(4) Not applicable but risk of heterogeneity was low. SR risk of bias: Low EB risk of bias: Low Authors’ conclusion: “Although publication bias cannot be excluded, risk of bias and heterogeneity among studies are low. There is strong evidence to conclude that low-dose transdermal estrogen at any dose is more effective than placebo in decreasing the daily number of moderate to severe hot flashes.” Elraiyah et al (2014)31, testosterone with or without oestrogen 35 RCTs (N=5053) Postmenopausal women with normal adrenal function. Information about history of breast cancer was not provided. Testosterone with or without oestrogen (dosage varied per study, generally it was used: 1.25mg/day esterified estrogen and 2.5mg/day methyl testosterone) Placebo or oestrogen alone (dosage varied per study, generally it was used: 1.25mg/day) Sexual function Sexual outcomes: Frequency of sexual activity (SMD 0.29, 95% CI 0.16 to 0.41, p<0.001) Number of satisfying sexual episodes (WMD 1.20, 95% CI 0.88 to 1.51, p<0.001) Interest in sex (SMD 0.35, 95% CI 0.19 to 0.52, <0.001) Orgasm (SMD 0.20, 95% CI 0.09 to 0.31, p<0.001) Arousal (SMD 0.25, 95% CI 0.09 to 0.40, I2=77%) Enjoyment of sex (SMD 0.31, 95% CI 0.12 to 0.51, p=0.002) Sexual self-image (SMD 0.20, 95% CI 0.05 to 0.35, p=0.008) Sexual responsiveness (SMD 0.29, 95% CI 0.17 (1)Yes. Included a comprehensive database search as well as a search for unpublished data. (2)Yes. Quality assessed by two independent assessors. (3)Yes. Results expressed as odds ratio or weighted mean difference. (4)Yes. Statistical and clinical heterogeneity was explored. SR risk of bias: Low EB risk of bias: Moderate
to 0.41, p<0.001) Satisfaction with sex and relationship (SMD 0.83, 95% CI 0.28 to 1.37, p=0.003) Less concerns about sexual function impairment (SMD 0.24, 95% CI 0.03 to 0.44, p=0.23) Authors’ conclusion: “Despite the improvement in sexual function associated with Testosterone use in postmenopausal women, long-term safety data are lacking.” Somboonporn et al (2005)6, testosterone with MHT 35 RCTs (N=4768) Peri menopausal women and women who had entered a naturally or menopause and were using hormone therapy. Participants with breast cancer were included Testosterone (all formulations) plus menopause hormone therapy (CEE 0.625 mg/day -CEE 1.25 mg/day (high dose) -CEE 0.625 mg plus mT 1.25 mg/day -CEE 1.25 mg plus mT 2.5 mg/day (high dose) or Oestrogen plus Testosterone 300 microgram/day or EE 0.625 mg/day -EE 1.25 mg/day Menopause hormone therapy alone (1.25mg/day) Menopausal symptoms; Sexual function; Unexplained fatigue; Breast cancer; Testosterone plus menopause hormone therapy versus menopause hormone therapy – sexual function Number of satisfying sexual events (SMD 0.29, 95% CI 0.20 to 0.38) Total number of sexual events (SMD 0.25, 95% CI 0.17 to 0.34) Number of orgasms (SMD 0.30, 95% CI 0.21 to 0.39) Degree of libido or desire (SMD 0.35, 95% CI 0.26 to 0.43) (1)Yes. Included a comprehensive database search as well as a search for unpublished data. (2)Yes. Quality assessed by two independent assessors. (3)Yes. Results expressed as odds ratio or weighted mean difference. (4)Yes. Statistical and clinical heterogeneity was explored. SR risk of bias: Low EB risk of bias: Moderate
-EE 0.625 mg plus mT 1.25/day -EE 1.25 mg plus mT 2.5 mg/day) Level of orgasm (SMD 0.28, 95% CI 0.19 to 0.37) Arousal (SMD 0.36, 95% CI 0.27 to 0.45) Pleasure or enjoyment of sex (SMD 0.33, 95% CI 0.22 to 0.43) Sexual concerns (SMD0.32, 95% CI 0.22 to 0.41) Responsiveness (SMD 0.32, 95% CI 0.23 to 0.40) Sexual self-image (SMD 0.26, 95% CI 0.16 to 0.35) Composite sexual function score (SMD 0.41, 95% CI 0.19 to 0.63) Authors’ conclusion: “There is good evidence that adding testosterone to HT has a beneficial effect on sexual function in post-menopausal women. However, the combined therapy is associated with a higher incidence of hair growth and acne and a reduction in HDL cholesterol. These adverse events may differ by the different doses and route of testosterone administration. There is insufficient evidence to determine the effect of testosterone in long term use.” Rahn et al (2014)27, vaginal oestrogen 44 RCTs and prospective comparative studies Women identified as having the genitourinary syndrome of menopause. Women with breast cancer Vaginal oestrogen (various concentrations of oestradiol administered through vaginal tablet, cream, 1. Placebo; 14 studies (N=4232) 2. Other vaginal oestrogens; 18 Genitourinary syndrome (vaginal dryness, itching or burning, and dyspareunia, Compared with placebo, vaginal estrogens improved dryness, dyspareunia, urinary urgency, frequency, SUI and UUI. Endometrial pathology (1)Yes. Searched Medline and Cochrane Library. (2)Yes. Quality assessment using GRADE.
