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Contents lists available at ScienceDirect

Maturitas

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erobic exercise as a treatment for vasomotor menopausalymptoms: Randomised controlled trial protocol

manda J. Daleya,∗, Helen Stokes-Lamparda, Adèle Thomasa, Margaret Reesb,arah Colemana, Andrea Roalfea, Myra S. Hunterc, Christine MacArthurd

Primary Care Clinical Sciences, School of Health and Population Sciences, College of Medical and Dental Sciences, University of Birmingham, B15 2TT,nited KingdomUniversity of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, United KingdomInstitute of Psychiatry, King’s College London, SE1 9RT, United KingdomPublic Health, Epidemiology and Biostatistics, School of Health and Population Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom

r t i c l e i n f o

rticle history:eceived 21 May 2013eceived in revised form 12 August 2013ccepted 13 August 2013

eywords:xerciseenopauseomen

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Background: Evidence suggests that a high proportion of perimenopausal and postmenopausal womenexperience vasomotor symptoms (hot flushes/night sweats) that can be severe and disruptive and whichare the principal reason for seeking medical intervention. Hormone therapy (HT) is known to be aneffective treatment for troublesome hot flushes/night sweats but research has raised questions about thesafety of HT and there have been negative high profile media reports about its use. Consequently manywomen are seeking alternatives and exercise might be one such option but there is a lack of high qualityevidence on its effectiveness.Aims: This RCT initially aims to investigate the feasibility/acceptability of two exercise interventions iden-tified from our previous preference study in 165 women, and if found to be feasible/acceptable, continueto 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 HTand 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

fectiv

whether exercise is an ef

. Introduction

Menopause is a normal physiological event usually experiencedy women aged between 40 and 58 years [1]. The menopauseransition is typically characterised by fluctuating and gradualowering levels of endogenous oestrogen, which can give rise toasomotor symptoms (hot flushes and night sweats) that can beevere and disruptive, and are the principal reason for seekingedical intervention. Evidence suggests that a high proportion

f perimenopausal and postmenopausal women experience suchymptoms [2]. Their duration varies, with a median of four years,

ut may continue for as many as 12 years in about 10% of women3].

∗ Corresponding author at: Primary Care Clinical Sciences, School of Healthnd Population Sciences, University of Birmingham, Birmingham B15 2TT, Unitedingdom. Tel.: +44 0121 414 3762.

E-mail address: a.daley@bham.ac.uk (A.J. Daley).

378-5122/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.maturitas.2013.08.004

e treatment for vasomotor symptoms in women not taking HT.© 2013 Elsevier Ireland Ltd. All rights reserved.

Hormone therapy (HT) is an effective treatment for troublesomehot flushes/night sweats but research [4,5] has raised questionsabout the safety of HT and high profile media reports have increaseduncertainty about its use. Consequently, many women are nowreluctant to consider HT as a therapeutic option for their symp-toms and doctors are also more cautious about prescribing it, asdemonstrated by the large reduction in prescriptions of HT in recentyears [6,7]. Current guidance also recommends that HT should betaken for as short a period as is necessary, at the lowest effectivedose [8], moreover, not all women, for example those who havehad breast cancer, are candidates for HT. Many women are nowseeking alternatives to HT [9] and it is increasingly important toidentify other evidence-based interventions that have the potentialto reduce the prevalence and/or severity of hot flushes/night sweatsand other symptoms associated with menopause. One option mightbe exercise, particularly given that there is already good evi-

dence [10] that regular exercise participation has positive effectsupon other symptoms and health concerns associated with themenopause, such as depression, quality of life, fatigue, osteoporosisand cardiovascular disease.

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The Scientific Advisory Committee of The Royal College ofbstetricians and Gynaecologists and their Patient Informationommittee [11] have advised that regular sustained aerobic exer-ise (e.g. running and swimming) may help reduce menopausalymptoms. Likewise, The North American Menopause Society [12]n their position statement concerning treatments for menopause-ssociated vasomotor symptoms recommended that symptomaticomen (mild-moderate) should first consider lifestyle changes,

ncluding participation in regular exercise.

