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Phytoestrogens for menopausal vasomotor symptoms

  1. Anne Lethaby1,*,
  2. Jane Marjoribanks1,
  3. Fredi Kronenberg2,
  4. Helen Roberts1,
  5. John Eden3,
  6. Julie Brown4

Editorial Group: Cochrane Gynaecology and Fertility Group

Published Online: 10 DEC 2013

Assessed as up-to-date: 30 JUL 2013

DOI: 10.1002/14651858.CD001395.pub4


How to Cite

Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001395. DOI: 10.1002/14651858.CD001395.pub4.

Author Information

  1. 1

    University of Auckland, Department of Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    College of Physicians & Surgeons, Columbia University in the City of New York, Department of Rehabilitation Medicine, New York, USA

  3. 3

    Royal Hospital for Women, Sydney Menopause Centre & Natural Therapies Unit, Randwick, NSW, Australia

  4. 4

    University of Auckland, The Liggins Institute and Department of Obstetrics and Gynaecology, Auckland, New Zealand

*Anne Lethaby, Department of Obstetrics and Gynaecology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. a.lethaby@auckland.ac.nz.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 10 DEC 2013

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Characteristics of included studies [ordered by study ID]
Albertazzi 1998

MethodsDesign: parallel-group
Number randomly assigned: 92 initially plus a further 12 from the reserve randomisation list = 104
Number dropped out: 21 (nine in active group: seven for gastrointestinal symptoms, one for lack of efficacy, one for non-compliance; seven in placebo group: two for gastrointestinal symptoms, three for lack of efficacy, one for non-compliance, one for other reasons)
Number lost to follow-up: four (two in each group)
Number analysed: 79
Intention-to-treat analysis: no
Power calculation: 90% power to detect a difference of three hot flushes per 24 hours (P = 0.05)
Duration: 12 weeks
Timing: not stated
Location: two Italian university hospitals
Funding: partial industry funding from Protein Technologies, Missouri


ParticipantsInclusion criteria: postmenopausal women requesting treatment for severe hot flushes, six months since last menstruation or six weeks since bilateral oophorectomy, minimum of seven moderate to severe hot flushes or night sweats per 24 hours during two out of four weeks before the study (threshold defined as warmth and sweating preventing normal daily activity), baseline FSH > 50 IU/mL, serum oestradiol < 35 pg/mL
Exclusion criteria: use of HT within six weeks of study or other drug used for climacteric symptoms during study period
Age, years: active arm 53 (48 to 61), placebo 52 (45 to 62)

Recruitment: not stated


Interventions
  • Phytoestrogen: Isolated soy protein


    • Formulation: 76 mg isoflavones (genistein 40 mg, daidzein 28 mg) per 60 mag sachet of powder


  • Placebo: 60 g casein powder


    • Dose, duration and timing of administration: one sachet per day for 12 weeks


OutcomesMenopausal symptoms: change in number of daily moderate and severe hot flushes or night sweats from baseline in each month of treatment; Kupperman Index
Compliance: self-report in daily diary and sachet count
Adverse effects: reported monthly at follow-up; for each woman, only the worst symptom (in her opinion) was taken into account


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBalanced computer-generated randomisation list

Allocation concealment (selection bias)Low riskInvestigator site personnel blinded to trial codes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout rate—12 participants added

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Aso 2012

MethodsDesign: parallel-group

Number screened for inclusion: 1,211

Number randomly assigned: 160

Number dropped out or withdrew: 34 (placebo group: three dropped out, eight did not comply, 12 met withdrawal criteria; equol group: eight did not comply, three met withdrawal criteria)

Intention-to-treat analysis: no

Power calculation: not stated

Duration: 12 weeks of intervention or placebo, assessments at week 12 and week 18

Location: four clinics/centres in Tokyo, Saitama, Chiba, Fukuoka

Funding: Otsuka Pharmaceutical Company Ltd provided the intervention and financial support


ParticipantsInclusion criteria: duration of amenorrhoea one to 10 years, oestradiol < 21 pg/mL, FSH > 30 mIU/d, frequency of hot flushes ≥ 1/d, equol non-producer, SMI score ≥ 25, BMI 18.6 to 25, SDS score < 53

Exclusion criteria: surgical menopause, severe menopausal symptoms requiring medical treatment, abnormal vital signs and clinical laboratory tests outside the normal range, current or past reproductive related cancer, thyroid dysfunction or other serious medical conditions, allergy to soy, milk or egg, use of prescription medication for menopausal symptoms, OTC medical agents or health foods for relief of menopausal symptoms

Age, years: 53.9 (mean) in placebo group, 53.2 (mean) in equol group

Recruited using fliers, advertisements and volunteer lists and registered at a clinical research organisation


Interventions
  • Natural S-(-) equol supplement containing 5.0 mg equol (also 1.2 mg daidzein, 1.4 mg genistein, 3.1 mg glycitein, 298 mg protein, 113 mg fat, 375 mg carbohydrate, 56 mg ash and 110 mg fiber
  • Placebo tablets containing lactose identical to equol tablets


    • Duration and timing of administration: two tablets per day at breakfast and dinner. Compliance measured


OutcomesMenopausal symptoms (as measured by the modified Climacteric Symptom Evaluation Form Checklist, Visual Analog Scale (VAS), subscales of the Greene Climacteric Scale and somatic symptom scales)

Quality of life (as measured by Short Form-36 and VAS)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskStratified permutation block method controlled for study site, years since menopause and BMI

Allocation concealment (selection bias)Low riskComputer-generated random permutation procedure

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and investigators blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStaff members and laboratory technicians blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskLarge proportion of participants dropped out and not analysed

Selective reporting (reporting bias)Low riskAll plausible outcomes reported

Baber 1999

MethodsRandomisation method: not stated
Blinding: double
Allocation concealment: not stated
Design: cross-over
Number screened for inclusion: not stated
Number randomly assigned: 51
Number dropped out: eight (seven for personal reasons, one for medical reasons not related to study)
Number lost to follow-up: none stated
Intention-to-treat analysis: no
Power calculation: not stated
Duration: three months × 2
Timing: not stated
Location: tertiary menopause clinic, Australia
Funding: industry (Novogen Ltd, Australia)


ParticipantsInclusion criteria: minimum of mean of three hot flushes per day in week preceding trial
Exclusion criteria: intercurrent medical problems, HT or antibiotics in previous three months, FSH < 30 mIU/mL, menstruation in previous six months, hysterectomy, vegetarian (> 10 g legumes/d)
Age, years: 54 (±4.1)
Recruitment method: volunteers. Not further specified


Interventions
  • Phytoestrogen: Promensil (red clover extract)


    • Formulation: 40 mg of standardised isoflavones (genistein, daidzein, Fourmentin and Biochemic) per tablet


  • Placebo tablet


    • Dose, duration and timing of administration: one tablet daily in the morning for three months, one month washout period, then cross-over to opposite arm for three months and two weeks


OutcomesMenopausal symptoms: daily flush frequency scored on daily diary card
Quality of life: Greene Climacteric Scale


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Allocated randomly and blindly," but method not reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind: analysis of data performed by separate group

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)High riskAdverse events not reported

Balk 2002

MethodsDesign: parallel-group
Number of women screened: "hundreds" (most not amenorrhoeic for one year)
Number randomly assigned: 27
Number dropped out: seven (five in active arm: two for family reasons, three for adverse effects; two in placebo arm: one for lack of efficacy, one disliked taste)
Number lost to follow-up: one (active arm)
Number analysed: 19
Intention-to-treat analysis: no
Power calculation: powered to detect endometrial changes, but baseline proliferation rate underestimated and study thus underpowered for primary outcome
Duration: six months
Timing: January 1998 to June 2000
Location: university hospital clinic
Funding: academic research grants


ParticipantsInclusion criteria: postmenopausal women 40 years of age with no vaginal bleeding for one year or over 30 years of age with oophorectomy or premature ovarian failure, omnivorous, intact uterus, normal endometrium on Pipelle biopsy, normal mammogram within previous year
Exclusion criteria: tamoxifen usage, endometrial cancer, allergy to soy, hormone therapy on past year, using phytoestrogen supplements (diet logged for two weeks before study)
Age, years: active arm 56.8 ± 5.9; placebo arm 57.9 ± 8.2
Recruitment method: primary and tertiary clinics, newspaper and radio advertisements, research institute website


Interventions
  • Phytoestrogen: isoflavone


    • Formulation: soy flour and corn cereal (Nutlettes): 3/8-cup serving contains 92 mg of isoflavones. Mixed with placebo cereal (3:1) to increase similarity of taste


  • Placebo: wheat cereal (Grapenuts)


    • Dose, duration and timing of administration: 100 mg daily (1/2 cup cereal) for three months


Given list of soy- and phytoestrogen-containing foods to avoid


OutcomesMenopausal symptoms: weekly log monitoring nine specific symptoms on 4-point scale
Compliance: daily dietary logs, check of unused cereal
Adverse effects: weekly log monitored specific symptoms such as nausea, breast tenderness and gastrointestinal effects


NotesAuthors reported that recruitment was difficult. Participants were not required to have menopausal symptoms to be eligible for the study, although these were measured at baseline. Mean symptom score at baseline indicated that, on average, participants had mild to moderate hot flushes and/or night sweats


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated in blocks of six

Allocation concealment (selection bias)Low riskSequentially numbered opaque sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskVery high dropout (8/27)

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Bicca 2004

MethodsDesign: parallel-group
Number of women screened: 90
Number analysed: 75
Number dropped out: one lost to follow-up in soy group, three lost in placebo group (two adverse events, one other)
Intention-to-treat analysis: no
Power calculation: yes
Duration: 25 weeks
Timing: not specified
Location: university in Brazil
Funding: not specified


ParticipantsInclusion criteria: women 42 to 61 years of age, symptomatic and no menses for 12 months
Exclusion criteria; oral HT in previous three months, topical HT in previous 30 days, use of medication that could influence the results, concomitant severe disease
Mean age, years: 54 in soy group, 52 in placebo group
Recruitment method: advertisements


Interventions
  • Standardised soy extract (33 mg/d isoflavones)
  • Placebo capsule


    • Dose, duration and timing of administration: one capsule per day for 25 weeks.


OutcomesDecrease in frequency of hot flushes and night sweats; vasomotor symptom intensity; change in vaginal pH


NotesStudy not published


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskTable of random numbers kept by separate organisation

Allocation concealment (selection bias)Low riskOpaque envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as triple-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as triple-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Brzezinski 1997

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 145
Number dropped out: 31 (17 in active group: two for unbearable symptoms, 15 for personal reasons; 14 in control group: seven for unbearable symptoms, seven for personal reasons)
Number lost to follow-up: none stated
Number analysed: 114
Intention-to-treat analysis: no
Power calculation: power calculation performed, but anticipated effect size not specified
Duration: 12 weeks
Timing: not stated
Location: menopause clinic in Jerusalem, Israel
Funding: academic grants


ParticipantsInclusion criteria: perimenopausal and postmenopausal women 43 to 65 years of age, natural or surgical menopause with at least three months of amenorrhoea, FSH > 30 IU, LH > 20 IU, plasma oestradiol < 200 pmol/mL, experiencing hot flushes, night sweats, insomnia, vaginal dryness or dyspareunia
Exclusion criteria: acute medical illness, use of gonadal hormones or any medicine known to influence menopausal symptoms or endocrine variables, known or suspected food allergies
Age, years: active arm 53.66 (SE 0.74), control arm 51.32 (SE 0.71)
Recruitment method: women requesting help for climacteric complaints at outpatient menopause clinic


Interventions
  • Phytoestrogens: isoflavones and lignans


    • Formulation: daily consumption of 80 g tofu (approx 75 mg/g daidzein, 200 mg/g genistein), 2 × 200 mL glasses of soy drink (approx 7 mg/g daidzein, 35 mg/g genistein), one teaspoon of miso (40 mg/g daidzein, 35 mg/g genistein), two teaspoons of ground flaxseed (approx 4 mg/g lignans): cooked if unpalatable uncooked


  • Control diet: regular omnivorous Israeli diet


    • Dose, duration and timing of administration: diet for 12 weeks


OutcomesMenopausal symptoms: menopause symptoms questionnaire


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number sequence, non-computerised

Allocation concealment (selection bias)Unclear riskUnclear

Blinding of participants and personnel (performance bias)
All outcomes
High riskNot reported and unlikely

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)High riskAuthors did not report on adverse events

Burke 2003

MethodsDesign: parallel-group
Number screened for inclusion: 1,571 (1,230 ineligible: main reasons: lack of menopausal symptoms (293), refusal to stop HT (241), cycle not perimenopausal (206))
Number randomly assigned: 241
Number dropped out: none stated
Number lost to follow-up: none stated
Number analysed: 211 (30 had data missing from symptom diaries)
Intention-to-treat analysis: no
Power calculation:
Duration: two years
Timing: August 1996 to August 1997
Location: Wake University Clinic,Carolina, USA
Funding: soy supplements supplied by industry (Soy Technologies, St Louis, Missouri, USA)


ParticipantsInclusion criteria: perimenopausal women (no more than one menstrual period in three months before randomisation), at least one vasomotor symptom per day, not using HT for three months before recruitment, willingness to participate in one-week run-in with isoflavone-free supplement
Exclusion criteria: acute MI or stroke within previous six months, history of breast or endometrial cancer, invasive cancer within previous five years, active thromboembolic disease, previous osteoporosis-related fractures treated with hormones, low baseline bone density, previous exposure to diethylboestrol, dyslipidaemia, endometrial biopsy showing hyperplasia, consumption of soy products on a daily basis and unwillingness to reduce consumption to once a week
Age, years: mean 50.8 (SE 0.2)
Recruitment method: "recruited from the community"


Interventions
  • High-dose phytoestrogens: isoflavones


    • Formulation: 25 g soy protein (58 mg isoflavones) in a drink


  • Medium dose phytoestrogens: isoflavones


    • Formulation: 25 g soy protein (42 mg isoflavones) in a drink


  • Control: 25 mg soy protein, washed to remove isoflavones (maximum 4 mg isoflavones) in a drink


    • Dose, duration and timing of administration: one 25 g ready-to-drink beverage daily, chocolate or orange flavoured, for two years


OutcomesMenopausal symptoms: hot flushes, night sweats recorded in monthly calendar with daily entry field: participants asked to record number and severity of symptoms for one full week per month
Compliance: compliance calendars