ring; 2 mg micronized 17B oestradiol with a constant release of 7.5 mcg oestradiol/24 hours for 90 days; Vaginal ring delivering 50or 100ug/day; conjugated equine oestrogen cream 2g/daily or 3 times a week; oestradiol vaginal ring 7.5mcg/24hours) 0.5mg daily for 2 weeks followed by maintenance dose 0.5 mg 3 times a week, or oestrogenic cream (Cilag), 0.5 mg daily for 2 weeks then 3 times a week for 3 months), or oestradiol pessary 0.5 mg (Ovestin), or tablets Oestrogen tablets versus oestrogen cream – effect size Vaginal pH (decrease), -0.20 [-0.38, -0.02] Dyspareunia, 0.53 [0.36, 0.78] Oestrogen versus Replens moisturising gel (non-hormonal) – effect size Maturation value (increased), -4.69 4.20] Vaginal pH (decrease), 0.20 [-0.12, 0.52] Dyspareunia, 3.5 [0.80, 15.34] Oestradiol tablets versus oestriol tablets – effect size Maturation (high or medium), 1.83 [0.59, 5.66] Withdrawal due to adverse events, 7.46 [0.37, 148.48] Vaginal pH (decrease), -0.36 [-0.52, -0.21] ratio or weighted mean difference. (4)Yes. Statistical and clinical heterogeneity was explored. SR risk of bias: Low EB risk of bias: Moderate
100mg (MD=-0.40, 95% CI -0.70 to -0.10); 150mg (MD=-0.46, 95% CI -0.7 to -0.22). Night-time awakenings: 100mg (MD=-3.60, 95% CI -0.52 to -2.81); 150mg (MD=-0.56, 95% CI -0.80 to -0.32). (4)Yes. Clinical heterogeneity was explored. Risk of bias: Low EB risk of bias: Low Authors’ conclusion: “The meta-analysis suggests that treatment with desvenlafaxine 100 mg/day is associated with a significant reduction of moderate to severe hot flashes in postmenopausal women. Desvenlafaxine appears both safe and effective for treating hot flushes for up to 12 months.” Shams et al (2014)10, escitalopram 11 RCTs reported in 14 studies on SSRIs, escitalopram (N=2304) Healthy peri- and postmenopausal women. Escitalopram daily for 8 weeks Placebo Hot flush frequency Escitalopram vs Placebo Frequency of hot flushes (mean effect 95% CI -4.82 to 0.62, 61% probability treatment is best). SSRIs vs Placebo Hot flush frequency (MD -0.93; 95% CI -1.49 to I2 = 21%), Significant. Pooled effects for adverse events on sleep disturbance (RR 1.32, CI 0.36 to 4.90) and decreased libido (RR 1.81, CI 0.21 to 15.48), Not significant. (1)Yes. Five databases were searched with appropriate search (2)Yes. Quality assessed by two independent assessors. (3)Yes. Results expressed as mean difference or standardized mean difference. (4)Yes. Clinical heterogeneity was explored. SR risk of bias: Low EB risk of bias: Moderate trial.
