Editor’s Note: This story has been updated with a new headline and additional information about the study’s limitations. 
 

Initiation of menopausal hormone therapy (HT) after age 65 was linked to significantly increased risks for cancer and vascular events in an observational retrospective study.

Among more than 80,000 women aged 50 years or older in an Israeli health system during 2000-2022, HT use overall was associated with several types of hormone-sensitive and nonhormone-sensitive cancers. While HT offered some cardiovascular benefit when started at age 50-65, it also raised stroke and cancer risks. And HT initiated in those aged 65 years or older significantly raised the risk for both cancer and cerebrovascular events.

The study was recently published in Menopause.

“Our findings largely reinforce current guidelines, which discourage initiating systemic HT after age 60 or more than 10 years post-menopause. The significantly elevated risks of stroke and cancer we observed in late initiators aged 65 and older provide…empirical support for these cautious recommendations,” study author Alon Carney, MD, told Medscape Medical News.

Clinicians should “move toward a model of individualized risk-benefit assessment,” said Carney of Clalit Health Services and the Department of Family Medicine and Siaal Research Center for Family Practice and Primary Care, Haim Doron Division of Community Health at Ben-Gurion University of the Negev, Beer-Sheva, Israel.

“While HT is the most effective treatment for vasomotor symptoms, the risk profile shifts significantly with age,” he added. “For women aged 65 and older, discussions should emphasize the substantially increased risks of stroke and malignancy.”

However, Carney and colleagues also called their study “exploratory and observational in nature” and listed several limitations including the fact that they couldn’t account for specific hormone formulations (monotherapy vs combined) or administration routes (oral vs transdermal). 

When asked to comment, Nanette Santoro, MD, professor and E. Stewart Taylor chair of obstetrics and gynecology at the University of Colorado School of Medicine in Aurora, told Medscape Medical News that these findings “support current guidelines in that risks of hormone therapy increase for women as they age because the background risk of the diseases they are slightly more likely to get, such as heart disease and cancers, just goes up if they take hormones.”

“It’s important to revisit the indications and need for hormone therapy over time and ensure that it still makes sense to continue it,” she added. 

Both the study authors and Santoro pointed out another limitation: The initial lower heart disease risk in those aged 50-65 years may be due to the fact that only those at low risk for heart disease were prescribed HT to begin with.

“This is not a randomized trial, so there is bias inherent in who gets hormones and who does not,” Santoro noted. “Most of the prescribing was past-[Women’s Health Initiative] when physicians were reluctant to give hormones for fear of increasing risks of heart disease and cancer.” 

Risks Increase at Older Age 

The study included 83,147 women aged 50 years or older, of whom 6.6% initiated HT at ages 50-65 years and 1% initiated HT at age 65 or older. Study participants were divided by age of HT initiation: those who initiated HT at ages 50-65 years (n = 5500), those who initiated HT after age 50 and continued use beyond age 65 (n = 854), those who initiated HT at age 65 or older (n = 847), and those who never used HT (n = 75,946).

“It is important to remember that real-world practice often diverges from guidelines. We found that nearly 40% of women in the 50-65 group continued therapy for over 10 years,” Carney noted.

In multivariable-adjusted analysis, women who initiated HT at age 50-65 years had significantly increased risks for cerebrovascular accident compared with those who never used HT (hazard ratio [HR], 16.69; P < .001), cancer (HR, 8.49; P < .001), and ischemic heart disease or myocardial infarction (HR, 9.17; P < .001). Among those initiating HT at age 65 or older, risks were significantly increased for both cancer (HR, 2.22; P < .001) and stroke (HR, 2.70; P < .001).

Those who initiated at ages 50-65 and continued use beyond age 65 had significantly increased risks for cerebrovascular accidents (HR, 4.15; P < .001), cancer (HR, 1.36; P = .048), and ischemic heart disease or myocardial infarction (HR, 2.34; P < .001).

Although the crude analysis suggested that women who initiated HT at ages 50-65 had lower risks for both ischemic heart disease or myocardial infarction (3.6% vs 9.2% in never-users; P < .001) and cancer (19.2% vs 31.9%; P < .001), those lost significance after adjustment, “indicating residual confounding in unadjusted comparisons,” the authors wrote.

Moreover, longer duration of therapy was associated with even greater morbidity risks. 

“This ‘long-term use’ carries a cumulative burden of risk. Clinicians should be proactive in discussing discontinuation or transitioning to nonhormonal alternatives as women age into their mid-60s,” said Carney.

Carney and the other study authors reported having no disclosures. Santoro reported being a scientific advisory board member for Astellas and Bayer. 

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.