The study included nearly 2,400 women taking semaglutide and nearly 1,500 taking tirzepatide. Participants were over 45 years old and had a body mass index above 27 kg/m², and they were receiving treatment for overweight or obesity. Investigators compared weight-loss responses between hormone-therapy users and nonusers. The release described the research as the first known large real-world cohort of midlife women treated with these GLP-1-based obesity medications.

The result was consistent with earlier, smaller retrospective studies in postmenopausal women, which had suggested an association between hormone therapy and greater weight-loss responses to semaglutide and tirzepatide. The new analysis was presented as a larger, independent cohort. Its stronger finding for semaglutide may point to an interaction specific to GLP-1 signaling, the researchers said, while emphasizing that the difference between the two drugs deserves further investigation.

Dr. Regina Castaneda of Mayo Clinic Florida, the lead study author, said the consistent signal should not be overlooked. She also said it was too early to draw firm conclusions and that the findings need confirmation in adequately designed prospective trials. Castaneda noted that the association was biologically plausible in light of preclinical data suggesting a potential synergistic effect between estrogen and GLP-1 signaling. Because the study was observational, its findings should not be interpreted as establishing a causal treatment effect or as grounds for prescribing hormone therapy to improve weight loss. Weight loss is not an indication for menopause hormone therapy, the release emphasized.

The results were scheduled for discussion at The Menopause Society’s 2026 Annual Meeting in San Diego in a presentation titled “Menopause Hormone Therapy and Weight Loss Response to GLP-1-Based Therapies in Midlife Women: A Retrospective Cohort Study.” Around 20% of women aged 50 to 64 report current or past use of a GLP-1-based obesity medication, according to the release. The practical scope of the findings therefore remains limited to the population and medicines studied: an association was observed between hormone-therapy use and greater, sustained weight loss with semaglutide, whereas the final difference for tirzepatide was not statistically significant.

Subject of Research: Menopause hormone therapy and weight-loss response to GLP-1-based obesity medications in midlife women

Article Title: Hormone therapy may increase weight loss effectiveness of GLP-1s

Article References: Hormone therapy may increase weight loss effectiveness of GLP-1s. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: semaglutide, tirzepatide, menopause, hormone therapy, weight loss, midlife women, GLP-1 medications, observational cohort, treatment response, Hormone, therapy, increase

The biological rationale behind the study is grounded in a growing appreciation of the midlife female brain as a uniquely dynamic organ. Neuropathological changes associated with Alzheimer’s disease begin to manifest during midlife, and in females this period coincides with perimenopause and early postmenopause, two reproductive stages characterized by dramatic fluctuations in hormones, cognition, and cerebrovascular function. During perimenopause, estradiol levels swing erratically before declining, follicle-stimulating hormone rises, and many women report subjective changes in memory and attention. Early postmenopause then ushers in a sustained low-estrogen state. Because estrogen receptors are abundant in the hippocampus and prefrontal cortex, and because estrogen influences cerebral blood flow and glucose metabolism, researchers have long suspected that the timing of an intervention relative to these hormonal shifts could matter enormously. Yet no randomized controlled trial had previously examined whether resistance training affects cognition differently across these two reproductive stages, or whether reproductive stage moderates the efficacy of exercise for brain health at all.

The SMART brain trial was designed to fill that gap with rigorous methodology. The parent trial, registered at ClinicalTrials.gov as NCT05961371, enrolled 40 perimenopausal and early postmenopausal females aged 45 to 60 years in an assessor-blinded randomized controlled design. Participants were randomized to either a nine-month, twice-weekly, supervised progressive resistance training program or a wait-list control group, with randomization stratified by menopause hormone therapy use and reproductive stage. Stratification by these variables was essential, since hormone therapy could itself influence cognitive and cerebrovascular outcomes, and reproductive stage was the moderator of primary scientific interest. Thirty-five of the participants volunteered for this pilot sub-study, seventeen in the resistance training arm and eighteen in the control group, providing the dataset for the analyses now reported.

