Table 1.
Randomized controlled trials of Trifolium pratense for alleviating menopause symptoms: studies’ characteristics.
| First Author Pub. Data (Ref.) Country |
Design Follow-up Period |
Sample Size: Randomized/Analyzed |
Participants Age, y (Range) Trial Inclusion Criteria |
Intervention: Isoflavone Daily Dose |
Baseline Hot Flush Frequency/d | Baseline Menopausal Score |
|---|---|---|---|---|---|---|
| Knight 1999 [33] Australia |
Placebo controlled 3-arm parallel trial 1 wk placebo run-in/12 wk follow-up |
37/37 | 54.6 ± 3.6 (40–65) Healthy postmenopausal women, bilateral oophorectomy or amenorrhea ≥ 6 mo, FSH > 40 mIU/mL, HF > 3/d |
RCG “a”; 160 mga RCG “b”: 40 mgb PG: placebo |
RCG “a”: 9.0 ± 5.2 RCG “b”: 6.9 ± 2.1 PG: 8.6 ± 4.6 |
GCS RCG “a”: 19.9 ± 4.4 RCG “b”: 19.9 ± 10.6 PG: 18.5 ± 11.4 |
| Baber 1999 [34] Australia |
Placebo controlled crossover trial 90 d active phase/ 7 d washout |
51/51 | 54.0 ± 4.1 (45–65) Healthy postmenopausal women, age of menopause 50.0 ± 3.6 y, FSH > 30 mIU/mL, HF > 3/d |
RCG: 40 mgb PG: placebo |
RCG: 6.2 ± 2.7 PG: 6.4 ± 2.6 |
GCS RCG: 10.9 ± 6.5 PG: 12.3 ± 9.0 |
| Jeri 2002 [35] Peru |
Placebo controlled parallel trial 16 wk follow-up |
30/30 | 51.0 ± 3.5 (<60) Healthy postmenopausal women, amenorrhea ≥ 12 mo, FSH > 30 mIU/mL, HF ≥ 5/d |
RCG: 40 mgb PG: placebo |
RCG: 7.0 ± 1.9 PG: 5.7 ± 1.6 |
- - |
| van de Weijer 2002 [36] Netherlands |
Placebo controlled parallel trial 4 wk placebo run-in/ 12 wk follow-up |
30/26 | 53.4 ± 6.3 (49–65) Healthy postmenopausal women, amenorrhea ≥ 12 mo, BMI 26.1 ± 4.2, HF ≥ 5/d |
RCG: 80 mgc PG: placebo |
RCG: 5.43 ± 2.6 PG: 5.6 ± 5.0 |
GCS RCG: 12.5 ± 11.2 PG: 13.8 ± 9.5 |
| Tice 2003 [37] United States |
Placebo controlled 3-arm parallel trial 2 wk placebo run-in/12 wk follow-up |
252/252 | 52.3 ± 3.1 (45–60) Healthy peri- and post-menopausal women, 3.3 ± 4.5 ysm, FSH > 30 mIU/mL, BMI 26.1 ± 4.9, HF ≥ 35/wk |
RCG “a”: 80 mgc RCG “b”: 57 mgd PG: placebo |
RCG “a”: 8.5 ± 5.8 RCG “b”: 8.1 ± 3.0 PG: 7.8 ± 2.4 |
- - - |
| Atkinson 2004 [38] United Kingdom |
Placebo controlled parallel trial 12 mo follow-up |
205/99 | 52.2 ± 4.8 (49–65) Healthy peri- and post-menopausal women, FSH > 30 mIU/mL, BMI 25.3 ± 3.7, HF > 3/d |
RCG: 40 mge PG: placebo |
RCG: 2.1 ± 2.7 PG: 2.5 ± 3.0 |
GCS RCG: 4.3 ± 4.3 PG: 4.3 ± 4.3 |
| Hidalgo 2005 [39] Ecuador |
Placebo controlled crossover trial 90 d active phase/ 7 d washout |
