Testosterone May Be Key to CVD Risk in Women

Pauline Anderson

June 14, 2018

An elevated ratio of testosterone to estradiol in a racially diverse group of postmenopausal women was associated with an increased risk for myocardial infarction, stroke, and heart failure over a 12-year period, a new study shows.

The study also linked higher total testosterone levels to increased risk for cardiovascular disease and elevated estradiol levels to lower risk for coronary heart disease.

In postmenopausal women, estrogen levels plummet while the ovaries continue to produce testosterone, the researchers point out.

"There has been so much focus on estrogen being protective, but it may be that testosterone is toxic," which might explain why men get heart disease earlier than women," study author Erin D. Michos, MD, associate professor of medicine, Division of Cardiology, and associate director of preventive cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, told theheart.org | Medscape Cardiology.

However, determining testosterone levels or testosterone/estradiol ratios is not routinely done, and even if it were, "until we know what to do about the levels, I don't think it's quite ready for prime time," said Michos.

The study was published in the June 5 issue of the Journal of the American College of Cardiology.

The analysis included 2834 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study that includes residents of six rural and urban areas in the US. Study participants were free of cardiovascular disease (CVD) at baseline (2000 to 2002).

About a third (n = 900) were receiving hormone therapy (HT). The MESA study was launched before the 2002 publication of the Women's Health Initiative study, which failed to show a beneficial effect of estrogen replacement —  at least in available preparations — on CVD in postmenopausal women.

For this new study, researchers measured sex hormone concentrations from fasting serum samples drawn at the baseline examination. They looked at levels of total testosterone, dehydroepiandrosterone (DHEA), sex hormone–binding globulin (SHBG), and estradiol.

They calculated concentrations of bioavailable testosterone (the sum of SHBG-bound and albumin-bound testosterone) and free testosterone (reported as a percentage of total testosterone).

There has been so much focus on estrogen being protective, but it may be that testosterone is toxic. Dr Erin D. Michos


They divided total testosterone by estradiol to calculate the testosterone/estradiol ratio for each participant.  

Information on cardiovascular status and hospital admissions was gathered through phone interviews conducted with participants every 9 to 12 months. As well, researchers obtained hospital records for 98% of reported hospitalized CVD events and had some medical record-based information for 95% of outpatient encounters.

Incident coronary heart disease (CHD) was defined as definite or probable myocardial infarction, resuscitated cardiac arrest, definite or probable angina (if followed by revascularization), and definite CHD death.

Incident CVD events included incident CHD plus stroke, stroke death, other atherosclerotic death, and other CVD deaths. Two physicians independently reviewed and adjudicated events.

The median follow-up was 12.1 years.

After adjustment for age, race, study site, use of HT, education, waist/hip ratio, physical activity, smoking status, and numerous cardiovascular risk factors (including diabetes, blood pressure, use of antihypertensive medications, and inflammatory markers), the hazard ratio (HR) for CVD associated with 1 standard deviation (SD) greater log-transformed testosterone/estradiol ratio was 1.19 (95% confidence interval [CI], 1.02 - 1.40).

For the ratios for CHD and all heart failure (HF), the corresponding HRs were 1.45 (95% CI, 1.19 - 1.78) and 1.31 (95% CI, 1.01 - 1.70).

Total testosterone levels were also associated with an increased risk for CVD (adjusted HR, 1.14; 95% CI, 1.01 - 1.29) and CHD (adjusted HR, 1.20; 95% CI, 1.03 - 1.40) but were not statistically significantly associated with all HF (adjusted HR, 1.09; 95% CI, 0.90 - 1.34).

The authors found  a U-shaped association between the testosterone/estradiol ratio and HF, with both extreme ends at higher risk for HF.

Estradiol levels were associated with a lower risk for CHD (adjusted HR, 0.77; 95% CI, 0.63 - 0.95), with a nonsignificant trend for lower HF risk.

Strongest Predictor

"Testosterone levels alone were associated with increased risk of CVD, and estradiol levels alone were inversely associated with coronary disease, but the ratio — when you took both into account at the same time — was the strongest predictor," commented Michos.

For HF, researchers also evaluated preserved ejection fraction HF (HFpEF), defined as an ejection fraction of 45% or greater, and reduced ejection fraction HF (HFrEF), marked by an ejection fraction less than 45%, separately from overall incident CVD .

The testosterone/estradiol ratio was positively associated, and both estradiol and DHEA inversely associated, with HFrEF, but not HFpEF, the type most commonly seen in older women.

"It is possible that the reduction in estradiol during menopause differentially affects vascular and cardiac remodeling processes that differentially lead to a HFrEF versus HFpEF phenotype," the authors write.

