Strength and Aerobic Training Against Hot Flushes in Postmenopausal Women

Study Overview
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Brief Summary
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The goal of this randomised controlled trial is to investigate the effects of and compare two modes of physical exercise (strength training and high-intensity aerobic exercise) to unchanged physical activity on vasomotor symptoms (hot flushes) in postmenopausal women. The main question it aims to answer is the effect of 15 weeks of strength training vs high intensity aerobic training vs unchanged physical activity on frequency and severity of hot flushes. Participants will be randomised to: strength training high-intensity aerobic training untreated control group. Researchers will compare strength training, high-intensity aerobic training and untreated control group to see if training can reduce hot flushes.

Detailed Description
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The overall aim is to investigate the efficacy of and compare two modes of physical exercise (strength training and high-intensity aerobic exercise) to unchanged physical activity on vasomotor symptoms (VMS), as well as secondary outcomes such as health-related quality of life, sleep quality, physical activity levels, clinical outcomes, biomarkers, perceptions of and adherence to the interventions. In a longer perspective, the goal is to find evidence-based treatment options for VMS in postmenopausal women that are safe and effective, and have positive effects on health and quality of life after menopause. Our hypothesis is that strength training and high-intensity aerobic exercise will reduce VMS in postmenopausal women and improve quality of life as well as clinical outcomes more than in a control group with unchanged physical activity. We also hypothesize that strength training and high-intensity aerobic training will have the same effect on the primary outcome (change in VMS) and that most of the changes in secondary outcomes will be superior in the high-intensity aerobic training group compared to the strength training group. This is an open, two-centre, parallel, randomized controlled study performed according to the SPIRIT and CONSORT statements Recruitment will take place by advertising on social media, in local newspapers and in the Women's clinics and primary care centers in Linköping and Kalmar. Women who respond to the advertisements will be contacted by a member of the research group or research nurse to receive information about the study and screen for inclusion and exclusion criteria. Women who are possibly eligible will be invited to a screening visit for further information and informed consent. At the visit, inclusion and exclusion criteria will be checked by a physician, and a clinical examination will be performed. Eligible participants will receive a VMS screening diary and invited to a second visit 2-3 weeks later where inclusion and randomization will be performed if the VMS inclusion criteria are fulfilled. Randomization An allocation sequence using a computerized random number generator will be prepared by a statistician not involved in recruitment. Opaque sealed and sequentially numbered envelopes with group allocation will be prepared and opened in the presence of the participant upon inclusion and randomization. Power analysis: A sample size calculation was made based on the results of our previous study on strength training for VMS (Berin et al 2019) and showed that to detect a 50% difference in moderate and severe hot flushes with 80% power and expected dropout rate of 20% 40 participants in total would be needed. For this three-armed set-up we estimate that 20 participants in each group will be needed, i.e. 60 in total. To also achieve sufficient power for some of the secondary outcomes the intended sample size is increased to 30 per group, 90 in total. Data analysis: The primary analysis will be performed according to the intention-to-treat principle, including all participants who provided more than baseline data for the primary outcome. For quantitative interval data mixed design ANOVAs will be used to analyze the effect over time between and within groups. For the between-group comparisons effect sizes will be calculated. For ordinal data, such as the questionnaires, Kruskal-Wallis and Friedman test will be used for statistical analysis of the effect. Participants who complete two or more training sessions per week will be considered adherent with their assigned intervention and included in a per-protocol analysis. Detailed description of adherence, such as the fidelity with the training interventions, will be presented descriptively.

