Appendix 2: Evidence Summaries

The Evidence Summaries are based on the evidence base identified in the Cancer Australia systematic reviews conducted for this guideline. Further details are available in the Cancer Australia systematic reviews and the Summary of Evidence sections. The systematic reviews focused on evidence for the management of menopausal symptoms in women who have received treatment for breast cancer and the general female menopausal population for the same interventions plus selected ones that have not been previously researched in a breast cancer population.

ES1

One RCT (with a moderate risk of bias; Brazil) in women after breast cancer found that 4 weeks of bupropion (300 mg/day) had no statistically significant effect on the severity of hot flushes compared with placebo.29

ES2

One RCT (with a low risk of bias; USA) in women after breast cancer found that paroxetine (10 or 20 mg/d for 4 weeks) significantly reduced hot flush frequency and severity compared with placebo.14

Three RCTs (with a low to moderate risk of bias; USA) in women after breast cancer found that neither fluoxetine (20 mg/d for 4 weeks)15 nor sertraline (25 to 100 mg/d for 4-6 weeks)16, 17 had a consistent effect on hot flushes compared with placebo.

ES3

One RCT (with low risk of bias; the Netherlands) in women after breast cancer found that 12 weeks of venlafaxine at 75 mg/d (slow release) significantly reduced hot flush frequency and severity compared with placebo.20

One RCT (with moderate risk of bias; USA) in women after breast cancer found that 14 weeks of venlafaxine at 37.5mg/d significantly reduced hot flush frequency and severity compared with placebo.21

One RCT (with a low risk of bias; the Netherlands) in women after breast cancer found that venlafaxine (75mg/d for 12 weeks) was equally effective as clonidine (0.1mg/d for 12 weeks) at reducing hot flush frequency and severity.20

One cross-over RCT (with a moderate risk of bias; the Netherlands) in women after breast cancer found that venlafaxine (75mg/d for 8 weeks) was equally effective as clonidine (0.1mg/d for 8 weeks) at reducing hot flush frequency and severity.22

One RCT (with a moderate risk of bias; Germany) in women after breast cancer found that venlafaxine (75mg/d for 4 weeks) was more effective than clonidine (0.15mg/d for 4 weeks) at reducing the frequency of hot flushes.23

One RCT (with a moderate risk of bias; Canada) in women after breast cancer found that 4 weeks of venlafaxine (37.5mg/d for 7 days and 75mg/d for 21 days) or gabapentin (300mg/d for 3 days, 900mg/d for 3 days, and 1200mg/d for 22 days) were associated with equivalent reductions in hot flash scores.24

One RCT (with a moderate risk of bias; USA) in women after breast cancer found 12 weeks of venlafaxine (37.5mg/d for 1 week and 75mg/d for 11 weeks) or a course of acupuncture (twice per week for 4 weeks, and once per week for 8 weeks) were associated with similar reductions in hot flash frequency and severity.25

ES4

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that augmentation of an SSRI or SNRI with 5 weeks of zolpidem (10mg/d) has no statistical significant additional effect on vasomotor symptoms compared to placebo.30

ES5

One RCT (with a low risk of bias; the Netherlands) in women after breast cancer found that clonidine (0.1 mg/d) significantly reduced the frequency and severity of hot flushes relative to placebo.20

ES6

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that 4-8 weeks of gabapentin (900 mg/d) was associated with a reduction in hot flush frequency and severity compared with placebo.31

Three RCTs (two with a moderate risk of bias and one with a high risk of bias; Canada, Iran, Italy) in women after breast cancer found that 4-12 weeks of gabapentin (900mg/d or 300mg/d) was associated with a significant reduction in hot flush frequency and severity compared with baseline24, 32, 33 and one of the RCTs found a significant reduction in hot flush frequency between groups.32 In one of these RCTs the effect size was equivalent to that observed with venlafaxine (37.5mg/d for 7 days and 75mg/d for 21 days,24 and in another the effect size was less than that observed with megestrol acetate (40mg/d)32.