60/53 | 51.3 ± 3.5 (>40) Healthy postmenopausal women, amenorrhea ≥ 12 mo, FSH > 35 mIU/ml, BMI 26.6 ± 3.9,KMI score ≥ 15 |
RCG: 80 mgc PG: placebo |
- - |
KMI RCG: 27.2 ± 7.7 PG: 27.2 ± 7.7 |
| del Giorno 2010 [40] Brazil |
Placebo controlled parallel trial 12 mo follow-up |
120/100 | 55.5 ± 4.9 (45–65) Healthy peri- and post-menopausal women, amenorrhea ≥ 12 mo, FSH > 30 mIU/mL, BMI 28.8 ± 5.4 |
RCG: 40 mg PG: placebo |
- - |
KMI RCG: 25.3 ± 10.2 PG: 25.1 ± 9.0 |
| Lipovac 2012 [41] Austria |
Placebo controlled crossover trial 90 d active phase/ 7 d washout |
113/109 | 54.1 ± 7.0 (>40) Healthy postmenopausal women, amenorrhea ≥ 12 mo, FSH > 35 mIU/mL, BMI 24.7 ± 3.9, HF > 5/d, KMI score ≥ 15/wk |
RCG: 80 mgc CG: placebo |
RCG: 11.7 ± 4.8 PG: 11.0 ± 5.1 |
KMIRCG: 32.5 ± 10.0 PG: 34.3 ± 10.4 |
| Clifton-Bligh 2015 [42] Australia |
Placebo controlled parallel trial 1 mo placebo run-in/ 2 y follow-up |
147/103 | 54.4 ± 3.9 Healthy postmenopausal women, amenorrhea ≥ 12 mo, FSH > 30 mIU/mL, BMI 24.8 ± 4.3 |
RCG: 57 mgd PG: placebo |
- - |
GCS RCG: 8.9 ± 7.3 PG: 11.0 ± 8.0 |
| Shakeri 2015 [43] Iran |
Placebo controlled parallel trial 12 wk follow-up |
72/71 | 54.8 ± 2.8 (50–59) Healthy postmenopausal women, 1.85 ± 0.9 ysm, BMD 21.1 ± 1.9 |
RCG: 80 mgc PG: placebo |
- - |
MRS RCG: 20.4 ± 6.3 PG: 20.8 ± 6.2 |
| Lambert 2017 [44] Denmark |
Placebo controlled parallel trial 12 wk follow-up |
62/59 | 52.5 ± 3.5 (40–65) Healthy perimenopausal women, FSH ≥ 35 mIU/mL, BMI 25.7 ± 4.3, HF > 5/d |
RCG: 37.1 mgf CG: placebo |
RCG: 9.5 ± 6.4 PG: 8.6 ± 6.9 |
GCS RCG: 18.6 ± 12.3 PG: 20.8 ± 2.3 |
Data are presented as mean ± standard deviation. Abbreviations: -, data not available; BIO, biochanin A; BMI, body mass index (kg/m2); DAI, daidzein; FOR, formononetin; FSH, follicle-stimulating hormone; GCS, Greene Climacteric Scale; GEN, genistein; GLY, glycitein; HF, hot flushes; KMI, Kupperman Menopausal Index; MRS, Menopause Rating Scale; PG, placebo group; pub. data, publication data; RCG, red clover group; ref., reference; VAS, vasomotor symptoms; ysm, years since menopause; mo, months; wk, week; d, day. Composition of isoflavones (aglycone, mg): a BIO (98.0), FOR (32.0), GEN (16.0), DAI (14.0); b BIO (24.5), FOR (8.0), GEN (4.0), DAI (3.5); c BIO (49.0), FOR (16.0), GEN (8.0), DAI (7.0); d FOR (44.6), BIO (5.8), DAI (1.8), GEN (0.8), GLY (0.8); e BIO (26.0), FOR (16.0), GEN (1.0), DAI (0.5); f FOR (19.0), BIO (9.0), GEN (4.2), DAI (1.6).