Official Title
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STrength and AeRobic Training Against Vasomotor Symptoms (START) in Postmenopausal Women

Conditions
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Postmenopausal Symptoms, Hot Flashes

Intervention / Treatment
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* Other: Strength training
* Other: High-intensity aerobic training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (one of: ≥ 12 months since last menstruation; amenorrhea due to intrauterine device or hysterectomy and Follicle Stimulating Hormone (FSH) >30 mIU/ml; bilateral oophorectomy; induced menopause due to chemotherapy or radiation and ≥2 years amenorrhea); ≥ 28 moderate to severe hot flushes per week during a 2-week screening period, registered through a daily VMS diary; Age ≥45 years; Physical ability to participate in strength training or high intensity aerobic exercise for 60 minutes, 3 times/week during 15 weeks; Understand Swedish orally and in writing Exclusion Criteria: Regular physical activity >30 minutes per week of vigorous intensity or ≥150 minutes of moderate intensity or combined activities representing maximum 150 minutes of moderate intensity; Use of systemic menopausal hormone therapy the last 2 months; Use of natural preparations such as herbal preparations for VMS, or other medications for VMS the last 2 months; Capillary hemoglobin <110 g/l; Blood pressure >160 mmHg systolic or >100 mmHg diastolic; Unstable medical condition with a potential to affect VMS (like unregulated thyroid disease); Medical condition that by a physician is judged not appropriate (because of potential to affect VMS or risk of injury with vigorous exercise)

