Hormones & Cardiovascular Health

Estrogen and Heart Health

For decades, the heart-healthy effects of estrogen have been studied, but only recently have researchers begun to understand the complex and profound role the hormone plays in women’s heart health. Estrogen protects the heart from a wide array of stressors by exerting an influence at a cellular level, both on the endothelium and in the muscular myocardium. In fact, current research shows some amount of estrogen may be produced locally in the heart tissue, where it plays a role in contraction and heart function1.

Estrogen receptors (ERs) in the heart tissue influence heart health in multiple ways, exerting positive anti-inflammatory effects as well as helping to prevent early cell death or apoptosis. ERs also assist in vasodilation and promote blood vessel health, all of which support optimal cardiovascular function and wellness.

Beyond protecting the heart directly, estrogen is also associated with other indicators of heart disease, specifically C-reactive protein (CRP). CRP plays a major role in chronic, low-grade inflammation, and it’s also one of the strongest predictive factors for developing atherosclerosis and cardiovascular disease. In one study, higher estrogen levels were associated with lower levels of highly-sensitive CRP as well as lower levels of serum triglycerides2.

Cardiovascular Disease and Women: More Common Than You Think

Data show women — and medical care providers — woefully underestimate the seriousness of cardiovascular disease among women. Research from the American Heart Association shows that heart disease is the leading cause of death in women in the U.S., causing more than 400,000 deaths per year, or about one death every 80 seconds3. Among American women, cardiovascular disease (CVD) causes more deaths than cancers, diabetes and lower respiratory diseases combined<4.

Despite the significant correlation, awareness among women is lacking; in fact, in a 2012 survey from the AHA, only a little more than half of women polled listed heart disease as the leading cause of death for females in the U.S. What’s more, many women say their doctors don’t discuss the risks of heart disease with them, leaving them unaware of their risks and of the steps they can take to improve their heart health and reduce the chances they’ll fall victim to heart disease or heart attacks5.

Heart Disease in Women vs. Men

Because heart disease has historically been more or less considered a “man’s disease,” a lot of cardiovascular disease research has focused on men and included primarily male subjects, with some assumption that when a woman did have cardiovascular disease, the disease and its treatments would essentially “translate” into similar results and interventions for women.

In fact, heart disease often presents very differently in women, and the factors that can lead to CVD can vary as well. For instance:

  • While researchers know obesity increases a person’s risk of having heart disease, what’s often not been as well appreciated is that women tend to have more difficulty maintaining a healthy weight, especially in the years before menopause (perimenopause) and during menopause.

  • Even though the link between diabetes and CVD risk has been well established, gender differences again have historically been underappreciated, even though women with diabetes are almost twice as likely to develop CVD as men with diabetes6.

  • Women who smoke are also more likely to have a heart problem compared to male smokers,

  • Women with metabolic syndrome are more likely to have earlier heart attacks than their male counterparts.

  • Women who took birth control pills increase their risks of heart disease & stroke7.

And that’s just for starters. When it comes to treatments, there are similar gender disparities. Compared to men with heart disease, women are 1.5 times less likely to be referred for cardiac rehabilitation services, less likely to receive statins to manage cholesterol levels, and more likely to be diagnosed with heart failure within five years of having a heart attack. And although women can — and do — develop heart disease at young ages, a woman’s risk for heart disease dramatically increases once her body’s production of estrogen begins to decline in the years leading up to menopause and when estrogen levels drop off once menopause begins.

What the Data Show

Hormone replacement therapy offers lots of potential health benefits for women nearing and in menopause, including some major benefits for heart health. So then, why aren’t all menopausal and perimenopausal women using HRT products? Like any medical treatment, HRT does have its downsides, especially when therapy isn’t optimized and tailored for the individual patient. And to some degree, those downsides are causing many women to be reluctant and even downright mistrustful of HRT products. But HRT use has also been hampered by some potentially questionable research, the results of which are even now being reconsidered by the researchers who conducted those early — and seminal — HRT studies. In fact, it's that early research that has spawned a lot of the concern over HRT. And now that the Women’s Health Initiative study itself has come into question, it's an ideal time for healthcare providers to revisit the benefits of HRT and determine if their patients might benefit from it.

The WHI Study

Conducted almost 20 years ago, the Women’s Health Initiative was developed to study the effects of HRT on women’s health — specifically, on the health of younger menopausal women. Partway in, the study was halted, and soon, word spread that the reason for the study’s early termination was because HRT was associated with significantly higher levels of breast cancer and heart attacks. Not surprisingly, once word was out, the news spread quickly, and women took the findings to heart, leaving HRT behind as a potential therapeutic option for better post-menopausal health.

