Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update

Nicoletta Biglia1, Valentina E Bounous1, Francesco De Seta2, Stefano Lello3, Rossella E Nappi4 and Anna Maria Paoletti5

1Division of Gynecology and Obstetrics, Department of Surgical Sciences, School of Medicine, University of Torino, Largo Turati 62, 10128 Torino, Italy 2Institute for Maternal and Child Health-IRCCS ‘Burlo Garofolo’, University of Trieste, via dell’Istria 65/1, 34137 Trieste, Italy 3Department of Woman and Child Health, Policlinico Gemelli Foundation, Largo Gemelli 1, 00168 Rome, Italy 4Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Viale Camillo Golgi 19, 27100 Pavia, Italy 5Department of Obstetrics and Gynecology, Department of Surgical Sciences, University of Cagliari, University Hospital of Cagliari, SS 554 km 4,500, 09042 Monserrato, Italy

Abstract

Vasomotor symptoms, particularly hot flushes (HFs), are the most frequently reported symptom by menopausal women. In particular, for young women diagnosed with breast cancer, who experience premature ovarian failure due to cancer treatments, severe HFs are an unsolved problem that strongly impacts on quality of life. The optimal manage- ment of HFs requires a personalised approach to identify the treatment with the best Review benefit/risk profile for each woman. Hormonal replacement therapy (HRT) is effective in managing HFs but it is contraindicated in women with previous hormone-dependent cancer. Moreover, many healthy women are reluctant to take HRT and prefer to manage symptoms with non-hormonal strategies. In this narrative review, we provide an update on the current available non-oestrogenic strategies for HFs management for women who cannot, or do not wish to, take oestrogens. Since isoflavones have oestrogenic properties and it is not known if they can be safely consumed by women with previous hormone- dependent cancer, they were excluded. Selective serotonin reuptake inhibitors/selective serotonin-norepinephrine reuptake inhibitors, as well as other neuroactive agents, some herbal remedies and behavioural strategies are considered. Correspondence to: Nicoletta Biglia Email: [email protected] Keywords: vasomotor symptoms, hot flushes, menopause, non-oestrogenic therapies, non- ecancer 2019, 13:909 hormonal therapies https://doi.org/10.3332/ecancer.2019.909 Published: 11/03/2019 Received: 09/10/2018 Introduction Publication costs for this article were supported by the ecancer Global Foundation. Hot flushes (HFs) are the most bothersome menopause-related symptom, affecting up Copyright: © the authors; licensee to 85% of menopausal women with various severity, frequency and duration [1, 2]. They ecancermedicalscience. This is an Open Access first begin during the menopausal transition and they last around 7–10 years, although it article distributed under the terms of the is reported that some women can experience HFs for longer periods of time [3, 4]. Hor- Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which mone replacement therapy (HRT) is considered the most effective treatment, but it is not permits unrestricted use, distribution, and indicated for all patients, such as for those with a personal history of hormone-dependent reproduction in any medium, provided the original cancer or of venous thromboembolism [5, 6]. work is properly cited.

ecancer 2019, 13:909; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2019.909 1 ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 and Drug Administration (FDA)-approved product for thetreatment of moderate-to-severe vasomotor symptoms inmenopausal women [20]. reducingHFsin SNRIsefficacyof and Eventhe SSRIs havemanyif assessed studies serotonin levels [19],theblockof serotonin andnorepinephrine receptors induced by SSRIs andSNRIs may thisimbalance. oppose in decrease consequent a with deprivation, oestrogenby induced thermoregulation in changes the to due occur to thought areHFs Since alternatives for vasomotor symptoms [15],reducing HFs intensity andfrequency inpercentages ranging from 20%to 65%[15–18]. non-hormonal effectiveare(SNRIs) serotonin-norepinephrinereuptake inhibitors selective and (SSRIs)reuptake inhibitorsserotonin Selective Selective serotonin reuptake inhibitors andselective serotonin-norepinephrine reuptake inhibitors Management of vasomotor menopausalsymptoms with non-hormonalstrategies pausal symptoms andtheir appropriate application onapatient-by-patient basis. reviewmerely reflectsofaddressing opinion experton authors the the the variousnon-oestrogenic strategiesmanage to vasomotormeno- safelytheybe bycan consumed previous cancer,women hormone-dependentwith they wereexcludedreview.from this present the Thus, if known not is it and propertiesoestrogenicisoflavoneshave Since topic. the on knowledgeHCPs’ broaden orderto HFspause-relatedin meno- for alternatives(RCTs) non-oestrogenic trials about controlled randomised from evidence summarised review,we narrative a in As symptoms, vasomotor symptoms, non-hormonaltreatment. Only thepublications written inEnglish were included. We searched through PubMed articles in an interval period (2000–2017) using the following keywords: menopause, hot flushes, climacteric to or cannot employ HRT. availablenon-oestrogenicalternativesnarrativefornotreview,the wish HFs this do on patientsIn treatment update who providein an we many physical and psychological changes interact, determining a higher susceptibility to the relationship between the woman and HCPs similar to that achieved by placebobe agood must one,even if itisnot significant. Moreover, menopauseisacomplex periodof life where the literature, the placebo effect is reported in up to 59% of the different studies on menopausal treatment. For this reason, a result which is Moreover, when discussing non-oestrogenic alternatives for menopausal symptoms, we have to keep in mind the placebo effect. Throughout For thesereasons, itisimportant that HCPs are to be well informed aboutalternative remedies for menopausalsymptoms. friends andrelatives) [12–14]. (media, sourcesdifferent from informationreceive to prefer and it about knowledge lack (HCPs)providers healthcare that feel they since effects.However,side or mild no having and generalCAM health using start informtonot theirphysicians decision oftendo about women that women prefer CAM to conventional therapies because they consider CAM natural and safe, having a positive effect on maintaining good showed by the Study of Women’s Health Across the Nation, being 48.5% in 2002 and 80% in 2008 HFs employ non-hormonal treatments As a consequence, a spread of non-hormonal therapies is observed: data from different surveys show that around 30%–80% of women with healthy women who seektreatment for menopausalsymptoms will not betreated HRTwith [5]. forfactorcancerbreast risk potential a Health Initiative (WHI) randomised trial in 2003, a progressiveWomen’s reductionthe in HRTof prescription publication happened worldwide because HRTthe afteremerged as particular, In treatment. hormonal refuse HRT to contraindication no with women Moreover,many ovarian suppression plusaromatase inhibitors shouldbeconsidered [8] consequentwith negative influence onclimacteric symptoms [9]. extended therapy adjuvantwith antihormonal treatment toup 10 years issuggested andfor premenopausal women, thecombination of lifeofquality on stronglyimpacts that problem unsolved an HFsare In particular, for young women diagnosed breastwith cancer, who experience premature ovarian failure dueto cancer treatments, severe [11–13]. The prevalence of complementary and alternative medicine (CAM) therapies is increasing as . Physicians are often reluctant in prescribing HRT for this reason, and nowadays,oftwo-thirdsHRTand prescribingreason, for in reluctantthis often arePhysicians [10]. . Nowadays, for hormone-dependent tumours in high-risk patients, high-risk in tumours Nowadays,forhormone-dependent [7]. , paroxetinemg/day[15], 7.5 onlyofficiallysalt the Food is [11]. Moreover, data from surveys show [14]. 2

