MILAN —Combining hormone replacement therapy (HRT) with exercise produced the largest observed improvement in insulin sensitivity among postmenopausal women compared to exercise or HRT alone, interim results from a 12-week randomized study showed.

Exercise, both with and without HRT, also substantially improved physical strength and increased peak aerobic capacity. HRT plus exercise produced a slightly greater reduction in fat mass than exercise alone, with both exercise groups showing significantly greater reductions than HRT alone.

While the combination of HRT and exercise showed greater benefits for some outcomes, "no significant overall effects on cardiovascular risk factors were observed," said Patrick Calders, PhD, professor in the Department of Rehabilitation Sciences at Ghent University, in Belgium.

The interim findings were presented by Calders here at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting. 

Can HRT Enhance the Response to Exercise? 

Menopause is accompanied by a fall in estrogen and changes in body composition, including increased fat mass and reduced lean mass, alongside insulin resistance, hypertension, and hyperlipidemia. These changes contribute to a distinct postmenopausal metabolic and cardiovascular risk profile, Calders explained. 

The study asked whether combining exercise and HRT would have a stronger effect on insulin sensitivity and cardiovascular risk than either intervention alone. 

A total of 84 menopausal women aged 45-65 years with a BMI of 18.5-30 were randomized to HRT alone (n = 30), exercise alone (n = 25), or combined HRT and exercise (n = 29). Women were naive to hormone therapy, although statin use was permitted. 

The intervention lasted 12 weeks, and HRT consisted of transdermal estrogen at 1.53 mg per dose, applied twice in the morning, plus oral progesterone 100 mg. The exercise program involved three sessions per week, two supervised by a physiotherapist and one performed at home using a Polar monitor. Sessions combined 20 minutes of aerobic exercise, including walking, stepping, and cycling at intensities based on ventilatory thresholds. Participants also did 30 minutes of strength training involving the upper and lower limbs and core. 

The three groups were well matched at baseline, with a mean age of approximately 55 years and mean BMI of 27 in the HRT alone group to 29 in the combined group. 

Impact on Insulin Sensitivity 

The reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score, indicating improved insulin sensitivity, was largest in the HRT-plus-exercise group, followed by exercise alone, with relatively little change in women receiving HRT alone.

"You can see that exercise has a clear positive effect, but the combination of HRT and exercise showed the largest effect [on insulin sensitivity]," reported Calders. 

The study also showed substantial improvements in physical capacity. Both HRT plus exercise, and exercise alone, showed substantial improvements in strength, while relative peak VO₂ increased by approximately 3-3.5 mL/kg/min, equivalent to around 1 metabolic equivalent of task, according to Calders, which he described as clinically relevant.

Changes in Body Composition 

Exercise also produced favorable changes in body composition, measured using bioimpedance. 

"Exercise has a positive effect on fat mass, with the largest effect in the group receiving HRT plus exercise," Calders reported. 

However, the apparent advantage of the combined intervention did not extend to fat-free mass, he said, explaining that the addition of HRT to exercise did not make a significant difference. 

Effects on Cardiovascular Risk Markers 

The effects on conventional cardiovascular risk factors were less pronounced, with no significant overall effects on blood pressure. Calders nevertheless pointed to an approximately 6-mm Hg reduction in blood pressure in the combined-treatment group. 

"We know from the literature that a reduction of around 5-mm Hg is associated with approximately a 10% reduction in cardiovascular events," he said. However, the between-group effect in the current study was not statistically significant.

The lipid profile also remained broadly stable, with no significant overall differences in high- or low-density lipoprotein cholesterol, triglycerides, or total cholesterol. high-density lipoprotein cholesterol decreased in the HRT-only group, although Calders said the change was not clinically relevant.

Effect on Insulin Sensitivity Notable 

Co-moderator of the session, Alexandra Kautzky-Willer, MD, Medical University of Vienna, highlighted the insulin-sensitivity finding. "We know that both exercise and hormone replacement therapy improve insulin sensitivity and glucose metabolism," she told Medscape Medical News. "What is interesting is that there are not many studies looking at the combination. Here, the effect was strongest with hormone replacement therapy and exercise together." 

She added that previous evidence has shown HRT to reduce the risk for developing diabetes, although the present study relied on HOMA-IR and did not assess measures such as A1c.

Kautzky-Willer also noted that exercise alone produced substantial benefits, with improvements in physical capacity and body composition and results similar to HRT plus exercise for some outcomes. "If women are worried about the side effects of HRT but are prepared to exercise, that is quite positive," she said. 

However, she cautioned that achieving these benefits requires women to follow a structured exercise program, and that diet may also play an important role in changes in weight and body composition.

Calders has received a grant from Gedeon Richter. Kautzky-Willer has declared no disclosures of relevance to this study. 

Becky McCall, PhD, is a UK-based medical journalist and researcher at University College London. Her research and academic publications focus on antimicrobial resistance and the use of digital storytelling to understand patients' and clinicians' experiences of healthcare. She has reported on medicine and health for more than 20 years, including from major international medical conferences, and writes primarily for Medscape Medical News. Her work has also appeared in The Lancet, Nature Medicine, Re:solve Global Health, The Times, and other publications.