Notes37 women (18%) took HT during trial: 16 in high-dose group (25%), 11 in middle group (16%), 10 in control group (13%). Data analysed with and without these women, and pattern of results not affected


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskModerate dropout: missing data from questionnaires because not filled in

Selective reporting (reporting bias)High riskAuthors did not report on all prespecified outcomes

Campagnoli 2005

MethodsDesign: cross-over
Number of women screened: not stated
Number randomly assigned: 36
Number analysed: 29
Number dropped out: seven (not clear which group: three medical reasons, four family reasons)
Intention-to-treat: no
Power calculation: yes: 95% power to detect at least a 20% greater reduction in hot flushes in active arm compared with placebo
Duration: 12 + 12 weeks
Timing: November 1999 to December 2000
Location: hospital in Torino, Italy
Funding: Medestea International (manufacturer of active treatment)


ParticipantsInclusion criteria: minimum of five moderate to severe hot flushes/d, good general health, 45 to 58 years, BMI 18 to 28, surgical menopause (bilateral oophorectomy for at least three months or in spontaneous menopause with no menses for over six months), menopausal hormone profile (oestradiol < 30 pg/mL, FSH > 40 UI/L)
Exclusion criteria: use of drugs that influence vasomotor symptoms, hormone therapy or tibolone in previous six months, consumption of soy-based food more than once per week, use of drugs that might reduce absorption of isoflavones
Mean age of completers, years: 51
Recruitment method: menopause clinic


Interventions
  • Standardised soy extract 200 mg (Soy select) capsules (60 mg/d isoflavones)
  • Placebo capsules


    • Dose, duration and timing of administration: two capsules per day in two doses for 12 weeks, then switched to alternate treatment without a washout period


OutcomesNumber of hot flushes per week after treatment (at end of first phase of study)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSchedule prepared by the manufacturer of the product using computer-generated randomisation list and distributed sequentially

Allocation concealment (selection bias)Low riskAdequate: investigators blind to treatment allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)Low riskAll potential outcomes reported

Carmigiani 2010

MethodsDesign: parallel-group

Number of women screened: 1,520

Number of women randomly assigned: 60

Number of women analysed: 60

Number of dropouts or lost to follow-up:

Intention-to-treat: yes

Power calculation: yes, 16 subjects required in each group to reach power of 90%, assuming a difference of three hot flushes in a 24-hour period and SD of 3.8 hot flushes/d

Duration: 16 weeks

Timing: January to October 2007

Location: two menopause outpatient clinics at the Centre for Women's Integrated Healthcare of the University of Campinas, Campinas, Sao Paolo, Brazil

Funding: Sao Paolo Foundation for the Support of Research


ParticipantsInclusion criteria: postmenopausal women between 40 and 60 years of age who had LMP > 12 months previously; FSH > 30 mUI/mL and oestradiol levels < 20 pg/mL; more than eight hot flushes in 24 hours; not using any form of hormonal treatment during previous six months; not currently using any lipid-lowering drugs, antidiabetic drugs, soybean-derived products or herbal supplements

Exclusion criteria: previous hysterectomy; chronic gastrointestinal disorder; contraindication to hormone therapy; patients participating in a conflicting clinical trial; known allergy or hypersensitivity to soy or cow's milk; not willing to cease consumption of soy products for the term of the trial

Mean age, years: 53 in HT and soy groups; 51 in placebo group

Recruitment method: menopause outpatient clinic


Interventions
  • Oestradiol 1 mg + 0.5 mg norethisterone acetate
  • Dietary soy supplementation (containing 90 mg of isoflavone)
  • Placebo


OutcomesPrimary: menopause rating scale. Also side effects, endometrial thickness, maturation index and compliance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation list

Allocation concealment (selection bias)Low riskComputer-generated randomisation list with numbered envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinded for the duration of the study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor was gynecologist, who did not participate in the screening process or dispense drugs

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropout or lost to follow-up

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Cheng 2007

MethodsDesign: parallel-group

Number of women screened: not reported

Number of women randomly assigned: 60

Number of women analysed: 51 (two dropped out during the first month, seven continued treatment but missed some examinations)

Intention-to-treat: no

Power calculation for sample size: no

Duration: 12 weeks

Timing: not stated

Location: Sweden; other details not reported

Funding: Stockholm County Council, Swedish Cancer Society, European Union Specific Targeted Research Project and Susan G. Komen Breast Cancer Foundation


ParticipantsInclusion criteria: postmenopausal women, at least one year since last menstruation, FSH levels > 30 IU/mL, at least six months without taking hormone therapy. All women experienced hot flashes and night sweats

Exclusion criteria: not stated

Age, years: between 49 and 69; mean age placebo group 56.9 ± 4.2; isoflavone group 58.4 ± 5.0

Recruitment method: not stated


Interventions
  • Isoflavones 60 mg daily in a fruit drink (n = 26)
  • Placebo (oatmeal drink) (n = 25)


Women were encouraged not to alter dietary, alcohol or physical activity habits


OutcomesCompliance, endometrial thickness, lipoprotein levels, hormone levels, immunohistochemistry, vasomotor symptoms


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Randomly assigned by computer to two groups'

Allocation concealment (selection bias)Unclear riskNo details of allocation concealment provided

Blinding of participants and personnel (performance bias)
All outcomes
Low risk'Treatment was blinded both to the women and doctor'

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssume that the doctors evaluated outcomes

Incomplete outcome data (attrition bias)
All outcomes
High riskTwo dropped out during the first month and seven women continued treatment but missed some of the examinations. ITT analysis was not conducted for all outcomes

Selective reporting (reporting bias)High riskSome prespecified outcomes not reported in the results section

Colli 2012

MethodsDesign: parallel-group randomised placebo-controlled trial

Number of women randomly assigned: 90

Number of women analysed: 75

Intention-to-treat analysis: no

Power calculation for sample size: no

Duration: six months

Timing: October 2009 to March 2010

Location: gynaecology service in Parana, Brazil

Funding: Conselho Nacional de Desenvolvimiento Cientifico e Tecnologico


ParticipantsInclusion criteria: women 46 to 68 years of age; FSH > 40 mIU/L, oestradiol < 30 pg/mL, amenorrhoea > 12 months; climacteric symptoms

Exclusion criteria: one or more contraindications to the use of synthetic HT, use of any synthetic HT in the past six months; use of antibiotics in past six months; signs of gastrointestinal malabsorption syndrome

Mean age of participants, years: 54 to 57

Recruitment: from gynaecology clinic


Interventions
  • Flaxseed extract (two 500-mg capsules daily, with each capsule containing 50 mg of standardised lignan)
  • Flaxseed meal (two tbsp (45 g) of ground whole flaxseed corresponding to 270 mg lignan)
  • Placebo (two 500-mg capsules of collagen daily)


    • Capsules taken in the morning before the first meal, and ground flaxseed mised with milk, yogurt or juice


Outcomes
  • Hot flash score (intensity)
  • Kupperman Index score
  • Vaginal epithelial maturation value
  • Endometrial thickness
  • Adverse events


NotesGroup 2 was not blinded, as the women took a different product from placebo


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Randomly distributed": method not described

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskGroup 1 blinded but group 2 not blinded (non-identical placebo)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated

Incomplete outcome data (attrition bias)
All outcomes
High riskSubstantial dropouts with no reasons stated and uneven between groups

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Crisafulli 2004

MethodsDesign: parallel-group
Number randomly assigned: 90
Number dropped out: seven (no reasons given)
Number lost to follow-up: zero
Number analysed: 90
Intention-to-treat analysis: yes
Power calculation: 90% power to detect a 2.5-mm difference in endometrial thickness among the three treatment groups (P = 0.05)
Duration: 12 months
Timing: not stated
Location: university clinic in Italy
Funding: not stated


ParticipantsInclusion criteria: healthy and ambulatory; 47 to 57 years of age; not undergone surgically induced menopause; no menstrual period in the preceding year; FSH > 50 IU/L; serum 17B-oestradiol level of 100 pmol/L or less
Exclusion criteria: clinical/laboratory abnormalities that suggested cardiovascular, hepatic or renal disorders; coagulopathy; use of oral or transdermal oestrogen, progestin, androgen or other steroids in the preceding year; smoking more than 10 cigarettes/d
Age, years: mean in placebo group 51; mean in other two groups 52

Recruitment: referred by university department


Interventions
  • Phytoestrogen genistein (54 mg/d)
  • Continuous HT (1 mg/d 17B-oestradiol plus norethisterone acetate)
  • Placebo (identical tablets)


All participants had a four-week stabilisation diet (isocaloric, fat restriction) before treatment


OutcomesMenopausal symptoms: daily number of hot flushes at three, six and 12 months
Adverse effects: endometrial thickness at six and 12 months


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer software

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind (participants and investigators)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout but no reasons given

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

D'Anna 2007

MethodsDesign: parallel-group

Number randomly assigned: 265 (substudy of larger trial)

Number dropped out: by year one, 10/125 in genistein group (after six months of follow-up) and 8/122 in placebo group (four after three months and four after six months). Reasons given for dropping out were mainly gastrointestinal side effects but also presence of other diseases, loss to follow-up and inadequate interaction with the woman's family doctor. None withdrew because of treatment inefficacy. By year two, 16/125 in genistein group and 13/122 in placebo group

Number analysed: year one: 247; year two: 236

Intention-to-treat analysis: no

Power calculation for sample size: yes: difference of at least 20% between groups required 97 participants in each group

Duration: one and two years (two publications)

Timing: not stated

Location: two separate university centres in Italy

Funding: Italian Ministry of Scientific Research and Technology and University of Messina, Italy


ParticipantsInclusion criteria: 50 to 70 years old; postmenopausal; FSH > 50 IU/L; serum oestradiol < 100 pmol/L. In the substudy of 247 participants, only women with vasomotor symptoms were evaluated

Exclusion criteria: clinical or laboratory abnormalities that suggested various disorders; coagulopathy; use of oral or transdermal oestrogen, progestin, androgen or other steroids; use of bisphosphonates, cholesterol-lowering therapy or cardiovascular medications in previous six months; smoking > 10 cigarettes/d; BMD of the femoral neck > 0.795 g/cm3

Age, years: mean 53 in both groups

Recruitment: women referred from university departments


Interventions
  • Phytoestrogen genistein twice per day (each tablet contained 27 mg of total isoflavone)
  • Placebo twice per day


OutcomesNumber and severity of hot flushes

Endometrial thickness


NotesThe study is a substudy of a larger study evaluating bone loss and CVD prevention. The substudy consisted of women with vasomotor symptoms, and characteristics of participants did not differ from those in the parent study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computerised database"

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as "double-blind"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as "double-blind"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAlthough dropouts were minimal at both one and two years, outcomes were measured in a subgroup of the total study population

Selective reporting (reporting bias)Unclear riskSide effects were presumably collected, as the authors stated that treatments were "well tolerated" but the results were not reported

Dalais 1998

MethodsDesign: cross-over

Number randomly assigned: 52

Number dropped out: eight (seven for personal reasons, one for lack of compliance)

Number lost to follow-up: none stated

Number analysed: 44

Intention-to-treat analysis: no

Power calculation: yes, 80% chance of detecting a 40% decrease in hot flush rate

Duration: 2 × 12 weeks with a four-week washout period

Timing: not stated

Location: Australia

Funding: industry support (George Weston foods)


ParticipantsInclusion criteria: postmenopausal women 45 to 65 years of age, FSH > 40 IU/mL, > 14 hot flushes/wk, 12 months of amenorrhoea, non-smoking, non-vegetarian

Exclusion criteria: antibiotics or hormone therapy during preceding three months

Age, years: mean 53.6 to 54.6

Recruitment method: not stated


Interventions
  • High-phytoestrogen diet: isoflavone. Formulation: 45 g daily of soy grits, totalling 52.64 (SD 8.68) mg of isoflavones daily (genistein and daidzein)
  • High-phytoestrogen diet: mammalian lignan precursors. Formulation: 45 g daily of linseed (secoisolariciresinol and matairesinol)
  • Low-phytoestrogen diet: wheat. Formulation: 45 g daily of kibbled wheat


    • Dose, duration and timing of administration: four slices of bread or two rolls (or equivalent combinations) substituted for daily bread intake for two 12-week periods


Participants completed a food diary for two weeks before randomisation and were asked to repeat the same two-weekly diet and to note in their hot flush diary if they diverged from it


OutcomesMeasures of frequency and severity of menopausal symptoms

Measures of change in quality of life


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout rate

Selective reporting (reporting bias)High riskAdverse events not measured

Del Giorno 2010

MethodsDesign: parallel-group

Number randomly assigned: 120

Number dropped out: eight because they did not take more than 80% of drug and 12 for personal reasons (not given per group)

Number analysed: 100

Intention-to-treat analysis: no

Power calculation: yes, 80% power, beta 10%, 38 participants per group

Duration: follow-up at four, eight and 12 months

Timing: December 2005 to December 2008

Location: University of Sao Paolo, Brazil

Funding: not stated


ParticipantsInclusion criteria: 45 to 65 years of age with menopausal symptoms; > 12 months amenorrhoea; FSH > 30 mIU/mL; oestradiol < 30 pg/mL

Exclusion criteria: diabetes mellitus; CVD; hypersensitivity to drugs used in the study; oestrogen-dependent cancer; liver failure; nephropathy; systemic lupus erythematosus; porphyia; altered cervicovaginal cytology; osteoporosis; endometrial thickness > 6 mm; uterine volume > 200 cm3; BI-RADS category 3, 4 or 5 mammograms; hormone treatment with sex steroids or phytoestrogens in past six months

Mean age, years: 56 in phytoestrogen group; 55 in placebo group

Recruitment: from outpatient clinic


Interventions
  • Trifolium pratense (red clover) 40 mg
  • Placebo


OutcomesVasomotor symptom score (Kupperman): sexual satisfaction (as measured by GRISS questionnaire)


NotesVasomotor symptoms not further defined


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer program"

Allocation concealment (selection bias)Low risk"Sample blinding codes" not disclosed during study

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as "double-blind"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as "double-blind"

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout; appears that women were allocated to groups after dropouts were excluded

Selective reporting (reporting bias)High riskInsufficient information on outcomes assessed

Evans 2011

MethodsDesign: parallel-group

Number randomly assigned: 84

Number dropped out: by 4 weeks, n = 2 (in genistein group); by 12 weeks, n = 14 more (eight in genistein group, six in placebo group). Reasons were given

Number analysed: 82

Intention-to-treat analysis: yes, modified; all those who had at least four weeks of treatment for efficacy

