Estrogen, the Heart, and the Hype

What the Studies Really Show About MHT and Protecting the Heart

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Many menopause and longevity influencers advocate for menopause hormone therapy (MHT) for the primary prevention of cardiovascular disease. However, if it were a done deal, the cardiology societies would be promoting MHT for this reason, and the Menopause Society would not have issued a statement last year specifically stating that MHT is not recommended for the primary prevention of cardiovascular disease.¹ And no, the guidelines are not out of date; no pivotal research about the heart and MHT has been published since the 2022 Guidelines on Menopause Hormone Therapy.

We must be honest about what the data shows and doesn’t show, because not only do women deserve scientific rigor, but misinformation about MHT protecting the heart is being used to scare women with no symptoms into starting hormone therapy under false pretenses. Perhaps even more concerning is that the purported benefits of estrogen for the heart are used to dissuade women from taking statins. We have good data about statins being protective for women, so if a woman chooses MHT over statins for her heart, she may be losing out on the known protective benefits. We even had a session on the fact that statins work for women at the 2023 Menopause Society conference!

What does the literature tell us about MHT and protecting the heart? Given the rise in misinformation in this space, I thought it was time to expand the section on the heart and MHT in The Vajenda’s Hormone Therapy Guide, so people can be armed with more facts for their evidence-based decisions. You can find the Table of Contents for the guide here.

This is a long post because I want to discuss the major studies, so when they are cherry-picked down the road, you can be prepared (and also horrified at their abuse). But if reading the whole thing isn’t your jam, I’ve got you covered with a practical summary at the end! If you just want to cut to the chase, skip ahead to the “Putting It All Together” section.

The Background

The hypothesis that estrogen in MHT might protect the heart originated from observational studies and animal data, which led to several proposed mechanisms by which estrogen could protect cardiovascular health. A significant limitation of observational studies is that women who access MHT are typically wealthier, more physically active, healthier, and have better access to healthcare (much more so in the United States than in other countries)–all factors that are associated with improved cardiovascular outcomes.² Social determinants of health are such an important variable that zip code is now included in the cardiovascular risk calculator, Prevent. And of course, animal data is, well, animal data. It’s great to find a potential mechanism this way, but we must prove that this mechanism applies to women taking a pharmaceutical.

Some Important Housekeeping: Combined versus Estrogen Therapy

This is very important. It is wrong to talk about “MHT protecting the heart,” because MHT is not a monolith. I consider this a red flag for someone who is misinformed or cherry-picking for an agenda. We need to be honest, because 2 mg of estradiol given orally without a progestogen may not be the same MHT for the heart as a 50 mcg patch combined with oral progesterone (for example), so lumping them all together is wrong medically and misleading to women and health care professionals alike. The dose, route, and type of estrogen may have different effects and the same with a progestogen.

The next time you see a broad “estrogen protects the heart,” as them what dose, what route, and what study? Make them show their work.

The Best Data

The best data for the heart would be randomized, double-blinded, placebo-controlled trials that show an impact on major cardiovascular events, like heart attack, stroke, or death from a cardiovascular cause. The only clinical trial that fits that bill is the Women’s Health Initiative (WHI), which was explicitly designed to test the hypothesis that Premarin-based MHT regimens were beneficial to protect the heart in otherwise healthy women. You can read more about the WHI here.

The results?

• During the five years of taking Premarin plus medroxyprogesterone acetate, there was a non-statistically significant increase in stroke and coronary heart disease for women ages 50-59, but this increase returned to baseline at 13 years.^3,4

• For the Premarin only arm, for women ages 50-59, during the 7 years while taking the medication, there was a non-statistically significant reduction in stroke, coronary heart disease, and heart attack. After 13 years, the reduction in coronary heart disease was now statistically significant, 35%, which sounds amazing. However, this is the relative risk, it is the absolute risk that is probably more valuable–Premarin decreased the risk of coronary heart disease by 11 per 10,000 women per year, or 0.11% of women a year taking Premarin saw a benefit for each year they took the medication. The increased risk of stroke was not statistically significant.

