TITLE: PCOS lifestyle program
AUTHORS: Geranne Jiskoot, J.S.E Laven, J.J. van Busschbach, C. de Klerk, J. de Niet

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block">Obesity in women with polycystic ovary syndrome (PCOS)</div><div class = "text-block">negatively affects all clinical features, and a 5 to 10% weight</div><div class = "text-block">loss has shown promising results on reproductive, metabolic</div><div class = "text-block">and psychological level. Incorporating a healthy diet,</div><div class = "text-block">increasing physical activity and changing dysfunctional</div><div class = "text-block"><span>thought patterns in women with PCOS are ke</span><span style = "font-weight:bold;">y po</span><span>ints in</span></div><div class = "text-block">losing weight. The present study is a longitudinal randomized</div><div class = "text-block"><span>controlled trial (RCT) to study the effecti</span><span style = "font-weight:bold;">ven</span><span>ess of a</span></div><div class = "text-block">three-component 1-year cognitive-behavioural lifestyle</div><div class = "text-block">intervention in overweight/obese women with PCOS. We</div><div class = "text-block">will also explore whether mobile phone applications are effective</div><div class = "text-block">in supporting behavioural change and sustainable</div><div class = "text-block">weight loss. The primary aim of the 12-month intervention</div><div class = "text-block">is to explore whether a three-component 1-year cognitivebehavioural</div><div class = "text-block">lifestyle intervention is effective to decrease</div><div class = "text-block">weight, when compared to usual care. We expect that CBT</div><div class = "text-block">provided by a multidisciplinary team, especially combined</div><div class = "text-block">with SMS, is effective in developing a healthy lifestyle and</div><div class = "text-block">achieving a long-term weight loss in women with PCOS.</div><div class = "text-block">Losing 5– 10% body weight will improve various PCOS</div><div class = "text-block">characteristics. Consequently, we expect to show that CBT</div><div class = "text-block">provided by a multidisciplinary team improves reproductive</div><div class = "text-block">and metabolic outcomes, as well as quality of life, while at</div><div class = "text-block">the same time being cost-effective in women with PCOS.</div></div>

[STEPS]
?. [Background]
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects 5–10% of women in their reproductive years [1]. According to the ESHRE/ASRM Rotterdam consensus [2], the diagnosis of PCOS requires at least 2 of the following 3 criteria: oligoovulation or anovulation (irregular or no menstrual cycle at all), clinical (hirsutism) and/or biochemical signs of hyperandrogenism (elevated free androgen index or elevated testosterone levels), polycystic ovarian morphology (on ultrasound), and the exclusion of other aetiologies that might cause hyperandrogenism. PCOS women will generally experience one or more of the following symptoms in varying degrees: hirsutism (excessive body hair growth), acne, anovulatory infertility, obesity, insulin resistance and dyslipidaemia [2, 3]. The incidence of overweight and obesity in PCOS women is between 50% and 60%[3]. The prevalence of obesity in the general population is increasing, and this might result in an even higher incidence of PCOS in the future [4, 5]. The current prevalence of overweight and obesity is significantly higher in PCOS women, especially in Caucasian women [6]. Overweight in women with PCOS negatively affects all clinical features [3, 7-9] and gaining weight aggravates also psychological aspects. Women with PCOS report a major impact on their quality of life (QoL) due to PCOS symptoms [10, 11] and experience more distress compared to women without PCOS [12]. Weight concerns in particular appear to have the largest impact on QoL, compared to other PCOS symptoms such as amenorrhea, oligomenorrhea, hirsutism and acne [13]. Obesity is also a risk factor for lower self-esteem and greater sexual dissatisfaction in women with PCOS, compared to age matched controls [14, 15]. PCOS women with amenorrhoea seem to have lower levels of self-esteem and greater fear of negative appearance compared to PCOS women with oligo-amenorrhea [16]. Whether PCOS women have a unique predisposition to obesity is not yet clear [17]. A recent study by Louwers et al, looking into the genetic predisposition for overweight or obesity, did not discover any differences in the number of risk alleles for obesity between women with PCOS and the controls [18]. Although women with PCOS generally do have a healthy diet, they seem to have a higher caloric intake and are physically less active, compared to controls without PCOS [19]. Also, women diagnosed with PCOS more often use a self-initiated inadequate diet than controls [20]. Insulin resistance might play a mediating role in the