Power calculation: yes, 42 participants per group required to detect a clinically important difference of 35% at 5% level of significance and 80% power

Duration: four, eight and 12 weeks of follow-up

Timing: not stated

Location: five study sites in southwestern Ontario, Canada

Funding: DSM Nutritional Products (manufacturer of the genistein tested)


ParticipantsInclusion criteria: minimum of 40 hot flushes/wk; between ages of 40 and 65 years; physiological state of natural or surgical menopause (amenorrhoeic for ≥ three months + serum FSH > 35 IU/mL or > 42 days post surgery)

Exclusion criteria: clinical or laboratory abnormalities; use of conventional hormone therapy or selective oestrogen receptor modulators within four weeks of study start; known allergy or hypersensitivity to soy, peanuts, purified isoflavones, genistein, lactose and/or cow's milk; consumed soy products within four weeks before screening visit; unpredictable vaginal bleeding; uterine fibroids or endometriosis that required treatment; untreated polycystic ovarian syndrome; history of abnormal PAP smear; use of gonadotropin agonists within 24 weeks; glucocorticoids or chronic high-dose prednisone or equivalent for the past 12 weeks

Mean age, years: 53

Recruitment: not stated


Interventions
  • Genistein (geniVida) 30 mg once daily
  • Placebo once daily


OutcomesPrimary: percentage change in number of daily hot flushes from pretreatment to week 12

Secondary: duration and severity of daily hot flushes, Greene Climacteric Scale score; FSH, 17B-oestradiol, endometrial thickness


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer-generated randomisation list"

Allocation concealment (selection bias)Low risk"Sealed envelopes for each randomisation number"

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Patient, Medical Directors and research staff blinded to the treatment assignment for the duration of the trial"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Patient, Medical Directors and research staff blinded to the treatment assignment for the duration of the trial"

Incomplete outcome data (attrition bias)
All outcomes
Low riskModified intention-to-treat analysis: very low dropout by week four

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Faure 2002

MethodsDesign: parallel-group
Number randomly assigned: 75
Number dropped out: 17 for inefficacy (six from active group, 11 from placebo group)
Number lost to follow-up: three (placebo group)
Number analysed: 75
Intention-to-treat analysis: yes (missing data imputed by "last observation carried forward" principle), also per-protocol analysis
Power calculation: 630 in each study arm required to give 90% power to detect a difference of three hot flushes per day, assuming a standard deviation of 3.8 hot flushes/d (P = 0.05)
Duration: 16 weeks
Timing: not stated
Location: outpatient clinic, Nimes, France
Funding: industry funded (Arkopharma Laboratories)


ParticipantsInclusion criteria: postmenopausal women requesting treatment for hot flushes, at least six months since last menstrual period, minimum of seven moderate to severe hot flushes or night sweats during two weeks before study. Baseline FSH > 40 IU/L and serum oestradiol < 35 pg/mL
Exclusion criteria: use of any other drug for treatment of climacteric symptoms during study period, HT within six weeks before the study
Age, years: active group 53 (SD 5.6), placebo group 53.9 (SD 4.1)

Recruitment: not reported


Interventions
  • Phytoestrogen: isoflavone


    • Formulation: Phytosa: soy extract 325 mg capsules containing 17.5 mg total isoflavones (genistein, daidzein, biochanin and formononetin)


  • Placebo (cellulose microcrystalline and sodium magnesium stearic)


    • Dose, duration and timing of administration: 2 × 2 tablets daily for 16 weeks


OutcomesMenopausal symptoms: daily diary card recording number of moderate/severe hot flushes and night sweats
Adverse events recorded at each follow-up


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDescribed as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskHigh dropout rates but missing data imputed

Selective reporting (reporting bias)Unclear riskInsufficient information on one of the prespecified outcomes: adverse events

Ferrari 2009

MethodsDesign: parallel-group

Number randomly assigned: 180

Number dropped out: 30/85 in genistein group (three before treatment intake); 29/95 in placebo group (one before treatment intake). Detailed reasons given

Number analysed: 170 (exclusions were those with violation of selection criteria at entry)

Intention-to-treat analysis: yes, modified; women excluded with violation of selection criteria at entry

Power calculation: yes, 20% reduction in frequency of hot flushes for isoflavone group compared with placebo group—required 176 participants

Duration: 12 weeks

Timing: September 2004 to April 2006

Location: 16 different hospitals in Italy

Funding: not stated


ParticipantsInclusion criteria: women 40 to 65 years of age; reporting a minimum of five moderate to severe hot flushes per day over the last seven days of the run-in period; absence of menstruation for at least six months or six weeks after bilateral oophorectomy; FSH ≥ 30 IU/mL; 17B-oestradiol ≤ 40 pg/mL

Exclusion criteria: HT or any other hormone therapy in last three months before inclusion or one month if participant had been treated with megestrol acetate, clonidine, vitamin E, phenobarbital, ergotamine or antidepressant drugs; presence of suspected or confirmed breast nodule; severe liver or renal dysfunction; type 1 or 2 diabetes mellitus; heart failure NYHA class II to IV, severe neurological disease; history of drug abuse or alcoholism; known hypersensitivity to soy or soy derivatives

Mean age, years: 53 in isoflavone group; 55 in placebo group

Recruitment: not reported


Interventions
  • Extract of soy phytoestrogens: isoflavone content 80 mg with high doses of genistein (60 mg); one tablet daily
  • Identical placebo


Initial two-week run-in period, then a baseline visit


OutcomesAverage number of hot flushes in last seven days compared with baseline; improvement in hot flushes; change in severity of hot flushes; satisfaction; Kupperman Index; compliance; adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer-generated randomisation list. . .generated by blocks of four patients"

Allocation concealment (selection bias)Low riskRandomisation done off-site, with consecutive random numbers

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskHigh dropout but modified intention-to-treat analysis, with the only exclusions those who violated inclusion criteria

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Geller 2009

MethodsDesign: parallel-group

Number randomly assigned: 67 (black cohosh treatment arm not included)

Number dropped out: seven (reasons given)

Number analysed: 67

Intention-to-treat analysis: yes, all women who had been in study for at least three months

Power calculation: yes, for primary outcomes only, comparing each treatment with placebo: 22 women per arm, treatments would reduce vasomotor symptoms by approx 60% with anticipated placebo effect of 35%

Duration: 12 months

Timing: February 2003 to December 2007

Location: two university medical centres in the USA

Funding: Office of Dietary Supplements, National Center for Complementary and Alternative Medicine, National Institute for General Medical Sciences and Office for Research on Women's Health


ParticipantsInclusion criteria: experiencing at least 35 vasomotor symptoms per week, perimenopausal or postmenopausal with intact uterus, amenorrhoea for longer than six months to < 10 years, FSH > 40 mlU/mL, hormone therapy not contraindicated, able to give informed consent

Exclusion criteria: previous hysterectomy, < 35 vasomotor symptoms/wk, last menstrual period > 10 years, positive pregnancy test or breastfeeding, BMI > 38 kg/m2, previous history of endometrial hyperplasia or neoplasia, previous history of cancers of the reproductive tract or breast cancer, history or presence of myocardial infarction or stroke, history of severe recurrent depression or severe psychiatric disturbances, history or presence of cerebrovascular accident, severe varicose veins, sickle cell anaemia, history of alcohol or drug abuse, abnormal vaginal bleeding of undetermined cause, untreated or uncontrolled hypertension defined as systolic blood pressure > 165 mmHg or diastolic > 95 mmHg, concurrent administration of medication-containing oestrogen/progestin, SERM, St John's Wort, bisphosphonates or dietary phytoestrogens, history of migraine associated with hormone use, history or presence of deep vein thrombosis, thrombophlebitis or thromboembolic disorder, current participation in any other clinical trial within 30 d of enrolment, >5 alcoholic drinks per week, smoker, diabetes, abnormal transvaginal ultrasound defined as > 7 mm thickness, abnormal endometrial biopsy or mammogram, vegans

Mean age, years: 52 in placebo and red clover groups; 53 in hormone therapy group

Recruitment: not reported


Interventions
  • 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 23)
  • Black cohosh (128 mg/d) (n = 21)
  • Red clover (398 mg/d including 120-mg isoflavones) (n = 22)
  • Placebo (n = 22)


    • Women consumed two capsules each evening


Women taking oral hormone therapy had a two-month washout period, and women using transdermal patches had a one-month washout period


OutcomesPrimary outcome: relief of vasomotor symptoms

Secondary outcomes: relief of somatic symptoms, mood changes, sexual dysfunction, health-related quality of life, use of validated questionnaires, adverse events

Participants completed diaries


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Random, computer-generated code'

Allocation concealment (selection bias)Unclear riskNo details

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalysis was by intention-to-treat

Placebo = one dropout due to life changes; CEE/MPA = four dropouts due to two adverse events, one relocation and one life change; black cohosh = two dropouts, one loss to follow-up and one lack of efficacy; red clover = two dropouts due to lack of efficacy

Selective reporting (reporting bias)Unclear riskAll prespecified outcomes reported, but insufficient information on adverse effects

Han 2002

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 82
Number of dropouts: two (one from each arm, one due to poor response, one due to nausea—not stated which arms they were on)
Number analysed: 80
Intention-to-treat analysis: no
Power calculation: none stated
Duration: four months
Timing: August 1999 to February 2000
Location: university clinic, Brazil
Funding: unclear. Investigators acknowledge the co-operation of a doctor employed by food supplement manufacturer Eugenbio


ParticipantsInclusion criteria: women 45 to 55 years of age; "in menopause" at least 12 months, no hormonal treatment for at least 12 months, intact uterus, FSH > 25 U/L, oestradiol < 20 pg/mL, having hot flushes
Exclusion criteria: taking lipid-lowering drugs, antidiabetic medications, soybean-derived products or herbal supplements; uncontrolled hypertension, stroke or transient ischaemic attack, cancer diagnosed within past five years, previous myocardial infarction
Age, years: mean active arm 48 (SE 1.1), placebo arm 49 (SE 1.3)
Recruitment method: not stated


Interventions
  • Phytoestrogen: isoflavone capsules


    • Formulation: soy protein 50.3 mg and isoflavone 33.3 mg (genistein 23.3 mg, daizein 6.2 mg, glycitein in aglycone form 3.8 mg) per capsule


  • Placebo


    • Dose, duration and timing of administration: one capsule eight hourly (= 100 mg isoflavone daily) for four months


OutcomesMenopausal symptoms: hot flashes (Kupperman Index)
Compliance: examination of prescriptions/pills

Endometrial thickness


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number generator

Allocation concealment (selection bias)Low riskNumbered coded envelopes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded researchers and participants

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes recorded by an independent gynaecologist

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout

Selective reporting (reporting bias)High riskAdverse events not reported

Hanachi 2008

MethodsDesign: parallel-group

Number randomly assigned: 37

Number dropped out: not reported

Number analysed: assume this is 37

Intention-to-treat analysis: not reported

Power calculation for sample size: not reported

Duration: three months

Timing: not stated

Location: not stated

Funding: not stated


ParticipantsInclusion criteria: non-smokers; free from diseases; not on any type of hormone treatment during previous 12 months; not currently using lipid-lowering drugs, antidiabetic medications, soybean-derived products or herbal supplements; intact uterus; FSH > 25 U/L; oestradiol < 100 pg/mL; presence of hot flushes

Exclusion criteria: history of uncontrolled hypertension, stroke or transient ischemic attack, cancer diagnosed less than five years ago, previous myocardial infarction

Mean age, years: 52

Recruitment method: not stated


Interventions
  • Soy milk product (12.5 g soy protein with genistein 13 mg and daidzein 4.13 mg day 1)
  • Soy milk + exercise (one hour walking per day)
  • Control


OutcomesKupperman Index (hot flushes); lipids


NotesBaseline values not given, only percentage decrease from baseline. Control values also not given. Nature of control not described


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk'Randomly assigned', but no other description provided

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
High riskBlinding not possible

Blinding of outcome assessment (detection bias)
All outcomes
High riskBlinding not possible

Incomplete outcome data (attrition bias)
All outcomes
Low riskDoes not appear there were any dropouts

Selective reporting (reporting bias)High riskOutcomes not clearly described

Heger 2006

MethodsDesign: parallel-group, multi-centre

Number of women randomly assigned: 110

Number of dropouts: n = 16 in ERr 731 group (one lack of efficacy, three violations of smoking ban, three adverse events, two organisational reasons, seven other reasons); n = 48 in placebo group (31 lack of efficacy, one violation of smoking ban, one adverse events, 16 other reasons)

Number analysed: n = 109 (one woman refused to take the intervention)

Intention-to-treat: yes, modified—only the women who took the interventions

Power calculation: yes, using a group sequential design according to O'Brien and Fleming

Duration: 12 weeks

Timing: February 2003 to May 2004

Location: nine gynaecological outpatient departments in the Ukraine

Funding: Health Research Services Ltd, Germany, and Chemisch-Pharmazeutische Fabrik Goeppingen, Carl Muller, Apotheker, GmbH u Co KG, Goeppingen, Germany (manufacturer of the supplement)


ParticipantsInclusion criteria: climacteric complaints with MRS II total score > 22 points; perimenopause, defined as 45 to 55 years of age with cycle irregularity during the past 12 months or LMP at least three but no longer than 12 months ago

Exclusion criteria: regular cycles during the past three months; mandatory indication for HT; treatment with drugs containing oestrogen/progestogen during past six months or any other Rx in past three months; PAP smear class III/IV and/or endometrial hyperplasia; known or suspected hypersensitivity to experimental intervention; concomitant medications that might influence trial results; BMI < 18 kg/m2 or > 30 kg/m2 and/or abnormal eating habits; wish to become pregnant or to be breast-feeding; previous or existing major diseases; previous or existing psychiatric disorders including depression; smoking, moderate alcohol intake, coffee/chocolate intake of 500 mg or more of caffeine per day and/or suspected drug abuse; participation in another clinical trial during past six months; incompetence or incapability of understanding the trial

Mean age, years: 49

Recruitment method: from outpatient departments (women seeking treatment for climacteric complaints)


Interventions
  • One tablet (250 mg) of ERr 731 per day—containing 4 mg of Rheum rhaponticum dry extract—identical to the product Phytoestrol N
  • One tablet of placebo per day


OutcomesPrimary

  • Change in total score of MRS II (this outcome not extracted in this review)