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that 8 weeks of gabapentin (300g/day for 3 days, then 900mg/day for 8 weeks) did not significantly reduce hot flush frequency and severity compared with placebo, but the gabapentin group experienced improvement in hot flushes compared with baseline.55

ES7

One RCT (with a low risk of bias; multinational) in women after breast cancer found that tibolone (2.5 mg/d) for up to 2.75 years significantly reduced the frequency and severity of hot flushes compared with placebo.34, 35

One RCT (with high risk of bias; Sweden) in women after breast cancer found that menopause hormone therapy (sequential or combined oestrogen/progestogen for 24 months) and electro-acupuncture (for 12 weeks) statistically significantly reduced the number of night-time hot flushes over 2 years37.  Menopause hormone therapy appeared to be more effective than electro-acupuncture although between‑group statistical significance was not reported36, 37.

ES8

One RCT (with a moderate risk of bias; UK) in women after breast cancer found that purpose-designed group CBT (90min per week for 6 weeks) alone versus usual care had no effect on the frequency of hot flushes, but reduced the problem rating of hot flushes and night sweats.45

One RCT (with a moderate risk of bias; the Netherlands) in women after breast cancer found that purpose-designed group CBT (90min per week for 6 weeks) in combination with physical exercise (2.5 to 3 hours per week) compared with no intervention reduced the problem rating of hot flushes and night sweats.46

ES9

One RCT (with a moderate risk of bias; USA) in women after breast cancer reported that a purpose-designed hypnotherapy protocol delivered once/week for 5 weeks reduced hot flush frequency and severity compared with no treatment.48

ES10

One RCT (with a low risk of bias; Norway) in women after breast cancer comparing acupuncture (needle inserted 0.5-3cm deep for 30min) with sham acupuncture (needle inserted 2-3mm deep for 30min), reported a reduction in frequency and severity of hot flushes with acupuncture.49

Two RCTs (with a moderate risk of bias; Sweden, USA) in women after breast cancer found no difference between acupuncture (needle inserted 5–20 mm deep for 20min or 0.25 to 0.5 inches deep) and sham acupuncture, in terms of frequency and severity of hot flushes.50, 51

One RCT (with a low risk of bias; Denmark) in women after breast cancer reported acupuncture (for 15-20min once a week) reduced the nuisance of hot flushes, but did not report between-group differences compared with sham or no treatment.52

One RCT (with a high risk of bias; USA) in women after breast cancer found that acupuncture (for 12 weeks) and venlafaxine (75mg/d for 12 weeks) were equally effective at reducing the frequency and severity of hot flushes.25

One RCT (with a high risk of bias; Sweden) in women after breast cancer found that electro-acupuncture (for 12 weeks) and menopause hormone therapy (for 24 months) were effective at reducing night-time hot flushes compared to baseline.36, 37

One RCT (with a high risk of bias; Sweden) in women after breast cancer found electro-acupuncture (for 12 weeks) and applied relaxation (for 12 weeks) were equally effective at decreasing the frequency of hot flushes and improving the Kuppermann Index compared to baseline.53, 54

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that electro-acupuncture (twice per week for 2 weeks, then once per week for 6 weeks) reported no statistically significant difference in hot flush frequency and severity compared with sham acupuncture, but electro-acupuncture was more effective at improving hot flush frequency and severity compared with baseline than the sham acupuncture, placebo and gabapentin groups (300mg/d for 2 weeks, then 900mg/day for 6 weeks).55

ES11

One RCT (with a low risk of bias; UK) in women after breast cancer reported reduced hot flush frequency and severity during relaxation therapy treatment at one month (one hour session and a 20min tape to use once a day) versus no treatment.58

ES12

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that an 8-week yoga program reduced the frequency and severity of hot flushes compared with no intervention.60

One RCT (with a moderate risk of bias; Germany) in women after breast cancer reported significant improvement in total menopausal symptoms with yoga and meditation (Hatha yoga, 90min/week for 12 weeks) compared with usual care.61

ES13

Two RCTs (with a low to moderate risk of bias; both from USA) in women after breast cancer reported no difference in severity and frequency of hot flushes between black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) and placebo.66, 67

One RCT (with a high risk of bias; Venezuela) in women after breast cancer compared tamoxifen (20mg/d) with black cohosh (1 capsule, Cimicifuga racemosa, CR BNO 1055) for 12 months, but did not adequately report data on the frequency or severity of hot flushes.68

ES14

Two RCTs (with a low and high risk of bias; UK and USA respectively) in women after breast cancer found no effect of homeopathy (in tablet, granule, or liquid form) compared with placebo on hot flush frequency or severity.70, 71