Review SNRIs =selective serotonin-norepinephrine reuptake inhibitors; HFs =hot flushes ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 Table 2.SNRIs for HFs. Table 1.SSRIs for HFs. shown abenefit in HF reduction ( also have O-desmethylvenlafaxine metabolite active its and venlafaxineduloxetine, SNRIs, regards(Table resultsAs 1). positive reporting Among SSRIs, paroxetine, sertraline, fluoxetine and escitalopram have been studied for HFs in menopausal women, with most of the studies HFs =hot flushes SSRIs =selective serotonin reuptake inhibitors; SNRIs =selective serotonin-norepinephrine reuptake inhibitors; FDA =Food andDrug Administration; [15, 16,17,21] (first-line option for HFs) 100–150 mg/day Desvenlafaxine [16, 17,21,24,25] (first-line option for HFs) 37.5–150 mg/day Venlafaxine Type of druganddose [16, 17] (first-line option for HFs) Escitalopram (first-line option for HFs) [16,17] Citalopram [16, 17,21] (s Sertraline [16, 17,21,22] (s Fluoxetine 10–30mg/day [15, 16,17,21,23] (first-line option for HFs) HFs by FDA) of menopausalmoderate-to-severe SNRIs approved for thetreatment (7.5 mgsaltistheonly SSRIs/ Paroxetine 10–25mg/day (first-line option for HFs) [16] 30–120 mg/day Duloxetine econd-line option for HFs) econd-line option for HFs) Type of druganddose 25–100mg/day 10–20mg/day 10–20mg/day Table 2). reduction 47% HFs frequency and24% reduction Up to 49%–55%HFs score Modest effect onHFs quency reduction 24% HFs score and19%HFs fre- improvement alsoof sleep Up to 64%HFs score reduction, in thefirst week of treatment 29% HFs severity reduction, already 60%–66% HFs frequency and24%– 37%–61% intheHFs score reduction inHFs frequency and HFs reduction, upto30%–58% Immediate effect andstrong score reduction 56% HFs frequency and62%HFs Effectiveness Effectiveness - nausea, weakness anddrowsiness - withdrawal rate of 4% - Best tolerability profile - 20% withdrawal rate -  - 10%dropout rate - - 18% withdrawal rate -  - The low dosage haslesstoxicity - Nausea at the20mgdose (nausea, dizzinessandheadache) Only inthefirst week of treatment appetite sleeplessness anddecreased dry mouth,headache, Nausea, constipation, constipation insomnia, mouthdrynessand Nausea, weakness, drowsiness, side effects tiveness of treatment rather thanto withdrawal dueto more ineffec function nausea anddecreased sexual with low doses low withdrawal rate, inparticular, Side effects Side effects - choices intamoxifen users CYP2D6 enzyme; they are the safest Low inhibitory effect onthe enzyme Moderate effect ontheCYP2D6 in tamoxifen users CYP2D6 enzyme;they canbeused Mild inhibitory effect onthe enzyme Moderate effect ontheCYP2D6 during tamoxifen use enzyme; they shouldbeavoided Potent inhibitors of CYP2D6 Interactionstamoxifenwith Interactiontamoxifen with

3

Review in the venlafaxine 75 mg and 150 mg groups than in the placebo group. In the double-blind, placebo-controlled RCT by Boeckhout frequentlyconstipation)morereportedsignificantlywere and nausea appetite, (xerostomia,decreasedeffects Side results. significant with mg/day).150 After weekof4 treatment, HFs severity decreased from bybaseline respectively61%, and 61% 37%, 27%, fourthe in groups, al (TableLoprinzibyRCTsurvivorscancer breast the HFsforin In 2 ), moststudiesfocussed on use 25]. venlafaxineSNRIsregards [24, As the lower dose was lessdiscontinued by women andeven significantly improved sleepcompared to placebo. of breast cancer, of which more than 80% were breast cancer survivors mainly under tamoxifen. Both doses significantly decreased HFs, but mg/dayParoxetine,20 and ofmg dose 10 RCTthe bothevaluatedthe wasby in Stearns weeks of treatment. fluoxetineshowedthat mg/day20 HFs’decreasein modest but significant wasa determinedtoleratedscore welland 68 after women,in 8 same way, thelowest doseshouldbegiven for 2 weeks before endingthetreatment. [16] initiated. Tothe be in can drug, dose standardthe the stop then and forweeks2 dose lowest the at started be to antidepressantsneed All [16, 17]. bipolaras uncontrolleddisease, seizures, liver or kidney insufficiency, hypertension for SNRIs usersor concurrent ofuse other orSSRI SNRI oxidase inhibitors [17]. The North American Menopause Society (NAMS) suggests caution also in subjects affected by other conditions, such Absolute contraindications to SSRIs and SNRIs use include previous neuroleptic and serotonin syndrome and the current use of monoamine are thesafest choices while usingtamoxifen [16](Table 2). escitalopram only have a limited inhibitory effect and can be used in tamoxifen users (Table 1). Among SNRIs, venlafaxine and desvenlafaxine paroxetineand fluoxetine are potentmost the inhibitors andthey shouldbeavoided duringtamoxifen use;onthecontrary, citalopram and SSRIs, tamoxifen.Among inactive from metabolite active the offormation the in decrease consequent a with enzyme CYP2D6 inhibit can SNRIs and SSRIs some since reported been has tamoxifen with antidepressants of interference potential cancer, breast with women For treatment andthelowest proportion of switching to other drugs[16,26,27]. able tolerability profile, itisconsidered theantidepressant with thehighestnumber of days of uninterrupted treatment, thebestadherence to in HFsfor clinical practice antidepressant for manyused widelyyears. moreNowadays, escitalopram the is also prescribed as a been first-line option for has menopausal HFs.venlafaxine Indeed,profile, due to its tolerabilityfavour safe the to and weeks 2 in action fast the to Due dropout rates reported intheliterature (up to 50%at 3months) [26]. Side effects, in combination with the fear of pharmacological interactions, may lead to early interruption of SSRIs/SNRIs treatment, with high tored inallpatients [16]. dizziness, xerostomia, constipation andsexual dysfunction paroxetine, citalopram and escitalopram carry thebestsafetyasthenia, nausea, profilesareeffectsfrequentlymore [16]. Theside reported treatmentof weeks 2 after as early as vasomotorsymptomsin decrease a rapidly, with act SNRIs and SSRIs cians shouldoffer SSRIs andSNRIs for HFs relief inbreast cancer survivors [9]. That being so, the American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO) recommend that primary care clini- loss. appetitesevere and constipation nausea, wereeffects side frequentlyreportedmore the group, venlafaxinethe In 0.001). < to baseline, p treatment (p < 0.01, compared to placebo). Interestingly, in the same study, a relevant placebo effect was seen (29% at 12 weeks, compared who received placebo. The decrease in HFs score in the venlafaxine group was evident very soon, in 42% of cases as early as after 4 weeks ofvenlafaxine 75 mg for 12 weeks significantly decreased by 41% HFs score in 38 breast cancer survivors (p < 0.001) compared to 17 patients ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 Loprinziby RCT (Tabledouble-blinded patients the cancer breast 1), in HFstreating for SSRIs of use the regards as particular, In fluoxetine andsertraline) conducted in451 women [21]. paroxetine,(venlafaxine,SSRIs/SNRIsRCTs on six including survivors, cancer breast in HFsfor therapies non-hormonal of efficacy the on breastIncancer SNRIsare patients,SSRIsprovenand CochranemoderatereducingReview effect a toHFs, in in havemild toassessed a as , 191 patients with or without previous breast cancer received placebo or venlafaxine at three different doses (37.5 mg, 75 mg and mg 75 mg, (37.5 doses differentthree at venlafaxineor placeboreceived cancer breastprevious without or with patients 191 [24], . SNRIsincrease[15]. can pressure; blood therefore, this moni - be variableshould et al on 107 historyorwomen on a with [23] without . Among SSRIs and SNRIs, and SSRIs Among[17]. etal et al [25], [22] et et 4 -

