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Aerobic exercise as a treatment for vasomotor menopausal symptoms: Randomised controlled trial protocol
Maturitas 76 (2013) 350–356
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Aerobic exercise as a treatment for vasomotor menopausal symptoms: Randomised controlled trial protocol Amanda J. Daley a,∗ , Helen Stokes-Lampard a , Adèle Thomas a , Margaret Rees b , Sarah Coleman a , Andrea Roalfe a , Myra S. Hunter c , Christine MacArthur d a Primary Care Clinical Sciences, School of Health and Population Sciences, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom b University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom c Institute of Psychiatry, King’s College London, SE1 9RT, United Kingdom d Public Health, Epidemiology and Biostatistics, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
a r t i c l e
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Article history: Received 21 May 2013 Received in revised form 12 August 2013 Accepted 13 August 2013
Keywords: Exercise Menopause Women Hot flushes
a b s t r a c t Background: Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience vasomotor symptoms (hot flushes/night sweats) that can be severe and disruptive and which are the principal reason for seeking medical intervention. Hormone therapy (HT) is known to be an effective treatment for troublesome hot flushes/night sweats but research has raised questions about the safety of HT and there have been negative high profile media reports about its use. Consequently many women are seeking alternatives and exercise might be one such option but there is a lack of high quality evidence on its effectiveness. Aims: This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study in 165 women, and if found to be feasible/acceptable, continue to recruit sufficient women (n = 261) to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. Method: We aim to recruit inactive perimenopausal and menopausal symptomatic women not using HT and randomise them to one of two exercise interventions or usual care for six months. Results: We will assess outcomes at baseline and 6 and 12 months from randomisation. Conclusion: We hope this RCT will contribute towards increasing the evidence regarding the question of whether exercise is an effective treatment for vasomotor symptoms in women not taking HT. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Menopause is a normal physiological event usually experienced by women aged between 40 and 58 years [1]. The menopause transition is typically characterised by fluctuating and gradual lowering levels of endogenous oestrogen, which can give rise to vasomotor symptoms (hot flushes and night sweats) that can be severe and disruptive, and are the principal reason for seeking medical intervention. Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience such symptoms [2]. Their duration varies, with a median of four years, but may continue for as many as 12 years in about 10% of women [3].
∗ Corresponding author at: Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom. Tel.: +44 0121 414 3762. E-mail address: [email protected] (A.J. Daley). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.08.004
Hormone therapy (HT) is an effective treatment for troublesome hot flushes/night sweats but research [4,5] has raised questions about the safety of HT and high profile media reports have increased uncertainty about its use. Consequently, many women are now reluctant to consider HT as a therapeutic option for their symptoms and doctors are also more cautious about prescribing it, as demonstrated by the large reduction in prescriptions of HT in recent years [6,7]. Current guidance also recommends that HT should be taken for as short a period as is necessary, at the lowest effective dose [8], moreover, not all women, for example those who have had breast cancer, are candidates for HT. Many women are now seeking alternatives to HT [9] and it is increasingly important to identify other evidence-based interventions that have the potential to reduce the prevalence and/or severity of hot flushes/night sweats and other symptoms associated with menopause. One option might be exercise, particularly given that there is already good evidence [10] that regular exercise participation has positive effects upon other symptoms and health concerns associated with the menopause, such as depression, quality of life, fatigue, osteoporosis and cardiovascular disease.
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The Scientific Advisory Committee of The Royal College of Obstetricians and Gynaecologists and their Patient Information Committee [11] have advised that regular sustained aerobic exercise (e.g. running and swimming) may help reduce menopausal symptoms. Likewise, The North American Menopause Society [12] in their position statement concerning treatments for menopauseassociated vasomotor symptoms recommended that symptomatic women (mild-moderate) should first consider lifestyle changes, including participation in regular exercise. 1.1. Current evidence In 2011 the authors published a Cochrane review of exercise for the management of vasomotor menopausal symptoms [13] which concluded that existing studies (6 trials) provided insufficient evidence to determine the effectiveness of exercise as a treatment for hot flushes/night sweats in symptomatic women due to a lack of robust studies. There was a weak trend where two (out of three) studies that compared exercise with no treatment/control tended to produce a small effect favouring exercise, but the number of participants in this analysis was also small. The largest published trial (n = 165) at the time of the Cochrane review, which was also of good methodological quality [14], found no significant differences between exercise and control groups but mental health was the primary outcome and as such the trial was not powered to detect differences in hot flushes/night sweats. One published RCT [15,16] of symptomatic women postdates the Cochrane review that warrants comment here. A total of 176 symptomatic women were randomised to a control group or followed a six month aerobic exercise programme. There was no significant difference in hot flushes/night sweats as measured by questionnaire at follow-up. When assessed by phone diaries, the intervention group reported significantly fewer night sweats, but not hot flushes, than the control group. While the study sample was relatively large, there was no long term follow up and all participants were of white ethnicity, limiting generalisability. Furthermore, it appears that an atypical sample of menopausal women was recruited, since the sample mean both groups suggests that on average participants were only marginally overweight at baseline (kg/m2 = 26.3 for intervention and 26.9 for control). In addition, some women with very low levels of flushes at were included; the lowest number of hot flushes reported by a participant at baseline was 0.11/day, indicating that women who vary rarely experienced hot flushes were included. 1.2. Potential mechanisms There are plausible biological mechanisms by which exercise could reduce vasomotor and other menopausal symptoms. Studies have reported that women with higher adiposity experience more severe hot flushes/night sweats [17–19] and weight loss has been linked with decreases in hot flushes/night sweats [20]. Exercise is known to have a beneficial effect on weight management and so could exert an effect on hot flushes in this way. It is hypothesised that endorphin concentrations in the hypothalamus decrease as oestrogen production declines, enhancing the release of norepinephrine and serotonin. Exercise may have a similar effect to HT in the amelioration of vasomotor symptoms by increasing the presence of hypothalamic and peripheral ß-endorphin production [21]. In addition, there is evidence that as endorphins increase, the frequency and amplitude of luteinizing hormone decreases, which regulate gonadotropin releasing hormone levels [22]. Research [23] has shown that active individuals have higher basal levels of ß endorphins than those who are inactive. By these mechanisms, exercise may help to stabilise the thermoregulatory centre and diminish the risk of hot flushes. It has also been suggested that
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exercise can improve mental health outcomes by providing a distraction or ‘time out’ strategy from daily worries [24] and that exercise can enhance individuals’ feelings of accomplishment, thereby improving self-esteem [25]. 1.3. Development work In addition to the Cochrane review [13], we have already completed two observational studies [26,27], both patient surveys. In the first study [26] 1206/2399 women aged 46–55, recruited from general practices responded to a questionnaire that asked them about their menopausal symptoms, HT use and levels of exercise participation. Approximately 67% (n = 845) of responders were perimenopausal or postmenopausal. Only 12% reported current use of HT and many were using a range of nonpharmacological alternatives. About 60% of responders were not regularly active and 74% indicated they might consider participating in a trial of exercise and menopausal symptoms. Of responders who were perimenopausal and postmenopausal (n = 845), 67% (n = 563) experienced vasomotor symptoms. This study indicated that the prevalence of hot flushes/night sweats was substantial, that most menopausal-aged women did not exercise regularly and that exercise may be an acceptable intervention. In our second observational study [27] we aimed to ascertain menopausal-aged (46–55 years) women’s preferences for different methods of delivering pragmatic exercise interventions. Women were recruited from general practices. A postal questionnaire was sent to 2766 eligible women by their GP, with a response rate of 61.2% (n = 1693/2766). In response to a series of options the questionnaire elicited their preferences in relation to how they would like an exercise intervention to be delivered (e.g. by consultations, telephone, email, internet) and type of intervener (e.g. GP, nurse, fitness advisor, peer support). The emphasis was on offering participants preference option/choices that were low cost and pragmatic in order to have the potential to be delivered relatively easily within NHS or community settings. Questions about preferences for modes of exercise/physical activities were also included. Strong preferences were expressed for exercise interventions to be delivered or promoted by consultation with a physical activity/fitness advisor, support groups with other women of similar age, DVDs, booklets and leaflets that give information about exercise/health concerns during the menopause. There was an overwhelming preference for walking based activities, followed by dancing, swimming, cycling and aerobics classes. Further analyses according to sub group (i.e. vasomotor symptomatic versus non-vasomotor symptomatic, BMI category, exercise behaviour category and menopausal status) did not alter these findings. 1.4. Summary Given that the risk-benefits profile of HT has been questioned recently and menopausal women are keen to use non-pharmacological alternatives [9,28] the proposed research is timely. There has been a lack of robust research on the effects of exercise upon vasomotor symptoms, consequently the question of whether exercise is an effective treatment for hot flushes/night sweats remains unclear, although studies have been promising. This might also suggest that the recommendations from RCOG [11] and the North American Menopause Society [12] about exercise for treatment of hot flushes/night sweats have been premature and research that can address this question in a robust way would certainly help clarify these recommendations. Our previous development work [26,27] has established that exercise is likely to be acceptable to menopausal aged women and we have established women’s preferences for different types of
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This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study, and if found to be feasible/acceptable, continue to recruit sufficient women to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. Cost data relating to the interventions will also be collected.