effect of obesity on metabolic and reproductive symptoms in PCOS [21]. Other authors do suggest that the high prevalence of obesity might be a result of selection and referral bias of obese PCOS women [22]. In summary, much about the link between PCOS and obesity remains unknown [1]. It is still unclear whether obesity is the cause, or an effect of the disease itself [6, 23]. There is a large number of small (one or two-component) studies demonstrating that losing 5 to 10% of initial body weight improves reproductive, metabolic and psychological features in PCOS women [24]. Moreover, it often leads to ovulation and subsequent pregnancy, [7, 25-27] as well as a reduction in miscarriage rates in PCOS women [4, 7]. Weight loss also reduces the risk of Type II Diabetes Mellitus and the incidence of the metabolic syndrome in the long term [7, 27]. Additionally, studies have indicated that decreasing intra-abdominal fat tissue in particular results in the restoration of ovulation [28], even when women remain within their World Health Organisation (WHO) weight class after weight loss [29, 30].Recent work from Mutsaerts et al [31] and Dokras et al [32] showed different results. A mean weight loss of 4.4 kg following a two-component lifestyle treatment of 26 weeks did not result in a significant difference in live birth rates compared to a weight loss of 1.1 kg in the control group. Also, there was no difference in pregnancy and neonatal complications between groups [31]. Weight loss by the Look AHEAD protocol (16 weeks) or the use of the oral contraceptive pill shows significant improvement in both groups at physicial and mental domains related to quality of life, depression and anxiety [32]. At the ESHRE/ASRM PCOS meeting in 2010, a consensus was reached that lifestyle should be optimized before conception [23] to improve the effectiveness of fertility treatment [33, 34] and to improve (mental)health across a woman’s lifespan as well as that of her child to be [27]. However, no international evidence based protocol exists for the long-term treatment of overweight and obesity in this particular group of obese women [35].The biggest challenge in weight management programs is to achieve a reasonable andsustainable weight loss [36, 37]. Many obesity interventions compare one-component (physical activity or nutrition intervention) with two-component (physical activity and nutrition or nutrition and counselling) interventions. Three-component (physical activity, nutrition and counselling) lifestyle interventions seems to have the biggest effect, compared to one or two components [38]. Weight loss programs in general seem to be effective in the short term [39]; however, most of the initial weight loss is regained within one year [36]. Long term weight-loss seems the biggest challenge for the “global obesity epidemic” according to the WHO [40]. Incorporating a healthy diet, increasing physical activity and changing dysfunctional thinking patterns in women with PCOS are key points in losing weight [41].However, treatment adherence is often low [36] and drop-out rates are high. The longer the treatment, the higher the chance for participants to drop-out, and indeed the highest dropout rates are reported in interventions that last 24 weeks or longer [42]. This relation between the drop-out rate and the duration of therapy is particular worrying, as long lasting lifestyle changes are preferred. Patients who are likely to drop out will benefit most from adherence to a long-term lifestyle program compared to patients not at risk to drop out. Fauser et al. commented that more research is needed to optimize lifestyle interventions, maximizing weight loss and minimizing drop-out rates for PCOS women with a wish to conceive [23]. A possible solution to increase therapy adherence and reduce the drop-out rate is support by mobile phone applications. Weight loss interventions making use of internet and mobile phone applications have emerged to induce behavioural changes [43]. There is a growing body of literature on Short Message Service (SMS) and smart phone interventions for obesity treatment, indicating that tailored text messages are more effective than generic ones [44, 45]. Smart phone and mobile phone applications seem effective when embedded in an intervention program [46]. Studies have indicated that sending SMS results in weight maintenance up to 12 months after completion of cognitive behavioural treatment (CBT), [47] and supports controlling the desire to eat and promoting an active lifestyle [48]. Moreover, the use of SMS has shown to improve adherence and decrease the drop-out rates in weight loss treatments [49], which is associated with improvement in weight-related behaviours and weight outcomes [50]. Fauser et al. commented that more research is needed to optimize lifestyle interventions, maximizing weight loss and minimizing dropout for PCOS women with a wish to conceive [23].