The primary outcome was cognitive function, assessed with a battery of validated neuropsychological instruments. These included the Rey Auditory Verbal Learning Test for episodic memory, the Trail Making Test and a set-shifting task derived from the Dimensional Change Card Sort Test for executive function, the Digit Symbol Substitution Test for processing speed, and the List Sorting Working Memory Test for working memory. The secondary outcome was arguably more novel: task-induced cerebral hemodynamics, measured with functional near-infrared spectroscopy, or fNIRS. This optical neuroimaging technique, provided by the Experimental Imaging Lab at Calgary’s Cumming School of Medicine, uses near-infrared light to track changes in oxygenated hemoglobin, deoxygenated hemoglobin, and total hemoglobin concentration in the cortex while participants perform cognitive tasks. Unlike functional magnetic resonance imaging, fNIRS is quiet, tolerable, and inexpensive, making it well suited to repeated testing in an exercise trial, though it samples only superficial cortical regions such as the dorsolateral prefrontal cortex and premotor cortex.

The statistical approach was deliberately conservative. The researchers used analysis of covariance to test both main effects and interaction effects of experimental group and reproductive stage, adjusting for baseline performance and relevant covariates. Critically, they analyzed the data with both multiple imputation and complete-case approaches, a dual strategy that guards against conclusions being driven by assumptions about missing data. The headline result was a set of significant experimental group-by-reproductive stage interactions for episodic memory and for the executive function task assessing set-shifting, with all interaction p-values below 0.05. In plain terms, the effect of resistance training on cognition was not uniform; it flipped direction of benefit depending on the reproductive stage of the participant.

Planned contrasts unpacked those interactions in a way that the investigators found striking. Resistance training improved episodic memory in perimenopausal women, whereas it improved set-shifting, the executive capacity to flexibly switch between mental rules or tasks, in early postmenopausal women. This dissociation suggests that the cognitive domains most responsive to strength training shift across the menopause transition, perhaps tracking which neural systems are under the greatest hormonal or vascular stress at each stage. Episodic memory, heavily dependent on hippocampal and temporal lobe circuits that are rich in estrogen receptors, may be most malleable during the hormonal turbulence of perimenopause, while set-shifting, which depends heavily on prefrontal networks, may become the dominant beneficiary once the postmenopausal state is established.

The neuroimaging data added a mechanistic layer to this story. A significant group-by-stage interaction was also found for the hemodynamic response function, again with p-values below 0.05. Resistance training increased task-induced total hemoglobin concentration in the left dorsolateral prefrontal cortex, but only in early postmenopausal women; no significant hemodynamic effects were observed in perimenopause. Total hemoglobin concentration is commonly interpreted as a proxy for regional cerebral blood volume and vascular engagement during cognitive effort, so the finding implies that nine months of progressive strength training enhanced the cerebrovascular response of the prefrontal cortex in early postmenopause. This aligns neatly with the behavioral result that set-shifting, a prefrontally mediated function, improved in that same group, and it hints that exercise-induced improvements in neurovascular coupling may be one pathway linking resistance training to cognitive benefit.

The authors are careful to frame these results as preliminary. This was a pilot sub-study, and thirty-five participants is a small sample by the standards of exercise neuroscience, where effect sizes are typically modest and individual variability is high. The wait-list control design, while ethically common, means control participants knew they were waiting for training, and the trial could not blind participants to their assignment, only the assessors. The researchers themselves emphasize that the findings support the need for future studies with larger sample sizes to examine resistance training for protecting brain health in midlife. Still, the consistency of the interaction pattern across behavioral and hemodynamic outcomes, and across both imputation and complete-case analyses, lends credibility to the central claim that reproductive stage moderates exercise responsiveness.

The broader implications reach into two of the most consequential conversations in women’s health and dementia prevention. First, the study suggests that perimenopause and early postmenopause may represent distinct windows of exercise responsiveness for brain health, a concept that echoes the broader timing-of-intervention literature in aging research. If confirmed, this would mean that exercise prescriptions for midlife women could one day be tailored not just to dose and modality but to reproductive stage, with memory-focused benefits expected during perimenopause and executive and cerebrovascular benefits during early postmenopause. Second, the trial highlights the importance of considering reproductive stage of females in exercise trials generally, since pooling perimenopausal and postmenopausal women into a single midlife category could obscure real, stage-specific effects and even make an effective intervention appear ineffective on average.