Review QoL = quality of life HFs =hot flushes; AEs: adverse events; BCSs =breast cancer survivors; =Pittsburgh PSQI Sleep Quality Index; MRS=Menopause Rating Scale; Table 3.Main studiesperformed ongabapentin for HFs treatment. ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 50% [29,30]. Results from clinical studies performed in healthy menopausal women demonstrated a reduction of frequency and severity of HFs by around (Table 3). women menopausal healthy in both seen was HFs on gabapentin of effect beneficial A hypothalamus and,consequently, better modulating thermoregulatory activity [7,28]. the in located channels calcium to binding byHFs of frequency the decrease to able drugs anticonvulsant are pregabalin and Gabapentin Gabapentin andpregabalin survivors cancer Breast women Healthy patients Type of N =115BCSs Biglia et [32]RCT al N =420BCSs multi-institutional trial placebo-controlled, double-blind, Randomised, Pandya et al [31] N =200 placebo-controlled trial double-blind, Randomised, Butt N =59 placebo-controlled trial double-blind, Randomised, Guttuso Author, year of publica number of patients (N) tion andtypeof study, et al[30] et al[29]

- for 12 weeks (N =55) vitamin E 800 IU/day (N =60) versus 900 mg/day Oral gabapentin weeks 8 over versus placebo mg/d gabapentin 300 mg/d or 900 4 weeks gabapentin for 900 mg 2)  1)  Type of treatment 2,700 mg/day gabapentin upto Extension phase: placebo 12 weeks versus gabapentin for 900 mgoral

4)  3)  2) For sleepquality:PSQI 1)  frequency andduration Diary for HFs severity, both frequency, score including Diary for HFs severity and score includingboth and frequency, composite Diary for HFs severity Type of measurement Survey For QoL: SF-36 Health Symptoms: MRS For other menopausal For HFs: daily HFs diary 2)  1)  900 mg/day tive inHFs control at adoseof 0.0001) →gabapentin iseffec placebo (15%for both, p mg gabapentin group versus severity reduction inthe900 44% HFs frequency and46% respectively, p<0.001) placebo (26.5%and24.7%, frequency reduction versus 51% HFs score and45.7% 2) 1)  score) frequency and67%inthe reduction of HFs (54%inHF With thehigher dose,further p <0.05). reduction: 21.33%, of sleep(PSQIscore Improvement inquality gabapentin group respectively, (p<0.05)inthe decreased by 57% and67%, HFs frequency andscore placebo (p <0.01),respectively, for with 29%( from baseline,compared 54% HFs score reduction 45% HFs frequency and [29, 30]andinbreast cancer survivors [31, 32] Main results p <0.02)and31%

< - and somnolence) BCSs for AEs (dizziness interrupted by 28%of of BCSs and was never started by 28.3% gabapentin was with The prescribed treatment -  - later AEs reduction treatment week, with placebo inthefirst groupgabapentinversus and drowsiness inthe unsteadiness More dizziness, -  -  -  weeks for AEs at 4 weeks and17%at 8 Withdrawal rate of 12% appetite Significant worsening of placebo) for AEs (versus 3%for the gabapentin group 13% withdrawal rate in placebo) AE (versus 27.6% for patients, at leastone In 50%of gabapentin rash Somnolence, dizziness, Adverse events (AEs)

5

Review et al No data are available for PPE in women with breast cancer, but the lack of oestrogenic effect demonstrated in a preclinical study by Hellstrom related symptoms, suchasdizziness,moodswingsandtiredness, which often accompany vasomotor symptoms. reduction in HFs was observed, compared to 38% in the placebo group (p < 0.006). PPE also showed positive effects on treatmentother HFquality ofin life-effective is PPE that showed women symptomatic postmenopausal 64 on RCTcontrolled PPE has proven clinical efficacy in the treatment of menopausal symptoms like HFs and insomnia in healthy women. A double-blind, placebo- contraindications of itsuseinpatients with pollenallergy [34]. any safety, without patient ensures PPE from allergens potential of elimination the allows which technology production the Furthermore, [34, 35]. SSRI ‘like’ mode of action Beneficialeffects of on PPE vasomotorsymptoms may derive from ofinhibition the serotonin uptake synaptosomalatthe junction, an with dismutase activity [34].Each tablet contains 40mgof GCFem, 120mgof PI82and5mgof vitamin E. pistil extracts (PI 82), from plants of the Poaceae family, and vitamin E. The pollen and pistil extracts have high antioxidant(GCsourcedFem).greenextractclimactericsupplement fromand of combinationpure pollen a pollen a is is It(PPE) extract enzyme pollen Purified superoxide Purified pollenextract ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 byperipheralreducingvascular reactivityflushing mayanti-hypertensive inhibit alpha-adrenergicagonist,which an is Clonidine Clonidine and behaviours with gabapentin andpregabalin [17]. women The mostcommon sideeffectson gabapentin are drowsiness, unsteadiness and dizziness [15, 30, 32], up to 50% in postmenopausal healthy patients never started thetreatment andafurther 28%of theminterrupted thetreatment dueto sideeffects [32]. pentinis aseffective has more but sideeffects Pregabalin (150 to 300 mg/day) is effective in HF relief but it is less studied than gabapentin ASCO [9]. HFs effect moderate to mild a with reducing in drugs effective the among gabapentin includes reviewCochrane a patients, cancer breastFor 900 mg/day inthese women [32]. respectivelysurvivors, cancer breast 115 and 420 on studies two in In breast cancer survivors, a 44%–57% decrease in HFs frequency and a 46%–67% decrease in HFs severity were reported with gabapentin Furthermore, in the double-blind, placebo-controlled RCT by Boeckhout frequency andseverity of HFs. For breast cancer patients, two placebo-controlled RCTs included in a Cochrane systematic review [18], clonidinesignificantly reduced thefrequency of HFs infour of out ten trialsincluded. ever, the exact mechanism of action is still unclear. In a systematic review and meta-analysis on non-hormonal therapies for menopausal HFs been often reported with clonidine However, significant side effects (xerostomia, dizziness, constipation, hypotension and potential hypertension, if suddenly interrupted) have of 38breast cancer patients employed venlafaxine inHFs andthedecline score was faster with venlafaxine than clonidine. with by 26% HFs score in 28 breast cancer survivors (p < 0.045) compared to 17 patients who received placebo. In the same study, another group . Furthermore, gabapentin is included among the suggested recommendationssuggestedfor the HFs among reliefbreastcancerFurthermore,byincluded survivors in [20]. is gabapentin and ACS suggests that PPE can be a suitable option. In this study, PPE was found to contain low, subeffective concentrations of daidzin, ofconcentrations subeffective low, contain to found was PPE study, this In option. suitable a be can PPE that suggests [35] [29]. Consequently, withdrawal rates ranging from 12% to 17% are reported [34]. PPE does not contain any of the common phytoestrogens and does not show uterotropic-oestrogenic effects [17, 18]and,dueto safety problems, itsclinicaluseispoor. . In a study on 115 breast cancer survivors using gabapentin 900 mg/day, 28.3% of the ofmg/day, 28.3% 900 gabapentin using survivors cancerbreast 115 on study a In [6]. . Furthermore, the quality of sleep improved with gabapentin improvedwith sleep of quality Furthermore,the [31, 32]. et al [25], clonidine 0.1 mg/day for 12 weeks significantly decreased [29, 31].NAMSalertsalsofor thoughts possiblesuicidal [7]. However, compared to SSRIs/SNRIs, gaba- [21] showed amoderate reduction inthe . In the PPE group, a 65% a group, PPE the In [34]. . How [33]. 6 -