?. [Research hypothoses]
Primary:1) A multidisciplinary 1-year cognitive-behavioural lifestyleintervention (with or without SMS) is more effective todecrease weight in 12 months, compared to usual care.Secondary:2) A multidisciplinary 1-year cognitive-behaviourallifestyle intervention (with or without SMS) iseffective to decrease weight by 4.0 BMI points at12 months, compared to usual care.3) SMS maintenance treatment in combination with amultidisciplinary 1-year cognitive-behavioural lifestyleintervention is more effective than the multidisciplinary1-year cognitive-behavioural lifestyle intervention alone,in terms of weight loss maintenance and drop-outreduction.4) A multidisciplinary 1-year cognitive-behaviourallifestyle intervention (with or without SMS) iseffective in improving the menstrual cyclicity as well as anthropomorphometric, ultra-sonographic,endocrine and psychological parameters in womenwith PCOS.
?. [Aim]
The aim of this study is to examine whether CBT, providedby a mental health professional working in amultidisciplinary team with a dietician and a physicaltherapist (a three-component intervention), is effectiveto decrease weight, compared to usual care at the end oftreatment in obese women with PCOS. Furthermore, weexplore whether mobile phone applications are effectivein supporting behavioural change and sustainableweight loss.
?. [Design]
The present study is a longitudinal RCT measuringthe effectiveness of a three-component multidisciplinary1-year cognitive-behavioural lifestyle interventionin overweight/obese women with PCOS. It is a threearmedRCT comparing three groups: 1) CBT providedby a multidisciplinary team or; 2) CBT provided by amultidisciplinary team and Short Message Service(SMS) or; 3) usual care: encouraged to lose weight bypublicly available services (control group), see Fig. 1. Patients will be included in the trial at the departmentof Obstetrics and Gynaecology of the ErasmusMC in Rotterdam, the Netherlands.
?. [Design]
ParticipantsWomen with menstrual cycle disorders are systematicallyscreened using the same standardised protocol i.e. the socalled CyclusOLigoAmenorroe (COLA) protocol. TheCOLA protocol includes a family and reproductive history,antropomorphometric, ultrasonographic assessments andscreening. Based on this screening, women are diagnosedaccording the World Health Organisation (WHO) classification.Women with WHO 2 normogonadotropic normoestrogenicanovulation are further classified using the Rotterdam consensus criteria for PCOS and non-PCOS.Patients who meet the inclusion and exclusion criteria(shown in Table 1) are eligible. At enrolment, all patientsreceive detailed information about the role of weight loss inPCOS and the benefits of lifestyle modification.The gynaecologist presents the patient informationabout the study using a patient information leaflet. After2 weeks, patients are contacted by telephone in order toassess whether they are willing to participate in thestudy. In order to participate, patients need to sign theinformed consent form and return it by regular mail. Assoon as this form is received out our research office,appointments for baseline measurements are made.
?. [Design]
RandomisationAt the baseline, after the initial assessment, participantsare randomized at a 2:1 ratio into the following groups:1-year CBT lifestyle intervention with SMS (n = 78), 1-year CBT lifestyle intervention without SMS (n = 78), orthe control group who receives usual care (n = 78) usinga computer-generated random numbers table. A researchnurse, who is not involved in the study, carriesout the randomisation. Assignment is made by sequentiallynumbered, identical, sealed envelopes, eachcontaining a letter designating the allocation (i.e. “A” forintervention with SMS, “B” for intervention withoutSMS and “C” for control,).
?. [Design]
InterventionThe 1-year multidisciplinary lifestyle intervention aims at:1) changing cognitions; 2) changing dietary habits; 3)encouraging and promoting physical activity; and 4) activatingsocial support; and consists of twenty 2.5 h groupsessions. The first 1.5-h of every group session is supervisedby a mental health professional and a dietician. Thelast hour of each session is supervised by a physical therapist.Each lifestyle intervention group consists of a maximumof 10 patients to ensure that there is sufficientindividual attention for every participant. Additionally, participants receive five individual counselling sessions of45 min with a mental health professional, five individualsessions with a physical therapist and five with a dietician.We developed the “PCOS lifestyle textbook” for participants,which describes the activities of each group sessionand the homework assignments. To standardize the treatmentand to facilitate the therapist’s treatment adherence,we developed a therapist manual, which includes protocolsfor each session. The manual also includes Power-Point slides to present at each group session.