It is essential to note that the long-term follow-up data from the WHI were collected after the trial medication was stopped, so this is unblinded. When those taking combined hormones stopped at about 5 years and those taking Premarin stopped at 7 years, the participants now knew who had been taking hormones and who placebo. That may then have affected their subsequent behaviors. For example, women who took the combined therapy that was reported by the press to cause breast cancer may now have become more active at reducing their risk, perhaps by exercising more or reducing alcohol intake. Or they may have made no change. In addition, the trial was never powered to look at subgroups by age, and once you start looking at multiple outcomes and subgroups, the risk of false-positives and false-negatives increases.⁴

The Next Best Data

To get around the size and length of a study needed to show a reduction in heart attacks and stroke, many studies use surrogate markers, which are outcomes associated with cardiovascular disease, such as progression of plaque in the carotid arteries (a.k.a coronary artery intima thickness or CIMT), cardiac calcium scores (a CT scan that looks at calcium in the blood vessels of the heart), or a decrease in LDL-C. Here we have at least three randomized, controlled trials worth discussing.

The first is ELITE, a six-year study of oral estradiol 1 mg with or without vaginal progesterone.⁵ Two groups of women were enrolled, specially to test the timing hypothesis, the idea that estrogen is safer, or even beneficial, closer to menopause, and riskier more than 10 years after. We’ll focus on the group of individuals under 6 years from their last period. There was no difference in cardiac calcium scores, but the study may not have been adequately powered to detect differences in the rate of calcium accumulation in heart arteries.

ELITE did show that women < 6 years from their last period taking estradiol had less accumulation of CIMT than those on placebo–the difference was a reduction of 0.0033 mm/year. While this is statistically significant, it is not clear that this is clinically meaningful. Each 0.01 mm reduction in CIMT progression/year may be associated with a 9% relative cardiovascular disease risk reduction, so is a reduction of 0.0033 mm/y meaningful?^5,6

For comparison, in the METEOR trial (a study of rosuvastatin vs placebo), the statin slowed the annual progression of CIMT by 0.0145 mm/yr, so the statin is running circles around oral estradiol.⁷ It is also important to point out that many cardiologists question the value of CIMT as a surrogate marker. Dr. Danielle Belardo (worth a follow, you can find her here), a cardiologist who specializes in the prevention of heart disease, told me that “the ACC/AHA Guidelines do not recommend routine use of CIMT for cardiovascular risk assessment.”

ELITE also examined atherogenic lipoproteins, and the decrease in LDL-C was 23.7 mg/dl for those who took estradiol and 14.14 mg/dl for the placebo, resulting in a 9.56 mg/dl greater decrease in LDL-C for those who took estradiol.⁸ When the investigators compared the LDL-C on therapy (not taking the baseline into consideration), the difference between estradiol and placebo was 6.8 g/dl (placebo higher), which may have been statistically significant, but this is so small it is likely clinically insignificant. Dr. Danielle Belardo also told me, “A change this small does NOT meet the thresholds associated with meaningful cardiovascular risk reduction, ie, statin/EZE/PCSK9i trials which consistently show LDL-C reductions of 50–80+ mg/dL that correlate with hard cardiovascular outcome reductions.”

The second study, KEEPS, examined two formulations: oral Premarin 0.45 mg and oral progesterone, as well as a transdermal estradiol 50 mcg patch and oral progesterone, all compared to placebo over a three-year period.⁹ The latter combination of transdermal estradiol and oral progesterone is the most common hormone combination today, so KEEPS is highly relevant. The findings? Transdermal estradiol and progesterone did not affect progression of CIMT, cardiac calcium scores (again, the study may not have been powered for this), or, most importantly, LDL-C.

The third trial is EPAT, Estrogen for the Prevention of Atherosclerosis, which is a 2-year randomized double-blinded placebo-controlled trial of 1 mg oral estradiol.¹⁰ No women received a progestogen. The average age is 61.8, and the results were not broken down by age, likely because this was published pre-WHI. Also, with a total of 199 women taking either estradiol or placebo, it’s also not likely powered for this kind of subgroup analysis. Looking at all the women together, oral estradiol reduced CIMT progression by 0.0053 mm/yr, which is likely not meaningful. Interestingly, for women not on a lipid-lowering agent, the reduction in CIMT progression was 0.0147 mm/year, but for women taking a statin, there was no change in CIMT. Given the small numbers and the lack of breakdown by age, it’s hard to say much.

