Table 1.

Descriptive information from interventions articles (N=37).

Author, year, country	Design	Sample size and characteristics	Measure, timepoints	Intervention	O or AE	QR
DRUG THERAPIES (n=19)
Hormonal agents (n=15)
Anarte et al., 1998 [36], Spain	2-group RT Unclear masking	n=73 (IG1 37, IG2 36) Age IG1 M=50.62 Age IG2 M=49.83 With severe and varied psychological sx Postmeno	Kupperman Index Baseline, post-intervention, 6 months	IG1: HT (transdermal 17 β-estradiol + medroxyprogesterone on days 14 and 25) + 6-month psychological treatment (educational, counselling, behavioral components) of 10–16 sessions x 30 min IG2: HT alone on days 14 and 25	O	II
Bhattacharya & Jha, 2010 [37], India	2-group single blind RT	n=76 (Estradiol 38, Tibolone 38) Age estradiol M=44.5 Age tibolone M=44.1 With meno sx Surgically postmeno	Not specified Not specified	Estradiol: Transdermal estradiol gel (1.5mg/d, 0.06%) for 6 months Tibolone: Oral tibolone 2.5 mg/d for 6 months	AE	NA
Carmignani et al., 2010 [38], Brazil	3-group double blind RCT	n=60 (HT 20, Isoflavone 20, CG 20 Age HT M=53.5 Age isoflavone M=52.9 Age CG M=50.9 With > 8 hot flashes/24 hour Postmeno	MRS Baseline, 16 weeks	HT: 1mg estradiol, 0.5mg norethisterone acetate) + 2 portion/d of placebo power for 16 weeks Isoflavone 90 mg + one placebo tablet for 16 weeks CG: One placebo tablet + 2 portions/d of placebo power for 16 weeks	O	II
Checa et al., 2005 [39], Spain	3-group evaluator blind RT	n=136 (HT 48, Raloxifene 48, Calcium 40) Age HT M=56.4 Age raloxifene M=54.9 Age calcium M=55.1 With current HT or osteoporosis Postmeno	Modified short form-36 focusing on selected menopausal symptoms Baseline, 6, 12 months	HT: Estrogen patches (3.9mg estradiol) / progesterone (100mg/day) for 1 year Raloxifene: 60mg/day for 1 year Calcium: 500mg elemental calcium, 400 IU Vitamin D3 daily for 1 year	O	II
Chittacharoen et al., 2004 [40], Thailand	1-group open-label pre-post trial	n=39 Age M=52.3 Peri and postmeno	MRS II Baseline, 3, 6 months	Oral Estradiol valerate (EV) and levonorgestrel (LNG): 2 mg EV and then 2 mg EV plus 0.15 mg LNG for 6 months	O	III
Elfituri et al., 2005 [41], Libya	2-group RT, unclear masking	n=100 Age HT M=44.8 Age tibolone M=43.8 With meno sx Postmeno	Green Climacteric Scale Baseline, 3, 6, 12 months	HT: 2mg 17 β-estradiol+10mg dydrogesterone for 12 months Tibolone: 2.5mg for 12 months	O	II
Fluck et al., 2002 [49], United Kingdom	Follow-up from 2-group open-label trial	n=50 (IG 25, CG 25) Age IG M=61 Age CG M=61.2 With anxiety and depression Postmeno	Visual analog scales 10 years post-treatment follow-up	IG: Tibolone 2.5mg daily for 10 years CG: Untreated	O	III
Kim et al., 2019 [42], Korea	2-group open-label trial	n=57 Age estrogen M=50.52 Age tibolone M=51.23 With meno sx Postmeno	MRS Retrospective record review before treatment and 6 months later	Estrogen: Transdermal estrogen gel mixed with progestogen 1.5 mg daily for 6 months Tibolone: 2.5 mg daily for 6 months	O	III
Moyer et al., 2018 [43], USA	3-group RCT, unclear masking	n=100 (pills 33, patch 33, CG 34) Age M=52.7 With meno sx Postmeno	Menopausal symptoms checklist Baseline, 6, 12, 24, 36 and 48 months	HT pills: oCEE 0.45mg/d + micronized progesterone 200mg/d for first 12 days of the month HT patch: Transdermal 17 β-estradiol 50ug/d with micronized progesterone 200mg/d for first 12 days of the month CG: Placebo pills and patch All for 48 months	O	II