recruit a pilot practice where 50% of patients will be asked to complete the hot flush rating scale only [29] and 50% asked to complete both the hot flush rating scale plus a prospective 7-day hot flush/night sweats diary. We will assess the response rate to both methods, and provided data obtained was acceptable, use the one with the highest response rate with the remaining practices. Patients who are currently experiencing, on average, five or more hot flushes/night sweats daily (as measured by diary or questionnaire in those who receive both), of any severity, will be eligible to be randomised (see below for inclusion criteria). In all patients the screening questionnaire will assess menopausal status, HT use, menstrual cycle length, contraception/medication use and current levels of exercise to further ascertain eligibility.
2. Methodology
2.3. Recruitment rate
2.1. Design
Based on our previous pilot work [27], we conservatively expect that about 10% of women per practice (assuming list size of 5000 adult patients) will be aged 48–57 years and of these 3% will be vasomotor symptomatic, inactive, perimenopausal or post menopausal, experiencing an average of 5 or more hot flushes/night sweats per day and willing to take part (i.e. about 15 patients per practice). Thus, we would need to recruit from 11 practices to recruit 165 participants and 17–18 practices to recruitment 261 women.
exercise and modes of delivery [27]. We now need to pilot and determine the acceptability of different exercise interventions to symptomatic menopausal women and investigate the effects of these preferred interventions on hot flushes/night sweats. 1.5. Aims
This study is a randomised controlled trial (individual randomisation) with participants allocated to one of two exercise interventions or usual care on a 1:1:1 ratio. The work described here will be carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. 2.2. Study population For feasibility/acceptability, we aim to recruit 165 inactive perimenopausal and menopausal symptomatic women, aged 48–57 years who have not used HT in the three months prior to baseline and randomise them to one of the three trial groups. However, if the interventions were deemed feasible and acceptable and the recruitment level high, we aimed to recruit 261 participants. In order for the interventions to be considered acceptable, in the first 165 participants more than 50% of consultations need to be delivered and of those invited to the support groups at least 50% should attend them. In our development work [27] we targeted women aged 46–55 years, but this age range included a large proportion of women who were not perimenopausal or postmenopausal. Therefore, in this trial we will recruit women aged 48–57 years to increase the likelihood that they will be perimenopausal or postmenopausal, and thus potentially eligible to participate. 2.2.1. General practices and PCTs Female patients aged 48–57 years will be identified from general practice records. Practices will then send a study invitation letter, information leaflet and screening questionnaire to identified patients on the list. Patients will be asked to return their screening questionnaire to the University research team. Non-responders will be sent a reminder about three weeks after the first mailing with no further contact thereafter. General practices from three Primary Care Trusts in the West Midlands will be informed about the trial and asked to assist with patient recruitment. 2.2.2. Pilot to assess symptom eligibility There are a number of ways in which we could assess eligibility for the trial in relation to typical hot flushes/night sweats per day. We could use a screening questionnaire that asks participants to recall the average number of flushes/night sweats they experience, or they could complete both the questionnaire and a prospective 7-day hot flush/night sweat diary. The approach we take might influence the response rate due to patient burden; therefore, it would be important to pilot these two approaches to assess average hot flush/night sweats frequency. Thus, we will
2.4. Inclusion/exclusion criteria 2.4.1. Planned inclusion criteria (a) Women aged 48–57 years who are currently experiencing vasomotor menopausal symptoms and not used HT in previous three months. (b) Surgically and spontaneously perimenopausal (irregular periods but at least one period in the previous 12 months) or postmenopausal women (no menstruation for >12 months prior to study). (c) Inactive (not currently meeting the public health guidelines for physical activity [10]). 2.4.2. Planned exclusion criteria (d) Using HT. (e) Oral contraceptive, tamoxifen, tibolone and raloxifene usage in previous three months. (f) Unable to provide written informed consent. (g) Not able to understand English sufficiently to complete the research questionnaires. (h) GP considers patient unsuitable for the trial. 2.5. Randomisation After providing written informed consent and returning the baseline questionnaires by post, participants will be randomised to one of two exercise interventions or usual care for six months. Group allocation will be by minimisation using menopausal status (perimenopausal or post menopausal) and BMI (underweight/normal weight or overweight/obese) (using self reported height and weight). A web based randomisation programme will be used to allocate participants to the groups. The allocation sequence will be generated using nQuery Advisor 7.0 with mixed blocked randomisation within strata (menopausal status and BMI). The methods of sequence generation will be concealed from researchers involved in recruiting and randomising participants to the groups. Participants, researchers and those delivering the intervention cannot be blinded to group allocation.
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2.6. Outcomes and allocation of patients to trial groups
3. Interventions
2.6.1. Primary outcome In the first instance the primary outcomes is the acceptability of the two exercise interventions. If the interventions are shown to be feasible, thereafter the primary outcome is the effectiveness of the interventions in reducing hot flushes/night sweats frequency.