.1. Current evidence

In 2011 the authors published a Cochrane review of exercise forhe management of vasomotor menopausal symptoms [13] whichoncluded that existing studies (6 trials) provided insufficient evi-ence to determine the effectiveness of exercise as a treatment forot flushes/night sweats in symptomatic women due to a lack ofobust studies. There was a weak trend where two (out of three)tudies that compared exercise with no treatment/control tendedo produce a small effect favouring exercise, but the number ofarticipants in this analysis was also small. The largest publishedrial (n = 165) at the time of the Cochrane review, which was also ofood methodological quality [14], found no significant differencesetween exercise and control groups but mental health was therimary outcome and as such the trial was not powered to detectifferences in hot flushes/night sweats.

One published RCT [15,16] of symptomatic women postdateshe Cochrane review that warrants comment here. A total of 176ymptomatic women were randomised to a control group or fol-owed a six month aerobic exercise programme. There was noignificant difference in hot flushes/night sweats as measured byuestionnaire at follow-up. When assessed by phone diaries, the

ntervention group reported significantly fewer night sweats, butot hot flushes, than the control group. While the study sampleas relatively large, there was no long term follow up and allarticipants were of white ethnicity, limiting generalisability. Fur-hermore, it appears that an atypical sample of menopausal womenas recruited, since the sample mean both groups suggests that

n average participants were only marginally overweight at base-ine (kg/m2 = 26.3 for intervention and 26.9 for control). In addition,ome women with very low levels of flushes at were included; theowest number of hot flushes reported by a participant at baseline

as 0.11/day, indicating that women who vary rarely experiencedot flushes were included.

.2. Potential mechanisms

There are plausible biological mechanisms by which exerciseould reduce vasomotor and other menopausal symptoms. Studiesave reported that women with higher adiposity experience moreevere hot flushes/night sweats [17–19] and weight loss has beeninked with decreases in hot flushes/night sweats [20]. Exercise isnown to have a beneficial effect on weight management and soould exert an effect on hot flushes in this way. It is hypothesisedhat endorphin concentrations in the hypothalamus decrease asestrogen production declines, enhancing the release of nore-inephrine and serotonin. Exercise may have a similar effect toT in the amelioration of vasomotor symptoms by increasing theresence of hypothalamic and peripheral ß-endorphin production21]. In addition, there is evidence that as endorphins increase, therequency and amplitude of luteinizing hormone decreases, whichegulate gonadotropin releasing hormone levels [22]. Research

23] has shown that active individuals have higher basal levels of

endorphins than those who are inactive. By these mechanisms,xercise may help to stabilise the thermoregulatory centre andiminish the risk of hot flushes. It has also been suggested that

76 (2013) 350– 356 351

exercise can improve mental health outcomes by providing adistraction or ‘time out’ strategy from daily worries [24] and thatexercise can enhance individuals’ feelings of accomplishment,thereby improving self-esteem [25].

1.3. Development work

In addition to the Cochrane review [13], we have alreadycompleted two observational studies [26,27], both patient sur-veys. In the first study [26] 1206/2399 women aged 46–55,recruited from general practices responded to a questionnairethat asked them about their menopausal symptoms, HT use andlevels of exercise participation. Approximately 67% (n = 845) ofresponders were perimenopausal or postmenopausal. Only 12%reported current use of HT and many were using a range of non-pharmacological alternatives. About 60% of responders were notregularly active and 74% indicated they might consider participat-ing in a trial of exercise and menopausal symptoms. Of responderswho were perimenopausal and postmenopausal (n = 845), 67%(n = 563) experienced vasomotor symptoms. This study indicatedthat the prevalence of hot flushes/night sweats was substantial,that most menopausal-aged women did not exercise regularly andthat exercise may be an acceptable intervention.