Secondary

  • Changes in individual symptoms of MRS II: number and severity of hot flushes; number of bleeding/spotting days; intensity of bleeding; time until onset of Rx effect; scores on the Integrative Medicine Outcomes Scale, Clinical Global Impressions, MENQOL; satisfaction with Rx; changes in climacteric complaints; health-related quality of life; endometrial biopsy findings; investigations of vagina, breast, cervix; tolerability of medication; adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer generated randomisation list with a balanced 1:1 randomisation using a block size of 4"

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants, investigators and data monitoring committee—all blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants, investigators and data monitoring committee—all blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOne woman did not take the intervention and was not included. When discontinuations were reported, the LOCF method was used for missing data

Selective reporting (reporting bias)Low riskMost prespecified outcomes reported; authors stated that an additional paper will report on the remaining outcomes

Heyerick 2006

MethodsDesign: parallel-group
Number of women screened: 84
Number randomly assigned: 67
Number of dropouts: 18% (12/67): four in high-phytoE group (three no efficacy, one other), one in low-phytoE group (no efficacy), seven in placebo group (all no efficacy)
Number analysed: 55
Intention-to-treat analysis: no
Power calculation: not reported
Duration: 12 weeks
Timing: December 2003 to April 2004
Location: Ghent, Belgium
Funding: IWT-Vlaanderen in Belgium; Biodynamics, Belgium


ParticipantsInclusion criteria: healthy, 45 to 60 years of age, intact uterus, no menses for past 12 months, at least two to five hot flushes per day, abstention from HT for past three months
Exclusion criteria: score < 2 on Kupperman Hot Flush Index
Mean age, years: 52 in placebo and low-dose groups; 53 in high-dose group
Recruitment method: not stated


Interventions
  • Hop extract (100 μg/d 8-prenylnaringenin)
  • Hop extract (250 μg/d 8-prenylnaringenin)
  • Placebo


Dose, duration and timing of administration: one capsule a day for 12 weeks


OutcomesHot flush score on Kupperman Index (severity)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskOn-line randomiser

Allocation concealment (selection bias)Low riskRandom codes kept separate

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)High riskAdverse events not measured

Hidalgo 2005

MethodsDesign: cross-over
Number of women screened: not stated
Number randomly assigned: 60
Number of dropouts: 12% (7/60): not clear which group: five no reason, two adverse events
Intention-to-treat analysis: no
Power calculation: yes, but insufficient
Duration: 12 weeks, seven-day washout, then another 12 weeks on alternate treatment
Timing: July 2003 to August 2004
Location: Guayaquil, Ecuador
Funding: Melbrosin International (provision of intervention and control)


ParticipantsInclusion criteria: over 40 years of age, no menses for past 12 months, non-users of HT, moderate to severe menopausal symptoms (Kupperman Index score ≥ 15, basal determination
Exclusion criteria: no consent, indication of non-compliance, conventional HT, isoflavone supplements, thyroid medication or history of thyroid disease, medication that could interfere with vasomotor symptoms and/or lipid serum levels
Mean age, years: 51
Recruitment method: clinical database, private practice or from the general population through advertising and flyers


Interventions
  • Red clover extract (80 mg/d isoflavones)
  • Placebo


Dose, duration and timing of administration: Participants acted as their own control—two capsules a day of the randomly assigned treatment for 90 days, a seven-day washout period, then alternate treatment for a further 90 days


OutcomesHot flush and night sweat Kupperman scores (severity) expressed as percentages
Vaginal cytology


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputerised random number generation

Allocation concealment (selection bias)Low riskOpaque containers with investigators blinded to codes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clear whether dropouts likely to influence results

Selective reporting (reporting bias)High riskAdverse effects not measured

Imhof 2006

MethodsDesign: cross-over
Number of women screened: not stated
Number randomly assigned: 113
Number dropped out: four (three in active arm and one in placebo arm—all started hormone therapy)
Number analysed: 109
Intention-to-treat analysis: yes—modified, based only on the women who started the trial and excluded the women who started hormone treatment
Power calculation: not reported
Timing: not stated
Location: general hospital and study centre in Vienna, Austria
Funding: Melbrosin International (manufacturer of interventions)


ParticipantsInclusion criteria: postmenopausal (no menses for > 12 months), 40+ years, negative pregnancy test, willingness for adherence to control dates and to take prescribed medications, moderate to severe menopausal symptoms (Kupperman Index ≥ 15)
Exclusion criteria: constant ET, known isoflavone hypersensitivity
Mean age, years: 55 in active arm and 54 in placebo arm
Recruitment method: menopause clinic


Interventions
  • Red clover extract (MF11RCE) (80 mg/d isoflavones)
  • Placebo capsules


    • Dose, duration and timing of administration: two capsules per day for 12 weeks, seven-day washout period and crossed over to other treatment for next 12 weeks


OutcomesEndometrial thickness, daily hot flush and night sweat frequency and side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Jeri 2002

MethodsDesign: parallel-group

Number screened for inclusion: not stated
Number randomly assigned: 30
Number dropped out: none stated
Number lost to follow-up: none stated
Number analysed: 30
Intention-to-treat analysis: not mentioned
Power calculation: not stated
Duration: 16 weeks
Timing: not stated
Location: Peru
Funding: not stated


ParticipantsInclusion criteria: healthy, non-vegetarian women; postmenopausal for longer than one year; younger than 60 years of age; FSH level > 30 mIU/mL; having at least five hot flushes daily, averaged over one week; not using HT, antidepressants or other medications, or soy or other oestrogen-active plant products for the past 16 weeks
Exclusion criteria:
Age, years: 51
Other characteristics of participants: All were Hispanic "with a middle class income and good education"

Recruitment method: not reported


Interventions
  • Phytoestrogen: Promensil


    • Formulation: 40 mg of standardised isoflavones (genistein, daidzein, formonetin and biochanin) per tablet


  • Placebo


    • Dose, duration and timing of administration: one tablet daily


OutcomesMenopausal symptoms: hot flush frequency and severity
recorded at beginning and end of study


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskApparently no dropouts

Selective reporting (reporting bias)High riskAdverse events not reported

Jou 2008

MethodsDesign: parallel-group

Number randomly assigned: 96

Number dropped out: 4/30 in placebo group (one unwell and three for personal reasons), 2/34 in the equol-producing group (personal reasons), one in the non–equol-producing group (personal reasons)

Number analysed: 89

Intention-to-treat analysis: no

Power calculation for sample size: 81 participants (27 per group) would have 85% power to detect a difference of 10 in total Kupperman score between groups

Duration: six months

Timing: April to December 2005

Location: clinics at hospital and university in Taiwan

Funding: not stated


ParticipantsInclusion criteria: healthy menopausal women (confirmed by FSH ≥ 40 mIU/mL); did not receive hormone therapy during previous year; Kupperman Index score > 0

Exclusion criteria: taking medications containing hormones; major systemic disease such as diabetes mellitus, hypertension, hypothyroidism, chronic renal disease, breast disease, CVD, cancer

Mean age, years: 54

Recruitment method: from gynaecology clinics


Interventions
  • Soy germ extract powder twice per day—135 mg isoflavones (1 g = 10.9 mg daidzein and 2.85 mg genistein) in two separate subgroups: equol producers (n = 34) and non–equol producers (n = 32)
  • Placebo (roasted wheat powder) (n = 30)


OutcomesHot flushes as measured by Kupperman Index together with other symptoms


NotesHot flush status at baseline not reported. Menopausal symptom score at baseline not comparable between groups (higher in the equol-producing group)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Random number generator'

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout

Selective reporting (reporting bias)High riskAdverse events not reported

Kaari 2006

MethodsDesign: parallel-group
Number of women screened: 150
Number randomly assigned: 79
Number of dropouts: 14% (11/79): seven from soy group (three medical, four personal), four from ET group (one medical, one no reason, one scared of biopsy, one personal)
Number analysed: 68
Intention-to-treat analysis: no
Power calculation: not reported
Duration: 24 weeks
Timing: July 2001 to November 2002
Location: University of Sao Paolo, Brazil
Funding: ACHE Laborotorio Ldta (made the intervention)


ParticipantsInclusion criteria: ≥ 45 years, good overall health, no menses for past 12 months, FSH ≥ 30 mU/mL, intact uterus, endometrial thickness < 5 mm, atrophic endometrium (biopsy)
Exclusion criteria: strict vegetarian, high-fiber/high-soy diet, regular consumption of vitamin and mineral supplementation > Recommended Dietary Allowances, antibiotic or hormone use in past six months, history of chronic disorders (incl benign breast disease), regular use of medication known to interfere with study endpoints, BMI > 30
Mean age, years: 54
Recruitment method: menopause clinic


Interventions
  • Standardised soy extract 300 mg (120 mg/d isoflavones)
  • Oestrogen replacement therapy (CEE 0.625 mg + placebo)


    • Dose, duration and timing of administration: two capsules per day


OutcomesIn those who were symptomatic at baseline: percentage of participants who reported any reduction in hot flush severity (Kupperman score)
Endometrial thickness
Endometrial proliferation
Adverse events


NotesParticipants were recruited from a menopause clinic, but 18% of soy group and 26% of ET group were asymptomatic


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer software

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskModerate dropout

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Khaodhiar 2008

MethodsDesign: parallel-group
Number of women screened: 235 recruited and 191 randomly assigned
Number of dropouts: 49/191 (26%) dropped out, were lost to follow-up or were excluded (not clear which group they came from: 30 unable to comply with protocol or lost to follow-up, eight withdrew because they started taking other meds, two were withdrawn because they resumed menstruation, two were withdrawn because of abnormal liver function tests, two discontinued because of side effects, five did not complete their diaries)

Number analysed: 142
Intention-to-treat analysis: no
Power calculation: yes, 50 women per group for 80% power to detect differences in hot flush activity of 0.58 SD, average shift of 1.2 hot flushes/d or a hot flush score of 3 units/d
Duration: 12 weeks
Timing: not stated
Location: medical centre in Harvard Medical School, Boston, USA
Funding: Nichimo Co Ltd, Japan—manufacturer of daidzein-rich isoflavone aglycone extract


ParticipantsInclusion criteria: postmenopausal, no menses for past six months, 38 to 60 years of age, between five and 15 hot flushes per day
Exclusion criteria: active smoker; use of dietary supplements containing soy isoflavones, vitamin E, flaxseed or red clover; use of HT or any medication for hot flushes within past six weeks; BMI ≥ 40; history of breast, endometrial or cervical cancer; positive pregnancy test; history of undiagnosed vaginal bleeding, thromboembolic disease, cardiovascular disease, liver or kidney disease, diabetes mellitus or major illness
Mean age, years: between 52 and 54 in the three groups
Recruitment method: referring physicians at the medical centre and newspaper advertisements


Interventions
  • Extract of isoflavones prepared from soy germ fermentation with Koji fungus, 40 mg/d (n = 48)
  • Soy extract (see above) 60 mg/d (n = 49)
  • Placebo (n = 45) (isoflavone quantity not known)


    • Dose, duration and timing of administration: one tablet per day in the morning for 12 weeks


OutcomesMean change from baseline to week 12 in frequency of hot flushes (daily diary)
Severity of hot flushes (measured morning and evening on a scale of 1 to 4) (daily diary)
Outcomes were measured as percentage change for both


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details provided on method of randomisation

Allocation concealment (selection bias)Unclear riskNo details provided on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskNo intention-to-treat analysis—30 women withdrew from study as unable to comply with protocol or lost to follow-up (not clear from which group); eight withdrew because they started to take other medications or supplements, two women resumed menses after randomisation and were excluded, two women were withdrawn after randomisation because of abnormal liver function tests, two women in the 60-mg isoflavone group withdrew because of side effects and five women did not complete hot flush diaries and were excluded Number analysed: 142 had analysable data

Selective reporting (reporting bias)Unclear riskInsufficient data on adverse events and quality of life

Knight 1999

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 37 initially. When one woman dropped out after randomisation and before commencing treatment, another was recruited to the same treatment
Number dropped out: two in high-dose group withdrawn on GP advice
Number lost to follow-up:
Number analysed: 35
Intention-to-treat analysis: no
Power calculation: not reported
Duration: 12 weeks
Location: hospital outpatient clinic, Sydney, Australia
Funding: industry funded (Novogen, Australia)


ParticipantsInclusion criteria: postmenopausal women (bilateral oophorectomy or amenorrhoea for least six months with typical symptoms of menopause, FSH > 40 IU/L), having at least three hot flushes daily, 40 to 65 years of age
Exclusion criteria: HT use within previous six weeks, allergy to isoflavones, current bowel, liver or gallbladder disease, diabetes requiring medication, malignancy other than skin cancers, contraindications to HT use, vegetarians, regular soy product users, taking liver enzyme–inducing medications
Age, years: high dose 51.1 (± 8.8), medium dose 54.5 (± 4.4), placebo 53.1 (± 2.5)
Recruitment method: through university department of obstetrics and gynaecology


Interventions
  • Phytoestrogen: isoflavones: one Promensil tablet plus three placebo tablets
  • Phytoestrogen: isoflavones: four Promensil tablets


    • Formulation: Each Promensil tablet contained 40 mg total isoflavones (genistein 4.0 mg, daidzein 3.5 mg and their methylated precursors biochanin 24.5 mg and formonetin 8.0 mg)


  • Placebo four tablets identical to active tablets


    • Dose, duration and timing of administration: four tablets daily (packed in individual sachets) for 12 weeks


Participants advised not to alter their usual diet during the study


OutcomesMenopausal symptoms: daily flush diary
Quality of life: Greene Menopause Scale
Compliance: pill counts


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random number generator

Allocation concealment (selection bias)Low riskRandomisation performed remotely by external statistician

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal dropout

Selective reporting (reporting bias)High riskAdverse events not reported

Knight 2001

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 24
Number dropped out: three (from active arm—all disliked taste)
Number lost to follow-up: one (from placebo arm)
Number analysed: 20
Intention-to-treat analysis: no
Power calculation: not stated
Duration: 12 weeks
Timing: not stated
Location: Australia
Funding: industry funded (Protein Technology Industries)


ParticipantsInclusion criteria: postmenopausal women (bilateral oophorectomy or amenorrhoea for least six months with typical symptoms of menopause, FSH > 40 IU/L), having at least three hot flushes daily, 45 to 60 years of age
Exclusion criteria: HT use within previous six weeks; allergy to isoflavones; current bowel, liver or gallbladder disease; diabetes requiring medication; malignancy other than skin cancers; contraindications to HT use; vegetarians; regular soy product users (> once a week), taking liver enzyme–inducing medications
Age, years:
Recruitment method: two university hospital obstetrics and gynaecology clinics