3.1. Rationale for the selected intervention – pilot work
2.6.2. Secondary outcomes Problem rating of hot flushes will be assessed using the hot flush rating scale [29]. Menopause specific quality of life will be measured by the Women’s Health Questionnaire (WHQ) [31], and generic QoL using the SF-12 [32]. Depression and anxiety will be measured using the Hospital Anxiety and Depression Scale [33]. Subjective vitality [34], self-efficacy for exercise [35] and social support for exercise [36] will also be assessed. Self reported physical activity will be measured using the International Physical Activity Questionnaire-short (IPAQ-short) [30]. Adverse events will be recorded. A 50% random sample of all participants will be asked to wear an actiheart (CamNtech Ltd., UK) monitor for five consecutive days at baseline and six months follow up, to provide objective data on changes in physical activity patterns over time. The actiheart monitor is an innovative, compact device that continuously records physical activity and heart rate with a high level of accuracy. Levels of caloric expenditure can also be determined using the information acquired by the monitor. 2.6.3. Demographic and process data In addition to collecting data concerning demographics, reproductive history etc. (see earlier comments) women will be asked about their use of complementary and alternative medicine for symptom control and health behaviours. Self reported height and weight will be collected in all participants, as well as objectively in those randomised to wear the actiheart monitor. Current medication use will also be recorded at baseline and follow-ups. Cost data from both the NHS and individual perspectives will be collected. All participants will be asked to complete prospective 7-day hot flush/night sweat diaries at weeks 7, 14, and 21 after randomisation to provide an indication of the profile of their symptoms during the intervention phase of the study. Participants will be asked to record the frequency and severity of their symptoms. In addition, those randomised to the intervention will also complete 7-day prospective exercise logs that will detail the amount and type of exercise they achieve during these weeks. The hot flush diaries and physical activity logs will be sent and returned by post. 2.7. Assessments Outcome measures will be assessed at baseline and six months (immediately post intervention) and 12 months from randomisation. Follow up at six months is deemed the primary time point of interest. Outcome questionnaires will be mailed to participants at the appropriate time points. The actiheart is worn at baseline and six month follow up and fitted at a home visit by a member of the research team. Those wearing the actiheart will complete the IPAQ after they have worn the actiheart. 2.8. Sample size A sample size of 87 participants per group is sufficient to detect a 50% reduction in the mean number of hot flushes/night sweats per week (e.g. 40 reduced to 20 (sd = 31.6)) [28] with 80% power and 5% significance level, allowing for 20% drop out between the intervention and usual care groups.
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As discussed earlier, our development work [27] examined menopausal aged women’s preferences for different types of exercise interventions and results were used to develop the two interventions used in this trial. Women’s strong and overwhelming preference for consultations with health and fitness trainers will be used as the basis of both exercise interventions, which will then vary according to participants’ preferences [27] for other types of additional support (see below). As women had a clear preference for walking [27] we will predominately encourage this mode of exercise, but this will not preclude participants from doing all types of exercise that they enjoy. In developing the exercise interventions, consideration was also given to the Cochrane review [37] of physical activity interventions which reported a greater consistency of effect estimates for those studies where there were four or more contacts between the staff delivering the intervention and participants, compared to studies where there were less than four contacts. This review [37] also showed that a mixture of professional guidance and self-direction plus on-going support leads to more consistent effect estimates. The intervention will incorporate behaviour modification techniques which are grounded in behaviour change theory and address the specific determinants of exercise behaviour change. Two commonly applied approaches to health behaviour change are social cognitive theory [38] and the transtheoretical model [39]. This approach is important because interventions based on theories of behaviour change that teach behavioural skills and that are tailored to individual needs, are associated with longer-term changes in behaviour [37]. 3.2. Behavioural goal of the interventions The intervention will last six months. Six months has been selected as the intervention duration as this is likely to be the maximum time period for which a pragmatic, low cost intervention can be viable. While current public health guidelines suggest that adults should achieve at least 30 min of moderate intensity exercise on at least 5 days per week [10] few people meet this target currently; and this target may not be initially desirable or achievable by previously sedentary women. Therefore, the intervention goal will be progressive over time. The initial goal of the interventions (weeks 1–12) will be for participants to progress towards accumulating 30 min of moderate intensity exercise on three days per week. During weeks 13–24, the interventions will encourage participants to work towards accumulating 30 min of moderate intensity exercise on 3–5 days per week, in broad agreement with current public health guidelines [10]. Patients will be encouraged to first focus on the frequency of their exercise, and then duration. 3.3. Exercise interventions components Intervention one will involve two one-to-one consultations with a physical activity facilitator (PAF) that last 40–60 min (during months 1 and 2). Intervention one will also involve participants being sent a DVD, booklet and five study leaflets at various points during the intervention. These materials will provide information about the menopause, benefits of exercise during menopause and describe strategies that can be used to enhance exercise levels. The importance of healthy eating will also be emphasised. The DVD has been developed specifically for this study and contains case studies of women who have experienced vasomotor symptoms during the menopause transition; these women discuss strategies that they used to motivate themselves to exercise and the impact
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menopausal status and BMI; and also antidepressant and HT use recorded at six months follow-up. Paired comparisons will be made between all three groups with p values being adjusted for multiple testing. 4.2. Secondary analysis
Fig. 1. Overview of intervention.
it had on their health and well-being. As women will receive the DVD, booklet and leaflets in the post they will also serve as regular prompts for action (see Fig. 1). Intervention two will involve the same consultations as used in intervention one (as described above), but in this group participants will also be invited to take part in three support groups. The primary purpose of these groups is to bring women together to share experiences about exercising during menopause and offer regular encouragement to each other. The support groups will also focus on giving information about the symptoms of menopause and the importance of healthy eating during menopause. Support groups will take place in participants’ local communities, facilitated by the research team and last 75–90 min (see Fig. 1). The personalised consultations will be centred on equipping women with the skills, knowledge and confidence needed to participate in regular exercise and delivered by a PAF in participants’ home or another setting of their choice. The first consultation will focus on uptake of exercise and on enhancing motivation, self-efficacy for exercise, overcoming barriers and developing appropriate activity goals. Participants will be given a pedometer as a motivational tool. Where possible a short ‘walk and talk’ session will be incorporated within the first consultation so that practical issues such as perceived exertion monitoring and exercise safety can be explored with women. Four weeks after this, a second consultation centred on the prevention of relapse back to sedentary behaviour and/or improving maintenance of an active lifestyle will be conducted.
To identify any longer term effects of the intervention on symptoms, repeated measures mixed modelling of hot flushes/night sweats will be undertaken to compare groups across all time points, adjusting for covariates and multiple comparisons as previously described. Secondary outcomes including the hot flushes/night sweats, quality of life, subjective vitality, depression/anxiety, self-efficacy for exercise and physical activity (objective and self-report) will also be compared at the six and 12 month follow-up using the same method. The frequency, intensity, type and duration of exercise will be summarised in MET/min. Bland–Altman plots will be used to compare the physical activity measured by the IPAQ with that measured objectively by the actiheart. The number of participants achieving varying thresholds of physical activity at follow-up will be documented according to BMI and menopausal status in both intervention groups. The number of adverse events that occur during the intervention period will be summarised by group. Bootstrapped estimates will be calculated where there is evidence of non-normality in the residuals. The impact of missing primary and secondary outcome data will be explored by sensitivity analysis including multiple imputation. All analyses will be by intention to treat. 5. Qualitative study
There will be no interference with usual care in participants randomised to this group. Usual care will be offered an exercise consultation and a pedometer at the end of their involvement in the study.