For now, the practical message for the millions of women navigating the menopause transition is cautiously encouraging rather than prescriptive. Resistance training, twice weekly for nine months under supervision, was feasible and produced measurable, stage-specific cognitive and cerebral hemodynamic changes in this pilot. Given that Alzheimer’s disease begins its silent pathological course in midlife, and given that women bear roughly two-thirds of the global dementia burden, an accessible, low-cost intervention like progressive strength training is an attractive candidate for brain-health protection. The SMART brain trial does not settle the question, but it opens a genuinely new one: not simply whether exercise protects the female brain, but when, across the arc of the menopause transition, it protects it best. Larger trials will now be needed to determine whether these distinct windows of responsiveness hold up, and whether the prefrontal blood-flow changes seen with fNIRS translate into durable protection against cognitive decline in the decades that follow.

Subject of Research: Effects of resistance training on cognition and cerebral hemodynamics across perimenopause and early postmenopause

Article Title: Study of Menopause and Resistance Training for Brain Health (SMART brain): a randomized controlled trial

Article References: Faridi, W., Burma, S. J., Nel, H. J., Whitman, W. P., Dunn, F. J., Gabel, L., & Barha, K. C. (2026). Study of Menopause and Resistance Training for Brain Health (SMART brain): a randomized controlled trial. BMC Medicine. https://doi.org/10.1186/s12916-026-05258-0

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05258-0

Keywords: resistance training, menopause, perimenopause, early postmenopause, cognition, episodic memory, executive function, fNIRS, cerebral hemodynamics, Alzheimer's disease, brain health, randomized controlled trial

Midlife is a particularly important period for cardiovascular prevention. Biological aging and the menopausal transition can alter blood pressure, metabolism and other risk factors, while physical activity often declines. The researchers focused on women who were insufficiently active and had at least one cardiovascular risk condition, including hypertension or prehypertension, prediabetes or type 2 diabetes, metabolic syndrome, high cholesterol or current smoking. Before joining the study, participants reported less than 90 minutes of moderate-to-vigorous activity per week or fewer than 7,000 steps per day. The group had an average age of 52 and an average body-mass index of 31 kilograms per square meter; 40 percent identified with a racial or ethnic minority group. Although the sample was not designed to represent all women in midlife—many participants had relatively high education and household income—it included a population for whom modest, repeatable changes in daily movement could have meaningful health implications.

The intervention combined techniques drawn from cognitive-behavioral therapy, acceptance and commitment therapy and motivational interviewing. Across six active intervention weeks, coaches introduced nine distinct skills involving behavior, cognition and acceptance. Participants learned to manage time, set goals, solve problems, communicate effectively, draw on partner support, engage with personal values, show willingness to act despite uncomfortable thoughts or feelings, and refocus after a lapse rather than treating it as a relapse. The distinction between a lapse and a relapse was central to the program’s flexible philosophy: missing one walk was not supposed to erase previous progress or trigger all-or-nothing thinking. “Willingness,” in this context, meant choosing a valued behavior even when motivation was low or negative thoughts were present. The researchers paired participants with partners of similar age, baseline activity and availability, allowing them to exchange encouragement between remote meetings with coaches.

The study’s most distinctive feature was its day-by-day measurement. Participants wore either a study-issued pedometer or their own activity tracker and completed an end-of-day survey intended to take no more than five minutes. They recorded their step count, identified the main barrier to physical activity that day and indicated which skills they had used. This intensive approach differs from asking someone at the end of a month how often they exercised, a method vulnerable to imperfect recall and broad, impressionistic answers. Daily reports can connect a person’s experience on a particular day with an objectively recorded behavior, while multilevel statistical models can separate differences between people from fluctuations within the same person. In this analysis, the investigators treated each skill as either used or not used on a given day, then examined how the total number of skills related to steps, barriers and time in the program.

Compliance was high enough to show that this kind of close monitoring is practical. During the intervention and immediate post-intervention period, participants completed 2,186 of the expected 2,600 surveys on time, an 84 percent completion rate that exceeded the researchers’ predefined feasibility threshold of 80 percent. Participants rated the acceptability of reporting daily skill use at an average of 4 out of 5. They rated their confidence in using the skills even higher, at 4.5 out of 5, while the effort required for the program’s daily demands averaged 3.1 out of 5. All 62 women remained in the study through the end of the program, 97 percent of intervention sessions were completed and 92 percent of participants attended every session. These figures indicate that repeated self-reflection did not become an insurmountable burden for this group, although adherence could be different in populations facing greater financial, technological or caregiving constraints.

