Meeting NewsPerspective

Early menopause raises risk for CVD

Michael C. Honigberg

PHILADELPHIA — In a new study, women with natural and surgical premature menopause before age 40 years had a small but significantly elevated risk for a variety of CVDs, researchers reported at the American Heart Association Scientific Sessions.

CV risk appears to increase with progressively earlier menopausal age and risks may be higher after surgical premature menopause, according to the new data.

“Even though a history of premature menopause is now included as a 'risk-enhancing factor' in American College of Cardiology/American Heart Association cholesterol and prevention guidelines, few physicians — and even fewer cardiologists — ask about menopause history when assessing cardiovascular risk. Our research reinforces that physicians should elicit this history, and women should share it with their physicians,” Michael C. Honigberg, MD, MPP, cardiology fellow at Massachusetts General Hospital, told Healio.

CV effects of premature menopause

Among 144,260 postmenopausal women in the UK Biobank cohort study enrolled between 2006 and 2010, 3.4% had natural premature menopause and 0.4% had surgical premature menopause. Natural premature menopause was defined as menopause occurring before age 40 years without oophorectomy, whereas surgical premature menopause was defined as menopause occurring as a result of bilateral oophorectomy before age 40 years.

In a new study, women with natural and surgical premature menopause before age 40 years had a small but significant elevated risk for CVDs, researchers reported at the American Heart Association Scientific Sessions.
Source: Adobe Stock

During a median follow-up of 7 years, the primary composite outcome of incident CAD, HF, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease and venous thromboembolism occurred in 3.9% of women without premature menopause, 6% with natural premature menopause and 7.6% with surgical premature menopause.

The incidence rate of the primary outcome was 5.7 per 1,000 woman-years in those without premature menopause compared with 8.78 per 1,000 woman-years in those with natural premature menopause (P < .001 for comparison) and 11.27 per 1,000 woman-years in those with surgical premature menopause (P < .001 for comparison).

The HR for the primary outcome was 1.36 (95% CI, 1.19-1.56) for women with natural premature menopause and 1.87 (95% CI, 1.36-2.58) for women with surgical premature menopause, after the researchers adjusted for traditional CVD risk factors and menopausal hormone therapy use.

The results were simultaneously published in JAMA.

The researchers also looked at individual components of the primary outcome, as well as incident hypertension, hyperlipidemia and type 2 diabetes. Results highlighted an independent association between natural premature menopause and aortic stenosis (HR = 2.37; 95% CI, 1.47-3.82), VTE (HR = 1.7; 95% CI, 1.27-2.29), ischemic stroke (HR = 1.5; 95% CI, 1.01-2.25), CAD (HR = 1.39; 95% CI, 1.06-1.82) and AF (HR = 1.25; 95% CI, 1-1.58), but no independent association with HF, mitral regurgitation or PAD after multivariable adjustment. Among women with surgical premature menopause, the researchers reported an independent association with mitral regurgitation (HR = 4.13; 95% CI, 1.69-10.11), VTE (HR = 2.73; 95% CI, 1.46-5.14), HF (HR = 2.57; 95% CI, 1.21-5.47) and CAD (HR = 2.52; 95% CI, 1.48-4.29), but no independent association with aortic stenosis, AF, ischemic stroke or PAD.

Further, these associations persisted regardless of a history of ever using menopausal hormone therapy, current use of menopausal hormone therapy, overall duration of menopausal hormone therapy use and delayed initiation of therapy 5 or more years after menopause, according to the results.

When the researchers looked at CVD risk by age, risk for the primary outcome was elevated with all lower menopause age thresholds, compared with menopause at age 50 years or older.

“Cardiovascular risk continues to increase with progressively earlier age at menopause and extends beyond atherosclerotic cardiovascular disease to include diverse cardiovascular conditions, including valvular heart disease and arrhythmia. Although cardiovascular risk was largely independent of conventional cardiovascular risk factors, women with premature menopause were also more likely to develop hypertension, hyperlipidemia and type 2 diabetes,” Honigberg told Healio.

In this cohort, the mean age at enrollment was 60 years and 95% were white. Mean age at menopause was 34.2 years among women with surgical premature menopause and 35.4 years among women with natural premature menopause, compared with 50.3 years among those without premature menopause.

‘Opportunity to incorporate lifestyle modification’

Avenues for future research may focus on the mechanisms underlying the associations observed in this study, Honigberg said, using detailed phenotyping, biomarkers and human genetics to discover novel pathways and disentangle causal relationships.