Nevinny-Stickel, 1983 [50], Germany	2-group single blind crossover RT	n=35 Age 48–69 With hot flashes Postmeno	Not specified Baseline, 6, 12 weeks	IG: Tibolone (Org OD 14) 2.5mg for 6 weeks for each period, no washout, the patients were switched over to the second 6-week treatment period CG: Placebo	O	II
Polo-Kantola et al., 1998 [44], Finland	2-group double blind crossover RCT	n=71 Age M=56.4 With sleep sx Peri and postmeno	Daily record for 14 days at baseline and last 14 days of each treatment period Baseline, 3 months, 1 month washout, 3 months later	Patch or gel: Estrogen patch (Evorel 50 ug) or Estrogen gel (Estrogel 2.5 gm) dependent on age CG: Placebo Three periods: 3-month estrogen/placebo, 1-month placebo washout, and then switched to 3-month placebo/estrogen	O	II
Pornel 1996 [45], United Kingdom, Australia, New Zealand, Italy, Belgium, France, Netherlands	1st trial: 2-group double blind RT 2nd trial: 2 group open label RT	1st trial: n=214 Age 40–65 With ≥ 21 hot flashes/week for the last 2 weeks Peri and postmeno 2nd trial: n=205 (Menorest 102, Estraderm 102) Age 40–65 years With ≥ 21 hot flashes/week for the last 2 weeks Peri and postmeno	Severity rating Baseline, 12 weeks	1st trial: Menorest: 50 twice weekly Premarin: 0.625mg/d All women received 10mg/day dydrogesterone on the last 21 days of each 28-day cycle All for 12 weeks 2nd trial: Menorest 50 Estraderm TTS 50 Both applied twice weekly for 25 out of 28-day cycle for 12 weeks	O	II
Takamatsu et al., 2001 [46], Japan	2-group open-label trial	n=67 (HT 23, Counseling 44) Age HT M=53 Age counseling M=51.4 With climacteric sx Postmeno	Keio modified menopause index Before and after counseling, 6 months after HT	HT: 0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone acetate daily for 6 months Counseling: Interview emphasis on psychodynamics, average counseling sessions of 2.9 (1.5) per patients for 6 months	O	III
Tit et al., 2017 [47], Romania	3-group open label trial	n=324 (IG1 95, IG2 124, CG 105) Age IG1 M=49.14 Age IG2 M=49.2 Age CG M=49.71 With meno sx Postmeno	MRS Baseline pre-treatment and 6- and 12-month of treatment	IG1: HT 1mg estradiol and 0.5mg norethisterone acetate po daily for 12 months IG2: Isoflavones 40mg po daily for 12 months CG: Untreated	O	III
Glaser et al., 2011 [48], USA & Greece	1-group open label trial	n=300 Age M=51.7 With meno sx Premeno, postmeno	MRS Baseline, 3 months	Testosterone subcutaneous implant varying 75–160mg based on weight	O	III
Non-hormonal drug therapies (n=4)
SSRI/SNRI (n=3)
Callegari et al., 2019 [51], Italy	2-group open label trial	n=39 (IG1 24, IG2 15) Age IG1 M=54.8 Age IG2 M=54.8 With depressive sx Postmeno	Antidepressant Side-Effect Checklist 8, 12 weeks	IG1: Paroxetine for 12 weeks IG2: Vortioxetine for 12 weeks	AE	NA
Freeman et al., 2017 [52], USA	1-group open label trial	n=27 Age M=52.1 With MDD Peri, postmeno	Patient Report of Incidence of Side Effects checklist 8 weeks	Vortioxetine flexible dosing from 5mg/d to 20mg/d for 8 weeks	AE	NA
Kornstein et al., 2015 [53], USA	2-group double blind RCT	n=798 in two RCTs (IG 147+ 316, CG 105+230) Age 40–70 With MDD Peri, postmeno	Treatment emergent adverse events scale 8 or 10 weeks	IG: Desvenlafaxine 100–200mg/d flexible dosing for 8 weeks or Desvenlafaxine 50mg/d for 10 weeks CG: Placebo for 8 weeks or 10 weeks	AE	NA
