Sex hormones are associated with cardiovascular (CV) risk in men but not women with type 2 diabetes (T2D), new research found.

The new findings, published online in Diabetes Care, come from an analysis of sex hormone data from the landmark 2013 LookAHEAD trial of a lifestyle weight-loss intervention in adults aged 45-75 years with T2D and BMI ≥ 25 at baseline.

“Our findings suggest that monitoring changes in sex hormones — especially estradiol and [sex hormone-binding globulin (SHBG)] — could offer additional insights into CV risk stratification in male patients, particularly in the context of weight loss. Incorporating these markers into individualized risk assessments may help identify patients who could benefit from closer CV follow-up or more aggressive lifestyle intervention,” wrote Teresa Gisinger, MD, PhD, a postdoctoral researcher in the Division of Endocrinology and Metabolism at the Medical University of Vienna in Vienna, Austria, and colleagues.

Such hormone assessment is routine at the Medical University of Vienna, Gisinger told Medscape Medical News. “What we do for every patient coming to us, especially if they [have obesity], is to check for sex hormones because we have to investigate in order to understand this better. But also, males with low testosterone will also have difficulty gaining muscle, and we know that muscle is also really important for insulin sensitivity.”

Moreover, she noted that many men lack testosterone even when they don’t complain of symptoms such as sexual dysfunction. “If you don’t ask, you don’t know it, right?”

Association Seen in Men, Not Women

The study population comprised 1092 postmenopausal women and 1167 men randomly selected from the original 5415 LookAHEAD participants, followed for a median of 11.9 years.

Baseline sex hormone levels were not associated with later CV risk in women. In men, those with the highest tertile of total testosterone had a significantly lower CV risk than those in the lowest tertile (hazard ratio [HR], 0.74; P = .030). However, neither baseline estradiol nor SHBG was associated with CV events in men.

From baseline to 1 year after the LookAHEAD intervention, no significant associations were seen in women. In men, the highest tertile for change in estradiol was associated with greater CV risk than the lowest tertile (HR, 1.47; P = .012). Changes in total testosterone and SHBG at 1 year were not associated with CV risk.

“In females, we didn’t see any effect…. Even though they were all postmenopausal, they may have very heterogeneous hormone levels,” Gisinger pointed out.

Effect Differed by Amount of Weight Loss

Significant hormonal differences were seen between men who lost 7% or more of their body weight and those who didn’t. The highest two tertiles for change in estradiol were associated with higher CV risk in men who lost less than 7% (HR, 1.64 for second vs first tertile and 1.88 for third vs first, both significant).

Conversely, in men who lost 7% or more of their body weight, the middle and highest changes in estradiol levels were associated with lower CV risk (HR, 0.88 for first vs third tertile, not significant).

For SHBG in men with weight loss of 7% or greater, the highest tertile of changes was associated with a lower CV risk (HR, 0.47 for third vs first tertile, a significant difference), whereas among those with weight loss of less than 7%, the highest SHBG change tertile was insignificantly associated with increased CV risk (HR, 1.39 for third vs first tertile).

“The SHBG is a really good marker for insulin sensitivity, and it increases if you lose weight. We saw that SHBG is related to lower cardiovascular risk, but only for men who lost 7% or more of their weight,” Gisinger said.

“Our study provides insights into how baseline and changes in sex hormone levels after a weight-loss intervention might influence CV risk over longer than a decade,” she and her colleagues wrote.

For their next study, “our new goal would be in the same study cohort to see how the sex hormones and the changes impact bone health,” Gisinger told Medscape Medical News.

Conclusions Overstated?

Commenting on the study, Frederick C.W. Wu, MD, emeritus professor of medicine and endocrinology at The University of Manchester in Manchester, England, told Medscape Medical News, “our publications show that only very low testosterone and very low estradiol are associated with higher risks of CVD [CV disease], somewhat different from this new publication.”

And, Wu noted, “the mechanisms linking sex hormones to CVD are multifaceted and complicated, and their proportionate contribution to the overall CVD risks may not be substantial compared to the many proven predisposing factors such as smoking, lipids, diabetes, etc. The authors’ conclusion that sex hormones and SHBG should contribute to overall CVD risk assessments may be overstated.”

Gisinger and Wu disclosed having no relevant financial relationships.

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.