Interventions
  • Phytoestrogen: isoflavones


    • Formulation: Take Care powder four scoops or 60 g in each sachet, containing total isoflavones 134.4 mg (genistein, daidzein, glycetein)


  • Placebo: isocaloric casein-based beverage packed in sachet


    • Dose, duration and timing of administration: one sachet per day made into a drink, for 12 weeks


Participants advised not to alter their usual diet during the study


OutcomesMenopausal symptoms: flush count
Quality of life: Greene Menopause Scale
Compliance: sachet counts
Adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomly permuted blocks of six, using computerised random number generator

Allocation concealment (selection bias)Low riskRandomisation performed remotely—external statistician

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskModerate dropout, which could influence findings—25% in active arm

Selective reporting (reporting bias)High riskAdverse events not reported

Kotsopoulos 2000

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 94
Number dropped out: 19 (10 on active treatment, nine on placebo, because of adverse effects)
Number lost to follow-up: none
Number analysed: 73 (two excluded from analysis as FSH in normal range)
Intention-to-treat analysis: no
Power calculation: not stated
Duration: three months
Timing: not stated
Location: Australia
Funding: academic research grant


ParticipantsInclusion criteria: 50 to 75 years of age, postmenopausal (12 months of amenorrhoea and FSH > 20 U/L)
Exclusion criteria: taking antibiotics within three months before study, receiving HT during 12 months before study, smoker, vegetarian, ingesting phytoestrogens or soy-based products
Mean age, years: 59
Recruitment method: subgroup of a larger trial


Interventions
  • Phytoestrogen: isoflavones


    • Formulation: soy dietary supplements containing 118 mg isoflavones daily (daidzein, genistein, glycitein and their respective glycosides: 2.11 mg total isoflavones per g of protein or 1.72 mg aglycone per g of protein); in powder form for mixing into a drink


  • Placebo powder (casein)


    • Dose, duration and timing of administration: drinks drinks daily for three months


OutcomesMenopausal symptoms: validated questionnaire to record psychological, vasomotor, musculoskeletal, genitourinary and other symptoms on 4-point scale. Completed at baseline and after treatment
Compliance: returned sachet count
Adverse effects: recorded adverse effects causing women to drop out


NotesNo requirement for vasomotor symptoms was given for eligibility for the study. 80% of participants had mild symptoms at baseline, and analyses were undertaken in this subgroup of women


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Levis 2011

MethodsDesign: parallel-group

Number randomly assigned: 248

Number dropped out: 11 in soy group (but they completed all study visits) and 12 in placebo group (but they completed all study visits)

Number lost to follow-up: 23 in soy group (18 before 12 months, five between 12 and 24 months), 43 in placebo group (40 before 12 months and three between 12 and 24 months)

Number analysed: 182 (99 in soy group and 83 in placebo group)

Intention-to-treat analysis: no

Power calculation: yes, 80% power to detect a 4% or greater difference in BMD of the lumbar spine, with the assumption that the control group will lose 4% to 5% of bone mass. Target total sample size was 306 with 15% attrition rate expected

Duration: two years

Timing: July 2004 to March 2009

Location: University of Miami Miller School of Medicine, South Florida, USA

Funding: National Institute of Arthritis, Musculoskeletal and Skin Diseases


ParticipantsInclusion: women 45 to 60 years of age, menopausal for longer than 12 months but less than five years; or absence of menses for six to 12 months and FSH > 40 IU/L

Exclusion: osteoporotic fractures, a bone mineral density T score in the lumbar spine or total hip of < -2, BMI of 32 or higher, abnormal mammogram findings, cancer in previous 10 years (except skin cancer), taking bone active drugs, corticosteroids, or herbal products. Taking menopausal hormone therapy within six months before trial

Mean age, years: 53 ± 3.3 in soy group; 52 ± 3.3 in placebo group

Recruitment method: from South Florida area by direct mailings, posters and presentations to community organisations


Interventions
  • Isoflavones 200 mg daily from soy protein (4 × 50-mg tablets) (n = 122). Each 200-mg dose contained 91 mg genistein, 103 mg daidzein
  • Placebo tablets (n = 126)


Treatment for two years taken in the morning before breakfast. Additional calcium supplements were provided to participants as required. Followed up at baseline and at 12 and 24 months


OutcomesBone mineral density

Bone collagen

Menopausal symptoms

Vaginal oestrogenisation

Serum lipids

Thyroid function


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation sequence in blocks of ten

Allocation concealment (selection bias)Unclear riskNo details

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and study personnel masked to treatment assignment

Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants and study personnel masked to treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
High riskOverall, 66 participants were lost to follow-up (26.6%)—18.8% from the soy group and 34.1% in the placebo group

Selective reporting (reporting bias)Unclear riskQuality of life was indicated as a secondary outcome in the protocol but was not reported in the 2011 paper and was not a primary outcome of this review. Not all of the exclusion criteria were listed in the paper

Lewis 2006

MethodsRandomisation method: separate site prepared randomisation codes
Blinding: double
Allocation concealment: adequate
Design: parallel-group
Number of women screened: 792
Number randomly assigned: 99
Number of dropouts: 12% (12/99): two in soy group (one could not accept Rx, one adverse event), five in flaxseed group (two could not accept Rx, one adverse event, one medical, one personal), five in placebo group (one could not accept Rx, one adverse event, two medical, one protocol violation)
Number analysed: 87
Intention-to-treat analysis: no
Power calculation: not reported
Duration: 16 weeks
Timing: not stated
Location: Toronto and Calgary, Canada
Funding: Canadian Institutes of Health Research


ParticipantsInclusion criteria: 45 to 60 years old, natural menopause with last menses in previous one to eight years, Menoquol vasomotor score > 3.0
Exclusion criteria: medical or surgical menopause; inflammatory bowel disease; malabsorption syndrome; uncontrolled thyroid disorder; known allergy or intolerance to muffin ingredients or any serious and active medical or social condition likely to affect quality of life during the study; no ET in past three months; no phytoestrogens, steroids or antibiotics in past month
Mean age, years: 53
Recruitment method: mailings to family practice, to previous participants of menopause workshops and to gynaecologists and family physicians


Interventions
  • Flaxseed muffins (50 mg/d lignans)
  • Soy muffins (42 mg/d isoflavones)
  • Placebo muffins (low levels of lignans and no isoflavones)


Dose, duration and timing of administration: one muffin per day


OutcomesPrimary: Menoquol vasomotor score (0 to 6)
Secondary: number of flushes per day
Severity of flushes (0 to 6)

Gastrointestinal side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSeparate site prepared the randomisation codes

Allocation concealment (selection bias)Low riskSeparate site ensured concealment

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskModerate dropout—not balanced between groups

Selective reporting (reporting bias)Unclear riskInadequate data on side effects

Nahas 2007

MethodsDesign: parallel-group

Number randomly assigned: 80

Number dropped out: four (two in each group—reasons given)

Number analysed: 76

Intention-to-treat analysis: no

Power calculation: not reported

Duration: 10 months

Timing: not stated

Location: Climacterium Outpatient Service of the Department of Gynecology in Sao Paolo University

Funding: Ativus Farmaceutica Brazil and Fundacao Lucentis de Apoio a Cultura, Ensino, Pesquisa e Extensao


ParticipantsInclusion: postmenopausal, 45 years of age or older with good overall health, spontaneous amenorrhoea for at least 12 months, FSH level > 40 mIU/mL, average of five or more vasomotor symptoms per day

Exclusion: strict vegetarian; high-fiber or high-soy diet; history of breast cancer, endometrial carcinoma, cardiovascular disease, thromboembolic disorders, undiagnosed vaginal bleeding, chronic alcoholism or chronic gastrointestinal diseases. Not on hormonal therapy or phytoestrogens for previous six months

Mean age, years: 55.7

Recruitment method: from outpatient menopause clinic at university


Interventions
  • Soy isoflavones extract (n = 40) 250 mg (Glycine max AT) corresponding to 100 mg/d of isoflavones, administered twice daily in capsules containing 125 mg soy extract plus 50 mg of isoflavones each (50% genistein and 35% daidzein)
  • Placebo (n = 40): two lactose tablets daily


Followed up for 10 months with evaluations at baseline and at four, seven and 10 months


OutcomesKupperman Menopausal Index

Daily diary of hot flushes

Symptoms

Body mass index

Vaginal cytology (maturational value, pH)

Transvaginal ultrasonography (endometrial thickness)

Adverse events

Mammography

Lipids, plasma levels of isoflavones


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk'Randomly assigned to one of two groups'. Computer randomised

Allocation concealment (selection bias)Low riskCentralised computerised randomisation using software by a statistician who was unaware of the study protocol

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskIsoflavone group: Two withdrew because of flatulance and epigastralgia; control group: two withdrew because of depression and family problems and not wishing to continue

Selective reporting (reporting bias)Low riskOriginal protocol was not viewed, but outcomes listed in the methods section of the paper were reported in the results

Penotti 2003

MethodsDesign: parallel-group
Number randomly assigned: 62
Number dropped out: 13 did not complete six months of treatment (six in active group: one because of diarrhoea and five because of persistent hot flushes; seven in placebo group because of persistent hot flushes)
Number analysed: 49 at six months
Number lost to follow-up: nil
Intention-to-treat analysis: no
Power calculation: not stated
Duration: six months
Timing: not stated
Location: outpatient menopause clinics, Italy
Funding: not stated


ParticipantsInclusion criteria: postmenopausal for at least six months; 45 to 60 years of age; FSH and 17-B E2 levels within postmenopausal range; experiencing at least seven hot flushes daily (evaluated by participant diary completed over 15 days prerandomisation); computerised bone mineralometry score greater than -2.5 at level of lumbar spine

Exclusion criteria: serious disease such as hypertension, heart disease, diabetes, renal disease, peripheral vascular disease

Age, years: 52.5 (49 to 58)

Recruitment method: from outpatient menopause clinic at gynaecology department


Interventions
  • Phytoestrogen: isoflavone tablets


    • Formulation: 36 mg soy-derived isoflavones (5.5 mg genistein, 18 mg daidzein, 12.5 mg glyciteine) and 48-mg soy saponine per tablet


  • Placebo: 0.5 g talc and 0.5 mg microcrystalline cellulose


    • Dose, duration and timing of administration: two tablets daily, one before lunch and one before dinner, for six months


OutcomesMenopausal symptoms: mean (=/-SD) daily number of hot flushes per month


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers list, balanced in blocks of 10

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh dropout

Selective reporting (reporting bias)High riskAdverse events not measured

Radhakrishnan 2009

MethodsDesign: parallel-group

Number randomly assigned: 100

Number dropped out: 15 (six in soy group and nine in control group)

Number analysed: 85

Intention-to-treat analysis: no

Power calculation: yes, 7% decrease in cholesterol with 80% power and 20% withdrawal rate

Duration: six months

Timing: not stated

Location: Department of Obstetrics and Gynecology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India

Funding: Dupont Protein Technology International–manufactured soy and protein supplements


ParticipantsInclusion: last menstruation at least 12 months previous or six weeks since bilateral oophorectomy; FSH level 40 mlU/mL; unwillingness to take or intolerance to HT; not currently taking lipid-lowering drugs, antidiabetic medications or herbal supplements; discontinued HT more than three months previously

Exclusion: unexplained vaginal bleeding, hypertension, diabetes, liver dysfunction, renal or cardiac disease, active thromboembolic disease, deep vein thrombosis, coronary artery disease, cerebrovascular accident or past history of thromboembolic disease associated with oestrogen use; present or past oestrogen-dependent malignancy such as breast or endometrial carcinomas, known peanut/legume allergy

Mean age, years: 48.07 ± 5.44 in the soy group; 49.71 ± 7.27 in the placebo group

Recruitment method: from outpatient clinic


Interventions
  • Soy group (n = 50): sachets containing 25 g of isoflavone-rich soy protein isolate with 75 mg of isoflavones in powder form, sweetened with aspartase with mild vanilla flavour
  • Placebo group (n = 50): sachets containing 25 mg of milk protein, which looked and tasted identical to the soy supplement


    • Both sachets contained equal amounts of elemental calcium (900 mg) and other trace elements and vitamins
    • Followed up at baseline and at three and six months


OutcomesKupperman Menopausal Index

Karyopyknotic Index

Maturation value

Endometrial thickness

Laboratory investigations

Bone mineral density

Acceptability of treatment


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomly assigned using computer-generated randomised numbers in blocks of 10

Allocation concealment (selection bias)Low riskPrecoded sachets were provided by DUPONT Protein Technology International

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk15 stopped the trial prematurely during the initial two months: six in the study group and nine in the control group. Main reasons were gastrointestinal side effects and food intolerance. Three cases in each group were lost to follow-up

Selective reporting (reporting bias)Low riskOriginal protocol not viewed. Outcomes listed in the methods sections were reported in the results

Sammartino 2003

MethodsDesign: cross-over (no washout)
Number of women screened: not stated
Number randomly assigned: 70
Number of dropouts: seven (three in genistein group: two no compliance, one personal; four in calcium group: three no compliance, one personal)
Number analysed: 63
Intention-to-treat analysis: no
Power calculation: not reported
Duration: one year
Timing: not stated
Location: menopause clinic at university department in Naples, Italy
Funding: not stated


ParticipantsInclusion criteria: minimum number of seven moderate to severe hot flushes (including night sweats)/d (defined), postmenopausal (hormones in the menopausal range: FSH > 40 IU/L; oestradiol < 20 pg/mL); no menses for 12 months
Exclusion criteria: neoplastic, metabolic and infectious diseases; concomitant use of any drug; BMI > 30; past or concomitant use of HRT or any other drug used for menopausal symptoms; endometrial thickness > 5 mm or endometrial abnormalities
Mean age, years: 52 in both groups
Recruitment method: menopause clinic


Interventions
  • Genistein
  • Calcium supplements


    • Dose, duration and timing of administration: 36 mg/d (two tablets) genistein and 3.3 g calcium phosphate + 8 mg/d cholecalciferol for 12 cycles of 28 days


OutcomesEndometrial thickness and adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation list

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy not blinded, but lack of blinding unlikely to affect measurement of the main outcome

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStudy not blinded, but lack of blinding unlikely to affect measurement of the main outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts balanced between groups and unlikely to affect results