Antihypertensives (n=1)
Kujala et al., 2014 [54], Finland	2-group RT Unclear masking	n=112 (IG1 57, IG2 55) Age IG1 M=53.4 Age IG2 M=53.4 With hypertension and overweight Postmeno	Questionnaire Baseline, 8 weeks	IG 1: Moxonidine 0.6 mg/d for 8 weeks IG 2: Atenolol 50 mg/d for 8 weeks	O	III
NON-DRUG THERAPIES (n=18)
Supplementary treatments – isoflavones and other phytoestrogens (n=5)
Agosta et al., 2011 [55], Italy	2-group RCT (unclear if open-label or masked)	n=634 (IG1 300, IG2 334) Age IG1 M=53.3 Age IG2 M=53.0 With meno sx and borderline anxious-depressive sx and/or sleep disorders Postmeno	Survey Baseline, 4, 8, 12 weeks	IG1: Estromineral supplement containing isoflavones 60mg + Lactobacillus sporogenes + calcium + vitamin D3 for 12 weeks IG2: Estromineral Serena supplement containing same ingredients as Estromineral (IG1) + Magnolia bark extract for 12 weeks	O	III
Ahsan & Mallick, 2017 [56], India	1-group open-label trial	n=50 (29 peri, 21 postmeno) Age M=42.3 peri, M=49.6 post With meno sx Peri & postmeno	MRS Baseline, 12 weeks	Isoflavones 100mg daily for 12 weeks	O	III
Auerbach et al., 2012 [57], Austria	2-group double blind RCT	n=100 (IG 51, CG 49) Age IG M=54 Age CG M=55 With ≥ 5 hot flashes daily Postmeno	MRS II Baseline, 4, 8, 12, 24 weeks	IG: Pomegranate seed oil 30mg containing 127ug steroidal phytoestrogens per day for 12 weeks CG: Placebo	O	II
Costa et al., 2017 [58], Brazil	2-group double blind RT	n=32 (IG1 17, IG2 15) Age M=54.4 Age IG1 M=56 Age IG2 M=52.7 Postmeno	MRS, Blatt–Kupperman Menopausal Index, Cervantes scale Baseline, 10 weeks	IG 1: Isoflavone 100mg/d + aerobic and resistance exercise 3x/week for 10 weeks IG 2: Placebo/d +aerobic and resistance exercise 3x/week for 10 weeks	O	II
Davinelli et al., 2017 [59], Italy	2-group double blind RCT	n=60 Age 50–55 With meno sx Postmeno	MRS Baseline, 1, 3 months	IG: Equopausa (200 mg fermented soy + 25mg resveratrol (Vitis vinifera) daily for 12 weeks CG: Placebo daily for 12 weeks	O	II
Supplementary treatments – Rheum rhaponticum or false rhubarb (n=3)
Hasper et al., 2009 [60], Ukraine	2-group double blind RCT	n=81 of 109 in Heger et al., 2006[61] n=80 study 1 (IG 39, CG 41) n=51 study 2, (IG 23, CG 28) Age IG M=49.5 Age CG M=49 With meno sx (hot flash) Perimeno	MRS II Baseline, 12, 24, 36, 48 weeks (study 1), 96 weeks (study 2)	IG: ERr 731 (400 mg enteric-coated tablet containing 4 mg of Rheum rhaponticum dry extract) daily for 12 weeks in both studies CG: Placebo daily for 12 weeks	O	II, IV
Heger et al., 2006 [61], Ukraine	2-group double blind RCT	n=109 (IG 54, CG 55) Age IG M=49.3 Age CG M=48.6 With meno sx (MRS II > 22) Perimeno	MRS II Baseline, days 28, 56, and 84	IG: ERr 731 (250 mg enteric-coated tablet containing 4 mg of Rheum rhaponticum dry extract) daily for 12 weeks CG: Placebo daily for 12 weeks	O	II
Kaszkin-Bettag et al., 2009 [62], Ukraine	2-group double blind RCT	n=112 (IG 56, CG 56) Age IG M=49.4 Age CG M=49.6 years With meno sx (MRS > 18) Perimeno	MRS Baseline (day 0), and days 28, 56, and 84	IG: ERr 731 (400 mg enteric-coated table containing 4 mg Rheum rhaponticum dry extract) daily for 12 weeks CG: Placebo	O	II
Supplementary treatments – Salvia officinalis or sage (n=3)