?. [Design]
Phase 1: first 3 months (session 1 to 11)We divided the 20 group sessions into four phases. Theoutline of each session is presented in Table 2. In the firstphase of the program, the group sessions are held weekly.CBT techniques are used to create awareness and torestructure dysfunctional thoughts about lifestyle (food &exercise), weight (loss) and self-esteem. The Dutch foodguide (DFG) is used as a guideline for healthy eating and isthe main guideline during the nutritional sessions run bythe dietician. Subjects receive the DFG guide for womenaged 19 to 50 (Table 3) [51]. Based on the DFG, a healthywoman with a normal weight and regular exercise, maytake in up to 2000 kilocalories in total, consisting of 1700kilocalories for breakfast, lunch and dinner, and another300 kilocalories for (healthy) snacking. The take-up of 2000kilocalories in total is normally advised for weight maintenance.Hence, for most women in the lifestyle program this(reduced intake) will result in weight loss. During phase 1,we emphasize that participants should start making healthy,sustainable food choices and to avoid “restrained” behaviourlike skipping meals and reducing food variance [52].The physical therapist encourages participants to useexercise as part of their daily routine, [53] according tothe Global Recommendations for physical activity by theWorld Health Organisation, [54] and advises:– To do 5 days of moderate physical activity for30 min each day; and– To do vigorous exercise 1 to 3 days a week, for atleast 20 min per session; and– To perform 8 to 10 muscle-strengthening activitiesinvolving major muscle groups twice a week.Phase 2: month 3 to 6 (session 12 to 16)In the second phase of the program, the group sessionsare held once every two weeks. During this phase participantsare motivated to develop a structured eating patternto avoid over-restriction and under-restriction, like bingeeating and restrained eating [55]. The frequency of faceto-face contact decreases over time, to stimulate participantsto maintain healthy eating and physical activity. Thisis based on the principles of ‘proactive coping’ to promote self-regulation [56]. Also, behavioural skills developed duringphase 1 of the intervention are reinforced [57].Phase 3: month 6 to 9 (session 17 to 19)In the third phase of the program, the group sessions areheld once a month. Participants learn about relapse managementand maintenance of their weight loss. By usingproactive coping, participants set new goals for the next 3 months aimed at maintaining a healthy lifestyle. Individualcounselling sessions are planned if needed at the requestof the participant.Phase 4: final 3 months (session 20)During the final 3 months of the program, there are noscheduled group sessions. Participants can contact the multidisciplinary team if individual counselling sessionsare needed.There is an outreach policy to motivate participants tocome to the measurement sessions, unless the participantindicates to withdraw from the study. Participationin the lifestyle intervention terminates if the participantmisses more than 3 out of 20 group sessions. In suchcases, the measurements will also stop. For obvious reasons,the intervention and the measurements will alsostop when the participant is pregnant.
?. [Design]
Maintenance intervention by SMSAt the 3 month point, participants are randomly assignedto SMS support or CBT without SMS support. Participantswill be sending weekly self-monitored informationregarding their diet, physical activity and emotions bySMS to the mental health professional for the next9 months (Table 4).A semi-automated software program generates feedbackin response to the incoming messages. These feedbackmessages provide social support, encourage positivebehaviour and empower behavioural strategies. Themental health professional assesses whether the suggestedfeedback is applicable before sending it to the participant.In addition, participants receive two messages per weekaddressing eating behaviour (self-monitoring, barriers,binge eating, eating pace, emotional eating, food choices,portions, planning, preparation, stimulus control, socialeating, sugar sweetened beverages) and physical activity(motivation, fun facts, sedentary behaviour). There are fivetypes of messages, as shown in Table 5.