In-depth interviews will be held with trial participants, who will be purposively sampled to ensure interviews are held with a range of women. Within this sampling approach, we will aim to recruit women who vary by age, ethnicity and social class. About 20 trial participants (15 intervention and five usual care) will be interviewed. This will take place once participants have completed the trial, so that data can be used to illuminate possible reasons for quantitative findings. Women will be approached to provide consent towards the end of their involvement in the trial. Interviews will be face-to-face and will explore participants’ views and experiences of vasomotor symptoms, the trial and usual care (Fig. 2). The interviews will be audio-taped and transcribed verbatim. Transcripts will be read and re-read in order to gain an overall understanding of each participant’s views and experiences, and to develop a coding framework. Each transcript will be imported into NVivo to allow electronic coding and retrieval of data. Transcripts will be coded by independent researchers in order to maintain reliability of coding. Analysis will rely upon “constant comparison” and will continue until no new themes emerge.
4. Analysis plan
6. Discussion
4.1. Primary analysis
Because menopausal women are increasingly reluctant to use HT and other pharmacological agents, finding evidence-based nonpharmacological alternatives has become critical. Exercise has shown some promise of being one such intervention, but current evidence does not allow any stronger conclusion than this at the present time. We hope that this trial will contribute towards increasing the evidence on the effectiveness of exercise as a treatment for vasomtotor symptoms. Moreover, whilst both the Royal College of Obstetricians and Gynaecologists in the UK [11] and
3.4. Usual care
The acceptability of the interventions will be determined by compliance/attendance with each of the intervention components; this data will be presented descriptively. To examine the effectiveness of the intervention on symptoms, comparisons will be made between the mean number of symptoms per week in the three groups at six months follow-up using analysis of covariance. Adjustments will be made for baseline symptom frequency,
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Practice sends study information letter to patients with hot flush/night sweats (HF/NS) screening questionnaire. 7 day HF/NS diary sent to patients at pilot practice
Not interested in participating in trial
Interested in participating in trial
No further action
Experiencing 5 or more HF/NS
Apply other trial criteria
Experiencing less than 5 HF/NS Not eligible–no further action
Ineligible – no further action
Baseline assessment of outcomes
Randomisation to trial groups
Exercise intervention 2
Exercise intervention 1 (Consultations plus leaflets & DVD)
(Consultations plus support groups)
Usual care
6 month assessment of outcomes
Semi-structured interviews with trial completers in interventions and usual care groups
12 month assessment of outcomes (except actiheart) Fig. 2. Trial flow.
the North American Menopause Society [12] recommend that women be advised to consider aerobic exercise as a treatment for vasomotor menopausal symptoms, this is not based on good evidence thus more high quality research is needed. We hope the findings of this research will inform future updates of clinical guidance around the world on treatments for vasomotor symptoms. Exercise may have additional benefits for women in terms of improving cardiovascular health and reducing weight, which have been identified as particular concerns for menopausal aged women. Moreover, exercise participation rates have been found to be low for menopausal aged women [26], which may indeed increase their risk of diseases in later life; therefore exercise could provide additional health benefits in this population of women at
a time in their lives when their risk of several chronic diseases is increased. Contributors AJD developed the initial idea for the study with assistance from CM, HSL, & MR. AT, SC and MH also contributed to the development of the trial protocol at a later stage. AR is the trial statistician and performed the power calculations and wrote the analysis plan. All authors have seen and agreed the final version of the manuscript. Competing interest None.
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Funding Amanda Daley is supported by a National Institute for Health Research Senior Research Fellowship. Ethical approval Favourable ethical opinion for this study was granted by the West Midlands Research Ethics Committee in March 2010 (ref: 10/H1208/3). Peer review Peer review was coordinated independently by Professor Tommaso Simoncini and Margaret Rees (Editor in Chief) and an author was blinded to the process. Acknowledgements The views expressed in this publication are those of the authors and not necessarily those of the NHS, The National Institute for Health Research or the Department of Health. References [1] National Institutes for Health state of science conference statement on management of menopause-related symptoms, NH, 2005. http://consensus.nih.gov/ [2] Greendale GA, Lee N, Arriola E. The menopause. Lancet 1999;353:571–80. [3] Politi MC, Schienitz MD, Col NF. Revisting the duration of vasomotor symptoms of menopause: a meta analysis. J Gen Intern Med 2008;23:1507–13. [4] Rossouw JE, Anderson G, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002;288:321–33. [5] Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the million women study. Lancet 2003;362:419–27. [6] Lawton B, Rose S, McLeod D, et al. Change in use of hormone replacement therapy after the report from the women’s health initiative: cross sectional survey of users. BMJ 2003;327:845–6. [7] Hersh A, Stefanick M, Stafford R. National use of postmenopausal hormone replacement therapy: annual trend and response to recent evidence. JAMA 2004;291:47–53. [8] UK Committee for Safety of Medicines. HRT: update on the risk of breast cancer and long-terms safety. Curr Prob Pharmacovigil 2003;29:1–3. [9] Newton K, Buist DS, Keenan NL, Anderson LA, LaCroix AZ. Use of alternative therapies for menopause symptoms: results of a population-based survey. Am Col Obstet Gynecol 2002;100:18–25. [10] Department of Health. At least five a week: evidence on the impact of physical activity and its relationship to health; 2004 http://www.dh.gov.uk/ en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/ DH 4080994 [11] Royal College of Obstetricians and Gynaecologists. Scientific Advisory Committee. Alternatives to HRT for the management of symptoms of the menopause; 2006. Opinion paper 6, May 2006 www.rcog.org.uk/index.asp?pageid=1561 [12] North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause 2004;11:11–33. [13] Daley A, Stokes-Lampard H, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2011;5:CD006108.
[14] Elavasky S, McAuley E. Physical activity and mental health outcomes during menopause: a randomized controlled trial. Ann Behav Med 2007;33: 132–42. [15] Luoto R, Moilanen J, Heinonen R, et al. Effects of aerobic training on hot flushes and quality of life—a randomized controlled trial. Ann Med 2012;44:616–26. [16] Moilanen JM, Mikkola TS, Railanen JA, et al. Effect of aerobic training on menopausal symptoms—a randomized controlled trial. Menopause 2012;19:691–6. [17] Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40–55 years of age. Am J Epidemiol 2000;152:463–73. [18] van Poppel MN, Brown W. “It’s my hormones, doctor”-does physical activity help with menopausal symptoms? Menopause 2008;15:78–85. [19] Thurston RC, Sowers MR, Chang Y, et al. Adiposity and reporting of vasomotor symptoms among midlife women: the study of women’s health across the nation. Am J Epidemiol 2008;167:78–85. [20] Huang AJ, Subka L, Wing R, et al. An intensive behavioural weight loss intervention and hot flushes in women. Arch Intern Med 2010;12:1161–7. [21] Bortz WM, Angwin P, Mefford IN. Catecholamines, dopamine and endorphin levels during extreme exercise. N Engl J Med 1981;305:466–7. [22] Reid RL, Hoff JD, Yen SS, Lee CH. Effects of exogenous beta h-endorphin on pituitary hormone secretion and its disappearance rate in normal human subjects. J Clin Endocrinol Metab 1981;52:1179–83. [23] Heitkamp HC, Huber W, Scheib K. Beta-endorphin and adrenocorticotropin after incremental exercise and marathon running—female response. Eur J Appl Physiol Occup Physiol 1996;72:417–24. [24] Bahrke MS, Morgan WP. Anxiety reduction following exercise and meditation. Cog Therapy Res 1978;2:323–33. [25] Taylor AH, Fox KR. Effectiveness of a primary care exercise referral intervention for changing physical self-perceptions over 9 months. Health Psychol 2005;24:11–21. [26] Daley AJ, MacArthur C, Stokes-Lampard H, et al. Exercise participation, body mass index and health-related quality of life in menopausal aged women. Br J Gen Pract 2007;57:130–5. [27] Daley AJ, Stokes-Lampard H, Wilson S, Rees M, Roalfe A, MacArthur C. What women want? Exercise preferences of menopausal women. Maturitas 2011;68:174–8. [28] Daley AJ, MacArthur C, McManus R, et al. Factors associated with the use of complementary medicine and non-pharmacological interventions in symptomatic menopausal women. Climacteric 2006;9:336–46. [29] Hunter MS, Liao KLM. A psychological analysis of menopausal hot flushes. Br J Clin Psychol 1995;34:589–99. [30] Craig CL, Marshall AL, Sjöström M, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 2003;35:1381–95. [31] Hunter MS. The women’s health questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychol Health 1992;7:45–54. [32] Ware JE, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical Care 1996;34:220–33. [33] Zigmond AS, et al. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–70. [34] Bostic TJ, Rubio DM, Hood M. A validation of the subjective vitality scale using structural equation modeling. Soc Indicators Res 2000;52:313–24. [35] Sallis JF, Pinski RB, Grossman RM, et al. The development of self-efficacy scales for health-related diet and exercise behaviours. Health Educ Res 1988;3:283–92. [36] Sallis JF, Grossman RM, Pinski RB, et al. The development of scales to measure social support for diet and exercise behaviours. Prev Med 1987;16:825–36. [37] Hillsdon M, Thorogood M, Foster C. Interventions for physical activity (Cochrane Review). Oxford: Update Software; 2005. [38] Bandura Albert. Social learning theory. Englewood Cliffs, NJ: Prentice Hall; 1976. [39] Prochaska JO, Velicer W. The transtheoretical model of health behaviour change. Am J Health Promot 1997;12:38–48.