Bommer et al., 2011 [63], Switzerland	1-group open-label trial	n=71 Age M=56.4 With ≥ 5 hot flashes daily Postmeno	MRS 7 days before treatment initiation, baseline, 8 weeks	Thujone-free Sage spissum extract tablet 280 mg (Salvia officinalis) for 8 weeks	O	III
Dadfar & Bamdad, 2019 [64], Iran	1-group open-label trial	n=30 Age M=52.6 With meno sx Postmeno	MRS Baseline, 4 weeks	Sage extract capsule 100mg (Salvia officinalis) daily for 4 weeks	O	III
Zeidabadi et al., 2020 [65], Iran	2-group double blind RCT	n=59 (IG 33, CG 28) Age unspecified With meno sx Postmeno	MRS Baseline, week 2, 4, 6, 8, 10, 12	IG: 100mg sage x 3 daily (Salvia officinalis extract for 3 months CG: Placebo	O	II
Supplementary treatments – other (n=4)
Fatima et al., 2017 [66], India	2-group patient blind RCT	n= 60 (IG 30, CG 30) Age IG M=43.7 Age CG M=43.9 With meno sx ≥ 2 months Postmeno	MRS Baseline, 2, 4, 6, 8, and 12 weeks	IG: Tribulus terrestris L. (fruits) 3g powder twice daily for 8 weeks CG: Placebo daily for 8 weeks	O	II
Modi et al., 2012 [67], India	1-group open-label trial	n=52 Age 40–55 Kupperman index ≥ 15 Postmeno	MRS Baseline, 1 month after 3-month treatment	Ayurvedic: Ashokarishta (25ml twice daily) + Ashwagandha Churna (3g twice daily) + Praval Pishti (250mg twice daily) for 3 months	O	III
Nayak et al., 2011 [68], India	1-group open-label trial	n=223 Age M=46.7 Peri and postmeno	DDCYSS Baseline, every week x 1 month, every 2 weeks x 3 months, monthly x 8 months	Individualized homeopathic consultation and medicine	O	III
Park & Kim, 2016 [69], South Korea	2-group double blind RCT	n=36 (IG 18, CG 18) Age IG M=51.78 Age CG M=52.78 With Kupperman index > 15 Peri or postmeno	Kupperman Index Baseline, 6 weeks, and followed at 12 weeks	IG: 784mg/day Schisandra chinensis for 6 weeks CG: Placebo	O	II
Psychological intervention (n=2)
Alder et al., 2006 [70], Switzerland	1-group open-label trial	n=30 Age M=52.3 With meno sx Peri and postmeno	MRS Baseline, 1, 2, 3 months post- intervention	Weekly 1.5-h group cognitive-behavioral sessions for 7 weeks	O	III
Qian et al., 2010 [71], China	3-group RT, partial factorial trial, unclear if masked	n=164 (Psychological 55, Herbals 53, Both 56) Age herbals M=51.25 Age psychological M=52.8 Age both M=51.43 With meno sx Unspecified meno status	Reformed Kupperman Scale Baseline, 6 months	Psych: Psychological intervention and 30–40 min weekly follow-up interview for 6 months Herbals: Chinese herbals (5g Kunbao Pill+ 6g Modified Xiaoyao Pill) twice a day for 6 months Both: Combined herbals and psych for 6 months	O	II
Auricular acupressure (n=1)
Kung et al., 2011 [72], Taiwan	1-group open-label trial	n=45 Age M=56.2 With insomnia Postmeno	MRS Baseline, 4 weeks	Auricular acupressure for 4 weeks	O	III

O = outcome, AE = adverse event, QR = level of evidence quality rating, R = randomized, C = controlled, T = trial, HT = hormonal therapy, IG = intervention group, CG = control group, M = mean, sx = symptoms, meno = menopausal, premeno = premenopausal, peri = perimenopausal, postmeno = postmenopausal, NA = not applicable, MRS = menopausal rating scale, SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin-norepinephrine reuptake inhibitor, MDD = major depressive disorder, oCEE = oral conjugated equine estrogen, ERr 731 = a special extract of Rheum rhaponticum, DDCYSS = Distress During Climacteric Years Symptom Scale.