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

St Germain 2001

MethodsDesign: parallel-group
Number screened for inclusion: 1,000 (of whom 102 passed first screening. Subsequently, 22 found to be ineligible, six could not tolerate treatment, one died, one had a family member die, two had medical conditions preventing continuance, one was non-compliant)
Number randomly assigned: 69
Number dropped out: nil
Number lost to follow-up: nil
Number analysed: 69
Intention-to-treat analysis: no
Power calculation: not stated
Duration: 24 weeks
Timing: not stated
Location: Human Metabolic Unit, Iowa State University, USA
Funding: academic grants and industry donations of muffin ingredients and laboratory tests


ParticipantsInclusion criteria: perimenopausal women, one or both ovaries remaining, FSH at least 30 IU/L, BMI 20 to 31,experiencing at least 10 hot flushes or night sweats per week, within 12 months of last menstrual cycle
Exclusion criteria: smokers, any chronic disease such as known cardiovascular disease or osteoporosis, long-term medication use, taking HT at time of study or during the previous 12 months
Age, years: median 50 (42 to 62)

Recruitment method: not reported


Interventions
  • High phytoestrogen: isoflavone


    • Formulation: 40 g daily of isoflavone-rich soy protein (80.4 mg/d aglycone components) plus daily vitamin/mineral supplement


  • Low phytoestrogen: isoflavone


    • Formulation: 40 g daily of isoflavone-poor soy protein (4.4 mg/d aglycone products) plus daily vitamin/mineral supplement


  • Placebo (whey protein) plus daily vitamin/mineral supplement


    • Dose, duration and timing of administration: one jumbo muffin daily, containing half the daily dose of protein, plus protein powder to be consumed as food or drink. Muffin and flour to be used as a meal replacement—not as a supplement


Participants advised to avoid food items containing soy isoflavones and not to take their own supplements


OutcomesMenopausal symptoms: Menopausal Index of hot flushes, night sweats and other symptoms
Measures of change in quality of life:
Compliance: self-reported


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskIt appears that all randomly assigned participants were analysed

Selective reporting (reporting bias)High riskAdverse effects not reported

Tice 2003

MethodsDesign: parallel-group, active arms versus placebo
Number screened: 1,191 (principal reasons for ineligibility: too few hot flushes (251), not interested (216) and medical conditions/medications (192))
Number randomly assigned: 252
Number dropped out: six (two taking Promensil (one too busy, one no improvement), two taking Rimostil (one nauseated, one on physician's advice), two taking placebo (one feared possible placebo, one too busy))
Number lost to follow-up:
Number analysed: 252
Intention-to-treat analysis: yes (also per-protocol analysis)
Power calculation: 90% power to detect at least a 15% greater reduction in hot flush frequency in the active arm compared with placebo; 25% placebo effect anticipated
Duration: 12 weeks
Timing: November 1999 to March 2001
Location: three US academic clinical research sites
Funding: industry (Novogen Inc)


ParticipantsInclusion criteria: women 45 to 60 years of age, experiencing at least 35 hot flushes/wk, FSH level 30 mIU/mL, documented bilateral oophorectomy or at least two consecutive months of amenorrhoea before enrolment, with at least six months of amenorrhoea during the year before entry
Exclusion criteria: vegetarian, ate soy products > once a week, taking medications affecting isoflavone absorption or hormonal preparations during previous three months, significant gastrointestinal disease, > two alcoholic beverages per day, allergic to red clover, consumed < 80% of expected study tablets during the two-week placebo run-in
Age, years: 52.3 (SD 2.8 to 3.4 in different arms)
Recruitment method: newspaper and radio advertising, flyers, directed mailings


Interventions
  • Phytoestrogen: isoflavones


    • Formulation: Promensil tablets, containing average of 41 mg total isoflavones per tablet (range 37 to 43 mg), with higher proportion of biochanin A and genistein than Rimostil


  • Phytoestrogen: isoflavones


    • Formulation: Rimostil tablets, containing average of 28.6 mg of total isoflavones per tablet (range 25.6 to 31.4 mg) with higher proportions of formononetin and daidzein than Promensil


  • Placebo: contained < 0.04 mg total isoflavones per tablet


    • Dose, duration and timing of administration: two tablets once daily for 12 weeks


OutcomesMenopausal symptoms: daily diary cards for recording hot flushes and night sweats
Quality of life: Greene Climacteric Scale
Compliance: pill count
Adverse effects: assessed at follow-up, specific method unclear


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated in random blocks of six, stratified by centre

Allocation concealment (selection bias)Low riskAllocation schedule maintained remotely, at pharmacy

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind: participants and researchers

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind: participants and researchers

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomly assigned participants analysed

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported

Upmalis 2000

MethodsDesign: parallel-group
Number screened for inclusion: not stated
Number randomly assigned: 177
Number dropped out: 40 (21 in active arm: one did not take supplement, nine ineligible, 11 violated protocol, one had urinary tract infection; 18 in placebo arm: one did not take supplement, four ineligible, 13 violated protocol)
Number lost to follow-up: 15 (nine in active group, six in placebo group) discontinued before week 12
Number analysed: 122 (for efficacy)
Intention-to-treat analysis: no
Power calculation: not stated
Duration: 12 weeks
Timing: not stated
Location: 15 outpatient sites in USA
Funding: industry funded (Advanced Care Products)


ParticipantsInclusion criteria: postmenopausal women experiencing average of at least five hot flushes per day, over 50 years of age, in good health, weight within ± 35% range for BMI, FSH at least 40 mIU/mL, oestradiol level 25 pg/mL or less, no menses for at least six months, discontinued HT at least 60 days before study entry
Exclusion criteria: history of breast cancer, hyperplasia, endometrial carcinoma or cervical neoplasia, positive pregnancy test, undiagnosed abnormal vaginal bleeding, bilateral oophorectomy or hysterectomy, thromboembolic disorders, cardiovascular disease, liver disease, chronic alcoholism, medication hypersensitivity, allergy to dietary supplement ingredients, uncontrolled addiction, severe depression, acute systemic infection or abnormal laboratory values
Age, years: mean 55

Recruitment method: not stated


Interventions
  • Phytoestrogen: isoflavone


    • Formulation: soy isoflavone extract tablet (50 mg genistein and daidzein daily, approximately 25 g of each)


  • Placebo


    • Dose, duration and timing of administration: two tablets at bedtime for 12 weeks


Intake of other soy products and dietary supplements restricted during the study


OutcomesMenopausal symptoms: daily diary card for number and severity of hot flushes and night sweats; 3-point scale for severity
Compliance: check of unused medication at week six and week 12

Endometrial thickness

Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot stated

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated as double-blind

Incomplete outcome data (attrition bias)
All outcomes
High riskVery high rate of dropout

Selective reporting (reporting bias)High riskQuality of life prespecified as an outcome in the methods section but not reported on in the results section

van de Weijer 2002

MethodsDesign: parallel-group
Number screened for inclusion: 42 (six ineligible, 24 did not return to clinic, tqo recorded inadequate data in diary during screening phase)
Number randomly assigned: 30
Number dropped out: six (three in each group, mainly because of lack of efficacy)
Number lost to follow-up: nil
Number analysed: 26
Intention-to-treat analysis: no
Power calculation: not stated
Duration: 12 weeks
Timing: not stated
Location: university clinic, The Netherlands
Funding: industry funded (Novogen Ltd, Australia)


ParticipantsInclusion criteria: postmenopausal women 49 to 65 years of age with at least 12 months' amenorrhoea, average of > five hot flushes daily
Exclusion criteria: HT or antibiotics within 12 weeks of study entry, undiagnosed vaginal bleeding, active liver or renal disease, history of allergy to foodstuffs, cardiovascular disease or thromboembolism
Age, years: active arm 52.5 (SD 5.2), placebo 54.2 (SD 7.4)

Recruitment method: not stated


Interventions
  • Phytoestrogen: isoflavones


    • Formulation: Promensil 40-mg tablets (daidzein, genistein, biochanin, formononetin)


  • Placebo tablets


    • Dose, duration and timing of administration: two tablets each morning for 12 weeks


Participants given list of foods to avoid, including legumes and isoflavone supplements


OutcomesMenopausal symptoms: daily diary for number of hot flushes, list of 21 symptoms to score on 4-point scale
Measures of change in quality of life


NotesBaseline hot flush count = average count of last seven days from four-week screening phase


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskBlank envelopes containing allocation shuffled, numbered consecutively, then given consecutively to participants

Allocation concealment (selection bias)Low riskParticipants took envelope to pharmacy, where number in envelope was matched with batch number of medication

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth participants and researchers blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBoth participants and researchers blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition > 10% and unbalanced between groups

Selective reporting (reporting bias)High riskAdverse events not reported

Ye 2012

MethodsDesign: parallel-group

Number of women randomly assigned: 90

Number of women analysed: 84 (two withdrew in low-dose group; four withdrew in high-dose group because of adverse events, traffic accident and emigration)

Intention-to-treat analysis: yes—last observation carried forward used for missing data

Power calculation: not stated

Duration: six months

Timing: not stated

Location: Sun Yat-sen University, Guangzhou, China

Funding: Guangzhou Sciences and Technology Bureau, Department of Health of Guangdong Province and extract provided by pharmaceutical company


ParticipantsInclusion criteria: Chinese, between 45 and 60 years of age, within the five-year period after natural menopause (12 months since last menstrual cycle), BMI < 30 kg/m2, FSH > 30 IU/L, Kupperman Climacteric Scale score > 15

Exclusion criteria: detectable diseases such as chronic diseases of the kidney, liver, heart or endocrine system; cancer; diabetes; taking medications known to affect bone health or lipid metabolism

Mean age of participants, years: 52 to 53

Recruitment method: advertisements in local media


Interventions
  • Low-dose isoflavones 84 mg daily
  • High-dose isoflavones 126 mg daily
  • Placebo (starch)


    • Three identical capsules taken morning and evening after meals. Participants were asked to stop taking other dietary supplements. Food frequency questionnaire administered at baseline and after treatment to check on dietary intake


Outcomes
  • Hot flushes
  • Kupperman Index
  • Serum lipids


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer randomisation (SPSS)

Allocation concealment (selection bias)Unclear riskNot stated

Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical capsules

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNot applicable as hot flushes assessed by participants

Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons given for dropouts and missing data imputed by last observation carried forward

Selective reporting (reporting bias)Unclear riskAdverse events not measured

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Albert 2001No control group

Albertazzi 2005Duration of trial only 6 weeks.

Aly 2009Used Black Cohosh

Amato 2005Low prevalence of menopausal symptoms

Atkinson 2003About half of the women in each group had hot flushes but this was not a requirement for participation in the study.

Bai 2007Used Black Cohosh

Baird 1995The study assessed oestrogenicity of dietary soy but did not assess any of the primary outcomes in this review, frequency or severity of vasomotor symptoms.

Cancellieri 2007The soy intervention included other plant extracts. It was not possible to separate out the effects of phytoestrogens alone.

Carranza-Lira 2001Only one month of treatment

Caserta 2005Not clear if women symptomatic at baseline and did not state that the two groups were randomised

Chandeying 2007No details on the dosage of phytoestrogens in the product and both groups received some form of oestrogen therapy

Chandeying 2007aDose comparison study

Chiechi 2003Analyses effects of soy-rich diet on vaginal epithelium of asymptomatic postmenopausal women. Symptomatic women excluded.

Cianci 2012Combination treatment: isoflavones and berberine combined

Cohn 2009Not clear if intervention is a phytoestrogen

Colacurci 2004There is no evidence that the control group was randomised.

Dodin 2005Women had very mild symptoms of hot flushes at baseline - women requesting treatment for hot flushes unlikely to agree to be randomised to the trial - only a subset of women analysed.

Duffy 2003Women had low incidence of symptoms - aim of study to assess effects on cognitive function

Duncan 1999No outcomes of interest - outcomes were physiological rather than clinical

Ehsanpour 2012Trial duration only 8 weeks

Erkkola 2010Only treated for 8 weeks in first arm of crossover

Hale 2001Women did not have vasomotor symptoms at baseline

Harding 1996Treatment only given for 2 months

Hochanadel 1999Only cognitive outcomes assessed; no flush outcomes or endometrial safety outcomes.

Ishiwata 2009A proportion of women were premenopausal at baseline (39/134) - not clear if they were symptomatic at baseline

Jenks 2012Treatment for only 8 weeks

Jou 2005Treatment for only 6 weeks.

Katz 2007Treatment was only for 6 weeks

Kok 2005Participants were asymptomatic and effects measured on quality of life, not vasomotor symptoms

Kolarov 2001Does not appear to be randomised.

Krzysztof 2007Study not randomised

Lamlertkittikul 2004This was a dose finding study with no control group

Manonai 2006No evidence that women had vasomotor symptoms at baseline.

Manonai 2008Dosage study

Mittal 2011Not clear if symptomatic at baseline - cannot separate out the effects of isoflavone on vasomotor symptoms

Murkies 1995It was not possible to determine the level of phytoestrogens in the experimental intervention.

Nahas 200438% of the participants had breast cancer.

Nasrin 2011Women were treated for only 6 weeks

Newton 2006The soy intervention was not standardised and was included with another preparation, a multibotannical tablet, so it was difficult to separate out the individual effects of soy alone. Also, women were given only dietary soy counseling and there was no measurement of their actual soy consumption.

Nikander 2005Women had a history of breast cancer

Palacios 2010Women were asymptomatic at the start of the trial and no control group - designed to assess endometrial safety

Pedro 2012No evidence that the participants had hot flushes at baseline

Pop 2008This was not a randomised trial. The women were randomly stratified based on equol production to placebo or soy group

Pruthi 2012Treated for only 6 weeks

Quaas 2012No evidence of hot flushes at baseline in the participants

Quella 2000Participants had breast cancer.

Rotem 2007Combination treatment with black cohosh, dong quai, milk thistle, red clover, American ginseng and chaste-tree berry

Russo 2003The intervention was a composite of phytoestrogens and black cohosh. It was not possible to determine whether effects solely due to phytoestrogens.

Sammartino 2006The intervention was a combination of isoflavones, lignans and cimicifugua racemosa. The effects of phytoestrogens alone could not be separated out.

Scambia 2000Co-intervention of HT. First part of the trial, soy vs placebo, only for 6 weeks.

Schwen 2010Animal model

Secreto 2003About 10% of the participants had breast cancer

Steinberg 2011Women were not symptomatic

Uesugi 2004The participants in the study were a mixture of asymptomatic and symptomatic women. Data were not available separately just for symptomatic women. Treatment also only for 4 weeks.