Vasomotor menopausal symptom scores, promensil vs. placebo: WMD 0.10 (- 1.54, 1.74); 1 RCT (N=165) There was no evidence that phytoestrogens effectively reduce hot flush frequency or severity. EB risk of bias: High Authors’ conclusion: “There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments.” Leach and Moore (2012)23, black cohosh 16 RCTs (N=2027) Peri- and postmenopausal women. Women with breast cancer were included. cohosh (40 mg/d over an average of 23 weeks) 1. Placebo 2. Hormone therapy 3. Red clover 4. Fluoxetine Hot flush frequency Hot flush severity sweat frequency Menopausal symptom scores Hot flush frequency, black cohosh vs. placebo: MD 0.07 (- 0.43, 0.56); 3 RCTs (N=393) Hot flush severity, black cohosh vs. placebo: MD 0.12 (- 0.06, 0.3); 3 RCTs (N=214) sweat frequency/score, black cohosh vs. placebo: MD 0.27 (- 0.16, 0.70); 1 RCT (N=164) (1)Yes. Searched Pubmed, EMBASE, CENTRAL, CINAHL and other databases. (2)Yes. Quality assessed by two reviewers using GRADE. (3)Yes. (4)Yes. SR risk of bias: Low EB risk of bias: Unclear Trial
Duration = 11 weeks Follow-up = at 8 or 12 weeks who have had a bi-lateral oophorectomy (surgical removal of both ovaries). without a uterus who still have ovaries, under certain conditions determined during screening Change in Daily Frequency of Hot Flashes Between Baseline and Week 8 as Assessed by Prospective Daily Diaries – Mean (95% CI) Escitalopram: -4.60 (-5.47 to -3.74) Placebo: -3.20 to -2.24) p<0.001* Daily Severity of Hot Flashes Assessed by Prospective Daily Diaries – Mean (95% CI) Escitalopram: 2.16 (2.07 to 2.24) Placebo: 2.19 (2.10 to 2.28) Change in Daily Severity of Hot Flashes Between Baseline and Week 8 as Assessed by Prospective Daily
Diaries – Mean (95% CI) Escitalopram: -0.53 (-0.64 to -0.40) Placebo: -0.3 to -0.17) p<0.001* Authors’ conclusion: Authors’ conclusion: “The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day; vasomotor symptom bother reduction was minimal.” Cohen et al (2014)24, non-pharmacologic interventions (omega-3) MsFLASH 02 - Efficacy of Omega-3 Treatment for Vasomotor Symptoms: A Randomized Controlled Trial: Omega-3 treatment for vasomotor symptoms N = 295 Age = 40-62 years Duration = 12 weeks Follow-up = at 8 or 12 weeks Menopausal including: with a uterus who have skipped 2 or more menstrual cycles with an amenorrhea interval ≥60 days in the past 12 months. who have had a bi-lateral oophorectomy (surgical removal of both ovaries). Women without a uterus who still have ovaries, under certain conditions Omega-3 (1.8 grams daily for 12 weeks) Placebo Vasomotor symptoms frequency and bother VMS frequency at 12 weeks, mean (95% CI) Omega-3: −2.5, (−3.0, −1.9) Placebo: −2.7, (−3.3, −2.2) Relative difference of 0.3 hot flashes per day (95% CI −0.5, 1.0, p=0.28) VMS bother at 12 weeks, mean (95% CI) −0.5 (−0.6, −0.4) (1) Yes** (2) Yes** (3) Yes** (4) Yes** (5) Yes** EB risk of bias: Low
Authors’ conclusion: “These findings provide strong evidence that 12-weeks of moderate-intensity aerobic exercise does not alleviate VMS but may result in small improvements in sleep quality, insomnia and depression in midlife, sedentary women.” Newton et al (2014)17, physical interventions (yoga) MsFLASH 02 - Efficacy of Yoga for Vasomotor Symptoms: A Randomized Controlled N = 249 Age = 40-62 years Duration = 12 weeks Follow-up = at 8 or 12 weeks Menopausal women, including: Women with a uterus who have skipped 2 or more menstrual