“One possible explanation for the observed associations is that ovarian hormones exert cardiometabolic effects that extend beyond the arterial vasculature to include the veins, valves and myocardium. It is notable, however, that risks did not change when we incorporated prior use of menopausal hormone therapy,” he told Healio.

Based on the current study and the knowledge base to date, there is an opportunity to discuss menopause history with patients, he said.

“A history of premature menopause presents an opportunity to incorporate lifestyle modification, including dietary changes, exercise and weight loss, to prevent or delay development of these cardiovascular disease risk factors,” Honigberg told Healio. – by Katie Kalvaitis, with additional reporting by Scott Buzby

References:

Honigberg MC, et al. Moderated poster MDP451. Female Specific Risk Factors for CVD. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Honigberg MC, et al. JAMA. 2019;doi:10.1001/jama.2019.19191.

Disclosures: Honigberg reports he received a training grant from the NHLBI. Please see the study for all other authors’ relevant financial disclosures.

Michael C. Honigberg

PHILADELPHIA — In a new study, women with natural and surgical premature menopause before age 40 years had a small but significantly elevated risk for a variety of CVDs, researchers reported at the American Heart Association Scientific Sessions.

CV risk appears to increase with progressively earlier menopausal age and risks may be higher after surgical premature menopause, according to the new data.

“Even though a history of premature menopause is now included as a 'risk-enhancing factor' in American College of Cardiology/American Heart Association cholesterol and prevention guidelines, few physicians — and even fewer cardiologists — ask about menopause history when assessing cardiovascular risk. Our research reinforces that physicians should elicit this history, and women should share it with their physicians,” Michael C. Honigberg, MD, MPP, cardiology fellow at Massachusetts General Hospital, told Healio.

CV effects of premature menopause

Among 144,260 postmenopausal women in the UK Biobank cohort study enrolled between 2006 and 2010, 3.4% had natural premature menopause and 0.4% had surgical premature menopause. Natural premature menopause was defined as menopause occurring before age 40 years without oophorectomy, whereas surgical premature menopause was defined as menopause occurring as a result of bilateral oophorectomy before age 40 years.

In a new study, women with natural and surgical premature menopause before age 40 years had a small but significant elevated risk for CVDs, researchers reported at the American Heart Association Scientific Sessions.
Source: Adobe Stock

During a median follow-up of 7 years, the primary composite outcome of incident CAD, HF, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease and venous thromboembolism occurred in 3.9% of women without premature menopause, 6% with natural premature menopause and 7.6% with surgical premature menopause.

The incidence rate of the primary outcome was 5.7 per 1,000 woman-years in those without premature menopause compared with 8.78 per 1,000 woman-years in those with natural premature menopause (P < .001 for comparison) and 11.27 per 1,000 woman-years in those with surgical premature menopause (P < .001 for comparison).

The HR for the primary outcome was 1.36 (95% CI, 1.19-1.56) for women with natural premature menopause and 1.87 (95% CI, 1.36-2.58) for women with surgical premature menopause, after the researchers adjusted for traditional CVD risk factors and menopausal hormone therapy use.

The results were simultaneously published in JAMA.

The researchers also looked at individual components of the primary outcome, as well as incident hypertension, hyperlipidemia and type 2 diabetes. Results highlighted an independent association between natural premature menopause and aortic stenosis (HR = 2.37; 95% CI, 1.47-3.82), VTE (HR = 1.7; 95% CI, 1.27-2.29), ischemic stroke (HR = 1.5; 95% CI, 1.01-2.25), CAD (HR = 1.39; 95% CI, 1.06-1.82) and AF (HR = 1.25; 95% CI, 1-1.58), but no independent association with HF, mitral regurgitation or PAD after multivariable adjustment. Among women with surgical premature menopause, the researchers reported an independent association with mitral regurgitation (HR = 4.13; 95% CI, 1.69-10.11), VTE (HR = 2.73; 95% CI, 1.46-5.14), HF (HR = 2.57; 95% CI, 1.21-5.47) and CAD (HR = 2.52; 95% CI, 1.48-4.29), but no independent association with aortic stenosis, AF, ischemic stroke or PAD.

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Further, these associations persisted regardless of a history of ever using menopausal hormone therapy, current use of menopausal hormone therapy, overall duration of menopausal hormone therapy use and delayed initiation of therapy 5 or more years after menopause, according to the results.