Review ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 a chemopreventive potential [48]. tradiol action of MCF-7 cells mechanism during chronic SERM–likeuse of black its cohosh show to that changes in due the genecontroversial expression pattern still are more is similar to patientstamoxifen cancerthan to oes- breast in cohosh black of use The clinical trialson1,020 women showed noevidence that blackcohosh hasany adverse effect onliver function[45]. controlleddouble-blind, hepatotoxicity randomised,of fivesuspected meta-analysiseffects,regards previously a side As was but reported, cohosh was not associated with changes intherate of HFs [44]. Another recent systematic review and meta-analysis, considering four RCTs on black cohosh, confirmed this data, showing that overall black of the plant or different kind of extract of black cohosh. In the review, at least five different oral preparations of black cohosh were included. The inconsistency of theevidence may beexplained also by the heterogeneity of results amongthestudies due to the use of different parts symptoms. menopausal controllingfor cohosh black of use the support to evidence insufficient is there that HFs,concludingfrequency of women menopausal symptomatic RCTs,2,027 16 on survivorscancer breast in and women menopausal healthy in RCTsreduction HF showed adverse endometrial outcome [42]. serious of or hyperplasia endometrial of case no and ultrasound on thickness endometrial in increase no showing treatment,of weeks 52 after and before assessed was cohosh black ofsafety endometrial the women, postmenopausal 400 on study open prospective large a In determined noeffects on vaginal epithelium,endometrium or sexual hormones[41]. In the Herbal Alternatives for Menopause (HALT) double-blind, placebo-controlled RCT on 351 patients, black cohosh given up to 52 weeks confirmed thelackof oestrogenic activity [38,41,42]. variation hormones sexual on or thickness endometrial or vaginal the on effect no showing trials clinical differentrecentMoreover, more assays suggested oestrogenic activity butthese data have not beenconfirmed subsequently [38,40]. suggested been have effectsanti-inflammatory and antioxidant mechanism, agonist partial serotonin (SERM), receptors oestrogen of modulation Selective unclear. still is cohosh black of bioactivity the underlying mechanism The cure for many different conditions. Nowadays, blackcohosh isindicated only for themanagement of climacteric symptoms [38]. (Actae racemosacohosh or black ofextract the used haveNative women American Black cohosh Available data onthesafety andefficacy of PPEare shown in metabolism an Furthermore, sex hormone-bindingglobulinbefore andafter thestudy perioddidnot suggest any hormoneeffect of PPE. and testosterone E2, (FSH), hormone stimulating follicle the ofMoreover,treatment.measurements PPE serum during change no showed In theclinicalstudy by Winther etal cells via PGRMC1,inadditiontotheproliferative effect via intracellularly located receptors [36]. important safety data since recent experimental data revealed that oestrogens could trigger a further proliferative effect on breast cancer proliferationtransfectedcellsprogesterone in bothapoptosis,the cell with and receptor orcomponent-1not.(PGRMC1) membrane is This Moreover, inarecent invitro study, PPE was neutral in the cell lines alone or in combination with oestradiol or growth factors in terms of cell with PPEinthehighdoseof 500mgkg/day. PPE was tested in the same study for oestrogenic activity in the immature female rat uterotrophic bioassay and no uterine growth was seen daidzein and genistin at high-performance liquid chromatography. Genistein, formononetin and biochanin could not be detected. Moreover, . In[47]. cohoshblack models, animal given torats for 40 weeksdetermines dose-dependenta reduction of breast cancer, suggesting [37]. study demonstrated that PPE does not inhibit the CYP2D6 enzyme and thus does not interfere with tamoxifen with interfere not does thus and enzyme CYP2D6 the inhibit not does PPE that demonstrated study in vitro [34], which employed PPE 2/day per 3 months, the evaluation of vaginal dryness and menstrual bleeding , did not show a significant difference between black cohosh and placebo in the in placebo and cohosh black betweendifference significant a show not did [43], Table 4. Cimicifugae racemosae) for centuries as a phytotherapic . However, a Cochrane systematic reviewofsystematic However,Cochrane [38]. a [38, 39]. Initial studiesusingin vitro andin vivo [38, [46]. In vitro studiesin 7

Review ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 spective study on 74 postmenopausal patients, Hirschberg use cohosh black invasivecancerunrelatedbreastto an developed patient who one in onlyobserveddensitybreast was cohosh black using densitybreastwhile mammary in modification significant no showed studies different risk, cancer breast forbiomarker a is density breast since Furthermore, E2 =estradiol; TT =testosterone; SHBG=hormone-bindingglobulin; AUB =abnormaluterinebleeding;ELISA = enzyme-linked immunoassay ponent-1; MTT test =3−(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide test; CDD =Cell death detection; FSH =follicle stimulating hormone; PPE =Purified pollenextract; MRS=Menopause Rating Scale; HFs =hot flushes;QoL =quality of life; PGRMC1 =progesterone receptor membrane com- Table 4.PPEfor HFs treatment. survivors breast cancer Safety in women in healthy Efficacy enzyme with CYP2D6 No interference activity No oestrogenic In vitro study Goldstein et al[37] trial placebo-controlled Double-blind, Winther et al[34] In vitro study Seeger et al[36] In vitro study Hellstrom et al[35] trial placebo-controlled Double-blind, Winther et al[34] publication and Author, yearof type of study . In the 52-weeks study byRausstudy 52-weeks the In 50]. 49, [42, months PPE 2/day per 3 N =64 months PPE 2/day per 3 N =64 tients (N)andtype Number of pa- of treatment et al [49] observed noincrease inbreast density, assessedby mammography, and a reference. liver microsome with Quinidine as concentrations inpooledhuman CYP2D6 enzymeby PPEat high Test for potential inhibitionof -  - Diary of AUB - 15QoL parameters - -  -  -  -  -  - 15QoL parameters - MRS CDD ELISA kit Apoptosis was determined by SHBG Blood samplesfor FSH, E2, TT, the MTT test Proliferation was determined by E2 or growth factor were tested alone andincombination with Different concentrations of PPE transfected with PGRMC1 MCF-7 and T47D cells were uterotrophic bioassay with PPE tion intheimmature female rat Oestrogenic activity evalua- phytoestrogens inPPE chromatography analyses of High-performance liquid measurement Type of et al on 400 postmenopausal women, increase in increase women, postmenopausal 400 on [42] -  - No AUB -  CYP2D6. Quinidine completely inhibited the PPE (6.53%to10.67%), whereas Negligible inhibitionof CYP2D6 with -  -  fected with PGRMC1or not and cell apoptosis, both incells trans- factors interms of cell proliferation or incombination with E2or growth PPE was neutral inthecell linesalone -  -  E2, TT, SHBG No change inbloodlevels of FSH, parameter No changes in vaginal dryness with PPE No uterine growth infemale rats detected. tin andbiochanincould not be and genistin. Genistein, formonone- concentrations of daidzin,daidzein kg/day contains low, subeffective PPE inthehighdoseof 500mg compared to baseline(p<0.031) and sensitiveness) inthePPEgroup headache, irritability, moodswings (tiredness, dizziness,mood,libido, Improvement intheQoL parameters group ( group versus 38%intheplacebo 65% HFs reduction inthePPE p <0.006) Main results [49, 50]. In a pro[49, - 8