Unfer 2004Participants were asymptomatic.

van Patten 2002Women had breast cancer

Verhoeven 2005Intervention was a combination of phytoestrogens and black cohosh. It was not possible to separate out the effects of phytoestrogens alone.

Virojchaiwong 2011Head to head study

Washburn 1999Treatment given for only 6 weeks.

Woo 2003Low prevalence of menopausal vasomotor symptoms

Xue 2004Outcome was a composite of menopausal symptoms. Effects on vasomotor symptoms could not be separated.

Yang 2012No control group - comparison of 2 different strengths of soy extract

 
Characteristics of studies awaiting assessment [ordered by study ID]
Agrawal 2005

MethodsRandomised placebo-controlled trial in menopause clinic of a hospital in India

ParticipantsNot reported

Interventions
  • Phytoestrogens given as a supplement in the form of capsules
  • Placebo

OutcomesQuality of life, hot flushes, night sweats, urinary outcomes, psychological symptoms, sexual desire, dyspareunia

NotesAuthor contacted and awaiting reply

Baker 2011

MethodsDouble-blind placebo-controlled randomised study (abstract)

ParticipantsSymptomatic perimenopausal and postmenopausal women (n = 51)

Interventions
  • Licogen (liquorice extract) 100 mg (n = 20)
  • Licogen 50 mg (n = 21)
  • Placebo (n = 10)

OutcomesNumber and severity of hot flushes, nighttime wakenings, vaginal dryness, endometrial thickness

NotesAbstract published in 2011; author contacted

Garcia-Martin 2012

MethodsParallel-group double-blind randomised trial

ParticipantsPostmenopausal Spanish women (n = 99)

Interventions
  • Milk product with soy isoflavones (50 mg/d)
  • "Product control"—assume that this is placebo, as the authors state that the trial is double-blind

Outcomes
  • Menopausal symptoms
  • Vasomotor symptoms
  • Quality of life (Cervantes scale)
  • Bone metabolism
  • Bone mass

NotesAuthor contacted for full text of the publication

Mucowski 2013

MethodsRandomised placebo-controlled trial

ParticipantsMenopausal women (n = 110), secondary analysis of WISH trial in women who reported at least seven weekly hot flushes of any level at baseline

Interventions
  • Isoflavone soy protein (ISP) supplementation
  • Placebo

OutcomesComposite flushing score (frequency times intensity)

NotesSecondary analysis of larger trial. Author contacted for data

Nahidi 2009

MethodsRandomised double-blind clinical trial

ParticipantsMenopausal women referred to healthcare centres (n = 68)

Interventions
  • Licorice root extract (n = 34)
  • Placebo (n = 34)

OutcomesNumber of nocturnal hot flushes

NotesAuthor contacted

Paixao 2005

MethodsDouble-blind randomised study, duration 12 months

ParticipantsMenopausal women (n = 34) with age ranging from 38 to 54 years

Interventions
  • Genistein 100 mg/d (n = 17)
  • Placebo (n = 17)

OutcomesClimacteric symptoms (as measured by Kupperman's Menopausal Index), endometrial thickness (as measured by vaginal echography)

Notes

Sekhavat 2012

MethodsNot reported

ParticipantsNot reported

InterventionsNot reported

OutcomesNot reported

NotesAwaiting translation to determine whether study meets eligibility criteria

Stanosz 2006

MethodsRandomised study, duration 12 months

ParticipantsWomen in the early postmenopausal period (n = 71)

Interventions
  • Two tablets of Soyfem twice a day, 400 mg extract, 104 mg genistein (n = 22)
  • One tablet of Soyfem, one tablet of placebo twice a day, 200 mg extract, 52 mg genistein (n = 26)
  • Two tablets of placebo twice a day

OutcomesKupperman Index

NotesNot clear whether vasomotor symptoms alone measured

 
Comparison 1. Promensil versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Incidence of hot flushes (number/d)5300Mean Difference (IV, Random, 95% CI)-0.93 [-1.95, 0.10]

    1.1 40 mg/d
3105Mean Difference (IV, Random, 95% CI)-1.45 [-2.26, -0.64]

    1.2 80 mg/d
2195Mean Difference (IV, Random, 95% CI)-0.76 [-3.28, 1.77]

 2 Change in frequency of hot flushes (% reduction)2199Mean Difference (IV, Random, 95% CI)20.15 [-12.08, 52.38]

 3 Improvement in hot flush severity rate127Risk Ratio (M-H, Fixed, 95% CI)17.06 [1.10, 264.52]

 4 Change in vasomotor score from baseline to end of study/vasomotor severity—Kupperman subscale1165Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.29, 0.32]

 5 Endometrial thickness (mm) after treatment151Mean Difference (IV, Fixed, 95% CI)0.06 [-4.94, 5.06]

 6 Adverse event rates1169Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.65, 1.40]

 7 Incidence of specific adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Cold or upper respiratory tract infection (URTI)
1169Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.30, 1.42]

    7.2 Headache
1169Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.17, 1.27]

    7.3 Myalgia
1169Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.58, 3.62]

    7.4 Nausea
1169Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.26, 3.91]

    7.5 Arthralgia
1169Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.27, 2.66]

    7.6 Diarrhoea
1169Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.12, 3.94]

    7.7 Vaginal spotting
1169Risk Ratio (M-H, Fixed, 95% CI)1.52 [0.26, 8.85]

 
Table 1. Summary of findings: efficacy outcomes

TrialNo.InterventionComparisonDurationEfficacy outcomesResults (between-group comparison)Overall risk of bias

SOY DIETARY SUPPLEMENTS

Albertazzi 199810460 g soy powder (76 mg isoflavones)Placebo (60 g casein)12 weeksNumber of flushes/d after treatment; percentage decrease in number of flushesAt end of study, significant difference between placebo and soy: -1.59 (-1.95 to -1.2; P < 0.01), representing mean reduction of 1.6 flushes/d in soy group compared with placebo. 45% reduction in flushes with soy versus 30% reduction with placebo (P < 0.01)Unclear

Balk 200227Soy and corn flour cereal (100 mg/d isoflavones)Placebo (wheat cereal)24 weeksHot flush and night sweat symptom score after Rx (1 to 4)NS all outcomesHigh

Brzezinski 1997145Phytoestrogen-enriched diet (individualised by dietician) (isoflavone amount not given)Control—regular diet (avoiding phytoestrogens)12 weeksMSQ hot flush severity reduction subscore (0 to 3)Greater reduction with PE-rich diet (P = 0.004; no CI given)High

Burke 2003241(1) soy drink 1 (42 mg/d isoflavones);

(2) soy drink 2 (58 mg/d isoflavones)
Placebo (soy drink with isoflavones removed)2 yearsNumber and severity of flushes/sweats per day after Rx (symptom diary); also subgroup analysis in women with 4+ symptoms/d at baselineNS all outcomesHigh

Carmigiani 201060(1) oestradiol 1 mg + 0.5 mg norethisterone acetate;

(2) dietary soy supplementation (90 mg isoflavone) in powder form + placebo tablet
Placebo (identical powder and placebo tablets)16 weeksSomatic score (hot flushes, heart discomfort, sleeping problems and muscle and joint problems) on the Menopause Rating ScaleReduction in somatic symptoms was -45.6% with HT and -49.8% with dietary soy compared with -28.6% with placeboLow

Cheng 200760(1) isoflavones 60 mg daily in fruit drinkPlacebo (oatmeal drink)12 weeksHot flush and night sweat scoresSignificant reduction in hot flush score with isoflavones compared with placeboHigh

Dalais 199852(1) soy diet (53 mg/d isoflavones);

(2) linseed diet (high in isoflavones—quantity not given)
Placebo (wheat diet (low isoflavones))12 weeks + 12 weeksPercentage decrease in number of hot flushesNS: 22% reduction with soy; 41% reduction with linseed; 51% reduction with wheatHigh

Hanachi 200837(1) soy milk product (12.5 g soy protein with 13 mg genistein and 4.13 mg daidzein);

(2) soy milk product + exercise
Control12 weeksHot flush score on Kupperman IndexHot flushes significantly improved with both soy interventions compared with controlHigh

Knight 200124Soy powder 60 g/d for beverage (134.4 mg/d isoflavones)Placebo (casein powder for beverage)12 weeksNumber of flushes per week after RxNS: 29 flushes/wk in soy group; 46 flushes/wk in placebo group (reduction in both from baseline)High

Kotsopoulos 200094Soy powder for beverage (118 mg/d isoflavones)Placebo (casein powder for beverage)12 weeksHot flush symptom score (severity) (0 to 3) after RxNS: 0.77 score with soy; 0.83 score with placeboHigh

Lewis 200699(1) soy flour muffins (42 mg/d isoflavones);

(2) flaxseed muffins (50 mg/d lignans)
Placebo (wheat flour muffins (low lignans and no isoflavones))16 weeksMenoquol vasomotor score; number of flushes per day; severity of flushes (1 to 7 scale) after RxNS: all outcomesUnclear

Radhakrishnan 2009100(1) soy sachets (25 mg isoflavone soy protein isolate containing 75 mg isoflavones in powder form)Placebo powder6 monthsNumber of daily hot flushes; karyopyknotic index; maturation value; endometrial thickness; acceptability of treatment; adverse eventsSignificantly greater proportion of women had reduction in hot flushes with soy (84%) when compared with placebo (60%) but no significant difference in hot flush score between groupsUnclear

St Germain 200169(1) soy protein + (80.4 mg/d isoflavones); (2) soy protein – (4.4 mg/d isoflavones) in muffins and powder for cookingPlacebo (whey protein)24 weeksPercentage of participants perceiving a decrease in (1) frequency, (2) duration and (3) severity of flushes; number of flushes per week after Rx; number of sweats per week after RxNSHigh

SOY EXTRACT

Bicca 200475Standardised soy extract (33 mg/d isoflavones)Placebo capsules25 weeksGreene Vasomotor Subscale (intensity); percentage who experienced a decrease in frequency of flushes and sweats from baselineNS: Greene Vasomotor Scale; 74% with soy versus 43% with placebo had decrease in number of hot flushes (P = 0.007); 68% with soy versus 46% with placebo had decrease in number of night sweats (P = 0.049). NS: severity of symptomsLow

Campagnoli 200536Standardised soy extract (soy select) (60 mg/d isoflavones)Placebo capsules12 weeks + 12 weeksNumber of flushes per week after RxNSHigh

Faure 200275Standardised soy extract capsules (70 mg/d isoflavones)Placebo capsules16 weeksPercentage decrease in flushes per day; percentage of 'responders' (participants who had reduction of at least 50%)61% decrease with soy versus 21% reduction with placebo (P value not reported); 66% of soy group were responders versus 34% in placebo group (P < 0.005). Repeated measures analysis confirmed the soy-placebo treatment effectUnclear

Han 200280Soy capsules (100 mg/d isoflavones)Placebo capsules16 weeksKupperman Vasomotor Symptom Score (severity)Vasomotor score 8.2 in soy group versus 9.9 in placebo group (P < 0.01)High

Jou 200896Soy germ extract powder (3 g) twice per day (135 mg isoflavones – 1 g = 10.9 mg daidzein and 2.85 mg genistein) in equol producers and non-producersPlacebo (roasted wheat powder)6 monthsHot flushes as measured by Kupperman IndexReduction in hot flush score of 79% in equol producers, 35% in non-equol producers and 78% in placebo group. Results from equol producers significantly different from placebo by repeated measures analysisHigh

Kaari 200679Soy extract capsules (S40/Ach-1) (120 mg/d isoflavones)Oestrogen + placebo capsules24 weeksPercentage of participants reporting reduction (subgroup)NSHigh

Khaodhiar 2008147Soy extract capsule (isoflavone quantity not known) (1) 40 mg/d; (2) 60 mg/dPlacebo capsules12 weeksPercentage reduction in frequency of hot flushes (from daily diary), percentage reduction in severity of hot flushes (daily diary)52% and 51% reduction in hot flush frequency in 40-mg and 60-mg soy groups at 12 weeks compared with 39% reduction with placebo (NS). When both treatment groups were combined, an average reduction of 52% was seen in hot flush frequency per day in women taking soy compared with women taking placebo (P = 0.048)Unclear

Levis 2011248Isoflavone tablets 200 mg from soy protein (each tablet 91 mg genistein, 103 mg daidzein)Placebo tablets2 yearsMenopausal symptoms (hot flushes and night sweats) were secondary outcomesSoy isoflavone group: 48.4% had hot flushes; 31.7% in placebo group had hot flushesUnclear

Nahas 200780Soy extract (isoflavones 100 mg)Placebo capsules10 monthsChange in daily hot flush number; change in hot flush severity scoreSignificant reduction from baseline in number of daily hot flushes in both groups and significantly greater in soy versus placebo. Hot flush severity significantly reduced in soy extract group when compared with placeboLow

Penotti 200362Soy tablets (72 mg/d isoflavones)Placebo tablets24 weeksNumber of flushes per day after RxNSHigh

Upmalis 2000177Standardised soy extract tablets (50 mg/d of genistein and daidzin)Placebo tablets12 weeksPercentage change in flush severity per week; percentage change in flush frequency per week; percentage change in sweat frequency per week34% change in severity with soy versus 21% change in severity with placebo (P = 0.01); NS for percentage change in frequency (P = 0.078 repeated measures analysis); NS for change in reduction of night sweatsHigh

Ye 201290Soy germ isoflavone extract powder in capsules in two doses (84 mg and 126 mg of isoflavones)Placebo capsules24 weeksHot flush frequency and percentage change per week44.3% and 48.5% change in hot flushes from baseline in the 84-mg and 126-mg isoflavone groups, respectively, compared with 27.8% change in placebo group (P < 0.01)Unclear

RED CLOVER EXTRACTS

Baber 199951Promensil (standardised red clover extract) (40 mg/d isoflavones)Placebo tablets12 weeks + 12 weeksNumber of flushes per day after Rx; percentage flush reductionNSHigh

Del Giorno 2010120Trifolium pratense (red clover) 40 mgPlacebo12 monthsVasomotor symptoms (Kupperman Index)NS between groupsHigh

Geller 200967(1) 0.625 mg CEE + 2.5 mg MPA;

(2) Black cohosh (128 mg/d);

(3) Red clover (398 mg/d including 120 mg isoflavones)
Placebo12 monthsVasomotor symptoms (hot flushes and night sweats); frequency of hot flushes; intensity of hot flushesNS: black cohosh and red clover versus placeboUnclear