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Aerobic exercise as a treatment for vasomotor menopausal symptoms: Randomised controlled trial protocol Amanda J. Daley a,∗ , Helen Stokes-Lampard a , Adèle Thomas a , Margaret Rees b , Sarah Coleman a , Andrea Roalfe a , Myra S. Hunter c , Christine MacArthur d a Primary Care Clinical Sciences, School of Health and Population Sciences, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, United Kingdom b University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom c Institute of Psychiatry, King’s College London, SE1 9RT, United Kingdom d Public Health, Epidemiology and Biostatistics, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
a r t i c l e
i n f o
Article history: Received 21 May 2013 Received in revised form 12 August 2013 Accepted 13 August 2013
Keywords: Exercise Menopause Women Hot flushes
a b s t r a c t Background: Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience vasomotor symptoms (hot flushes/night sweats) that can be severe and disruptive and which are the principal reason for seeking medical intervention. Hormone therapy (HT) is known to be an effective treatment for troublesome hot flushes/night sweats but research has raised questions about the safety of HT and there have been negative high profile media reports about its use. Consequently many women are seeking alternatives and exercise might be one such option but there is a lack of high quality evidence on its effectiveness. Aims: This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study in 165 women, and if found to be feasible/acceptable, continue to recruit sufficient women (n = 261) to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. Method: We aim to recruit inactive perimenopausal and menopausal symptomatic women not using HT and randomise them to one of two exercise interventions or usual care for six months. Results: We will assess outcomes at baseline and 6 and 12 months from randomisation. Conclusion: We hope this RCT will contribute towards increasing the evidence regarding the question of whether exercise is an effective treatment for vasomotor symptoms in women not taking HT. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Menopause is a normal physiological event usually experienced by women aged between 40 and 58 years [1]. The menopause transition is typically characterised by fluctuating and gradual lowering levels of endogenous oestrogen, which can give rise to vasomotor symptoms (hot flushes and night sweats) that can be severe and disruptive, and are the principal reason for seeking medical intervention. Evidence suggests that a high proportion of perimenopausal and postmenopausal women experience such symptoms [2]. Their duration varies, with a median of four years, but may continue for as many as 12 years in about 10% of women [3].
∗ Corresponding author at: Primary Care Clinical Sciences, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom. Tel.: +44 0121 414 3762. E-mail address: [email protected] (A.J. Daley). 0378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2013.08.004
Hormone therapy (HT) is an effective treatment for troublesome hot flushes/night sweats but research [4,5] has raised questions about the safety of HT and high profile media reports have increased uncertainty about its use. Consequently, many women are now reluctant to consider HT as a therapeutic option for their symptoms and doctors are also more cautious about prescribing it, as demonstrated by the large reduction in prescriptions of HT in recent years [6,7]. Current guidance also recommends that HT should be taken for as short a period as is necessary, at the lowest effective dose [8], moreover, not all women, for example those who have had breast cancer, are candidates for HT. Many women are now seeking alternatives to HT [9] and it is increasingly important to identify other evidence-based interventions that have the potential to reduce the prevalence and/or severity of hot flushes/night sweats and other symptoms associated with menopause. One option might be exercise, particularly given that there is already good evidence [10] that regular exercise participation has positive effects upon other symptoms and health concerns associated with the menopause, such as depression, quality of life, fatigue, osteoporosis and cardiovascular disease.