In our second observational study [27] we aimed to ascer-tain menopausal-aged (46–55 years) women’s preferences fordifferent methods of delivering pragmatic exercise interventions.Women were recruited from general practices. A postal ques-tionnaire was sent to 2766 eligible women by their GP, with aresponse rate of 61.2% (n = 1693/2766). In response to a seriesof options the questionnaire elicited their preferences in relationto how they would like an exercise intervention to be deliv-ered (e.g. by consultations, telephone, email, internet) and typeof intervener (e.g. GP, nurse, fitness advisor, peer support). Theemphasis was on offering participants preference option/choicesthat were low cost and pragmatic in order to have the potentialto be delivered relatively easily within NHS or community set-tings. Questions about preferences for modes of exercise/physicalactivities were also included. Strong preferences were expressedfor exercise interventions to be delivered or promoted by con-sultation with a physical activity/fitness advisor, support groupswith other women of similar age, DVDs, booklets and leafletsthat give information about exercise/health concerns during themenopause. There was an overwhelming preference for walkingbased activities, followed by dancing, swimming, cycling and aero-bics classes. Further analyses according to sub group (i.e. vasomotorsymptomatic versus non-vasomotor symptomatic, BMI category,exercise behaviour category and menopausal status) did not alterthese findings.

1.4. Summary

Given that the risk-benefits profile of HT has been ques-tioned recently and menopausal women are keen to usenon-pharmacological alternatives [9,28] the proposed research istimely. There has been a lack of robust research on the effects ofexercise upon vasomotor symptoms, consequently the question ofwhether exercise is an effective treatment for hot flushes/nightsweats 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 exercisefor treatment of hot flushes/night sweats have been prematureand research that can address this question in a robust way would

certainly help clarify these recommendations.

Our previous development work [26,27] has established thatexercise is likely to be acceptable to menopausal aged women andwe have established women’s preferences for different types of

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52 A.J. Daley et al. / Mat

xercise and modes of delivery [27]. We now need to pilot andetermine the acceptability of different exercise interventions toymptomatic menopausal women and investigate the effects ofhese preferred interventions on hot flushes/night sweats.

.5. Aims

This RCT initially aims to investigate the feasibility/acceptabilityf two exercise interventions identified from our previous pref-rence study, and if found to be feasible/acceptable, continue toecruit sufficient women to examine the effect of these interven-ions on hot flushes/night sweats and other outcomes relevant to

enopausal women. Cost data relating to the interventions willlso be collected.

. Methodology

.1. Design

This study is a randomised controlled trial (individual ran-omisation) with participants allocated to one of two exercise

nterventions or usual care on a 1:1:1 ratio. The work describedere will be carried out in accordance with The Code of Ethics of theorld Medical Association (Declaration of Helsinki) for experiments

nvolving humans.

.2. Study population

For feasibility/acceptability, we aim to recruit 165 inactive per-menopausal and menopausal symptomatic women, aged 48–57ears who have not used HT in the three months prior to baselinend randomise them to one of the three trial groups. However, if thenterventions were deemed feasible and acceptable and the recruit-

ent level high, we aimed to recruit 261 participants. In order forhe interventions to be considered acceptable, in the first 165 par-icipants more than 50% of consultations need to be delivered andf those invited to the support groups at least 50% should attendhem.

In our development work [27] we targeted women aged 46–55ears, but this age range included a large proportion of womenho were not perimenopausal or postmenopausal. Therefore, in

his trial we will recruit women aged 48–57 years to increase theikelihood that they will be perimenopausal or postmenopausal,nd thus potentially eligible to participate.

.2.1. General practices and PCTsFemale patients aged 48–57 years will be identified from gen-

ral practice records. Practices will then send a study invitationetter, information leaflet and screening questionnaire to identifiedatients on the list. Patients will be asked to return their screeninguestionnaire to the University research team. Non-responders wille sent a reminder about three weeks after the first mailing witho further contact thereafter. General practices from three Primaryare Trusts in the West Midlands will be informed about the trialnd asked to assist with patient recruitment.