Review symptoms isstillnot defined [60]. prevention of weight gain after diagnosis can help in controllingHFs HFs,in reduction whereasa the with rolewomen healthy ofobese orintentional overweight weightin loss associated after is diagnosis loss on weight vasomotorthat gesting Data from the WHI trial in healthy women show that weight loss determines a reduction in HFs Weight loss treatment for HFs, both inhealthy women [55]andinbreast cancer survivors [56]. Studiessuggest thatoxybutynin, an anticholinergic generally employed for urinary incontinence dueto overactive bladder, isaneffective Oxybutinin ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 cohosh group. black The the RCT and by placebo Pockaj the between differ not did (LH) hormone luteinizing and FSH of levels blood in changesInterestingly, observed. sweatingwas improvement in significant a group, cohosh black treatments;however,the both intensityHFsin frequencywith and in seen were et al Onlyfew RCTs have performedbeen order in safetyand use the understandto of breastcohoshin black cancer patients. RCTInthe by Jacobson significantly increased with HRT usebutnot with placebo or black cohosh. mg/norethisterone acetate or tibolone) or placebo, breast density assessed by mammography performed at baseline and after 24 weeks was use. In thecomparative study of Lundström etal cohosh black of weeks 24 after and baseline at performed both agobiopsy,through determination 67 Ki byproliferation cancer breast of A summary of theevidence ontheefficacy andsafety of blackcohosh onHFs relief isdescribedin its efficacy onHFs [43,44,46]. havecohoshto black seems Although gooda safety profile, more high-quality arestudies reachto needed definitivea conclusion regarding cohosh with tamoxifen isunlikely [38]. Regarding tamoxifen users, a potential survival after breast cancer, showed nodetrimental effect onrecurrence rate [54]. diseases-free analysing cohosh, black receiving ofwhich 1,102 survivors,cancer breast 18,861 on studyretrospective, cohort observational, An cancer patients show that there is currently a lack of evidence to support the use of black cohosh for HFs relief in breast cancer survivors in HFs score: 20% in the black cohosh group versus 27% in the placebo group, KI =Kupperman Index; GCS=Green Climacteric Scale; MRS=menopauserating scale;RCT =randomised controlled trial;BCSs =breast cancer survivors Table 5.Black cohosh for HFs treatment. Safety profile (KI, GCSandMRS) Menopausal symptom score Night sweats frequency HFs frequency andintensity , 85 breast cancer survivors, most of whom were on tamoxifen, were assigned to black cohosh or placebo. No significant differences significant No placebo. or cohosh black to assigned weretamoxifen, on were whom of most survivors, cancer breast 85 [51], Black cohosh versus placebo et al [52] failed to provide any evidence that black cohosh 40 mg/day reduces HFs more than the placebo (mean decrease in vitro inhibition of CYP2D6 has been described, but clinical data suggest that the interaction of black - No detrimental effect onrecurrence rate inBCSs [54]andunlikely interaction with tamoxifen [38] - No endometrial thicknessincrease [41,42] - Good safety profile inthegeneral population [38,45] No statistically significant difference insystematic reviews andmeta-analysis [43,44] - In anRCT inBCSs significant improvement [51] - No statistically significant difference insystematic reviews andmeta-analysis [43,44] - Same results inRCTs inBCSs [51,52] - No statistically significant difference insystematic reviews andmeta-analysis [43,44] on 65 postmenopausal patients using black cohosh and 154 under HRTunder(oestradiol 154 2 and cohosh black using patients postmenopausal 65 on [50] p = 0.53). Results from the only available RCTs performed in breast Outcome [57]. Two RCTs confirm these findings, sug- Table 5. [58, 59]. In breastcancer survivors,[58, [38, 53]. 9

Review ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 proximity of criticalstructures may hinder the spread of option thisnon-hormonal for non-HF relief. safe is practitioners byskilled performed SGB thatreported is efficacy.Evenit ifevaluateits order to in HFs SGB in with reduction 45%–90% a showed studies fouropen-label frequencyoverallwhile HF afterSGB, thetic nervous system. Only one RCT on 40 postmenopausal women focussed on SGB for HFs sympa- and central the between connections the interrupting by mechanisms temperature-regulating the resets SGB that suggested was treatment.ItforHFproposed been has injection, anaesthetic bylocal block cervicalvertebral a of consisting (SGB), block Stellateganglion Stellate ganglion block evidence [17]. light,with cotton clothing andstandingaway from sources of warming); however, theefficacy of strategies such isnot supported by scientific layers, HFs(dressingin reduce toorder in proposed been also have strategies cooling flushing, oftrigger a Moreover,is temperaturesince Cooling strategies prove apositive effect of acupuncture and,eventually, to predict which subset of patients could benefit from it. HFsreducing effectivenessin its confirmReview Cochraneto However, a failed cancerpatients,breast in [69]. severityorperi in postmenopausal women, improvementwith health-relatedin also quality of lifeeffectsand itemsside significant without Athreesystematicincluding meta-analysisreviews fourand RCTs effectivenessthe ofassessed reducing HFacupuncture in frequency and Acupuncture hasbeenshown to reduce HFs inhealthy women, compared with notreatment [68]. Acupuncture the effectiveness of relaxation techniques less, in healthy perimenopausal and postmenopausal women, a more recent Cochrane review concluded that evidence is insufficient to prove For breast cancer patients, a Cochrane Review assessed that relaxation therapy has a mild to moderate effect in reducing HFs Relaxation therapy benefits to mood,sleepandquality of life were observed [66]. additional and randomisation from weeks 26 at maintained wasimprovement The care. usual with compared weeks 9 after HFs reduced reduced vasomotorsymptoms postmenopausal healthy for both women andbreast HFs cancer survivors [17]. In forthe MENOS 2 treatmenttrial, an RCT effective conducted on 140 an healthy postmenopausal women, techniques, CBT significantly mind-body among is, (CBT) therapy behavioural Cognitive Cognitive behavioural therapy toms, HFs, psychological andurogenital symptoms adversewithout serious events [64] RCTssystematicreviewof13 meta-analysisa In and symp - treatment1,306 women,menopausal comparedreduced yogatotalno on with breast cancer survivors. HFsseverityof the decreasemay training A Cochrane review failed to demonstrate a positive effect of exercise and yoga on HFs Yoga andexercise [65]. The MENOS 1 trial was an RCT specifically addressed to breast cancer patients in which CBT significantly [67]. and in an RCT by CramerbyRCT an in and [62] etal [63], yoga was effective inreducing vasomotor symptoms in [61]. However, a recent study reported that exercise [70], showing nosignificant difference inthe [70], concerns related to the close . Further data are needed to needed Furtherare [21]. data . LargerRCTs[7]. needed are [21]. Neverthe- 10