There was a 16% reduction in LDL-C with estradiol, which sounds good, except there was a decrease by 10.4% with placebo.¹⁰ (Side note, this really suggests that people do change their diet in some way when they are in a study and prescribed what may be estrogen). The decrease in LDL-C with estradiol was 27 mg/dl (from a baseline of 166 mg/dl), so again, less change than we would expect with a statin or other lipid-lowering agents. But if we factor in the decrease from placebo, the additional reduction in LDL-C women had from estradiol over placebo was only 10.8 mg/dl, which is extremely close to what was seen with ELITE, which was 9.56 mg/dl.

Another Important, But Flawed Trial

The Danish Osteoporosis Prevention Study, or DOPS, which, as the title indicates, is a study for osteoporosis and included women between the ages of 45 and 58 years.¹¹ The active arm of the study was a triphasic oral estradiol hormone regimen for women with a uterus (2 mg estradiol for 12 days, 2 mg estradiol plus 1 mg norethisterone acetate for 10 days, and 1 mg estradiol for six days), and women who had undergone hysterectomy took 2 mg 17-β-estradiol a day. The control group did not take a placebo. This was not a blinded trial, so the women knew if they were taking MHT or not, which introduces a big potential confounder as women taking MHT may well have engaged in other healthy behaviors.

The findings that are often quoted are a 50% reduction in deaths from heart attacks or a 50% reduction in heart attacks. And this sounds impressive, and the results do show a 52% reduction when the cardiac outcomes of heart failure, heart attack, and mortality were all combined. However, combining endpoints this way in a composite score can exaggerate the results. Here is a direct quote from the article on heart attacks (myocardial infarction) at 10 years of follow-up:

“Myocardial infarction was diagnosed in five participants (4 in control group v 1 in treated group”

This was not statistically significant, and was still not statistically significant when the group was reevaluated again at 16 years. Also, people seem to forget that overall mortality was not different for those who took hormones versus those who did not.

There are other issues with DOPS. The control group was older by an average of 6 months, which was statistically significant. The study was designed to evaluate the effects on osteoporosis, and the cardiac data were from a secondary analysis, which makes the findings weaker. The authors of the 2012 Cochrane review on MHT and the heart did not include DOPS due to the numerous flaws mentioned above (and other issues).

A Cadre of Observational Data and Meta-Analysis

Many observational studies do show benefit, but there are also some that show none, although they tend to favor protecting the heart. However, not only can we not ascribe cause and effect with an observational study, but often many types of estrogens and progestogens are lumped together, and the doses of the estrogen and whether they are oral are transdermal are usually unknown, so it’s not possible to say much in terms of how to use this data for medical care.

Dr. Marty Makary highlighted a Finnish database study in his book and has mentioned it in interviews that he claims shows that women are much more likely to die from a heart attack in their first year after stopping MHT, so much so that they are basically dropping like flies.¹² (I am only exaggerating a little). Since he played fast and loose with DOPS, I figured he did here as well, so I took a deeper dive. The study also has significant limitations. It doesn’t report on the type of MHT, so estrogen alone and estrogen plus a progestin are lumped together, and no doses are given. In one arm, women on MHT were compared to national averages—not age-, health-, or risk-matched controls, so that’s another issue. In this arm, when women under age 60 years stopped MHT, they had a 27% increased risk of death from heart attacks in the first year. That sounds alarming—until you consider that once the women got past that year, there was a 25% reduction in heart attack deaths. KIND OF IMPORTANT. So, depending on how you slice the data, you could just as easily claim that stopping MHT protects the heart in the long-term.

In this study, they also compared women who stopped MHT versus those who stayed on it, but there is even a greater potential for confounding here. Women who stayed on MHT may well have had lower cardiac risk, because a primary reason for stopping MHT is a new, serious cardiovascular concern or blood clot. In this group, death from heart attacks was significantly higher among those who stopped MHT, whether it was within 1 year or stopping or more than a year after. But without knowing anything tangible about the groups we can’t say anything at all!