"Lower levels of estradiol are associated with risk for hypertension, a risk factor for HFrEF. In our study, estradiol was associated with CHD, and CHD may contribute more to HFrEF than to HFpEF."

DHEA and SHBG levels were not associated with CVD, CHD, or overall HF. However, SHBG was associated with increased risk for CHD in women not taking HT.

The associations between sex hormones and CVD outcomes were generally consistent across the various race/ethnic subgroups and the different ages.

"We did not find any interaction by age," said Michos. "The results were pretty consistent above and below the median age of 65 years."

These results differ from those of previous studies in several ways. This new study was large, included a multiethnic population (whites, blacks, Chinese-Americans, and Hispanics), and looked at the ratio of male to female sex hormones rather than just at individual hormones, the researchers note. As well, the new study was relatively long and examined different types of CVD.

Now What?

Now that it seems clear that the ratio of testosterone to estradiol is important to the heart health of postmenopausal women, "the main question now is what do we do about it," said Michos.

She stressed that this was not an intervention study, so it doesn't point to the best strategy to modify sex hormone levels to affect CVD risk.

As well, because the study did not establish a specific cut-point for the testosterone/estradiol ratio, above which interventions might be warranted, screening would not be appropriate at this stage.

However, the results "match what we know" about higher-risk women, said Michos. For example, "giving hormone therapy doesn't seem to be the right strategy."

Researchers also know that polycystic ovarian disease, where testosterone levels are typically elevated, increases the risk for glucose intolerance and diabetes and is a marker of risk for CVD.

As well, researchers learned from another recent study in MESA participants, published in Circulation, that coronary artery calcium (CAC) scores provide clues as to which patients might benefit from more intensive preventive therapies.  

In her own practice, Michos considers these and other factors.

"If I was seeing an older postmenopausal woman in clinic and I was unsure about her cardiovascular risk but was concerned about her because of a family history of premature heart disease, or other risks such as a history of polycystic ovarian disease, pre-eclampsia, autoimmune disease, or possibly increased androgens, I might order a coronary artery calcium score."

If that patient's CAC is 0, lifestyle changes — such as smoking cessation, healthier diet and regular physical activity — might be all that's indicated, if her blood pressure and other risk factors are controlled, she said. 

But if she has plaque in her arteries, as indicated by a CAC score above 0, especially if it's higher than in the 75th percentile for her age and sex, or her score is greater than 100, "I would treat a bit more aggressively with aspirins and statins for prevention, if not already indicated," said Michos.

Screening Premature

But she stressed that these are her personal approaches  and that more studies are needed to determine the best plan of action for such women.

"Maybe we need to pay more attention to hormone levels in understanding these women, and maybe in future, we will be screening hormone levels, but I don't think we're quite ready to do that."

Virginia M. Miller, PhD, and Rekha Mankad, MD, both from the Department of Cardiovascular Disease, Women's Heart Clinic, Mayo Clinic, Rochester, Minnesota, wrote an accompanying editorial.

The inclusion of the ratio of testosterone to estradiol differentiates this study from others, Miller told theheart.org | Medscape Cardiology.

"It's time for us to stop thinking about these hormones in isolation because their metabolism is connected, and measuring one or the other isn't going to tell us the whole story," said Miller.

"For example, estrogen is derived from testosterone, so when you think about those two in a woman, you really need to think about the balance between the two."

Another strength of the study was that it looked at different cardiac conditions and evaluated HFpEF and HFrEF separately from overall incident CVD, whereas other studies tend to "lump" CVD or HF together, said Miller.

"Things that regulate development of plaque in the artery, or calcification of the artery, or enlargement of the heart, or how the heart functions, involve separate control mechanisms and the cells involved are different. We need to really begin to be more precise in our language and how we assess some of these parameters."

Only when the underlying biology of the various heart-related conditions is better understood — and how this differs between men and women —  can therapeutics in women be targeted, said Miller.

Researchers also need to better understand estrogen metabolism in women, she added. "Even though the ovary may be pumping out all kinds of estrogen, it may be chewed up faster."

Genetics may play a role in the bioavailability of estradiol as well as testosterone. Miller noted a study she and her colleagues carried out showing that multiple copies of genetic variants for one enzyme — SULT1A1, which sulfonates estradiol for elimination, rendering it no longer bioavailable — are associated with an early age of menopause.

"If we understand more about the variation in women, probably based on some of their genetic makeup in terms of how steroids are produced, we will be better able to target therapy when they reach menopause," said Miller.

Michos has received an honorarium from Siemens Diagnostics for being a blinded events adjudicator in a clinical trial. Miller is supported in part by a National Institutes of Health grant. Mankad has disclosed no relevant financial relationships.

J Am Coll Cardiol. Published online May 28, 2018. Abstract, Editorial

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