Review ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 References Financial supportfor medical writing (table preparation) andeditorial services (English supervision) was provided by Shionogi. Funding financial relationship with Shionogi (medical writing, tablespreparation). NovoNordisk, Pfizer, Shionogi and Teva. ValentinaBounousE relationship financial a had Italfarmacowith (medicalS.p.A. a has and writing) (lecturer,tionship ofmemberand/oradvisoryboards Bayerconsultant) with HealthCare, Richter, GedeonEndoceutics, MSD,HRA Pharma, memberof advisory boards and/or consultant) GedeonRichter,with Shionogi Italfarmaco.and Limited Rossella NappirelaE financial a has - Anna Maria Paoletti, Francesco De Seta and Stefano Lello declare no conflict of interests. Nicoletta Biglia had a financial relationship (lecturer, Conflicts of interest The authors thank Editamed srl, Tommaso Sacco M.D. for medical writing services andRaquel Carvalhosa, Ph.D. for editorial services. Acknowledgments must bemadetoperform RCTs with large samplesand methodologywith astrict to allow comparison of thedifferent strategies. Sincelimitationsof availablethe evidence are particularin studyimprecision the the greatin ordataa and details,method the in lack effort improve themanagement of HFs inboth healthy menopausal women andin women with contraindications to oestrogens. Future research on the molecular mechanisms of flushing during menopause and on the effects of available and novel treatments will further Research agenda then selectanindividualisedandsafe therapy. In order to manage HFs in menopausal women effectively, clinicians should identify the patient’s health profile and personal preferences and physical activity inthemanagement of HFs. of role positive a supports evidenceRecent research.further requiring far so collected data ofinconsistency the of spite in used widely is menopausal women, with consequent improvement in the quality of life. Black cohosh is a well-known traditional medicine treatment, which non-oestrogeniceffectivebe showntoeffect been has decreasingand in HFs, nightsweats, irritability improvingand qualitythe of in sleep approachesotherforhaveCAM the On hand, periods. provided short interestingrecentconfirmed in a data has studies. PPE them, Among and drugs off-label as used mostlytheyare is, drugs Whateverperceptionothers.towardthese the in patients and byacceptedphysicians well less are but USA the as such countries, some in HFstreat to used commonly are agentsPsychoactive HFs.of num cases untreatedthe of berreduce may women menopausal ofpreferences and needs the to attention more Paying life. of quality patient’s the on impact negative a undertreated, with and underdiagnosed frequentlyHFs,remainparticular, in and symptoms,vasomotor women, menopausal In Conclusion 2. 1. Freeman EW and Sherif K (2007) K Sherif and EW Freeman 778–785 https://doi.org/10.1097/gme.0b013e318207851d multinationalstudy of vasomotor symptom prevalence, duration, andimpacton quality of life in middle-aged women Blümel JE, Chedraui P, and Baron G, 197–214 https://doi.org/10.1080/13697130601181486 PMID: Prevalence of hotand night flushes sweats around the world: asystematic review etal (2011) Collaborative group for research of theclimacteric inLatin a largeAmerica (REDLINC), 17487647 Menopause Climacteric 11 18 10 -

Review 18. 17. 16. 15. 14. 13. 12. 11. 10. ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 8. 7. 9. 6. 5. 4. 3. ysis NelsonD, VescoHaneyand KK, E, GME.0000000000000546 (2015) (NAMS) statementtoms: 2015 position of The North MenopauseAmerican Society Society Menopause American North women: asystematicPract reviewNurse JAmAssoc Handley AP and Williams M (2015) Obstet Gynecol 123(1)202–216https://doi.org/10.1097/01.AOG.0000441353.20693.78 PMID: American College of Obstetricians and Gynaecologists (2014) review Maturitas 9979–85https://doi.org/10.1016/j.maturitas.2017.01.013 PMID:28364873 TonobMelby(2017) and MK D Curigliano G, Burstein HJ, and Winer EP, Oncologist 1196–110https://doi.org/10.1634/theoncologist.11-2-96 Knobf MT (2006) GME.0b013e3182a46a3e focuson prevalence, motivation,communicationand decision-making, DW, Sibbritt and J, Adams W, Peng women: asystematic review of surveys Maturitas 7534–43https://doi.org/10.1016/j.maturitas.2013.02.005 PMID:23497959 TW, Moon and MS, LeeP, Posadzki resultsnal from the study of women’sacrosshealth the nation Bair YA, Gold EB, and Zhang G, doi.org/10.1001/jama.289.24.3243 PMID: mammography inhealthy postmenopausal women:the women’s healthinitiative randomized trial LangerRT,RD,Chlebowski and SL, Hendrix vivorship care guideline RunowiczCD,HenryLeachand NL, CR, doi.org/10.1093/annonc/mdx308 PMID: len internationalexpert consensusconference ontheprimary therapy of early breast cancer 2017 Climacteric Baber RJ, Panay N, and Fentonand AT, PanayN, RJ, Baber PMCID: symptomsin five Europeancountries osatn G, rhm , n Ceix C, Clerinx and S, Graham GD, Constantine doi.org/10.1111/j.1471-0528.2011.03166.x cohortstudy of 10418British womenaged 54–65:Prevalence, frequency andproblem rating of hot flushes menopausal women:of impact age, bodyindex, mass hysterectomy, hormonetherapy use,lifestyle andmoodinacross-sectional RyanA, and Gentry-MaharajA, M, Hunter org/10.1001/jamainternmed.2014.8063 PMID: the nation,duration of menopausal vasomotor symptomsover themenopausetransition Avis NE, Crawford SL, and Greendale G, JAMA 2952057–2071https://doi.org/10.1001/jama.295.17.2057 PMID: 5019289 19(2)109–150https://doi.org/10.3109/13697137.2015.1129166 PMID: The influence of endocrine effects of adjuvant therapy on quality of life outcomes in younger breast cancer survivors JClinOncol 34(6)611–635https://doi.org/10.1200/JCO.2015.64.3809 PMID: PMID: et al (2008) Broadeningour perspectivescomplementary on andalternative medicinefor menopause: anarrative 24104604 26382310 The efficacytolerability and of SSRI/SNRIs inthetreatment of vasomotor symptoms inmenopausal (2006) et al , (2016) etal, (2013) et al Post Reprod Health (2013) et al et al (2015) (2016) et al et al (2017) 28838210 PMCID: Useof complementary andalternative transition: medicine duringthemenopause longitudi- (2012) et al 12824205 (2003) et al (2016) etal Nonhormonaltherapies for hotmenopausal flashes: systematic review and meta-anal- IMS RecommendationsIMS on women’s midlife healthandmenopausehormonetherapy PMCID: 4433164 25686030 PMCID: Prevalence of complementary andalternative (CAM) medicine useby menopausal Study of women’s healthacross thenation (SWAN), study of women’s healthacross 2754–61 Criticalreview of complementary andalternative medicineuseinmenopause: De-escalating andescalating treatments for early-stage breast cancer: theSt. Gal- American cancerAmerican society/American society of clinicaloncology breast cancer sur Prevalence, frequency andproblem rating of hot flushespersist inolder post- WHI investigators,WHI influence of estrogen plusprogestin onbreast cancer and

22 112–122 Nonhormonal management of menopause-associated vasomotor symp- Behaviours andattitudes influencing treatment decisionsfor menopausal 6246241 ACOG practice bulletin No.141: management of menopausalsymptoms Menopause PMID:16476831 https://doi.org/10.1177/2053369116632439 PMID: 15 32–43 16670414 Menopause Menopause https://doi.org/10.1097/gme.0b013e31813429d6 26872610 JAMA Intern Med InternJAMA 5 536–548 21(5) 1155–1174 22 24463691 JAMA Ann Oncol (24) 3243–3253 289(24) 531–539 175 BJOG https://doi.org/10.1097/ https://doi.org/10.1097/ 1700–1712 28 119 40–50 https://doi. 26895640 https:// https:// https:// 12 -

