindicated.
- How and when the treatment plan will be reassessed.
The decision should be individualized rather than based on a single cholesterol measurement or generalized claims about hormone therapy.
For women with significant cardiovascular risk, nonhormonal treatments for menopausal symptoms may be preferable.
What Are the Limitations of the 2025 Study?
Despite its valuable findings, the WHI biomarker analysis has limitations.
1. It Studied Blood Markers Rather Than New Cardiovascular Events
The analysis examined laboratory measurements such as cholesterol and insulin resistance.
It was not designed to establish whether these biomarker changes reduced heart attacks, strokes, or cardiovascular deaths.
Those clinical outcomes must be considered using evidence from the original WHI trials and other studies.
2. The Results Apply to Specific Oral Hormone Formulations
The research investigated conjugated equine estrogens alone and conjugated equine estrogens combined with medroxyprogesterone acetate.
The findings cannot be assumed to apply equally to all estrogen formulations, doses, delivery methods, or progestogens.
3. The Analysis Used a Subset of Trial Participants
Although the original WHI trials involved more than 27,000 women, this biomarker analysis included 2,696 participants with relevant blood samples.
The subset provides useful information but does not represent every participant in the original trials.
4. Treatment Adherence and Other Medications Changed Over Time
During follow-up, some participants stopped taking study medication or became less consistent with treatment.
Statin use also increased over time.
These factors complicate interpreting long-term biomarker changes.
5. Treatment Began in the 1990s
The WHI hormone therapy trials started during a period when cardiovascular prevention practices differed from those used today.
Contemporary statin use, cardiovascular risk assessment, and menopause treatment options have evolved.
For these reasons, the results are most informative when considered alongside newer clinical evidence and current treatment recommendations.
What Does This Research Mean for Women’s Heart Health?
The WHI findings remind a that cardiovascular health cannot be assessed by cholesterol levels alone.
Hormone therapy may improve some markers of metabolic and cardiovascular health, but it can also produce effects that require caution.
Women considering treatment should focus on two separate questions:
First, will hormone therapy meaningfully improve my menopausal symptoms and quality of life?
Second, do my personal cardiovascular and medical risk factors make the treatment appropriate for me?
Both questions matter.
Regardless of whether hormone therapy is used, established measures for cardiovascular prevention remain important.
These include maintaining a healthy blood pressure, managing LDL cholesterol when indicated, exercising regularly, avoiding tobacco, following a balanced diet, and managing diabetes or other metabolic conditions.
Hormone therapy does not replace these approaches.
Conclusion: Hormone Therapy Requires a Balanced, Personalized Approach
The 2025 Women’s Health Initiative analysis adds valuable insight into how oral hormone therapy affects cardiovascular and metabolic biomarkers over time.
Researchers found reductions in LDL cholesterol, lipoprotein(a), and insulin resistance markers, alongside increases in HDL cholesterol.
However, triglycerides also increased, and previous WHI findings demonstrated that improving cardiovascular biomarkers does not necessarily prevent serious cardiovascular events.
Developments in 2026, including FDA labeling changes, highlight how scientific and regulatory understanding of menopausal hormone therapy continues to evolve.
For women experiencing difficult menopausal symptoms, the most appropriate decision is not based on whether hormone therapy is universally good or bad.
Instead, it depends on the individual’s symptoms, age, time since menopause, cardiovascular risk, and the specific treatment being considered.
The central lesson from the Women’s Health Initiative remains clear: hormone therapy can be valuable for symptom relief, but cardiovascular protection should not be assumed from favorable laboratory results alone.
References
Nudy, M., Aragaki, A. K., Jiang, X., et al. (2025). Long-Term Changes to Cardiovascular Biomarkers After Hormone Therapy in the Women’s Health Initiative Hormone Therapy Clinical Trials. Obstetrics & Gynecology, 145(4), 357–367.
https://doi.org/10.1097/AOG.0000000000005862
2. Free Full-Text Research Article
National Library of Medicine, PubMed Central.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11972549
3. The Menopause Society Hormone Therapy Position Statement (2022)
The North American Menopause Society Advisory Panel. The 2022 Hormone Therapy Position Statement.
https://pubmed.ncbi.nlm.nih.gov/35797481
4. American College of Obstetricians and Gynecologists
Hormone Therapy for Menopause — Frequently Asked Questions.
https://www.acog.org/womens-health/faqs/hormone-therapy-for-menopause
5. US Food and Drug Administration (February 2026)
FDA Approves Labeling Changes to Menopausal Hormone Therapy Products.
6. US Office on Women’s Health
Hormone Therapy Safety.
https://womenshealth.gov/menopause/hormone-therapy-safety
7. Women’s Health Initiative
Official research program and study information.