ES15

Three RCTs (with a low to high risk of bias; Canada, Finland, UK) in women after breast cancer found no effect of phytoestrogens (tablets, 114 mg of isoflavonoids or soybean beverage or 235 mg of soy extract with 17.5 mg of Isoflavones 70mg/d) versus placebo on the Kupperman’s Index, as well as no effect on the frequency or severity of hot flushes.72-74

ES16

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that 3 days of magnetic therapy (6 magnets on acupuncture pressure sites per participant) had no effect on the severity of hot flushes compared with placebo, while placebo was reported to have had a greater effect on frequency of hot flushes compared with magnetic therapy.77

ES17

One RCT (with a low risk of bias; USA) in women after breast cancer found that paroxetine (10 or 20 mg/d for 9 weeks) was associated with an improvement in sleep compared with placebo.14

One RCT (with a low risk of bias; USA) in women after breast cancer found that there fewer reports on trouble sleeping in the fluoxetine (20 mg/d) arm at 9 weeks relative to baseline, but did not report between group differences for sleep disturbance compared with placebo.15

ES18

One RCT (with a moderate risk of bias; USA) in women after breast cancer found no difference in sleep disturbance between venlafaxine 75 mg/d and placebo.21  

Three RCTs (one with a low risk of bias and two with a moderate risk of bias; Germany, the Netherlands) in women after breast cancer compared venlafaxine versus clonidine (Boekhout 2011, Buijs 2009, Loibl 2007), and only one of the three studies found an improvement in sleep for venlafaxine compared to clonidine.22

One RCT (with a moderate risk of bias; USA) in women after breast reported no statistical comparison between venlafaxine versus acupuncture.25

ES19

One RCT (with a moderate risk of bias; USA) in women after breast cancer receiving an SSRI or SNRI for vasomotor symptoms found an improvement in sleep disturbance with 5 weeks of zolpidem (10 mg/d) augmentation compared with placebo.30

ES20

One RCT (with a moderate risk of bias: USA) in women after breast cancer reported that gabapentin (300mg/d or 900mg/d) had no effect on sleep compared to placebo.31

One cross-over RCT (with a moderate risk of bias; Canada) in women after breast cancer reported that gabapentin (900mg/d for 4 weeks) had no difference in sleeplessness compared to venlafaxine (75mg/d for 4 weeks).24

One RCT (with a moderate risk of bias; Italy) in women after breast cancer reported that gabapentin (900mg/d for 12 weeks) improved sleep quality (measured using the Pittsburgh Sleep Quality Index score) compared to Vitamin E (800 IU/d for 12 weeks).33

ES21

One RCT (with a low risk of bias; multinational) in women after breast cancer found that tibolone (2.5mg/d) was associated with an improvement in sleep quality compared with placebo (LIBERATE study) (Sismondi 2011). An earlier analysis from the LIBERATE study reported insomnia as an adverse event, but did not report between-group differences.34 

One RCT (with a high risk of bias; Sweden) in women after breast cancer found menopause hormone therapy (2mg of oestradiol with different progestogens) improved sleep compared with no treatment.78  One RCT (with a moderate risk of bias; Sweden) in women after breast cancer found that menopause hormone therapy (for 24 months) and electro-acupuncture (for 12 weeks) improved sleep relative to baseline, but did not report between group differences.37

ES22

One RCT (with a moderate risk of bias; UK) in women after breast cancer found that CBT (90min per week for 6 weeks) significantly improved sleep compared with usual care.45

One RCT (with a low risk of bias; USA) in women after breast cancer reported a statistically significant improvement in sleep efficiency scores and sleep latency scores with cognitive behavioural therapy for insomnia (CBTI, 30-60min once a week for 6 weeks) compared with behavioural placebo treatment (BPT); but found no significant improvement on wake after sleep onset scores or number of awakenings with CBTI compared with BPT.79

One RCT (with moderate risk of bias; USA) in women after breast cancer found that hypnotherapy (once a week for 5 weeks) improved sleep compared with no treatment .48

ES23

One RCT (with moderate risk of bias; USA) in women after breast cancer found that an 8-week yoga program significantly improved sleep compared with no intervention.60