cycles with an amenorrhea interval ≥60 days in the past 12 months. who have had a bi-lateral oophorectomy (surgical removal of both ovaries). without a uterus who still have ovaries, under certain conditions determined during screening Yoga (12 weekly 90-minute classes) Usual activity Vasomotor symptoms frequency and bother Hot flashes / day at 12 from baseline, mean (95% CI) Yoga: −2.9 (−3.6, −2.2) Usual activity: −2.6 (−3.2, −2.0) Difference: −0.3 (−1.2, 0.6) p= 0.119 VMS bother at 12 weeks from baseline, mean (95% CI) Yoga: −0.6 (−0.7, −0.4) Usual activity: −0.5 (−0.6, −0.4) Difference: 0.0 (−0.2, p= 0.417 (1) Yes** (2) Yes** (3) Yes** (4) Yes** (5) Yes** EB risk of bias: Low Authors’ conclusion: “Among healthy women, 12 weeks of yoga class plus home practice compared with usual activity did not improve VMS frequency or bother, but reduced insomnia symptoms.” Joffe et al (2014)26, pharmacologic interventions (low-dose estradiol) MsFLASH 03 - Randomized Peri- and postmenopausal Low-dose oral Placebo Mean frequency of VMS Frequency - Mean (95% CI) (1) Yes** (2) Yes**
Controlled of Low-Dose Estradiol and the SNRI Venlafaxine for Vasomotor Symptoms N = 339 Age = 40-62 years Duration = 8 Follow-up = at 8 or 12 weeks women with ≥2 bothersome vasomotor symptoms per day (mean 8.1, SD 5.3/day) 17-beta-estradiol 0.5-mg/day, venlafaxine XR 75-mg/day for 8 weeks vasomotor symptoms Estradiol vs Placebo, difference Baseline: 8.5 (7.4, 9.7) vs 7.7 (6.9, 8.5), 0.9 (−0.5, 2.2) Week 4: −3.1 (−4.0, −2.3) vs −1.9 (−2.5, −1.3), −1.2 (−2.2, −0.2) Week 8: −4.5 (−5.4, −3.6) vs −2.2 (−2.8, −1.6), −2.3 (−3.4, −1.3) p<0.001* Venlafaxine vs Placebo, difference Baseline: 8.2 (7.1, 9.3) vs 7.7 (6.9, 8.5), 0.5 (−0.8, 1.8) Week 4: −3.3 (−4.0, −2.5) vs −1.9 (−2.5, −1.3), −1.4 (−2.3, −0.4) (3) Yes** (4) Yes** (5) Yes** EB risk of bias: Low dose
Table 6 Summary of adverse events, by intervention Interventions Daily dose Adverse Events – reported when use in the treatment of menopausal symptoms in peri- and postmenopausal Authors Desvenlafaxine* 100mg or 150mg (greater discontinuation with dosage ≥150mg) asthenia hypertension anorexia constipation diarrhea dry mouth nausea dizziness insomnia somnolence mydriasis Berhan 201411; Sun 201312 Transdermal oestradiol (Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel* 1.5 and 0.5 mg; Menostar, Evamist, Divigel, Vivelle, Dermestril, Elestrin, Fempatch, Esclim: 0.003mg-0.125mg) 0.25mg to 1.5mg / 0.003 to postmenopausal bleeding headache breast pain infection nausea rash vaginitis Derzko Corbelli 2015**9 Ospemifene 60mg endometrial thickness* hot flushes Cui 20147 Acupuncture 2 times per week for 4 weeks, stainless-steel filiform 0.20 x 30 mm needles) needling pain bleeding at the site of needling Not all RCTs in the SR reported adverse events Dodin 201320 Testosterone with or without oestrogen 2.5mg methyl testosterone, with or without 1.25mg esterified oestrogen acne hirsutism reduction in total cholesterol androgenic side effects Elraiyah 201431 Tibolone 2.5mg breast cancer endometrial cancer venous thromboembolic events cardiovascular events cerebrovascular events mortality from any cause Nastri 2013**25; Formoso