.2.2. Pilot to assess symptom eligibilityThere are a number of ways in which we could assess eligi-

ility for the trial in relation to typical hot flushes/night sweatser day. We could use a screening questionnaire that asks partic-

pants to recall the average number of flushes/night sweats theyxperience, or they could complete both the questionnaire and a

rospective 7-day hot flush/night sweat diary. The approach weake might influence the response rate due to patient burden;herefore, it would be important to pilot these two approacheso assess average hot flush/night sweats frequency. Thus, we will

76 (2013) 350– 356

recruit a pilot practice where 50% of patients will be asked tocomplete the hot flush rating scale only [29] and 50% asked tocomplete both the hot flush rating scale plus a prospective 7-dayhot flush/night sweats diary. We will assess the response rate toboth methods, and provided data obtained was acceptable, usethe one with the highest response rate with the remaining prac-tices.

Patients who are currently experiencing, on average, five ormore hot flushes/night sweats daily (as measured by diary or ques-tionnaire in those who receive both), of any severity, will be eligibleto be randomised (see below for inclusion criteria). In all patientsthe screening questionnaire will assess menopausal status, HT use,menstrual cycle length, contraception/medication use and currentlevels of exercise to further ascertain eligibility.

2.3. Recruitment rate

Based on our previous pilot work [27], we conservatively expectthat about 10% of women per practice (assuming list size of5000 adult patients) will be aged 48–57 years and of these 3%will be vasomotor symptomatic, inactive, perimenopausal or postmenopausal, experiencing an average of 5 or more hot flushes/nightsweats per day and willing to take part (i.e. about 15 patients perpractice). Thus, we would need to recruit from 11 practices torecruit 165 participants and 17–18 practices to recruitment 261women.

2.4. Inclusion/exclusion criteria

2.4.1. Planned inclusion criteriaa) Women aged 48–57 years who are currently experiencing vaso-

motor menopausal symptoms and not used HT in previous threemonths.

b) Surgically and spontaneously perimenopausal (irregularperiods but at least one period in the previous 12 months)or postmenopausal women (no menstruation for >12 monthsprior to study).

(c) Inactive (not currently meeting the public health guidelines forphysical 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 thebaseline questionnaires by post, participants will be randomisedto one of two exercise interventions or usual care for six months.Group allocation will be by minimisation using menopausalstatus (perimenopausal or post menopausal) and BMI (under-weight/normal weight or overweight/obese) (using self reportedheight and weight). A web based randomisation programme willbe used to allocate participants to the groups. The allocationsequence will be generated using nQuery Advisor 7.0 with mixed

The methods of sequence generation will be concealed fromresearchers involved in recruiting and randomising participantsto the groups. Participants, researchers and those delivering theintervention cannot be blinded to group allocation.

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.6. Outcomes and allocation of patients to trial groups

.6.1. Primary outcomeIn the first instance the primary outcomes is the acceptability

f the two exercise interventions. If the interventions are shown toe feasible, thereafter the primary outcome is the effectiveness ofhe interventions in reducing hot flushes/night sweats frequency.

.6.2. Secondary outcomesProblem rating of hot flushes will be assessed using the hot

ush rating scale [29]. Menopause specific quality of life will beeasured by the Women’s Health Questionnaire (WHQ) [31], and

eneric QoL using the SF-12 [32]. Depression and anxiety will beeasured using the Hospital Anxiety and Depression Scale [33].

ubjective vitality [34], self-efficacy for exercise [35] and social sup-ort for exercise [36] will also be assessed. Self reported physicalctivity will be measured using the International Physical Activ-ty Questionnaire-short (IPAQ-short) [30]. Adverse events will beecorded.

A 50% random sample of all participants will be asked to wearn actiheart (CamNtech Ltd., UK) monitor for five consecutive dayst baseline and six months follow up, to provide objective datan changes in physical activity patterns over time. The actiheartonitor is an innovative, compact device that continuously records

hysical activity and heart rate with a high level of accuracy. Levelsf caloric expenditure can also be determined using the informationcquired by the monitor.