Participants did not use the skills uniformly. Willingness was reported on 44 percent of days with timely surveys, followed by time management on 31 percent and partner support on 30 percent. Engaging personal values appeared on 17 percent of days, while effective goal-setting was reported on only 3 percent during the main intervention period. The researchers suggest that willingness may have resonated because it matched the program’s rejection of an all-or-nothing approach and offered a direct response to low motivation. Time management and partner support addressed barriers commonly reported by women in midlife. Values-based strategies, by contrast, may have seemed more abstract and therefore less immediately actionable. Goal-setting may also have been understood as a weekly activity completed with a coach rather than a technique to use independently each day. By the three-month follow-up, however, goal-setting appeared on 22 percent of observed days, hinting that its role may shift as people move from adopting a behavior to maintaining it.

The data also revealed that skill use was highly dynamic, even within the same person. Depending on the skill, between 44 and 67 percent of the variation in daily reports reflected within-person fluctuation rather than stable differences between participants. In other words, a woman who used a strategy one day might not use it the next, likely because the circumstances she faced had changed. The average participant reported using 1.82 skills per day during the intervention and immediate follow-up, with daily totals ranging from zero to eight. The number of skills used increased as the program progressed, while the frequency of reported barriers declined by about 30 percent per week. Participants used slightly fewer skills on days when they attended intervention sessions than on days without sessions, perhaps because coaching days themselves structured activity or because participants had less time to apply additional strategies. The number of reported barriers, however, did not differ significantly between session and non-session days.

The strongest associations appeared when the researchers compared different days for the same participant. After controlling for each woman’s typical level of skill use and for the week of the intervention, every additional skill reported on a day corresponded to approximately 550 more steps. This was a within-person association, meaning the result compared a participant with herself across days rather than claiming that people who generally use more skills are inherently more active. Days without reported barriers were associated with about 2,000 more steps than days on which a barrier was reported. The relationship between skills and steps was even stronger on barrier days, suggesting that the strategies may have been most useful when movement was difficult. On days when barriers were present, participants used an average of 1.41 skills, compared with 2.23 on days without barriers, and they reported using no skills at all on 10 percent of barrier days. The study cannot establish that the skills caused the additional walking, but it identifies a plausible day-level pathway worth testing in controlled trials.

A smaller exploratory follow-up offered an early look at whether the tools survived beyond coaching. Of the 54 participants invited, 35 completed a seven-day assessment three months after the program, with surveys completed on time on 77 percent of expected days. Willingness and time management remained the most frequently reported skills. Goal-setting was more common than during the intervention, while problem-solving, cognitive defusion and communication were less frequent. Partner support fell from 30 percent of intervention days to 9 percent at follow-up, consistent with the loss of structured contact after the formal program ended. The researchers emphasize that this follow-up was optional and added after the study had begun, so participants who took part may have been especially engaged or may have benefited more from the intervention. Even so, the pattern suggests that some skills may become personally maintained practices, whereas others depend more heavily on coaching or social reinforcement.

The findings come with important limitations. This was a single-arm study without a control or attention-matched comparison group, so the investigators cannot determine whether the intervention itself caused the increase in skill use, the decline in barriers or the association with steps. The sample of 62 women limits the precision of between-person conclusions, and many participants had relatively high socioeconomic status and education. Step counts were obtained from different devices, including a study pedometer and personal Fitbit, Apple Watch, Garmin or Samsung monitors; participants also copied their step totals into the evening survey. Such measurement differences may introduce imprecision, although the researchers argue that consistent device-specific error within each participant would have less effect on within-person comparisons. The surveys measured whether a skill was used, not how skillfully or effectively it was applied. A higher number of skills might indicate a versatile toolkit, but it could also mean that participants had to try several strategies before one worked. Future studies should test specific skills and combinations, assess their quality and timing in real time, and include more diverse participants. For now, the study’s central message is less that everyone needs nine new techniques than that successful physical-activity programs may work best when they help people select practical responses to the barriers confronting them on a particular day.