Venlafaxine** 75mg No reported adverse events related to sexual dysfunction Guthrie 20152; Reed et al (2014) - (MsFLASH 03)36 Escitalopram 10-20mg nausea fatigue dry somnolence/drowsiness sleep disturbance sweatiness dizziness/vertigo headache decrease libido rash vivid dreams appetite change Shams 201410; Guthrie 2015**2; Freeman 2011 - (MsFLASH 01)13 Low-dose oral oestradiol conjugated oestrogens: 0.45 mg, oestradiol gel: 0.87g/d - 2.6 g/d 0.5mg insomnia fatigue Guthrie 2015**2; Nastri 2013**25; Joffe et al (2014) - (MsFLASH 03)26 Oral oestradiol** 0.5mg No women reported adverse events related to sexual dysfunction Reed et al (2014) - (MsFLASH 03)3 Exerciseᶧ 45min 5 times a week; 60min 3 times a week back pain muscle aches and pains heart palpitations dizziness fainting Woods 2014**15; Daley 2014**14; Guthrie 2015**2; Sternfeld et al (2014) - (MsFLASH 02)16 Yogaᶧ 12 weekly 90-minute classes muscle ache and pains low back pain changes in strength or sensation in the arms or legs Woods 2014**15; Guthrie 2015**2; Newton et al (2014) - (MsFLASH 02)17 Omega-3ᶧ 1.8g Burping / belching Bad breath or aftertaste Heartburn Nausea Vomiting Guthrie 2015**2; Cohen et al (2014) - (MsFLASH 02)24
Diarrhea Constipation Mild flu-like symptoms Dizziness or fainting palpitations Skin rash Muscle aches / strains Strength / sensations of arms / legs change Back pain Bruising or bleeding cohoshᶧ 6.5 mg to 160 mg gastrointestinal musculoskeletal connective tissue complaints Leach 201223 Phytoestrogens bloating nausea weight gain concerns about bowel function Lethaby 201321 Oral hormone therapy 0.87g -2.6 g; 1- 2mg oestradiol; 0.625 to 1.25 mg CEE breast tenderness oedema joint pain psychological symptoms Adverse events related to HT were not included as outcomes because Nastri 2013 only included trials that reported sexual function MacLennan Nastri 2013**25 Tibolone or SERMs with or without estrogens bazedoxifene: 20 mg plus conjugated estrogens: 0.45 mg bazedoxifene: 20 mg plus conjugated estrogens: 0.625 mg conjugated equine estrogens: 0.625 mg raloxifene: 60mg or 150mg transdermal estradiol therapy: 50mcg/24 hours Adverse events related to HT were not included as outcomes because Nastri 2013 only included trials that reported sexual function Nastri 2013**25
oral medroxyprogesterone acetate: 2.5/5.0mg Testosterone with MHT 300mg; 0.625mg plus 1.25mg; 1.25mg plus 2.5mg decreased high-density lipoprotein (HDL) cholesterol levels increased incidence of hair growth acne Somboonporn Vaginal oestrogen oestradiol vaginal tablet 10, 25mg Conjugated estrogen cream 0.5 g estriol gel 50mg oestradiol vaginal tablet 25mg oestriol 1mg ovule Estriol 3.5mg vaginal suppository twice/wk Conjugated estrogen cream 1g twice/wk oestriol 0.2mg or 0.03mg ovule oestriol 0.5mg cream oestradiol vaginal tablet 10 or 25mg; oestradiol-releasing ring; 2 mg micronized 17B oestradiol with a constant release of 7.5 mcg oestradiol/24 for 90 days; Vaginal ring delivering 50or 100ug/day; conjugated equine oestrogen cream 2g/daily or 3 times a week; oestradiol vaginal ring 7.5mcg/24hours Abdominal pain Arthralgia, myalgia Breast pain, enlargement, engorgement Bullous eruption Cervical ulceration, inflammation Depression Dysuria Oedema generalised Flatulence Genital eruption Headache Heart disorder Hypothesia Increased appetite Leukorrhea Moniliasis Pruritis Skeletal pain Sweating, hot flushes Urinary incontinence Urinary tract infection Vaginal bacterial growth asymptomatic Vaginal fungal growth asymptomatic Vaginal haemorrhage Vaginal pain Vaginitis Vulvar irritation, vulvitis Rahn 201427; Suckling 200628 Isoflavones 10mg, 30mg, 45gm, 90mg bloating nausea weight gain changes in bowel function Ghazanfarpour 201529; Thomas 201414