Effects of Combined Exercise Training on Functional Brain Alterations During the Menopausal Transition: A Randomized Controlled Trial based on the Critical Window Hypothesis

To examine the effects of combined training on brain (fALFF, functional connectivity), cognitive (working memory, executive function, cognitive flexibility), vasomotor/quality-of-life, and functional indices in premenopausal and menopausal women, and to compare the two groups’ responsiveness based on the critical window hypothesis.

A randomized trial with 60 participants; blinding of participants and trainers is not possible, but outcome assessors and data analysts are blinded; 16-week combined training intervention; assessments at pre-test and post-test.

16 weeks of combined training (aerobic + resistance), 3 days per week, at Shahid Beheshti University gym; outcome assessors and data analysts are blind to the participants' group allocation.

Inclusion: Premenopausal or menopausal women with an intact uterus; PAR-Q+ clearance for physical activity; no severe chronic or neurological disease; no hormonal medication, specific supplements, or regular exercise in the past six months. Exclusion: Neurodegenerative disease; cognitive impairment; high cardiac risk during exercise; mobility-limiting disease; any hormone therapy; PCOS; chemotherapy; premature ovarian failure; claustrophobia; orthopedic devices or metal implants.

Combined training group (16 weeks of aerobic + resistance training), control group (16 weeks of continuing usual lifestyle without physical activity)

Brain imaging indices (fractional amplitude of low-frequency fluctuations and functional connectivity), cognitive function (working memory, executive function, cognitive flexibility), vasomotor symptom interference with daily life and quality of life, and functional indices (maximal oxygen consumption, body composition, maximal voluntary contraction, rate of force development, fatigue index, grip strength).

After confirming the inclusion criteria and obtaining written informed consent, participants are stratified into two strata—perimenopause and menopause—based on the STRAW+10 system. Subsequently, within each stratum, random allocation to either the combined exercise training group or the control group is performed at a 1:1 ratio. The randomization sequence is generated using Random Allocation software (version 1.0) with a block randomization method employing variable block sizes (4 and 6). Block sizes are selected randomly and unpredictably to prevent selection bias. To ensure allocation concealment, the randomization sequence is placed in opaque, sealed, and sequentially numbered envelopes. These envelopes are prepared by an individual independent of the research (who has no role in the enrollment and assessment of participants) and are opened only after complete enrollment of the participant, verification of eligibility, and signing of the consent form. Consequently, the enroller remains unaware of the upcoming allocation, thereby eliminating the possibility of selection bias. The randomization sequence is generated by an independent researcher who has no role in the enrollment and assessment of participants, and is placed in the numbered envelopes. Enrollment of participants is conducted by another researcher who is unaware of the contents of the envelopes. Final allocation to the groups is performed by the same independent researcher by opening the corresponding envelope after complete enrollment.

De-identified individual participant data including all demographic, imaging, cognitive, functional, and questionnaire variables, along with the protocol and statistical analysis plan. Available from six months after publication of primary results for five years to qualified researchers.

Access begins 6 months after publication of primary results and remains available for 5 years.

Only researchers affiliated with accredited academic and scientific institutions, upon submission of a research proposal and signing a data sharing agreement; industry access is not permitted.

For meta-analysis, reproduction of results, and secondary analyses related to midlife women's brain health; upon submission of a research proposal, signing a no-re-identification agreement, prohibition of commercial use, source citation, and ethics approval.

To request data, applicants should contact the corresponding author, via email.

Applicant submits request to the corresponding author's email; after review by the research team and ethics committee approval, the agreement is signed and data are transferred within 2–4 weeks.