One RCT (with low risk of bias; Denmark) in women after breast cancer found that acupuncture (for 15-20min once a week) significantly improved sleep compared with sham-acupuncture and no treatment groups, but did not report between-group differences from baseline.52

ES24

One RCT (with moderate risk of bias; Italy) in women after breast cancer found that gabapentin (900mg/d for 12 weeks) improved sleep quality (measured using the Pittsburgh Sleep Quality Index score, PSQI), compared with Vitamin E (800 IU/d for 12 weeks) which had no effect on the PSQI score.33

ES25

Three RCTs (two with low and one with a moderate risk of bias; Brazil; two from USA) in women after breast cancer reported no difference in sexual function as measured by the ASEX, BDI single item, MOS SPI or SAQ, after 4-12 weeks of treatment with antidepressants, including bupropion 300 mg/d29, fluoxetine 20 mg/d15 or paroxetine 10-20 mg/d14 compared with placebo.

One cross-over RCT (with a low risk of bias; the Netherlands) in women after breast cancer found that neither venlafaxine (75mg/d for 8 weeks) nor clonidine (0.1mg/d for 8 weeks) had an effect on sexual activity as measured by the Sexual Activity Questionnaire Scales.22

One RCT (with a moderate risk of bias; the Netherlands) in women after breast cancer found no differences in sexual function as measured by the Sexual Activity Questionnaire for venlafaxine (75mg/d for 12 weeks), clonidine (0.1mg/d for 12 weeks) or placebo.20

One RCT (with moderate risk of bias; Canada) in women after breast cancer reported increase in difficulty achieving orgasm as measured using a symptom diary for venlafaxine (75mg/d) compared to gabapentin (300mg/d or 900mg/d).24

ES26

One RCT (with a low risk of bias; multinational) in women after breast cancer found an improvement in sexual behaviour and vaginal dryness for tibolone (2.5 mg/d for 2.75 years) compared with placebo.35

Two RCTs (with a high risk of bias; Sweden, UK) in women after breast cancer found inconsistent effects of menopause hormone therapy on sexual enjoyment, sexual activity and discomfort compared with no treatment control.78, 82

ES27

One RCT (with a low risk of bias; South Korea) in women after breast cancer found that 12 weeks with a non-hormonal vaginal gel was associated with a statistically significant improvement in a range of vaginal symptoms, compared with placebo.80

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that 8 weeks of topical lidocaine treatment (4% solution for 3 minutes) was associated with a statistically significant improvement in vulvovaginal symptoms including dyspareunia, compared with placebo.81

ES28

One RCT (with a moderate risk of bias; the Netherlands) in women after breast cancer found that CBT alone or in combination with physical exercise improves sexual function compared with wait list control.46

One RCT (with a moderate risk of bias; USA) in women after breast cancer found that a 5 weeks course of hypnotherapy had no statistically significant effect on the impact of hot flushes on sexuality compared to no treatment control.48

ES29

One RCT (with a low risk of bias; multinational) in women after breast cancer found that tibolone (2.5 mg/d) was associated with a significantly higher rate of new breast cancer events compared with no treatment.34  

One RCT (with a high risk of bias; Sweden) of menopause hormone therapy (combined oestradiol/medroxyprogesterone) in women after breast cancer was terminated early due to safety concerns related to breast cancer recurrence.91

One RCT (with a high risk of bias; Sweden) in women after breast cancer found that menopause hormone therapy (sequential or continuous combined oestrogen/progestogen) was associated with a significantly higher rate of new breast cancer events compared with no treatment, resulting in the early termination of this study.90

ES30

Two RCTs (overall risk of bias of included studies not reported; both USA identified in one Systematic Review (with a low risk of bias; USA; Shams 2014)18in peri- and postmenopausal women (women with breast cancer were not included) found that 8 weeks of escitalopram (10-20 mg/d) significantly reduced hot flush frequency compared with placebo. One of these RCTs (with a low risk of bias), also identified in one pooled analysis  in peri- and postmenopausal women (with at least 14 bothersome vasomotor symptoms per week), found that 8 weeks of escitalopram (10 mg/d) significantly reduced vasomotor symptom frequency and bother compared with placebo.19, 102

ES31

One RCT (with a low risk of bias; USA) identified in a pooled analysis in peri- and postmenopausal women (with at least 14 bothersome vasomotor symptoms per week) found that 8 weeks of low-dose venlafaxine XR (37.5 mg/d for the first week, then 75 mg/d) significantly reduced vasomotor symptom frequency and bother compared with placebo.19, 26