When the researchers looked at CVD risk by age, risk for the primary outcome was elevated with all lower menopause age thresholds, compared with menopause at age 50 years or older.

“Cardiovascular risk continues to increase with progressively earlier age at menopause and extends beyond atherosclerotic cardiovascular disease to include diverse cardiovascular conditions, including valvular heart disease and arrhythmia. Although cardiovascular risk was largely independent of conventional cardiovascular risk factors, women with premature menopause were also more likely to develop hypertension, hyperlipidemia and type 2 diabetes,” Honigberg told Healio.

In this cohort, the mean age at enrollment was 60 years and 95% were white. Mean age at menopause was 34.2 years among women with surgical premature menopause and 35.4 years among women with natural premature menopause, compared with 50.3 years among those without premature menopause.

‘Opportunity to incorporate lifestyle modification’

Avenues for future research may focus on the mechanisms underlying the associations observed in this study, Honigberg said, using detailed phenotyping, biomarkers and human genetics to discover novel pathways and disentangle causal relationships.

“One possible explanation for the observed associations is that ovarian hormones exert cardiometabolic effects that extend beyond the arterial vasculature to include the veins, valves and myocardium. It is notable, however, that risks did not change when we incorporated prior use of menopausal hormone therapy,” he told Healio.

Based on the current study and the knowledge base to date, there is an opportunity to discuss menopause history with patients, he said.

“A history of premature menopause presents an opportunity to incorporate lifestyle modification, including dietary changes, exercise and weight loss, to prevent or delay development of these cardiovascular disease risk factors,” Honigberg told Healio. – by Katie Kalvaitis, with additional reporting by Scott Buzby

References:

Honigberg MC, et al. Moderated poster MDP451. Female Specific Risk Factors for CVD. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Honigberg MC, et al. JAMA. 2019;doi:10.1001/jama.2019.19191.

Disclosures: Honigberg reports he received a training grant from the NHLBI. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Chrisandra Shufelt

    Chrisandra Shufelt

    What the new study adds is a need to recognize that the timing of menopause is an important risk factor for CVD. The AHA has also emphasized this, making it a modifiable risk factor and adding it to the ASCVD risk score.

    The Nurses’ Health Study previously looked at these associations in a similar cohort of women with premature surgical menopause. Those researchers found that being on hormone therapy attenuated the elevated risk for CVD. In the current study, hormone therapy use over 5 years was associated with reduced risk for CVD, but the reduction was not statistically significant.

    There are several important considerations of the current study. One, the researchers focused on data from 2006 to 2010. While this study did control for menopausal hormone therapy, the formulations that many women were using during that period are likely different than what we are currently using today. For example, transdermal route of delivery is more often used in women with CV risk factors as opposed to oral estrogens.

    I believe that the menstrual cycle should be a vital sign, like BP and pulse. Taking the menstrual cycle into account is very important. If you have a women who is younger than 40 in your office for a CV evaluation, you shouldn’t just assume that she is getting her menstrual cycle every month because, while a small percentage of women go into premature menopause, it speaks volumes to the additive impact early menopause could have in terms of CV risk.

    The researchers acknowledged that further investigation is needed. I believe the root of these associations are most likely related to inflammation, and the loss of endogenous estrogen at an earlier age may create more of a pro-inflammatory environment within the body. Studies have not shown CV benefit with hormone therapy after menopause and such, hormone therapy is not used to prevent CVD.

    We need to look at other areas of women’s health, particularly in women under 40 years who are losing estrogen at an early age. For example, hypothalamic amenorrhea is a increasing condition that occurs in young women who stop having their regular menstrual cycles. This condition is due to stress, over-exercise and/or lower caloric intake and results in significant loss of endogenous estrogen. In these women, it is likely the abrupt loss of estrogen that is similar to what occurs following surgical menopause that should be investigated. We need to phenotype these same-aged women who might be losing their own estrogen levels at an early age and see if they’re an increased risk for CVD.

    Taken together, this study speaks volumes to the fact that CVD risk factors and CVD patterns are very different in women and men.

    • Chrisandra Shufelt, MD, MS, FACP, NCMP
    • Barbra Streisand Women’s Heart Center & Preventive and Rehabilitative Cardiac Center
      Director, Women’s Hormone and Menopause Program
      Associate Professor, Cedars-Sinai Medical Center

    Disclosures: Shufelt reports that she has conducted research funded by the NIH.

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