I would be remiss if I did not point out that the purpose of the study was to evaluate the safety of stopping MHT once a year to see if women still needed it! The authors conclude that they “question the safety of the annual discontinuation practice,” and “Our data also warrant further studies to compare the cardiovascular safety of immediate vs tapered HT discontinuation.”

There is also a Danish national registry study with over 700, 000 women, and unlike the Finnish study, there is data about some important variables, such as education level and lipid-lowering drugs, as well as data about the type of MHT.¹³ Overall, they found no association between menopause hormone therapy and myocardial infarction, but among some subgroups:

• Women taking estrogen plus a daily progestogen had an increased risk of heart attack

• Women using transdermal estradiol had a lower risk of heart attack

• Vaginal estrogen use had the lowest risk of heart attack, which seems biologically implausible and suggests there is some confounder that isn’t accounted for.

• No differences in risk were seen between different progestogens.

There are several meta-analyses, all with the problem that comparing the clinical trials is challenging when different estrogens or study endpoints are used. Many menopause influencers make a big deal of the latest Cochrane review from 2015, claiming that it proves estrogen protects the heart when started within 10 years of menopause, but the authors are very clear that if DOPS (considering all of its inherent problems noted above) is removed, there is no benefit from MHT.¹⁴ Also, the people who promote the Cochrane review always conveniently forget that it shows that oral estrogen increases the risk of stroke.

Another meta-analysis reaches the same conclusion: “In this systematic review and meta-analysis, HRT use was found to reduce all-cause mortality and cardiac mortality in younger HRT initiators but not in older initiators, and significant heterogeneity of treatment effect was found between these groups in terms of CHD events. However, this analysis has important limitations, and the findings should be viewed with caution as the reduction in cardiac mortality was eliminated when excluding open-label trials.”¹⁵ We can’t make decisions based on open-label trials.

There is a meta-analysis of transdermal estradiol and oral medroxyprogesterone acetate, but the studies are small (some are only a few months) and short-term, and it’s not possible to draw a robust conclusion here.¹⁶ This is essentially a garbage-in, garbage-out situation.

Putting It All Together

The good news is that we can be assured with a high degree of certainty that MHT doesn’t negatively affect the heart for women under age 60 who are at low risk for cardiovascular disease. And that is a really good thing! Really, we should be happy about that.

As for protecting the heart, let’s sum it up:

1. Premarin: we have the most data here. Combined therapy has no benefit. While Premarin by itself is associated with a reduction in coronary heart disease, the absolute numbers are small and what is the relevance for a therapy used by so few women? Can’t apply to other forms of MHT.

2. Oral estradiol: We have data from two randomized-placebo controlled trials with 1 mg of oral estradiol that show a reduction in LDL-C of 24-27 mg/dl with oral estradiol, but this is only 9-11 mg/dl over what was seen with placebo. This is much less than we expect to see with lipid lowering agents. The clinical relevance of the small reduction in LDL-C and CIMT progression is unknown. The one unblinded clinical trial that shows a reduction in cardiovascular events (DOPS) has many issues. And oral estrogen increases the risk of blood clots, so it’s always important to weigh any prospective benefits against the risks.

3. Transdermal estradiol: We have almost no data. This is the most common estrogen that is prescribed in MHT. How can we make blanket statements claiming MHT protects the heart when we have very little clinical trial data and the data that we do have shows that transdermal estradiol has a neutral or minimal effect on LDL-C.? This is important, because one hypothesis is that a big part of the estrogen protecting the heart hypothesis is via a reduction in LDL-C!

Many people cherry-pick data. For example, Dr. Marty Makary and many influencers dismiss the WHI’s findings for breast cancer with Premarin and medroxyprogesterone acetate as trivial–for each 10,000 women taking that combination between the ages of 50-59, there were nine more invasive cases of breast cancers per year at the 13-year mark, a 34% increase over placebo. Okay, if that is trivial, it’s hypocritical to say that the reduction in coronary heart disease of 11 per 10,000 per year with Premarin is resounding proof of success for the heart. With DOPS (and all of its problems), 4 of 504 women in the control group had a heart attack at 10 years versus 1 of 502 in the estradiol group, and this was not statistically significant! Relative risk (a 34% increase, for example) can make a therapy sound more impressive or scary, and so absolute risk–how many women were potentially helped or harmed–is generally more valuable.