ES32

Six RCTs (all with a low risk of bias; countries not reported) identified in one Systematic Review (with a low risk of bias; Sun 2013) in postmenopausal women (healthy with an unknown breast cancer history) found that 12 weeks of desvenlafaxine (100 mg or 150 mg daily) significantly reduced hot flush frequency compared with placebo.27

Seven RCTs (with an unclear risk of bias; Europe, North America, South Africa) identified in one Systematic Review (with a moderate risk of bias; Berhan 2014) in postmenopausal women (with at least seven moderate to severe hot flushes per day) found that 12 or more weeks of desvenlafaxine (≥100 mg/d) significantly reduced hot flush frequency and severity compared with placebo.28

ES33

Four RCTs (with a high risk of bias; Austria, Denmark, Spain, Sweden, Switzerland, the Netherlands, Turkey, UK, USA) identified in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women (including women surgically treated for breast cancer) found that tibolone (2.5 mg/d) significantly reduced hot flush frequency compared with placebo.38

ES34

Nine RCTs (overall risk of bias of included studies not reported; France, Norway, Russia, two from UK, four from USA) identified in a Systematic Review (with a low risk of bias; MacLennan et al 2004) in peri- and postmenopausal women (not including women with breast cancer) found that oral hormone therapy (oestrogen and combined oestrogen/progestogen therapy) significantly reduced the frequency and severity of hot flushes compared with placebo.39

ES35

One RCT (with a low risk of bias; USA) in menopause transition and postmenopausal women found a significant reduction in vasomotor symptom frequency and severity with low dose oestradiol (0.5mg/d for 8 weeks) and with venlafaxine (37.5mg/d for 1 week, then 75mg/d for 7 weeks) compared with placebo. Reduction of vasomotor symptom frequency was greater in the low estradiol group (53%) compared with the venlafaxine group (48%). Reduction in vasomotor symptom bother was found to be significant with the low oestradiol group compared with placebo, but not significant with the venlafaxine group compared with placebo.19, 26

ES36

Five RCTs (all with a low risk of bias; Finland, four from USA) identified in a Systematic Review (with a low risk of bias; Cui et al 2013) in postmenopausal women with vulvovaginal dyspareunia and atrophy found that at 12 weeks, ospemifene (60 mg/d) significantly increased hot flushes compared with placebo.43

ES37

Seven RCTs (with a low risk of bias; USA) and two RCTs (with a high risk of bias; Italy, USA) identified in a Systematic Review (with a low risk of bias; Corbelli et al 2014) in postmenopausal women (at least seven hot flushes per day and/or at least 50 hot flushes per week) found that transdermal low-dose oestradiol (< 0.05 mg/d) significantly reduced hot flush frequency compared with placebo; greater reductions were seen with the higher dose range (0.029 mg/d to 0.045 mg/d) than the lower doses.40

ES38

Five RCTs (with an unknown risk of bias; locations not reported) identified in a Systematic Review (with a moderate risk of bias; Derzko et al 2016) in postmenopausal women (natural or surgically induced) found that transdermal oestradiol gel preparations (0.25-1.5 mg/day) significantly reduced hot flush frequency and severity compared with placebo. The greatest effect was seen with dosing around 1mg/day but this also caused the greatest number of adverse events.41

ES39

Two RCTs (overall risk of bias of included studies not reported; both from USA) analysed in a Systematic Review (with a low risk of bias; Somboonporn et al 2005) in peri- and postmenopausal women (natural or surgically-induced, with or without a history of breast cancer) found no significant differences in vasomotor symptoms between combined testosterone and menopause hormone therapy versus menopause hormone therapy alone.44

ES40

Three RCTs (one with a low and two with moderate risk of bias; Australia, UK, USA) identified in a Systematic Review (with a moderate risk of bias; Whelan et al 2013) in postmenopausal women reported on compounded progesterone cream and vasomotor symptoms. One of the RCTs found a significant improvement in vasomotor symptom severity for a compounded progesterone cream compared with placebo, while two of the RCTs found no significant difference in vasomotor symptom severity between commercially available progesterone creams and placebo.42