Review 23. 22. 21. ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 28. 27. 26. 25. 24. 20. 19. 33. 32. 31. 30. 29. 34. 36. 35. Stearns V, Slack R, and Greep N, 1583 https://doi.org/10.1200/JCO.2002.20.6.1578 PMID: Loprinzi CL, Sloan JA, and Perez EA, Cochrane Database Syst Rev (9)CD004923PMID: PantojaT, and D, Capurro G, Rada https://doi.org/10.1056/NEJMp1402080 PMID: HayesLP, Carroll Kelleyand DG, KW (2011) org/10.3111/13696990903093537 major depressive disorder:comparisona between escitalopramand other SSRI/SNRIs E, Yang and PE, Greenberg EQ, Wu period 2003–2009 Aguglia E, Ravasio R, and Simonetti M, JCO.2010.33.1298 PMID: a randomized,faxineclonidine: and placebo-controlled double-blind, trial OB, Dalesio and AD,Vincent AH, Boekhout controlled trial Loprinzi CL, Kugler JW, and Sloan JA, clinical trial MJ, Kim and L, Li RJ, Orleans Vilar-González S, Pérez-Rozos A, and Cabanillas-Farpón R, Sassarini J, Fox H, and FerrellW, and H, FoxJ, Sassarini vitamin E P,Sgandurra N, BigliaPeanoE, and 1627210 placebo-controlledble-blind trial RoscoeMorrowPandyaand KJ, JA, GR, Menopause JE, Lewis and M, Lock DA, Butt controlled trial Guttuso TJ Jr, Kurlan R, and McDermott MP, Pharmacother quality of life inmenopausal women:randomized,a placebo-controlled, parallel study (2005) C Hedman and E, Rein K, Winther 332–338 https://doi.org/10.3109/13697137.2011.636847 22208784 PMID: cancer cells Seeger H, Ruan X, and Neubauer H, pausal symptoms Hellström Muntzing(2012) AC and J org/10.1080/13697130500117987 PMID: Climacteric J Int Menopause Soc 12310–318https://doi.org/10.1080/13697130902736921 15310–318https://doi.org/10.1097/gme.0b013e3180dca175 JClinOncol 23(28)6919–6930https://doi.org/10.1200/JCO.2005.10.081 PMID: Gynecol Endocrinol 34(4)353–356https://doi.org/10.1080/09513590.2017.1407751 45388–394https://doi.org/10.1345/aph.1P366 Lancet 356(9247)2059–2063https://doi.org/10.1016/S0140-6736(00)03403-6 Obstet Gynecol 101337–345PMID: Menopause , Curr Med Res Opin 28(9)1475–1484https://doi.org/10.1185/03007995.2012.713341 PMID:22809113 21911720 19825–829https://doi.org/10.1097/gme.0b013e31824017bc (2014) etal et al (2005) (2008) etal (2012) etal Lancet (2010) etal et al (2017) (2009) et al et al (2002) etal (2000) Theextract pollen femal-a nonestrogenic alternative totherapy hormone in women with meno- et al (2012) (2009) etal (2005) etal 818–824 366 FDA approvalof paroxetine for menopausalhot flushes Paroxetineeffectivean is treatment for hot results flashes: from aprospective randomized 16096172 Use of gabapentin for themanagement of natural or surgical menopausalhot flashes Femal,remedya herbal madefrom pollenextracts, reduces hot flushesand improves etal (2003) (2011) et al Gabapentin for thetreatment of hot menopausal flashes:arandomized controlled trial Hot flushes, vascular reactivity and the role of the α-adrenergic system α-adrenergic the of role the and reactivityvascular flushes, Hot Membrane-initiated effects of serelys® onproliferation apoptosis and of humanbreast Non-hormonal interventions for hot in flushes women with ahistory of breast cancer Non-hormonal treatment of hot inbreast flushes cancer survivors: gabapentin versus Phase III evaluationPhaseIII of fluoxetine for treatment of hot flashes Venlafaxine in management of hot flashesin survivors of breast cancer: randomiseda 24806158 20824841 Usetreatment and modalitiesfor SSRIandSNRIantidepressants inItaly duringthe 12576259 Gabapentin for hot flashesin420 women with breast cancer: arandomised dou- Treatment persistence, healthcare utilisation and costs in adult patients with Gabapentin’s effects onhot flashesinpostmenopausal women: arandomized https://doi.org/10.1016/S0140-6736(05)67215-7PMID: Management of hot flashesinpatients havewho breast cancer with venla- Mechanism of hot flashes 11896107 PMID:21343402 J ClinOncol Clin TranslOncol (29) 3862–3868 29(29) Md Econom Med J 16192581 Climacteric N Engl J Med J Engl N 13(3) 143–147 PMID: 124–135 12 https://doi.org/10.1200/ 162–170 8 J ClinOncol (19) 1777–1779 370(19) PMCID: PMCID: 16139656 Climacteric 20(6) 1578– https://doi. https://doi. 21421458 Ann 15 13

Review 52. 51. 50. 49. 48. 47. 46. 45. 44. 43. 42. 41. 40. 39. 38. ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 37. JCO.2005.05.4296 PMID: cohoshblack in themanagement of hotNCCTG flashes: Trial CL, N01CC1 Loprinzi and JG, Gallagher BA, Pockaj a history of breast cancer JClinOncol 19(10)2739–2745https://doi.org/10.1200/JCO.2001.19.10.2739 PMID: Jacobson JS, Troxel AB, and Evans J, maturitas.2011.08.009 combined therapy,hormone cohoshblack and tibolone compared to placebo (2011) G Söderqvist and AL, Hirschberg E, Lundström or breast cellproliferation in postmenopausal women Hirschberg AL, Edlund M, Svane G, ley rats Anticancer Res 32(1)21–30PMID: Einbond LS, Soffritti M, and Degli Esposti D, et al (2012) PMID: the estrogenon receptor positivebreast human cancer cellMCF-7line F,Gaube L, Pusch Wolfl and S, doi.org/10.1177/1534735413477191 Fritz H, Seely D, and McGowan J, gme.0b013e3181fcb2a6 PMID: domizedcontrolled fortrials clinical isopropanoliccohoshblack extract MJ, Minkin and J, Schnitker B, Naser meta-analysis FrancoChowdhuryOH, and R, Troup J, Leach MJandMoore V (2012)Black cohosh (Cimicifuga for spp.) menopausalsymptoms Cochrane Database Syst Rev 9CD007244 16837890 racemosaCimicifuga extract) 1055 CR BNO C, Gorkow and C, Brucker K, Raus (HALT) study controlledoftrial cohosh, black multibotanical dietaryand herbs, soy for vasomotor symptoms: theherbalalternatives for menopause LaCroixAZ, and KM, Newton SD, Reed https://doi.org/10.1016/S0378-5122(02)00346-8 Jarry H, Metten M, and Spengler B, org/10.4137/117863370800300002 PMID: RuhlenSun RL, GY, andSauter(2008) Black ER cohosh: insights into itsmechanism(s) of actionIntegr Med Insights 321–32https://doi. cancer patients SpringerPlus 465https://doi.org/10.1186/s40064-015-0808-y Drewe J, Bucher KA, and Zahner C (2015) 26325084 toms,system?enzyme inhibit theCYP2D6 Goldstein SR, Espié M, and Druckmann R (2015) 17880733 PMCID: Menopause JAMA 3152554–2563https://doi.org/10.1001/jama.2016.8012 PMID: PMID: 15(1)51–58PMID: 16782922 2194763 21958943 (2007) et al 21228727 et al (2014) et al (2007) et al (2003) (2006) etal et al (2001) (2016) et al (2011) et al (2008) et al A systematic review of non-hormonaltreatments of vasomotor symptoms inclimacteric and 22213284 Gene expressionprofiling reveals effects of cimicifugaracemosa NUTT.(L.) (black cohosh) (2006) et al Blackcohosh and breast cancer: asystematic review 21614156 PMCID: 18257142 An isopropanolic extract of blackcohosh not does increase mammographic breast density Menopause Menopause In vitro effects of theCimicifugaracemosa extract BNO1055 First-timeproof of endometrial safety of thespecialblackcohosh extract (Actaea or Randomized trialof blackcohosh for thetreatment of hot flashesamong women with Doespurified Swedish pollen extract, anonhormonaltreatment for vasomotor symp- PMID: Use of plant-based therapies symptoms: andmenopausal asystematic review and Vaginal,endometrial, andreproductive randomized, hormonefindings: placebo- Suspectedcohosh black hepatotoxicity:evidence no by meta-analysis of ran-