While we have observational data, we should not use this to make treatment decisions about preventative therapy. The best we can say is there is a weak signal that maybe oral estradiol has some benefit of unknown clinical relevance for cardiovascular disease, because we must remember that changes in CIMT and LDL-C with oral estradiol are far less impressive than what we see with statins. And we have no data to say the possibility of a weak signal extends to transdermal estradiol.

To the menoinfluencers and longevity influencers banging on about MHT being definitively proven to protect the heart while playing loose and fast with the data, I challenge you to spend some of the millions you get from supplements and partnerships on a clinical trial. There are a a few of you, so you could probably fund something of value.

Until we have high-quality evidence showing that a specific formulation and dose of MHT prevents cardiovascular disease, or has a significant impact on a relevant surrogate marker, MHT should not be promoted as such. Women deserve facts, not fantasy and manipulated statistics.

And statins work for women!

References

1. The Menopause Society Statement on Misinformation Surrounding Hormone Therapy https://menopause.org/wp-content/uploads/2024/09/TMS-statement-on-HT-Misinformation.pdf

2. Fugh-Berman A, Scialli AR. Gynecologists and estrogen: an affair of the heart. Perspect Biol Med. 2006; 49(1): 115-130.

3. Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative Randomized Trials and Clinical Practice: A Review. JAMA. Published online May 01, 2024. doi:10.1001/jama.2024.6542

4. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials.  JAMA. 2013;310(13):1353-1368

5. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241.

6. Willeit P, Tschiderer L, Allara E, PROG-IMT and the Proof-ATHERO Study Groups. Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients. Circulation. 2020 Aug 18;142(7):621-642. doi: 10.1161/CIRCULATIONAHA.120.046361. Epub 2020 Jun 17.

7. Crouse JR, Raichlen JS, Riley WA, et al. Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis: The METEOR Trial. JAMA. 2007;297(12):1344–1353. doi:10.1001/jama.297.12.1344

8. Sriprasert I, Kim SS, Mohammed IE, Kono N, Karim R, Allayee H, Hodis HN, Mack WJ, Krauss RM. Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women. J Clin Endocrinol Metab. 2025 Jan 21;110(2):e301-e309

9. KEEPS Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal-Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014 Aug 19;161(4):249-60. doi: 10.7326/M14-0353. PMID: 25069991.

10. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu Cr CR, Liu Ch CH, Azen SP; Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001 Dec 4;135(11):939-53. doi: 10.7326/0003-4819-135-11-200112040-00005. PMID: 11730394.

11. Schierbeck L L, Rejnmark L, Tofteng C L, Stilgren L, Eiken P, Mosekilde L et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial BMJ 2012; 345 :e6409 doi:10.1136/bmj.e6409

12. Mikkola TS, Tuomikoski P, Lyytinen H, Korhonen P, Hoti F, Vattulainen P, Gissler M, Ylikorkala O. Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy. J Clin Endocrinol Metab. 2015 Dec;100(12):4588-94

13. Løkkegaard E, Andreasen AH, Jacobsen RK, Nielsen LH, Agger C, Lidegaard Ø. Hormone therapy and risk of myocardial infarction: a national register study. Eur Heart J. 2008 Nov;29(21):2660-8. doi: 10.1093/eurheartj/ehn408. Epub 2008 Sep 30. PMID: 18826989.

14. Roberts H, Hickey M. Should hormone therapy be recommended for prevention of cardiovascular disease?. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: ED000097. DOI: 10.1002/14651858.ED000097.

15. Nudy M, Chinchilli VM, Foy AJ. A systematic review and meta-regression analysis to examine the 'timing hypothesis' of hormone replacement therapy on mortality, coronary heart disease, and stroke. Int J Cardiol Heart Vasc. 2019 Jan 18;22:123-131. doi: 10.1016/j.ijcha.2019.01.001. PMID: 30705938; PMCID: PMC6349559.

16. Zhou F, Prabahar K, Shu J. The effects of transdermal estrogens combined with Medroxyprogesterone Acetate on cardiovascular disease risk factors in postmenopausal women: a meta-analysis of randomized controlled trials. Diabetol Metab Syndr. 2025 Apr 1;17(1):111.