.6.3. Demographic and process dataIn addition to collecting data concerning demographics, repro-

uctive history etc. (see earlier comments) women will be askedbout their use of complementary and alternative medicine forymptom control and health behaviours. Self reported height andeight will be collected in all participants, as well as objectively in

hose randomised to wear the actiheart monitor. Current medica-ion use will also be recorded at baseline and follow-ups. Cost datarom both the NHS and individual perspectives will be collected.

All participants will be asked to complete prospective 7-day hotush/night sweat diaries at weeks 7, 14, and 21 after randomisationo provide an indication of the profile of their symptoms during thentervention phase of the study. Participants will be asked to recordhe frequency and severity of their symptoms. In addition, thoseandomised to the intervention will also complete 7-day prospec-ive exercise logs that will detail the amount and type of exercisehey achieve during these weeks. The hot flush diaries and physicalctivity logs will be sent and returned by post.

.7. Assessments

Outcome measures will be assessed at baseline and six monthsimmediately post intervention) and 12 months from randomisa-ion. Follow up at six months is deemed the primary time point ofnterest. Outcome questionnaires will be mailed to participants athe appropriate time points. The actiheart is worn at baseline andix month follow up and fitted at a home visit by a member of theesearch team. Those wearing the actiheart will complete the IPAQfter they have worn the actiheart.

.8. Sample size

A sample size of 87 participants per group is sufficient to detect 50% reduction in the mean number of hot flushes/night sweatser week (e.g. 40 reduced to 20 (sd = 31.6)) [28] with 80% powernd 5% significance level, allowing for 20% drop out between thentervention and usual care groups.

76 (2013) 350– 356 353

3. Interventions

3.1. Rationale for the selected intervention – pilot work

As discussed earlier, our development work [27] examinedmenopausal aged women’s preferences for different types of exer-cise interventions and results were used to develop the twointerventions used in this trial. Women’s strong and overwhelmingpreference for consultations with health and fitness trainers willbe used as the basis of both exercise interventions, which will thenvary according to participants’ preferences [27] for other types ofadditional support (see below). As women had a clear preference forwalking [27] we will predominately encourage this mode of exer-cise, but this will not preclude participants from doing all types ofexercise that they enjoy.

In developing the exercise interventions, consideration was alsogiven to the Cochrane review [37] of physical activity interventionswhich reported a greater consistency of effect estimates for thosestudies where there were four or more contacts between the staffdelivering the intervention and participants, compared to studieswhere there were less than four contacts. This review [37] alsoshowed that a mixture of professional guidance and self-directionplus on-going support leads to more consistent effect estimates.The intervention will incorporate behaviour modification tech-niques which are grounded in behaviour change theory and addressthe specific determinants of exercise behaviour change. Two com-monly applied approaches to health behaviour change are socialcognitive theory [38] and the transtheoretical model [39]. Thisapproach is important because interventions based on theories ofbehaviour change that teach behavioural skills and that are tailo-red to individual needs, are associated with longer-term changesin behaviour [37].

3.2. Behavioural goal of the interventions

The intervention will last six months. Six months has beenselected as the intervention duration as this is likely to be the max-imum time period for which a pragmatic, low cost intervention canbe viable. While current public health guidelines suggest that adultsshould achieve at least 30 min of moderate intensity exercise on atleast 5 days per week [10] few people meet this target currently;and this target may not be initially desirable or achievable by pre-viously sedentary women. Therefore, the intervention goal will beprogressive over time. The initial goal of the interventions (weeks1–12) will be for participants to progress towards accumulating30 min of moderate intensity exercise on three days per week. Dur-ing weeks 13–24, the interventions will encourage participants towork towards accumulating 30 min of moderate intensity exerciseon 3–5 days per week, in broad agreement with current publichealth guidelines [10]. Patients will be encouraged to first focuson the frequency of their exercise, and then duration.