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The Scientific Advisory Committee of The Royal College of Obstetricians and Gynaecologists and their Patient Information Committee [11] have advised that regular sustained aerobic exercise (e.g. running and swimming) may help reduce menopausal symptoms. Likewise, The North American Menopause Society [12] in their position statement concerning treatments for menopauseassociated vasomotor symptoms recommended that symptomatic women (mild-moderate) should first consider lifestyle changes, including participation in regular exercise. 1.1. Current evidence In 2011 the authors published a Cochrane review of exercise for the management of vasomotor menopausal symptoms [13] which concluded that existing studies (6 trials) provided insufficient evidence to determine the effectiveness of exercise as a treatment for hot flushes/night sweats in symptomatic women due to a lack of robust studies. There was a weak trend where two (out of three) studies that compared exercise with no treatment/control tended to produce a small effect favouring exercise, but the number of participants in this analysis was also small. The largest published trial (n = 165) at the time of the Cochrane review, which was also of good methodological quality [14], found no significant differences between exercise and control groups but mental health was the primary outcome and as such the trial was not powered to detect differences in hot flushes/night sweats. One published RCT [15,16] of symptomatic women postdates the Cochrane review that warrants comment here. A total of 176 symptomatic women were randomised to a control group or followed a six month aerobic exercise programme. There was no significant difference in hot flushes/night sweats as measured by questionnaire at follow-up. When assessed by phone diaries, the intervention group reported significantly fewer night sweats, but not hot flushes, than the control group. While the study sample was relatively large, there was no long term follow up and all participants were of white ethnicity, limiting generalisability. Furthermore, it appears that an atypical sample of menopausal women was recruited, since the sample mean both groups suggests that on average participants were only marginally overweight at baseline (kg/m2 = 26.3 for intervention and 26.9 for control). In addition, some women with very low levels of flushes at were included; the lowest number of hot flushes reported by a participant at baseline was 0.11/day, indicating that women who vary rarely experienced hot flushes were included. 1.2. Potential mechanisms There are plausible biological mechanisms by which exercise could reduce vasomotor and other menopausal symptoms. Studies have reported that women with higher adiposity experience more severe hot flushes/night sweats [17–19] and weight loss has been linked with decreases in hot flushes/night sweats [20]. Exercise is known to have a beneficial effect on weight management and so could exert an effect on hot flushes in this way. It is hypothesised that endorphin concentrations in the hypothalamus decrease as oestrogen production declines, enhancing the release of norepinephrine and serotonin. Exercise may have a similar effect to HT in the amelioration of vasomotor symptoms by increasing the presence of hypothalamic and peripheral ß-endorphin production [21]. In addition, there is evidence that as endorphins increase, the frequency and amplitude of luteinizing hormone decreases, which regulate gonadotropin releasing hormone levels [22]. Research [23] has shown that active individuals have higher basal levels of ß endorphins than those who are inactive. By these mechanisms, exercise may help to stabilise the thermoregulatory centre and diminish the risk of hot flushes. It has also been suggested that
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exercise can improve mental health outcomes by providing a distraction or ‘time out’ strategy from daily worries [24] and that exercise can enhance individuals’ feelings of accomplishment, thereby improving self-esteem [25]. 1.3. Development work In addition to the Cochrane review [13], we have already completed two observational studies [26,27], both patient surveys. In the first study [26] 1206/2399 women aged 46–55, recruited from general practices responded to a questionnaire that asked them about their menopausal symptoms, HT use and levels of exercise participation. Approximately 67% (n = 845) of responders were perimenopausal or postmenopausal. Only 12% reported current use of HT and many were using a range of nonpharmacological alternatives. About 60% of responders were not regularly active and 74% indicated they might consider participating in a trial of exercise and menopausal symptoms. Of responders who were perimenopausal and postmenopausal (n = 845), 67% (n = 563) experienced vasomotor symptoms. This study indicated that the prevalence of hot flushes/night sweats was substantial, that most menopausal-aged women did not exercise regularly and that exercise may be an acceptable intervention. In our second observational study [27] we aimed to ascertain menopausal-aged (46–55 years) women’s preferences for different methods of delivering pragmatic exercise interventions. Women were recruited from general practices. A postal questionnaire was sent to 2766 eligible women by their GP, with a response rate of 61.2% (n = 1693/2766). In response to a series of options the questionnaire elicited their preferences in relation to how they would like an exercise intervention to be delivered (e.g. by consultations, telephone, email, internet) and type of intervener (e.g. GP, nurse, fitness advisor, peer support). The emphasis was on offering participants preference option/choices that were low cost and pragmatic in order to have the potential to be delivered relatively easily within NHS or community settings. Questions about preferences for modes of exercise/physical activities were also included. Strong preferences were expressed for exercise interventions to be delivered or promoted by consultation with a physical activity/fitness advisor, support groups with other women of similar age, DVDs, booklets and leaflets that give information about exercise/health concerns during the menopause. There was an overwhelming preference for walking based activities, followed by dancing, swimming, cycling and aerobics classes. Further analyses according to sub group (i.e. vasomotor symptomatic versus non-vasomotor symptomatic, BMI category, exercise behaviour category and menopausal status) did not alter these findings. 1.4. Summary Given that the risk-benefits profile of HT has been questioned recently and menopausal women are keen to use non-pharmacological alternatives [9,28] the proposed research is timely. There has been a lack of robust research on the effects of exercise upon vasomotor symptoms, consequently the question of whether exercise is an effective treatment for hot flushes/night sweats remains unclear, although studies have been promising. This might also suggest that the recommendations from RCOG [11] and the North American Menopause Society [12] about exercise for treatment of hot flushes/night sweats have been premature and research that can address this question in a robust way would certainly help clarify these recommendations. Our previous development work [26,27] has established that exercise is likely to be acceptable to menopausal aged women and we have established women’s preferences for different types of
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This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions identified from our previous preference study, and if found to be feasible/acceptable, continue to recruit sufficient women to examine the effect of these interventions on hot flushes/night sweats and other outcomes relevant to menopausal women. Cost data relating to the interventions will also be collected.
recruit a pilot practice where 50% of patients will be asked to complete the hot flush rating scale only [29] and 50% asked to complete both the hot flush rating scale plus a prospective 7-day hot flush/night sweats diary. We will assess the response rate to both methods, and provided data obtained was acceptable, use the one with the highest response rate with the remaining practices. Patients who are currently experiencing, on average, five or more hot flushes/night sweats daily (as measured by diary or questionnaire in those who receive both), of any severity, will be eligible to be randomised (see below for inclusion criteria). In all patients the screening questionnaire will assess menopausal status, HT use, menstrual cycle length, contraception/medication use and current levels of exercise to further ascertain eligibility.
2. Methodology
2.3. Recruitment rate
2.1. Design
Based on our previous pilot work [27], we conservatively expect that about 10% of women per practice (assuming list size of 5000 adult patients) will be aged 48–57 years and of these 3% will be vasomotor symptomatic, inactive, perimenopausal or post menopausal, experiencing an average of 5 or more hot flushes/night sweats per day and willing to take part (i.e. about 15 patients per practice). Thus, we would need to recruit from 11 practices to recruit 165 participants and 17–18 practices to recruitment 261 women.
exercise and modes of delivery [27]. We now need to pilot and determine the acceptability of different exercise interventions to symptomatic menopausal women and investigate the effects of these preferred interventions on hot flushes/night sweats. 1.5. Aims
This study is a randomised controlled trial (individual randomisation) with participants allocated to one of two exercise interventions or usual care on a 1:1:1 ratio. The work described here will be carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. 2.2. Study population For feasibility/acceptability, we aim to recruit 165 inactive perimenopausal and menopausal symptomatic women, aged 48–57 years who have not used HT in the three months prior to baseline and randomise them to one of the three trial groups. However, if the interventions were deemed feasible and acceptable and the recruitment level high, we aimed to recruit 261 participants. In order for the interventions to be considered acceptable, in the first 165 participants more than 50% of consultations need to be delivered and of those invited to the support groups at least 50% should attend them. In our development work [27] we targeted women aged 46–55 years, but this age range included a large proportion of women who were not perimenopausal or postmenopausal. Therefore, in this trial we will recruit women aged 48–57 years to increase the likelihood that they will be perimenopausal or postmenopausal, and thus potentially eligible to participate. 2.2.1. General practices and PCTs Female patients aged 48–57 years will be identified from general practice records. Practices will then send a study invitation letter, information leaflet and screening questionnaire to identified patients on the list. Patients will be asked to return their screening questionnaire to the University research team. Non-responders will be sent a reminder about three weeks after the first mailing with no further contact thereafter. General practices from three Primary Care Trusts in the West Midlands will be informed about the trial and asked to assist with patient recruitment. 2.2.2. Pilot to assess symptom eligibility There are a number of ways in which we could assess eligibility for the trial in relation to typical hot flushes/night sweats per day. We could use a screening questionnaire that asks participants to recall the average number of flushes/night sweats they experience, or they could complete both the questionnaire and a prospective 7-day hot flush/night sweat diary. The approach we take might influence the response rate due to patient burden; therefore, it would be important to pilot these two approaches to assess average hot flush/night sweats frequency. Thus, we will
2.4. Inclusion/exclusion criteria 2.4.1. Planned inclusion criteria (a) Women aged 48–57 years who are currently experiencing vasomotor menopausal symptoms and not used HT in previous three months. (b) Surgically and spontaneously perimenopausal (irregular periods but at least one period in the previous 12 months) or postmenopausal women (no menstruation for >12 months prior to study). (c) Inactive (not currently meeting the public health guidelines for physical activity [10]). 2.4.2. Planned exclusion criteria (d) Using HT. (e) Oral contraceptive, tamoxifen, tibolone and raloxifene usage in previous three months. (f) Unable to provide written informed consent. (g) Not able to understand English sufficiently to complete the research questionnaires. (h) GP considers patient unsuitable for the trial. 2.5. Randomisation After providing written informed consent and returning the baseline questionnaires by post, participants will be randomised to one of two exercise interventions or usual care for six months. Group allocation will be by minimisation using menopausal status (perimenopausal or post menopausal) and BMI (underweight/normal weight or overweight/obese) (using self reported height and weight). A web based randomisation programme will be used to allocate participants to the groups. The allocation sequence will be generated using nQuery Advisor 7.0 with mixed blocked randomisation within strata (menopausal status and BMI). The methods of sequence generation will be concealed from researchers involved in recruiting and randomising participants to the groups. Participants, researchers and those delivering the intervention cannot be blinded to group allocation.