It turns out that researchers involved in the study say the news that followed the study’s termination resulted in “misinformation and hysteria” that continues to influence women’s healthcare decisions. In fact, the study’s lead researcher, Dr. Robert Langer, now says, “Good science became distorted and ultimately caused substantial and ongoing harm to women for whom appropriate and beneficial treatment was either stopped or never started.”8

According to Langer, the news reports weren't the only things that were flawed. The study itself didn’t adjust the results based on women’s pre-existing medical conditions or other critical factors. And rather than finding a significant increase in cancer or heart disease, the only significant findings from the study were an increase in venous blood clots and a decrease in hip fractures among women receiving HRT. Those were the actual findings — but the actual outcome of the study has been a palpable reluctance among women to initiate HRT, despite the real benefits it could offer. According to Langer, "Critically, the ‘facts’ that most women and clinicians consider in making the decision to use, or not use, HRT are frequently wrong or incorrectly applied."

The "Timing" Hypothesis and Tailored Therapy

How early should therapy be initiated? Data shows HRT is most beneficial when it’s begun in women under 60 years of age, or within 10 years of the onset of menopause9. Specifically, earlier initiation of HRT is associated with a reduction in CHD events as well as overall mortality benefits; when initiated at older ages or after 10 years since the onset of menopause, those benefits are not achieved. In fact, one meta-analysis of nearly 40,000 women followed for more than 190,000 patient years showed consistently that only earlier initiation of HRT resulted in benefits, and that those benefits were significant with regard to reducing CHD risks and mortality10.

As beneficial as it can be for some women, HRT is not a one-size-fits-all therapy. Like other medical treatments, HRT the dose and hormonal balance needs to be tailored to the symptoms, health, and general needs of the individual patient. As mentioned, studies have found the timing of HRT also plays a substantial role in ensuring women experience the greatest benefits.

In general, HRT is most effective when provided earlier and at a younger age than many clinicians (and patients) realize. That means that in order to reduce the risks of cardiovascular disease, you can’t wait until those risks increase (or cause symptoms) before initiating treatment. This understanding has led to what’s become known as the timing hypothesis — the notion that early treatment is more likely to result in substantial health benefits, especially in terms of cardiovascular health.

Revisiting HRT for CHD Prevention

The research suggests HRT should play a primary and pivotal role for preventing CHD in many women, especially those under age 60 and those in the early years of menopause.

Although it’s been nearly 20 years since the WHI study released its results, unfortunately, there is still some negative perception of HRT, both for women and the clinicians who treat them. The amount of research conducted since that time clearly show the time has come for clinicians to revisit HRT and to consider customized therapy for patients who meet the suggested criteria. When used in the appropriate population of patients, today’s bioidentical HRT can potentially reduce the risk of heart disease and mortality risks, enabling women to lead healthier lives throughout menopause.


REFERENCES

1. Luo T, Kim JK. The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview. Can J Cardiol. 2016;32(8):1017-1025.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853290/pdf/nihms746460.pdf

2. Das DV, Saikia UK, Sarma D. Sex Hormone Levels - Estradiol, Testosterone, and Sex Hormone Binding Globulin as a Risk Marker for Atherosclerotic Coronary Artery Disease in Post-menopausal Women. Indian J Endocrinol Metab. 2019;23(1):60-66
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446685/

3. American Heart Association. Cardiovascular Disease: Women’s No. 1 Health Threat. Updated March 2018. Accessed Aug 27, 2019.
http://www.heart.org/-/media/files/about-us/policy-research/fact-sheets/facts-cvd-womens-no-1-health-threat.pdf?la=en&hash=F6AD6FC4FD546ABA0E18D4D6C456C666EE4D5C0F

4. Kochanek KD, Murphy SL, Xu J, Tejada-Vera B. Deaths: Final Data for 2014. Natl Vital Stat Rep. 2016;65(4):1-122.
https://www.cdc.gov/nchs/data/nvsr/nvsr65/nvsr65_04.pdf

5. Mosca L, Hammond G, Mochari-Greenberger H, et al. Fifteen-year trends in awareness of heart disease in women: results of a 2012 American Heart Association national survey. Circulation. 2013;127(11):1254-1263, e1251-1229
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684065/pdf/nihms468530.pdf

6. Harvard University. Gender matters: Heart disease risk in women. Harvard Health Publishing. Published Sept 2006. Updated March 25, 2017. Accessed Aug 27, 2019
https://www.health.harvard.edu/heart-health/gender-matters-heart-disease-risk-in-women

7. Nettleton W, King V. The Risk of MI and Ischemic Stroke with Combined Oral Contraceptives. Am Fam Physician. 2016;94(9):691-692
https://www.aafp.org/afp/2016/1101/p691.html

8. CMAJ News. Landmark trial overstated HRT risk for younger women. CMAJ News. Published April 12, 2017. Accessed Aug 27, 2019.
https://cmajnews.com/2017/04/12/landmark-trial-overstated-hrt-risk-for-younger-women-109-5421/

9. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 1: comparison of therapeutic efficacy. J Am Geriatr Soc. 2013;61(6):1005-1010.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660423/pdf/nihms424700.pdf

10. Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21(4):363-366.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1484709/

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