3.3. Exercise interventions components

Intervention one will involve two one-to-one consultations witha physical activity facilitator (PAF) that last 40–60 min (duringmonths 1 and 2). Intervention one will also involve participantsbeing sent a DVD, booklet and five study leaflets at various pointsduring the intervention. These materials will provide informationabout the menopause, benefits of exercise during menopause anddescribe strategies that can be used to enhance exercise levels. Theimportance of healthy eating will also be emphasised. The DVD

has been developed specifically for this study and contains casestudies of women who have experienced vasomotor symptomsduring the menopause transition; these women discuss strategiesthat they used to motivate themselves to exercise and the impact

354 A.J. Daley et al. / Maturitas

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t had on their health and well-being. As women will receive theVD, booklet and leaflets in the post they will also serve as reg-lar prompts for action (see Fig. 1). Intervention two will involvehe same consultations as used in intervention one (as describedbove), but in this group participants will also be invited to takeart in three support groups. The primary purpose of these groups

s to bring women together to share experiences about exercis-ng during menopause and offer regular encouragement to eachther. The support groups will also focus on giving informationbout the symptoms of menopause and the importance of healthyating during menopause. Support groups will take place in par-icipants’ local communities, facilitated by the research team andast 75–90 min (see Fig. 1). The personalised consultations will beentred on equipping women with the skills, knowledge and con-dence needed to participate in regular exercise and delivered by

PAF in participants’ home or another setting of their choice. Therst consultation will focus on uptake of exercise and on enhanc-

ng motivation, self-efficacy for exercise, overcoming barriers andeveloping appropriate activity goals. Participants will be given aedometer as a motivational tool. Where possible a short ‘walknd talk’ session will be incorporated within the first consultationo that practical issues such as perceived exertion monitoring andxercise safety can be explored with women. Four weeks after this,

second consultation centred on the prevention of relapse backo sedentary behaviour and/or improving maintenance of an activeifestyle will be conducted.

.4. Usual care

There will be no interference with usual care in participantsandomised to this group. Usual care will be offered an exerciseonsultation and a pedometer at the end of their involvement inhe study.

. Analysis plan

.1. Primary analysis

The acceptability of the interventions will be determined byompliance/attendance with each of the intervention components;his data will be presented descriptively. To examine the effec-

iveness of the intervention on symptoms, comparisons will be

ade between the mean number of symptoms per week in thehree groups at six months follow-up using analysis of covari-nce. Adjustments will be made for baseline symptom frequency,

76 (2013) 350– 356

menopausal status and BMI; and also antidepressant and HT userecorded at six months follow-up. Paired comparisons will be madebetween all three groups with p values being adjusted for multipletesting.

4.2. Secondary analysis

To identify any longer term effects of the intervention on symp-toms, repeated measures mixed modelling of hot flushes/nightsweats will be undertaken to compare groups across all time points,adjusting for covariates and multiple comparisons as previouslydescribed.

Secondary outcomes including the hot flushes/night sweats,quality of life, subjective vitality, depression/anxiety, self-efficacyfor exercise and physical activity (objective and self-report) willalso be compared at the six and 12 month follow-up using thesame method. The frequency, intensity, type and duration of exer-cise will be summarised in MET/min. Bland–Altman plots willbe used to compare the physical activity measured by the IPAQwith that measured objectively by the actiheart. The number ofparticipants achieving varying thresholds of physical activity atfollow-up will be documented according to BMI and menopausalstatus in both intervention groups. The number of adverse eventsthat occur during the intervention period will be summarised bygroup.

Bootstrapped estimates will be calculated where there is evi-dence of non-normality in the residuals. The impact of missingprimary and secondary outcome data will be explored by sensi-tivity analysis including multiple imputation. All analyses will beby intention to treat.