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Three-armed randomised trial where participants are randomised to 1) strength training, 2) high-intensity aerobic training or 3) untreated control group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Strength training<br>Standardised programme with the following exercises: chest press, leg press, row, leg curl, latissimus dorsi pull down and leg extension in seated resistance machines. Training will be preceded by 7-10 minutes of warm-up and followed by two body-weight exercises for the abdominal and back muscles for two sets as many repetitions as possible, and thereafter cool down and stretches. The set-up of each machine will be recorded in the training diary. Weeks 1-3 will include two sets of training with 15-20 repetition-maximum (RM) and weeks 4-15 two sets with 8-12 RM. Throughout the intervention, loads will be adjusted to achieve muscle fatigue and approach training to failure during each set with the intent to maximize beta-endorphin release. | Other: Strength training<br>* Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.<br>|
| Active Comparator: High-intensity aerobic training<br>Participants will be recommended to attend spinning classes three times per week. During their first visit to the training venue, they will meet a sports physiotherapist or personal trainer to be introduced to the spinning bike intervention. The intended intensity is ≥ 14 on the Borg rating of perceived exertion scale, equivalent to high intensity training (>70% of VO2max) with the aim of attaining sufficient stimulus for beta-endorphin release. During weeks 1-3 participants will attend spinning classes for beginners with lower intensity and predominantly seated cycling. They will progress to higher intensity classes with greater variation between seated and standing cycling during week 4-15. | Other: High-intensity aerobic training<br>* Both interventions (strength training and high intensity aerobic training) will be introduced with a 3-week adaptation period with lower loads (strength training) or intensity (aerobic training) followed by a 12-week period on the intended load/intensity. All participants in the intervention groups will be recommended to exercise three times per week (one hour per session) and in addition be active with everyday low-intensity physical activity. A structured and detailed training diary will be used in both groups to register frequency of each training session, as well as everyday physical activity. For the strength training, load and dose will also be registered for each training session.<br>|
| No Intervention: Control group<br>The control group will be recommended to carry on physical activity as usual and not to change their training or dietary habits during the 15-week study period. The control group will be contacted every fourth weeks by a research nurse to follow up on their general well-being and any questions they might have about menopause. After the study period they will be offered individual advise about training from a physiotherapist or personal trainer. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of moderate and severe hot flushes | Frequency of hot flushes per 24 h daily recorded in hot flush diary from baseline throughout 15 weeks of intervention. | baseline to 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of moderate and severe hot flushes | Frequency of hot flushes per 24 h daily recorded in hot flush diary 2 weeks at baseline and 2 weeks at each of the time points. | baseline to 6 months, 1, 2 and 5 years | 
| Severity of hot flushes | Severity of hot flushes per 24 hours recorded in hot flush diary from baseline throughout 15 weeks of intervention and two weeks during follow-up. | baseline to 15 weeks, 6 months, 1, 2 and 5 years | 
| Generic health-related quality of life | Short-form 36, 36 questions in 8 scales. Scores for each domain range from 0-100, and a high score represents a higher health-related quality of life. | baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention | 
| Women specific health-related quality of life | Women's health questionnaire nine sub-scales with four-point scales (yes definitely, yes sometimes, not not much, no not at all) that are reduced to binary options (0/1). The subscale items are summated and divided by the number of items in each subscale.A higher score represents worse outcome. | baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention | 
| Physical activity levels | International Physical Activity Questionnaire short form, the participant describes the amount of time (minutes and hours) that is spent on different physical activities each week, the more time, the better, except for the question about the amount of time spent in sitting. | baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention | 
| Sleep quality | Pittsburgh sleep quality index, 7 domains. For the total instrument, the lower score, the better, from 0 (best) to 21 (worst). | baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention | 
| Diet | Bespoke questionnaire, primarily to control for changes during the intervention period. Registration of amounts or portions. Results are presented question by question descriptively. | baseline to 15 weeks, 6 months, 1, 2 and 5 years | 
| Accomplished physical activity | Bespoke training diary | baseline to 15 weeks, 6 months, 1, 2 and 5 years after intervention | 
| Bioimpedance | Fat mass (%) and fat-free (muscle) mass (%) | baseline to 15 weeks | 
| Weight | kilogram (kg) | baseline to 15 weeks | 
| Lenght | meters (m) | baseline to 15 weeks | 
| Body mass index | kilograms/meters2 (kg/m2) | baseline to 15 weeks | 
| Waist circumference | millimeters (mm) | baseline to 15 weeks | 
| Systolic and diastolic blood pressure | Unit millimetre of mercury (mmHg) | baseline to 15 weeks | 
| Hematologic and ironstatus changes | Hemoglobin full body count, Transferrin(gram/Litre), and Ferritin (microgram/Litre) | baseline to 15 weeks, and 1 year | 
| Changes in blood-lipids | apolipoprotein A1, apolipoprotein B (gram/Litre) and total cholesterol, low-density lipoprotein, high-density lipoprotein (mmol/L) and leptin (ng/mL) | baseline to 15 weeks, and 1 year | 
| Changes in sex hormones and gonadotrophins | Estradiol (pmol/Litre), Sex hormone bindning globulin, Testosterone (nmol/Litre), follicle-stimulating hormone, luteinizing hormone (IE/Litre) | baseline to 15 weeks, and 1 year | 
| Changes in glucose profile | HbA1c (mmol/Litre) and fasting blood glucose (mmol/L) | baseline to 15 weeks, and 1 year | 
| Changes in inflammatory biomarkers | high-sensitive C-reactive Protein (microgram/Litre), Brain-derived neutrophic factor, Matrix metalloproteinase-2 and -9 (ng/mL), Interleukin -4, -6, -7, -8, 10, -15, tumour necrosis factor, monocyte chemoattractant protein-1 (pg/mL) | baseline to 15 weeks, and 1 year | 
| Changes in the lenght of telomeres in white blood cells | Telomeres (kilobase) pair | baseline to 15 weeks, and 1 year | 
| Change in exercise capacity | Change in exercise capacity is primarily used as a measure of adherence and obtained through cardiopulmonary exercise testing assessing maximum oxygen uptake milliliter/kilogram/minute (ml/kg/minute) and analysed according to local clinical routines. | baseline to 15 weeks | 
| Experiences of the interventions, facilitators and barriers | Bespoke questionnaire, only for intervention groups. Results will be presented descriptively question by question. | baseline to 15 weeks | 
| Adherence to the interventions | Assessed through bespoke training diary where each training session is registered and the total number of training sessions as well as training sessions/week will be calculated. | baseline to 15 weeks | 
| Muscle strength | For strength training group only, measured using 8 repetition-maximum tests. | baseline to 15 weeks | 
| Adverse events | Adverse events of taking part in the study | baseline to 15 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aerobic training, strength training