ES41

One RCT (with an unknown risk of bias; UK) identified in a Systematic Review (with a moderate risk of bias; Velez Toral 2014) in peri- and postmenopausal women found that CBT (120 min per week for 4 weeks) significantly reduced hot flushes and night sweats compared with no intervention.47

ES42

One RCT (with a low risk of bias: USA) in menopause transition and postmenopausal women found that exercise (3 times per week of either treadmill, elliptical trainer, or stationary bicycle for 12 weeks) had no significant reduction in vasomotor symptom frequency and bother compared with the usual activity control group.19, 65

A meta-analysis of three RCTs (one low risk of bias, two with a high risk of bias; Finland, two from USA), including Sternfeld et al (2014), identified in a Systematic Review (with a low risk of bias; Daley et al 2014) in peri- and postmenopausal women (excluding women with breast cancer) found that exercise (of any type) did not significantly reduce the frequency of hot flushes/night sweats compared with no active treatment.64, 65

One RCT (with an unknown risk of bias; USA) identified in a Systematic Review (with a moderate risk of bias; Woods et al 2014) in menopausal women (excluding trials exclusively conducted in women with breast cancer) found that exercise did not significantly reduce vasomotor symptoms compared with no exercise or oestradiol.63

ES43

One RCT (with a low risk of bias; USA; Newton 2014 and Guthrie 2015) in menopause transition and postmenopausal women found that yoga (90min weekly class for 12 weeks) did not significantly reduce vasomotor symptom frequency and bother compared with usual activity.19

One RCT (with an unknown risk of bias; India) identified in a Systematic Review (with a moderate risk of bias; Woods et al 2014) in menopausal women (excluding trials exclusively conducted in women with breast cancer) found that 8 weeks of integrated yoga therapy (1 h/day, 5 days/week) significantly reduced vasomotor symptoms compared with exercise.63

One additional RCT (with a high risk of bias; USA) identified in a Systematic Review (with a low risk of bias; Daley et al 2014) in peri- and postmenopausal women (excluding women with breast cancer) found that there was no significant difference between yoga (up to 12 sessions) and exercise in reducing vasomotor symptoms.64

ES44

Four RCTs (overall risk of bias of included studies not reported; Sweden, UK, USA) identified in a Systematic Review (with a low risk of bias; Saensk et al 2014) in peri- and postmenopausal women (including women with breast cancer) found that 12 weeks of relaxation techniques did not significantly reduce hot flush frequency or severity compared with placebo/no treatment or acupuncture/superficial needling.59

ES45

Nine RCTs (overall risk of bias of included studies not reported; Denmark, Korea, Norway, Sweden, five from USA) identified in a Systematic Review (with a low risk of bias; Dodin et al 2013) in peri- and postmenopausal women (including women with breast cancer) found that acupuncture significantly reduced hot flush severity, but not frequency, compared with sham acupuncture. Three RCTs (with a high risk of bias; China, Sweden) identified in the same Systematic Review found that hormone therapy significantly reduced hot flush frequency, but not severity, compared with acupuncture.56

One RCT (with a low risk of bias; Australia) in peri- and postmenopausal women reported no statistically significant difference in hot flush frequency or severity for acupuncture compared with sham acupuncture (10 treatments over 8 weeks for both).57

ES46

15 RCTs (with an unknown risk of bias; Brazil, Canada, Ecuador, Iran, Italy, Japan, Korea, Taiwan, UK, USA) identified in a Systematic Review (with a moderate risk of bias; Thomas 2014) in peri- and early postmenopausal women (with hot flushes and at least one co-occurring symptom) found an inconsistent benefit of soy and other isoflavones on vasomotor symptoms compared with placebo and other nutritional comparators.75

ES47

One RCT (with a low risk of bias; USA) in menopause transition and postmenopausal women found that 12 weeks of omega-3 supplement (1.8 grams daily: EPA; 425mg, DHA; 100mg, omega-3 90mg) did not significantly improve vasomotor symptoms frequency or bother compared with placebo.19, 76

ES48

Five RCTs (overall risk of bias of included studies not reported; Switzerland, four from USA) identified in a Systematic Review (with a low risk of bias; Leach and Moore 2012) in peri- and postmenopausal women (including women with breast cancer) found that black cohosh (40 mg/d) did not reduce vasomotor symptom frequency or bother compared with placebo.69