5. Qualitative study

In-depth interviews will be held with trial participants, whowill be purposively sampled to ensure interviews are held witha range of women. Within this sampling approach, we will aim torecruit women who vary by age, ethnicity and social class. About20 trial participants (15 intervention and five usual care) will beinterviewed. This will take place once participants have completedthe trial, so that data can be used to illuminate possible reasonsfor quantitative findings. Women will be approached to provideconsent towards the end of their involvement in the trial. Inter-views will be face-to-face and will explore participants’ viewsand 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 overallunderstanding of each participant’s views and experiences, and todevelop a coding framework. Each transcript will be imported intoNVivo to allow electronic coding and retrieval of data. Transcriptswill be coded by independent researchers in order to maintain reli-ability of coding. Analysis will rely upon “constant comparison” andwill continue until no new themes emerge.

6. Discussion

Because menopausal women are increasingly reluctant to useHT and other pharmacological agents, finding evidence-based non-pharmacological alternatives has become critical. Exercise hasshown some promise of being one such intervention, but cur-rent evidence does not allow any stronger conclusion than this at

the present time. We hope that this trial will contribute towardsincreasing the evidence on the effectiveness of exercise as a treat-ment for vasomtotor symptoms. Moreover, whilst both the RoyalCollege of Obstetricians and Gynaecologists in the UK [11] and

A.J. Daley et al. / Maturitas 76 (2013) 350– 356 355

Practice sends study in formation le tter to patients with ho t flus h/n igh t swe ats (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

Exper ienc ing 5 or more HF/NS

Exper ienc ing less than 5 HF/NS

Not eligible–no further ac tion

No further action

Apply other trial criteria

Baseline as sessment of ou tcomes

Randomis atio n to trial gro ups

Exercise intervention 1 (Con sulta tions plus leaflets & DVD)

Exerci se intervent ion 2 (Con sulta tions plus support grou ps)

Usual care

6 mont h assess ment of outco mes

Semi-structuredintervie ws with trial com pleter s in inter ventions and usual care groups

Ineligible – no further ac tion

12 month assessment of outcomes (except actiheart )

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he North American Menopause Society [12] recommend thatomen be advised to consider aerobic exercise as a treatment

or vasomotor menopausal symptoms, this is not based on goodvidence thus more high quality research is needed. We hopehe findings of this research will inform future updates of clinicaluidance around the world on treatments for vasomotor symp-oms.

Exercise may have additional benefits for women in termsf improving cardiovascular health and reducing weight, whichave been identified as particular concerns for menopausal aged

omen. Moreover, exercise participation rates have been found

o be low for menopausal aged women [26], which may indeedncrease their risk of diseases in later life; therefore exercise couldrovide additional health benefits in this population of women at

flow.

a time in their lives when their risk of several chronic diseases isincreased.

Contributors

AJD developed the initial idea for the study with assistance fromCM, HSL, & MR. AT, SC and MH also contributed to the developmentof the trial protocol at a later stage. AR is the trial statistician andperformed the power calculations and wrote the analysis plan. Allauthors have seen and agreed the final version of the manuscript.

Competing interest

None.

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unding

Amanda Daley is supported by a National Institute for Healthesearch Senior Research Fellowship.

thical approval

Favourable ethical opinion for this study was granted by theest Midlands Research Ethics Committee in March 2010 (ref:

0/H1208/3).

eer review

Peer review was coordinated independently by Professor Tom-aso Simoncini and Margaret Rees (Editor in Chief) and an authoras blinded to the process.

cknowledgements

The views expressed in this publication are those of the authorsnd not necessarily those of the NHS, The National Institute forealth Research or the Department of Health.

eferences

[1] National Institutes for Health state of science conference statement on manage-ment 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 estro-

gen plus progestin in healthy postmenopausal women: principal resultsfrom the Women’s Health Initiative randomised controlled trial. JAMA2002;288:321–33.

[5] Million Women Study Collaborators. Breast cancer and hormone replacementtherapy in the million women study. Lancet 2003;362:419–27.

[6] Lawton B, Rose S, McLeod D, et al. Change in use of hormone replacementtherapy after the report from the women’s health initiative: cross sectionalsurvey of users. BMJ 2003;327:845–6.

[7] Hersh A, Stefanick M, Stafford R. National use of postmenopausal hormonereplacement therapy: annual trend and response to recent evidence. JAMA2004;291:47–53.