Hidalgo 200560Red clover supplement capsules (80 mg/d isoflavones)Placebo capsules12 weeks + 12 weeksKupperman Index score for hot flushes and sweats (severity) (expressed as percentage)Hot flushes: 15% with red clover versus 98% with placebo; night sweats: 30% with red clover versus 93% with placebo; P value not givenHigh

Imhof 2006109Red clover extract capsules (80 mg/d isoflavones)Placebo capsules90 days + 7 days washout + 90 daysHot flush daily frequency, night sweats daily frequency

Mean percentage decrease in hot flushes and night sweats
Mean (SD) daily frequency (hot flushes) in red clover group (3.1 (3.5)); in placebo group (10.1 (5.5))

Mean (SD) daily frequency (night sweats) in red clover group (1.5 (2.1)); in placebo group (5.0 (2.6))

Mean percentage decrease in hot flushes in red clover group 73.5%; in placebo group 8.2%

Mean percentage decrease in night sweats in red clover group 72.2%; in placebo group 0.9%

All differences significant (P = 0.0001)
Unclear

Jeri 200230Promensil (standardised red clover extract) (40 mg/d isoflavones)Placebo tablets16 weeksPercentage reduction in number of flushes per day; severity of flushes per day (scale)Frequency: 49% reduction with red clover versus 11% reduction with placebo (P < 0.001); severity: reduction from 2.53 to 1.33 with red clover versus no reduction with placebo (P < 0.001)High

Knight 199937Promensil (standardised red clover extract) (40 mg/d isoflavones)Placebo tablets12 weeksNumber of flushes per dayNSLow

Tice 2003252(1) Promensil (standardised red clover extract) (82 mg/d isoflavones—two tablets);

(2) Rimostil (standardised red clover extract) (57 mg/d isoflavones—two tablets)
Placebo tablets12 weeksNumber of flushes per day; percentage reduction in flushes; rate of reduction over timeNumber of flushes per day NS; percentage reductions NS; Promensil had faster reduction over time versus placebo (P = 0.03)Low

van de Weijer 200230Promensil (standardised red clover extract) (80 mg/d isoflavones—two tablets)Placebo tablets12 weeksNumber of flushes per day; median percentage change in number of flushes3.4 flushes/d with Promensil versus 6 flushes/d with placebo (P value not reported); 44% reduction with Promensil versus 0% reduction with placebo (P = 0.01; variation not reported)High

GENISTEIN

Crisafulli 200490(1) genistein extract (54 mg/d isoflavones);

(2) continuous HT (17B-ostradiol 1 mg/d + norethisterone acetate)
Placebo tablets1 yearPercentage change in number of flushes per day24% reduction with genistein when compared with placebo (P < 0.01); 30% reduction with HT when compared with genistein (P < 0.05)Unclear

D'Anna 2007247Genistein extract twice per day (each tablet containing 27 mg total isoflavone)Placebo twice per day2 yearsNumber and severity of hot flushesSignificant reduction in frequency (56.4%) and severity (37.5%) of hot flushes compared with placeboUnclear

Evans 201184Genistein (geniVida) 30 mg once dailyPlacebo12 weeksPercentage change in number of daily hot flushes; duration and severity of daily hot flushesSignificant reduction in frequency (51.2% vs 27.2%) and duration of hot flushes (12 minutes/d vs 23 minutes/d) at the end of treatment compared with placebo. NS severity of hot flushesLow

Ferrari 2009180Soy isoflavone extract (80 mg) with high dose of genistein (60 mg)Placebo12 weeksChange in daily frequency of hot flushes; improvement (as assessed by investigator)Significant reduction in number of hot flushes in genistein group (41.2%) when compared with placebo (29.3%); improvement in genistein group 56.7% and in placebo group 53.1% (P value not reported)Low

OTHER PHYTOESTROGENS

Aso 2012160Natural S-(-)equol supplement twice per day (5.0 mg equol, 1.2 mg daidzein, 1.4 mg genistein)Placebo12 weeksChange in frequency and severity of hot flushesSignificant reduction in frequency of hot flushes with equol supplement (62.8%) compared with placebo (23.6%) in women with more than three hot flushes per day. Significant improvement in severity of hot flushes with equol supplement (61.2%) when compared with placebo (45%)High

Colli 201290Flaxseed extract (1 g/d) (at least 100 mg secoisolariciresinol diglucoside (SDG)) and flaxseed meal (90 g/d) (at least 270 mg SDG)Placebo (1 g/d collagen)24 weeksIntensity of hot flush score (Kupperman Index)In both flaxseed groups, hot flush intensity score was reduced significantly from baseline, but no significant difference was seen in the placebo group. Comparison of groups by ANOVA showed no significant difference between groups at end of studyHigh

Dalais 199852See above for results in the flaxseed armHigh

Heger 2006110Extract of ERr 731, an extract of the roots of Rheum rhaponticumPlacebo12 weeksChanges in number and severity of hot flushesNumber and frequency of hot flushes significantly reduced with ERr 731 compared with placebo (P < 0.0001) (average of 5.5 fewer per day compared with 0 fewer per day)Unclear

Heyerick 200667(1) Hop extract 1 (100 μg 8-prenylnaringenin);

(2) Hop extract 2 (250 μg 8-prenylnaringenin) (Menohop)
Placebo capsules12 weeksKupperman hot flush score (severity)NS at the end of the study periodHigh

Lewis 200699See above for results in the flaxseed armUnclear

 CEE: conjugated equine oestrogen.
MPA: medroxyprogesterone acetate.
 
Table 2. Summary of findings: safety outcomes

TrialNo.InterventionComparisonDurationSafety outcomesResults (between-group comparison)Overall risk of bias

SOY DIETARY SUPPLEMENTS

Albertazzi 199810460 g soy powder (76 mg isoflavones)Placebo (60 g casein)12 weeksAdverse eventsNSUnclear

Balk 200227Soy and corn flour cereal (100 mg/d isoflavones)Placebo (wheat cereal)24 weeksEndometrial stimulation; adverse eventsEndometrial stimulation: NS (all participants had atrophic endometrium). Adverse events: NSHigh

Carmigiani 201060(1) oestradiol 1 mg + 0.5 mg norethisterone acetate;

(2) dietary soy supplementation (90 mg isoflavone) in powder form + placebo tablet
Placebo (identical powder and placebo tablets)16 weeksEndometrial thickness, vaginal maturation value; side effectsNS: side effects, endometrial thickness or vaginal maturation value with soy compared with placeboLow

Cheng 200760(1) isoflavones 60 mg daily in fruit drinkPlacebo (oatmeal drink)12 weeksEndometrial thicknessNo difference in endometrial thicknessHigh

Dalais 199852(1) soy diet (53 mg/d isoflavones);

(2) linseed diet (high in isoflavones— quantity not given)
Placebo (wheat diet—low isoflavones)12 weeks + 12 weeksVaginal maturation index (percentage increase from baseline)Increase of 103% with soy diet (P = 0.03), 6% increase with linseed (NS), 11% increase with placebo (NS)High

Knight 200124Soy powder 60 g/d for beverage (134.4 mg/d isoflavones)Placebo (casein powder for beverage)12 weeksAdverse events; vaginal maturation indexTotal adverse events: 75% with soy versus 17% with placebo (P < 0.001); vaginal maturation index NSHigh

Kotsopoulos 200094Soy powder for beverage (118 mg/d isoflavones)Placebo (casein powder for beverage)12 weeksAdverse eventsTotal adverse events: NSHigh

Radhakrishnan 2009100(1) Soy sachets (25 mg isoflavone soy protein isolate containing 75 mg isoflavones in powder form)Placebo powder6 monthsKaryopyknotic index; maturation value; endometrial thickness; adverse eventsNo difference in vaginal cytology, endometrial thickness or adverse eventsUnclear

SOY EXTRACTS

Bicca 200475Standardised soy extract (33 mg/d isoflavones)Placebo capsules25 weeksVaginal maturation index; vaginal pH (percentage with improvement)Maturation: NS; pH: 21% with soy versus 11% with placebo had improvement in pH (P = 0.008)Low

Campagnoli 200536Standardised soy extract (Soyselect) (60 mg/d isoflavones)Placebo capsules12 weeks + 12 weeksVaginal maturation indexNSHigh

Faure 200275Standardised soy extract capsules (7 mg/d isoflavones)Placebo capsules16 weeksAdverse eventsNSUnclear

Han 200280Soy capsules (100 mg/d isoflavones)Placebo capsules16 weeksEndometrial thicknessNSHigh

Kaari 200679Soy extract capsules (S40/Ach-1) (120 mg/d isoflavones)Oestrogen + placebo capsules24 weeksVaginal pH; vaginal maturation index; endometrial thickness; endometrial stimulation; adverse eventspH: 5.5 in soy group versus 4.8 in HT group (P = 0.0012); maturation index: significant difference in intermediate and superficial cell frequency in ET group when compared with soy group (P value not given); endometrial thickness: 5.9 mm in HT group versus 3.0 mm in soy group (significant; P value not given); non-atrophic endometrium: 54% in HT group versus 88% in soy group (P < 0.01); adverse events: 17% genital bleeding in HT group versus 0% in soy groupHigh

Khaodhiar 2008207Soy extract capsules (isoflavone quantity not known)—two different doses:

(1) 40 mg/d;

(2) 60 mg/d
Placebo12 weeksAdverse eventsVery few events reported—no group comparisons reportedUnclear

Levis 2011248Isoflavone tablets 200 mg from soy protein (each tablet 91 mg genistein, 103 mg daidzein)Placebo tablets2 yearsAdverse events7/99 had fractures in soy group compared with 1/83 in placebo group (P = 0.03)Unclear

Nahas 200780Soy extract (isoflavones 100 mg)Placebo capsules10 monthsMedian endometrial thickness (mm); maturation value; vaginal pH; adverse events2.4 mm in intervention group and 2.8 mm in placebo group (NS)

NS in vaginal outcomes and adverse events
Low

Penotti 200362Soy tablets (72 mg/d isoflavones)Placebo tablets24 weeksEndometrial thicknessNSHigh

Upmalis 2000177Standardised soy extract tablets (50 mg/d of genistin and daidzin)Placebo tablets12 weeksAdverse effects; vaginal pH; vaginal maturation index; endometrial thicknessAdverse events: 34% (30/89) of soy group reported 70 events versus 45% (39/86) in placebo group reported 79 events (no P value); pH: NS; maturation index NS; endometrial thickness: NSHigh

RED CLOVER EXTRACTS

Baber 199951PromensilPlacebo12 weeks + 12 weeksEndometrial thicknessNSHigh

Geller 200967(1) 0.625 mg CEE + 2.5 mg MPA;

(2) black cohosh (128 mg/d);

(3) red clover (398 mg/d including 120 mg isoflavones)
Placebo12 monthsEndometrial thickness; adverse eventsNSUnclear

Hidalgo 200560Red clover supplement capsules (80 mg/d isoflavones)Placebo12 weeks + 12 weeksVaginal cytology (karyopyknotic index, cornification index, maturation index)Significant changes (P < 0.05) in all indexes when compared with placeboHigh

Imhof 2006113Red clover extract capsules (80 mg/d isoflavones)Placebo12 weeks + 12 weeksEndometrial thicknessSignificant decrease in thickness with red clover (15%) but not with placebo (placebo values not given) (P < 0.001)

No side effects reported
Unclear

Tice 2003252(1) Promensil (standardised red clover extract) (82 mg/d isoflavones— two tablets);

(2) Rimostil (standardised red clover extract) (57 mg/d isoflavones—two tablets)
Placebo12 weeksAdverse eventsNSLow

GENISTEIN EXTRACTS

Crisafulli 200490(1) genistein extract (54 mg/d isoflavones);

(2) continuous HT (17B-oestradiol 1 mg/d + norethisterone acetate)
Placebo1 yearEndometrial thicknessNSUnclear

D'Anna 2007247Genistein extract twice per day (each tablet containing 27 mg total isoflavone)Placebo twice per day2 yearsEndometrial thickness; vaginal maturation valuesNSUnclear

Evans 201184Genistein (geniVida) 30 mg once dailyPlacebo12 weeksEndometrial thickness; adverse eventsNSLow

Ferrari 2009180Soy isoflavone extract (80 mg) with high dose of genistein (60 mg)Placebo12 weeksAdverse eventsNSLow

Sammartino 200370Genistein extract tablets (quantity of isoflavones not given)Placebo tablets1 yearEndometrial thicknessNSUnclear

OTHER PHYTOESTROGENS

Colli 201290Flaxseed extract (1 g per day) (at least 100 mg secoisolariciresinol diglucoside (SDG)) and flaxseed meal (90 g per day) (at least 270 mg SDG)Placebo (1 g per day collagen)24 weeksEndometrial thickness; vaginal epithelial maturation valueNSHigh

Dalais 199852See above for results in the linseed armHigh

Heger 2006110Extract of ERr 731, an extract of the roots of Rheum rhaponticumPlacebo12 weeksEndometrial thickness; adverse eventsNSUnclear

Sammartino 200370Genistein extract tablets (quantity of isoflavones not given)Placebo tablets1 yearEndometrial thicknessNSUnclear

 HT: Hormone therapy.
 
Table 3. Summary of findings: acceptability outcomes

TrialNo.InterventionComparisonDurationOutcomesResults (between-group comparison)

Albertazzi 199810460 g soy powder (76 mg/d isoflavones)Placebo12 weeksWithdrawal due to adverse events20% in soy group versus 23% in placebo group (P value not reported)

Ferrari 2009180Soy isoflavone extract (80 mg) with high dose of genistein (60 mg)Placebo12 weeksSatisfaction rates79.1% in genistein group; 69.1% in placebo group (P value not reported)

Heger 2006110Extract of ERr 731, an extract of the roots of Rheum rhaponticumPlacebo12 weeksSatisfaction rates63% in ERr 731 group satisfied at end of treatment; 32% in placebo group (P value not reported)

Knight 200124Soy powder 60 g/d for beverage (134.4 mg/d isoflavones)Placebo12 weeksWithdrawal due to adverse events25% in soy group versus 8% in placebo group (P value not reported)

Kotsopoulos 200094Soy powder for beverage (118 mg/d isoflavones)Placebo12 weeksWithdrawal due to adverse events or inability to tolerate treatment20% in soy group versus 18% in placebo group (P value not given)

Radhakrishnan 2009100Soy sachets (25 mg isoflavone soy protein isolate containing 75 mg isoflavones in powder form)Placebo powder6 monthsAcceptability of treatment according to taste, odor or bulk of preparationNot reported