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2.6. Outcomes and allocation of patients to trial groups
3. Interventions
2.6.1. Primary outcome In the first instance the primary outcomes is the acceptability of the two exercise interventions. If the interventions are shown to be feasible, thereafter the primary outcome is the effectiveness of the interventions in reducing hot flushes/night sweats frequency.
3.1. Rationale for the selected intervention – pilot work
2.6.2. Secondary outcomes Problem rating of hot flushes will be assessed using the hot flush rating scale [29]. Menopause specific quality of life will be measured by the Women’s Health Questionnaire (WHQ) [31], and generic QoL using the SF-12 [32]. Depression and anxiety will be measured using the Hospital Anxiety and Depression Scale [33]. Subjective vitality [34], self-efficacy for exercise [35] and social support for exercise [36] will also be assessed. Self reported physical activity will be measured using the International Physical Activity Questionnaire-short (IPAQ-short) [30]. Adverse events will be recorded. A 50% random sample of all participants will be asked to wear an actiheart (CamNtech Ltd., UK) monitor for five consecutive days at baseline and six months follow up, to provide objective data on changes in physical activity patterns over time. The actiheart monitor is an innovative, compact device that continuously records physical activity and heart rate with a high level of accuracy. Levels of caloric expenditure can also be determined using the information acquired by the monitor. 2.6.3. Demographic and process data In addition to collecting data concerning demographics, reproductive history etc. (see earlier comments) women will be asked about their use of complementary and alternative medicine for symptom control and health behaviours. Self reported height and weight will be collected in all participants, as well as objectively in those randomised to wear the actiheart monitor. Current medication use will also be recorded at baseline and follow-ups. Cost data from both the NHS and individual perspectives will be collected. All participants will be asked to complete prospective 7-day hot flush/night sweat diaries at weeks 7, 14, and 21 after randomisation to provide an indication of the profile of their symptoms during the intervention phase of the study. Participants will be asked to record the frequency and severity of their symptoms. In addition, those randomised to the intervention will also complete 7-day prospective exercise logs that will detail the amount and type of exercise they achieve during these weeks. The hot flush diaries and physical activity logs will be sent and returned by post. 2.7. Assessments Outcome measures will be assessed at baseline and six months (immediately post intervention) and 12 months from randomisation. Follow up at six months is deemed the primary time point of interest. Outcome questionnaires will be mailed to participants at the appropriate time points. The actiheart is worn at baseline and six month follow up and fitted at a home visit by a member of the research team. Those wearing the actiheart will complete the IPAQ after they have worn the actiheart. 2.8. Sample size A sample size of 87 participants per group is sufficient to detect a 50% reduction in the mean number of hot flushes/night sweats per week (e.g. 40 reduced to 20 (sd = 31.6)) [28] with 80% power and 5% significance level, allowing for 20% drop out between the intervention and usual care groups.
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As discussed earlier, our development work [27] examined menopausal aged women’s preferences for different types of exercise interventions and results were used to develop the two interventions used in this trial. Women’s strong and overwhelming preference for consultations with health and fitness trainers will be used as the basis of both exercise interventions, which will then vary according to participants’ preferences [27] for other types of additional support (see below). As women had a clear preference for walking [27] we will predominately encourage this mode of exercise, but this will not preclude participants from doing all types of exercise that they enjoy. In developing the exercise interventions, consideration was also given to the Cochrane review [37] of physical activity interventions which reported a greater consistency of effect estimates for those studies where there were four or more contacts between the staff delivering the intervention and participants, compared to studies where there were less than four contacts. This review [37] also showed that a mixture of professional guidance and self-direction plus on-going support leads to more consistent effect estimates. The intervention will incorporate behaviour modification techniques which are grounded in behaviour change theory and address the specific determinants of exercise behaviour change. Two commonly applied approaches to health behaviour change are social cognitive theory [38] and the transtheoretical model [39]. This approach is important because interventions based on theories of behaviour change that teach behavioural skills and that are tailored to individual needs, are associated with longer-term changes in behaviour [37]. 3.2. Behavioural goal of the interventions The intervention will last six months. Six months has been selected as the intervention duration as this is likely to be the maximum time period for which a pragmatic, low cost intervention can be viable. While current public health guidelines suggest that adults should achieve at least 30 min of moderate intensity exercise on at least 5 days per week [10] few people meet this target currently; and this target may not be initially desirable or achievable by previously sedentary women. Therefore, the intervention goal will be progressive over time. The initial goal of the interventions (weeks 1–12) will be for participants to progress towards accumulating 30 min of moderate intensity exercise on three days per week. During weeks 13–24, the interventions will encourage participants to work towards accumulating 30 min of moderate intensity exercise on 3–5 days per week, in broad agreement with current public health guidelines [10]. Patients will be encouraged to first focus on the frequency of their exercise, and then duration. 3.3. Exercise interventions components Intervention one will involve two one-to-one consultations with a physical activity facilitator (PAF) that last 40–60 min (during months 1 and 2). Intervention one will also involve participants being sent a DVD, booklet and five study leaflets at various points during the intervention. These materials will provide information about the menopause, benefits of exercise during menopause and describe strategies that can be used to enhance exercise levels. The importance of healthy eating will also be emphasised. The DVD has been developed specifically for this study and contains case studies of women who have experienced vasomotor symptoms during the menopause transition; these women discuss strategies that they used to motivate themselves to exercise and the impact
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menopausal status and BMI; and also antidepressant and HT use recorded at six months follow-up. Paired comparisons will be made between all three groups with p values being adjusted for multiple testing. 4.2. Secondary analysis
Fig. 1. Overview of intervention.
it had on their health and well-being. As women will receive the DVD, booklet and leaflets in the post they will also serve as regular prompts for action (see Fig. 1). Intervention two will involve the same consultations as used in intervention one (as described above), but in this group participants will also be invited to take part in three support groups. The primary purpose of these groups is to bring women together to share experiences about exercising during menopause and offer regular encouragement to each other. The support groups will also focus on giving information about the symptoms of menopause and the importance of healthy eating during menopause. Support groups will take place in participants’ local communities, facilitated by the research team and last 75–90 min (see Fig. 1). The personalised consultations will be centred on equipping women with the skills, knowledge and confidence needed to participate in regular exercise and delivered by a PAF in participants’ home or another setting of their choice. The first consultation will focus on uptake of exercise and on enhancing motivation, self-efficacy for exercise, overcoming barriers and developing appropriate activity goals. Participants will be given a pedometer as a motivational tool. Where possible a short ‘walk and talk’ session will be incorporated within the first consultation so that practical issues such as perceived exertion monitoring and exercise safety can be explored with women. Four weeks after this, a second consultation centred on the prevention of relapse back to sedentary behaviour and/or improving maintenance of an active lifestyle will be conducted.