[8] UK Committee for Safety of Medicines. HRT: update on the risk of breast cancerand long-terms safety. Curr Prob Pharmacovigil 2003;29:1–3.

[9] Newton K, Buist DS, Keenan NL, Anderson LA, LaCroix AZ. Use of alternativetherapies for menopause symptoms: results of a population-based survey. AmCol Obstet Gynecol 2002;100:18–25.

10] Department of Health. At least five a week: evidence on the impact ofphysical 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 Commit-tee. 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-associatedvasomotor symptoms: position statement of The North American MenopauseSociety. Menopause 2004;11:11–33.

13] Daley A, Stokes-Lampard H, MacArthur C. Exercise for vasomotor menopausalsymptoms. Cochrane Database Syst Rev 2011;5:CD006108.

[

[

76 (2013) 350– 356

14] Elavasky S, McAuley E. Physical activity and mental health outcomes dur-ing 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 flushesand 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 train-ing on menopausal symptoms—a randomized controlled trial. Menopause2012;19:691–6.

17] Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle fac-tors to symptoms in a multi-racial/ethnic population of women 40–55 years ofage. Am J Epidemiol 2000;152:463–73.

18] van Poppel MN, Brown W. “It’s my hormones, doctor”-does physical activityhelp with menopausal symptoms? Menopause 2008;15:78–85.

19] Thurston RC, Sowers MR, Chang Y, et al. Adiposity and reporting of vasomo-tor symptoms among midlife women: the study of women’s health across thenation. Am J Epidemiol 2008;167:78–85.

20] Huang AJ, Subka L, Wing R, et al. An intensive behavioural weight loss inter-vention and hot flushes in women. Arch Intern Med 2010;12:1161–7.

21] Bortz WM, Angwin P, Mefford IN. Catecholamines, dopamine and endorphinlevels 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 pitu-itary 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 adrenocorticotropinafter incremental exercise and marathon running—female response. Eur J ApplPhysiol 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 interven-tion for changing physical self-perceptions over 9 months. Health Psychol2005;24:11–21.

26] Daley AJ, MacArthur C, Stokes-Lampard H, et al. Exercise participation, bodymass index and health-related quality of life in menopausal aged women. Br JGen 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. Maturitas2011;68:174–8.

28] Daley AJ, MacArthur C, McManus R, et al. Factors associated with the use of com-plementary medicine and non-pharmacological interventions in symptomaticmenopausal women. Climacteric 2006;9:336–46.

29] Hunter MS, Liao KLM. A psychological analysis of menopausal hot flushes. Br JClin Psychol 1995;34:589–99.

30] Craig CL, Marshall AL, Sjöström M, et al. International physical activityquestionnaire: 12-country reliability and validity. Med Sci Sports Exerc2003;35:1381–95.

31] Hunter MS. The women’s health questionnaire: a measure of mid-agedwomen’s perceptions of their emotional and physical health. Psychol Health1992;7:45–54.

32] Ware JE, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construc-tion of scales and preliminary tests of reliability and validity. Medical Care1996;34:220–33.

33] Zigmond AS, et al. The Hospital Anxiety and Depression Scale. Acta PsychiatrScand 1983;67:361–70.

34] Bostic TJ, Rubio DM, Hood M. A validation of the subjective vitality scale usingstructural equation modeling. Soc Indicators Res 2000;52:313–24.

35] Sallis JF, Pinski RB, Grossman RM, et al. The development of self-efficacyscales for health-related diet and exercise behaviours. Health Educ Res1988;3:283–92.

36] Sallis JF, Grossman RM, Pinski RB, et al. The development of scales to measuresocial support for diet and exercise behaviours. Prev Med 1987;16:825–36.

37] Hillsdon M, Thorogood M, Foster C. Interventions for physical activity

38] Bandura Albert. Social learning theory. Englewood Cliffs, NJ: Prentice Hall;1976.

39] Prochaska JO, Velicer W. The transtheoretical model of health behaviourchange. Am J Health Promot 1997;12:38–48.