ES49

One RCT (overall risk of bias of included study not reported; USA) identified in a Systematic Review (with a low risk of bias; Shams et al 2014) in peri- and postmenopausal women found that escitalopram had no statistical effect on sleep disturbance compared to placebo.18

ES50

Three RCTs (with a low risk of bias; all USA) identified in a Systematic Review (with a low risk of bias; Sun et al 2013) in postmenopausal women (healthy with an unknown breast cancer history) found that 12 weeks of desvenlafaxine (100mg or 150mg daily) significantly reduced the number of night-time awakenings compared with placebo.27

ES51

One RCT (overall risk of bias of included studies not reported; multinational: Asia, Australia, Europe, USA) identified in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women (including women surgically treated for breast cancer) found that tibolone (2.5 mg/d for more than two years) did not reduce the frequency of insomnia compared with placebo.38

ES52

Two RCTs (with an unknown risk of bias; India, USA) identified in a Systematic Review (with a moderate risk of bias; Woods et al 2014) in menopausal women (excluding trials exclusively conducted in women with breast cancer) found that physical activity/exercise had no significant effect on sleep symptoms.63

One RCT (with a low risk of bias: USA) in menopause transition and postmenopausal women found that exercise (3 times per week of treadmill, elliptical trainer, or stationary bicycle for 12 weeks) significantly improved sleep quality and insomnia symptoms compared to the usual activity control group.19, 65

ES53

One RCT (with an unknown risk of bias; India) identified in a Systematic Review (with a moderate risk of bias; Woods 2014) in menopausal women (excluding trials exclusively conducted in women with breast cancer) found that yoga significantly improved sleep symptoms compared to baseline, but there was no significant difference between the effect of yoga and exercise on sleep symptoms.63

One RCT (with a low risk of bias; USA) in menopause transition and postmenopausal women found that yoga (90min weekly class for 12 weeks) significantly improved insomnia symptoms compared with usual activity. 19, 62

ES54

One small RCT (with an unknown risk of bias; USA) identified in a Systematic Review (with a moderate risk of bias; Woods et al 2014) in menopausal women (excluding trials exclusively conducted in women with breast cancer) found that relaxation therapy significantly improved sleep symptoms compared with a waitlist control.63

ES55

One RCT (with an unknown risk of bias; Italy) identified in a Systematic Review (with a moderate risk of bias; Thomas et al 2014) in peri- and early postmenopausal women (with hot flushes and at least one co-occurring symptom) found that an isoflavones combined with magnolia bark extract, magnesium, lactobacillus, calcium and Vitamin D3 significantly reduced insomnia at 12 weeks compared to calcium and Vitamin D3 alone; other trials in this systematic review found that soy and other isoflavones did not significantly improve sleep symptoms.75

ES56

One RCT (with a low risk of bias; USA) in peri- and postmenopausal women reported no significant effect on sleep quality and insomnia with omega-3 fatty acid supplementation compared to placebo.76

ES57

One RCT (overall risk of bias of included studies not reported; USA) identified in a Systematic Review (with a low risk of bias; Shams et al 2014) in peri- and postmenopausal women reported no significant effect on libido with escitalopram compared to placebo.18

ES58

One RCT (with a low risk of bias; USA) in menopause transition and postmenopausal women found that 8 weeks of low-dose oestradiol (0.5mg/day) or venlafaxine (37.5mg/day for 1 week and 75mg/day for 7 weeks) did not significantly altered sexual function (measured with Female Sexual Function Index) compared to placebo; but venlafaxine significantly improved vaginal dryness compared to the placebo group.83

ES59

Nine RCTs (overall risk of bias of included studies not reported; Australia, USA and multinational) identified in a Systematic Review (with a low risk of bias; Somboonporn et al 2005) in peri- and postmenopausal women (natural or surgically-induced, with or without a history of breast cancer) found a statistically significant improvement in sexual function with testosterone in combination with menopause hormone therapy compared with menopause hormone therapy alone.44

ES60

Thirty five RCTs (various locations) identified in a Systematic Review (with a low risk of bias; Elraiyah et al 2014) in postmenopausal women (with an unknown history of breast cancer) found a statistically significant improvement in sexual function with therapy containing testosterone compared with therapy without testosterone.87