To identify any longer term effects of the intervention on symptoms, repeated measures mixed modelling of hot flushes/night sweats will be undertaken to compare groups across all time points, adjusting for covariates and multiple comparisons as previously described. Secondary outcomes including the hot flushes/night sweats, quality of life, subjective vitality, depression/anxiety, self-efficacy for exercise and physical activity (objective and self-report) will also be compared at the six and 12 month follow-up using the same method. The frequency, intensity, type and duration of exercise will be summarised in MET/min. Bland–Altman plots will be used to compare the physical activity measured by the IPAQ with that measured objectively by the actiheart. The number of participants achieving varying thresholds of physical activity at follow-up will be documented according to BMI and menopausal status in both intervention groups. The number of adverse events that occur during the intervention period will be summarised by group. Bootstrapped estimates will be calculated where there is evidence of non-normality in the residuals. The impact of missing primary and secondary outcome data will be explored by sensitivity analysis including multiple imputation. All analyses will be by intention to treat. 5. Qualitative study
There will be no interference with usual care in participants randomised to this group. Usual care will be offered an exercise consultation and a pedometer at the end of their involvement in the study.
In-depth interviews will be held with trial participants, who will be purposively sampled to ensure interviews are held with a range of women. Within this sampling approach, we will aim to recruit women who vary by age, ethnicity and social class. About 20 trial participants (15 intervention and five usual care) will be interviewed. This will take place once participants have completed the trial, so that data can be used to illuminate possible reasons for quantitative findings. Women will be approached to provide consent towards the end of their involvement in the trial. Interviews will be face-to-face and will explore participants’ views and experiences of vasomotor symptoms, the trial and usual care (Fig. 2). The interviews will be audio-taped and transcribed verbatim. Transcripts will be read and re-read in order to gain an overall understanding of each participant’s views and experiences, and to develop a coding framework. Each transcript will be imported into NVivo to allow electronic coding and retrieval of data. Transcripts will be coded by independent researchers in order to maintain reliability of coding. Analysis will rely upon “constant comparison” and will continue until no new themes emerge.
4. Analysis plan
6. Discussion
4.1. Primary analysis
Because menopausal women are increasingly reluctant to use HT and other pharmacological agents, finding evidence-based nonpharmacological alternatives has become critical. Exercise has shown some promise of being one such intervention, but current evidence does not allow any stronger conclusion than this at the present time. We hope that this trial will contribute towards increasing the evidence on the effectiveness of exercise as a treatment for vasomtotor symptoms. Moreover, whilst both the Royal College of Obstetricians and Gynaecologists in the UK [11] and
3.4. Usual care
The acceptability of the interventions will be determined by compliance/attendance with each of the intervention components; this data will be presented descriptively. To examine the effectiveness of the intervention on symptoms, comparisons will be made between the mean number of symptoms per week in the three groups at six months follow-up using analysis of covariance. Adjustments will be made for baseline symptom frequency,
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Practice sends study information letter to patients with hot flush/night sweats (HF/NS) screening questionnaire. 7 day HF/NS diary sent to patients at pilot practice
Not interested in participating in trial
Interested in participating in trial
No further action
Experiencing 5 or more HF/NS
Apply other trial criteria
Experiencing less than 5 HF/NS Not eligible–no further action
Ineligible – no further action
Baseline assessment of outcomes
Randomisation to trial groups
Exercise intervention 2
Exercise intervention 1 (Consultations plus leaflets & DVD)
(Consultations plus support groups)
Usual care
6 month assessment of outcomes
Semi-structured interviews with trial completers in interventions and usual care groups
12 month assessment of outcomes (except actiheart) Fig. 2. Trial flow.
the North American Menopause Society [12] recommend that women be advised to consider aerobic exercise as a treatment for vasomotor menopausal symptoms, this is not based on good evidence thus more high quality research is needed. We hope the findings of this research will inform future updates of clinical guidance around the world on treatments for vasomotor symptoms. Exercise may have additional benefits for women in terms of improving cardiovascular health and reducing weight, which have been identified as particular concerns for menopausal aged women. Moreover, exercise participation rates have been found to be low for menopausal aged women [26], which may indeed increase their risk of diseases in later life; therefore exercise could provide additional health benefits in this population of women at
a time in their lives when their risk of several chronic diseases is increased. Contributors AJD developed the initial idea for the study with assistance from CM, HSL, & MR. AT, SC and MH also contributed to the development of the trial protocol at a later stage. AR is the trial statistician and performed the power calculations and wrote the analysis plan. All authors have seen and agreed the final version of the manuscript. Competing interest None.
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Funding Amanda Daley is supported by a National Institute for Health Research Senior Research Fellowship. Ethical approval Favourable ethical opinion for this study was granted by the West Midlands Research Ethics Committee in March 2010 (ref: 10/H1208/3). Peer review Peer review was coordinated independently by Professor Tommaso Simoncini and Margaret Rees (Editor in Chief) and an author was blinded to the process. Acknowledgements The views expressed in this publication are those of the authors and not necessarily those of the NHS, The National Institute for Health Research or the Department of Health. References [1] National Institutes for Health state of science conference statement on management of menopause-related symptoms, NH, 2005. http://consensus.nih.gov/ [2] Greendale GA, Lee N, Arriola E. The menopause. Lancet 1999;353:571–80. [3] Politi MC, Schienitz MD, Col NF. Revisting the duration of vasomotor symptoms of menopause: a meta analysis. J Gen Intern Med 2008;23:1507–13. [4] Rossouw JE, Anderson G, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002;288:321–33. [5] Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the million women study. Lancet 2003;362:419–27. [6] Lawton B, Rose S, McLeod D, et al. Change in use of hormone replacement therapy after the report from the women’s health initiative: cross sectional survey of users. BMJ 2003;327:845–6. [7] Hersh A, Stefanick M, Stafford R. National use of postmenopausal hormone replacement therapy: annual trend and response to recent evidence. JAMA 2004;291:47–53. [8] UK Committee for Safety of Medicines. HRT: update on the risk of breast cancer and long-terms safety. Curr Prob Pharmacovigil 2003;29:1–3. [9] Newton K, Buist DS, Keenan NL, Anderson LA, LaCroix AZ. Use of alternative therapies for menopause symptoms: results of a population-based survey. Am Col Obstet Gynecol 2002;100:18–25. [10] Department of Health. At least five a week: evidence on the impact of physical activity and its relationship to health; 2004 http://www.dh.gov.uk/ en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/ DH 4080994 [11] Royal College of Obstetricians and Gynaecologists. Scientific Advisory Committee. Alternatives to HRT for the management of symptoms of the menopause; 2006. Opinion paper 6, May 2006 www.rcog.org.uk/index.asp?pageid=1561 [12] North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause 2004;11:11–33. [13] Daley A, Stokes-Lampard H, MacArthur C. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2011;5:CD006108.
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