Menopause Digitized assessment of mammographic breast density–effects of continuous Chemopreventive potential ofcohosh black onbreast cancer inSprague–Daw-

678–691 13 12609557 Phase IIIdouble-blind,randomized, placebo-controlled crossover trialof 1212–1214 22

14(1) 89–96 3046019 https://doi.org/10.1097/01.gme.0000196813.34247.e2 PMID: BMC PharmacolBMC https://doi.org/10.1097/GME.0000000000000535 PMID: J Clin Oncol https://doi.org/10.1097/01.gme.0000230346.20992.34 PMID:25713759PMCID:4331402 Menopause Maturitas 27327802 7 11https://doi.org/10.1186/1471-2210-7-11 1) 2836–2841 24(18) 4 361–364 70(4) 4 366–375 18(4) IntegrCancer Ther https://doi.org/10.1016/j. https://doi.org/10.1200/ https://doi.org/10.1097/ Maturitas 11352967 13 12–29 44(1) S31–S38 https:// 14

Review 69. 68. 67. 70. 66. 65. 64. 63. 62. 61. 60. 59. 58. 57. 56. 55. ecancer 2019, 13:909; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.909 54. 53. Befus D, Coeytaux RR, and Goldstein KM, Goldstein and D,BefusCoeytauxRR, Systematic Reviews (Chichester, UK: John Wiley &Sons Ltd)http://doi.wiley.com/10.1002/14651858.CD007410.pub2 [ Dodin S, Blanchet C, and Marc I, Database Syst Rev 7CD008582 S, SaensakVutyavanich T,W,Somboonporn and GME.0000000000000194 ings froma randomized controlled in postmenopausal trial clinical women S, Banuvar and LH, Rubvvbounoussin DR, Walega atic review andmeta-analysis PMID: cancer treatment1): arandomised (MENOS controlled trial Mann E, Smith MJ, and Hellier J, gme.0b013e31823fe835 PMID: hotmenopausal nightand flushes sweatsrandomizeda 2): (MENOS controlled trial HellierJ, and M, Smith AyersB, https://doi.org/10.1016/j.maturitas.2017.12.005 Cramer H, Peng W, and Lauche R (2018) ized controlled trial Cramer H, Rabsilber S, and Lauche R, J Physiol 594657–667https://doi.org/10.1113/JP271456 Bailey TG, Cable NT, and Aziz N, CD006108 PMID: Daley A, Stokes-Lampard H, and Thomas A, survivors JClinOncol 301492–1497https://doi.org/10.1200/JCO.2011.36.8597 PMID:22430275PMCID:4874147 BJ,Caan Emond JA,Suand HI, 170 1161–1167https://doi.org/10.1001/archinternmed.2010.162 PMID:20625026PMCID:3030922 Huang AJ, Subak LL, and Wing R, Menopause Lowand LJ,EwingCA, RC, Thurston initiative Menopause Kroenke CH, Caan BJ, and Stefanick ML, 10 2018(Abstract GS6-02,presented 7December 2018) San Antonio Breast Cancer Symposium (SABCS) (2018) clinical trial Simon JA, Gaines T, and LaGuardia KD (2016) breast cancer Int J ClinPharmacol Ther Henneicke-von Zepelin HH, Meden H, and Kostev K, cal guideline National Institute for Care and Health Excellence (NICE) (2017) 22340966 PMCID: 2259–65https://doi.org/10.1097/GME.0000000000000274 Menopause [ nice.org.uk/guidance/cg80] Date accessed: 24/2/2019 25431132 Cancer 132175–2184https://doi.org/10.1002/cncr.29330 19980–988https://doi.org/10.1097/gme.0b013e31824f606e PMID: 23(11)1214–1221https://doi.org/10.1097/GME.0000000000000773 PMID:27760081 3314999 PMID: J Altern Complement Med 4314–323https://doi.org/10.1089/acm.2016.0408 et(2012) al et al (2012) etal (2013) (2012) et al etal (2016) 22336748 et al (2010) 24496086 PMCID: et al (2015) (2015) et al 45(3)143–154https://doi.org/10.5414/CPP45143 PMID:17416109 etal (2012) Yogafor symptoms-A menopausal systematic review andmeta-analysis (2018) et al Effect of postdiagnosis weight change onhot status flash amongearly-stage breast cancer et al (2014) Cognitive behavioural treatment for women havewho symptoms menopausal after breast Acupuncturefor menopausal hotflushes ed The Cochrane Collaboration, Cochrane Database Exercise trainingreduces theacute physiological severity of post-menopausalhot flushes An intensive behavioral weight loss intervention and hot flushes inwomen Effectivenessof group andself-help cognitive behavior therapy inreducing problematic Extended-release oxybutynin therapy for vasomotor symptoms in women: arandomized Yogameditation and for menopausalsymptoms inbreast cancer survivors-A random - PMID: (2014) et al Behavioral weight lossfor themanagement of hot menopausal flashes:apilot study Effects of adietary intervention and weight change on VMS inthe women’s health etal (2007) (2014) et al 4110158 Management of symptoms menopause with acupuncture: anumbrella system- ‘It’sGoing to Be aUseful Agent’: Oxybutynin for Hot Flashes Exercise for vasomotor menopausalsymptoms 29452777

Lancet Oncol Relaxation for perimenopausalandpostmenopausalsymptoms Early and locally advanced breast cancer: and diagnosis treatment Isopropanolic blackcohosh extract andrecurrence-free survival after Effects of stellateon block ganglion vasomotor symptoms: find- 13 309–318 Menopause https://doi.org/10.1016/S1470-2045(11)70364-3 Menopause 22781782 PMCID: 8 807–814 21(8) 749–759 19

Cochrane Database Syst Rev (11) https://doi.org/10.1097/ https://doi.org/10.1097/ 3428489 Maturitas Medscape Arch Intern Med ] 109 13–25 Cochrane 10 Dec Clini- 15

Review