?. [Design]
Control group: usual careJust like the lifestyle intervention group, the controlgroup visits the hospital after the initial assessment duringthe 4 consecutive occasions at which they are similarlyassessed as the CBT lifestyle intervention group.During these 5 measurement moments they have ashort, unstructured consult with their treating physician.Participants in the control group are encouraged to lose weight through publicly available services (i.e. diets, visitinga dietician, going to the gym or participating inpublic programs such as Weight Watchers®) and usesimple strategies, including self-monitoring of their diet.The physician also mentions the risk of overweight forboth mother and child, and the relation between overweightand fertility. If patients fail to achieve their targetweight during the 12-month study period (see below),they can participate in the lifestyle intervention, but arenot included in the trial. At the Erasmus MC, patients diagnosed with PCOSreceive ovulation induction treatment when shifted to alower BMI category. Meaning: 1) a weight loss of 4.0BMI points; 2) a BMI over 3 months. The intervention group receivesovulation induction treatment after 1) a weight loss of4.0 BMI points; 2) a BMI the intervention group for more than 1 year.
?. [Outcome measures]
The primary outcome of this study is to test whether CBTprovided by a mental health professional, working in amultidisciplinary team with a dietician and a physical therapist(a three-component intervention), is effective todecrease weight compared to usual care (control) at theend of the treatment. Secondary outcomes include: reproductive,drop-out, quality of life, healthy diet, physicalactivity, metabolic and endocrine improvements, thehealth of the (unborn) child. All outcome variables aremeasured at the start of the study, and again at 3 months,6 months, 9 months and 12 months. All outcome measuresare displayed in Table 6. Below we give more detailsabout the collection of the secondary outcomes.
?. [Sample size]
The original sample size calculation in 2009 was basedon an anticipated effect of a difference between thegroups of 0.45 in terms of Cohen’s d in the primary outcomevariable (BMI), with a power (1-beta) of 0.80 andan alpha level of 0.05 (two-sided) in a 2:1 ratio. This ratiowas required for analysis of the secondary outcome:the effect of SMS within the intervention group. This resultedin 156 patients to be enrolled in the interventiongroup and 78 patients in the control group, a total of 234. This number was registered at the Dutch TrialRegistry (TC 2450). On behalf of the Grant Foundation(MRace), an interim analysis was performed in May2014. After inclusion of 150 patients, we applied an interimpower analysis to the complete cases. The controlgroup had a reduction from 33.3 ± 6.8 kg/m2 to 32.6 ±6.6 kg/m2, an effect of Cohen’s d = 0.10, whereas the lifestyleintervention group showed a reduction from 33.8 ±4.8 kg/m2 to 31.3 ± 5.1 kg/m2, an effect of d = 0.52 and adifference of 0.42. For the sample size calculation, weapplied the method described by Aberson [71], with apower of 0.90, a two-sided alpha of 0.025 (corrected forthe interim analysis) and five repeated measures linearlydecreasing. We observed an intercorrelation of about0.90 between all measurements. Maintaining a ratio of2:1, the required sample is 84 participants in the lifestyleintervention and 42 in the control group, a total of 126complete cases. With an observed drop-out proportionof 40%, a total of 210 participants are needed for thestudy. We anticipated to have a relatively high drop-outrate, because pregnancy leads to exclusion. Note thatthis sample size calculation is a conservative number, asit is based on a complete case analysis of variance. Theintended multilevel analysis provides more power.
?. [Statistical analyses]
Mixed modelling will be applied for longitudinal analyses ofthe data by using SPSS version 21. Mixed modelling can efficientlydeal with missing data and unbalanced time-points[72]. This analysis will include two levels: the patients willconstitute the upper level, and their repeated measures thelower level. First, for each outcome variable a saturatedmodel will be postulated, with the primary or/and secondaryoutcomes as dependent variables. The saturated modelswill include treatment group, time, quadratic time, logarithmof time, and all treatment-time interactions as fixedeffects. The deviance statistic [73] using restrictedmaximum likelihood [74] will be applied to determine thecovariance structure. Next, the saturated fixed part of themodels will be reduced by eliminating insignificant fixedeffects using Wald tests, respecting that interaction effectsmust be nested under their main effects [75]. The significanceof the difference between the saturated models andthe parsimonious final models will be determined with thedeviance statistic using ordinary maximum likelihood. Theresiduals of the model will be checked for normal distribution,which is necessary for a correctly fitted mixed model.Effect sizes will be calculated by dividing the differencesbetween time-point and baseline estimations and the estimatedbaseline standard deviation. The definition of Cohenwill be used for the interpretation of the effects sizes: aneffect size of 0.20 is considered a small effect, 0.50 mediumand 0.80 a large effect [76].
?. [Citations]
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