ES61

Four RCTs (with a high risk of bias; multinational: Asia, Australia, Europe, USA) identified in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women (including women surgically treated for breast cancer) found that tibolone (2.5 mg/d for more than two years) did not significantly reduce vaginal dryness or dyspareunia compared with placebo.38

ES62

Twenty seven RCTs (overall risk of bias of included studies not reported; 30 countries in Asia, Australia, Europe, South America, USA) identified in a systematic review (with a low risk of bias, Nastri el al 2013) in postmenopausal women found that menopause hormone therapy (oestrogen transdermal patch 0.014 mg/day; oestrogen gel 0.87 g/d, oestrogen gel 1.7 g/d, 2.6 g/d; oestrogen spray 150mcg/day or 300mcg/day; oestrogen vaginal ring 50mcg/day or 100mcg/day or conjugated equine estrogen 0.625mg plus medroxyprogesterone acetate 2.5mg daily; for 12 weeks) did not significantly improve sexual function (composite score) compared with control, but did show a small to moderate benefit in sexual function compared with control.84

ES63

Nineteen RCTs (overall risk of bias of included studies not reported; Australia, Europe, North America, Thailand) identified in a Systematic Review (with a low risk of bias; Suckling et al 2006) in postmenopausal women with vaginal atrophy (without a history of hormone-dependent neoplasia) found that at least three months of vaginally administered oestrogen rings, creams or tablets were each equally effective at relieving the symptoms of vaginal atrophy, while being more effective than placebo.85

Fourteen RCTs and prospective comparative studies (seven with a low risk of bias, six with a moderate risk of bias and one with a high risk of bias; Europe, Israel, UK, USA) identified in a Systematic Review (with a low risk of bias; Rahn et al 2014) in postmenopausal women with genitourinary syndrome of menopause (excluding women with breast cancer) found that vaginal oestrogen was more effective than placebo in the relief of vaginal dryness, itching, and dyspareunia.86

ES64

Six RCTs (overall risk of bias of included studies not reported; locations not reported) identified in a Systematic review (with a moderate risk of bias; Ghazanfarpour et al 2015) in menopausal women found that soy isoflavones had an uncertain effect on vaginal dryness and dyspareunia compared to placebo.88

ES65

Two RCTs (USA) identified in a Systematic Review (with a low risk of bias; Cui et al 2013) in postmenopausal women with vulvovaginal dyspareunia and atrophy found that oral ospemifene (60 mg/d) significantly reduces dyspareunia compared with placebo.43

Twenty seven RCTs (overall risk of bias of included studies not reported; Brazil, Denmark, Estonia, Italy, Poland, Romania, Sweden, Taiwan, the Netherlands, USA and multinational) identified in a systematic review (with a low risk of bias, Nastri el al 2013) in postmenopausal women found that SERMs (bazedoxifene 20 mg alone or plus conjugated estrogens 0.45mg or 0.625mg daily; for 12 weeks) did not significantly improve sexual function (composite score) compared with control; but showed a small benefit in sexual function when compared with control.84

ES66

Thirty-five RCTs (overall risk of bias of included studies not reported; Australia, Brazil, Canada, Italy, Sweden, UK, USA and multinational) identified in a Systematic Review (with a low risk of bias; Somboonporn et al 2005) in peri- and postmenopausal women (natural or surgically-induced, with or without a history of breast cancer) did not report the effect of long term use of testosterone. The authors acknowledged that testosterone should be used with caution as the dose, duration, safety and long-term effects have not been established.44

ES67

Two RCT (overall risk of bias of included studies not reported; multinational and USA) in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women reported that tibolone (1.25 mg/day) was associated with a significant reduction in breast cancer occurrence compared with placebo.38

Two RCTs (overall risk of bias of included studies not reported; Brazil and USA) in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women reported no significant difference in the risk of breast cancer with tibolone (2.5 mg/day) compared to placebo.38

Four RCTs (overall risk of bias of included studies not reported; multinational: Chile, Europe, USA) in a Systematic Review (with a low risk of bias; Formoso et al 2012) in postmenopausal women reported no significant difference in breast cancer occurrence for tibolone (2.5 and 1.25 mg/day) compared with menopause hormone therapy. The authors acknowledge that the follow-up duration in these studies may be insufficient to fully assess the risk of breast cancer associated with tibolone.38