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Combined Red Clover isoflavones and probiotics potently reduce menopausal vasomotor symptoms.
Lambert, MNT, Thorup, AC, Hansen, ESS, Jeppesen, PB
PloS one. 2017;12(6):e0176590
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Plain language summary
Menopausal symptoms, such as hot flushes and night sweats, significantly impact the quality of life for women. These, also called, vasomotor symptoms (VMS) are a consequence of the natural decline and dysregulation of the body’s own oestrogen. While hormone therapy is the standard treatment for VMS, it is associated with an increased risk of cancers. Isoflavones, phytoestrogens that selectively interact with human oestrogen receptors, offer a potential alternative. The selective nature of isoflavones, like those from Red Clover (RC), can provide beneficial effects while minimizing cancer risks. These extracts have shown an even greater efficacy if isoflavones undergo fermentation processes. While recent clinical trials of RC for VMS have shown promising results, some of the challenges around research into VMS have been that they are primarily based on subjective experiences. Hence this study also employed hot flush analysis technology to generate objective data, besides blood samples, blood pressure readings, and subjective questionnaires. This randomised, double-blind, placebo control trial assessed the effect of bioavailable RC-derived isoflavones and probiotics in peri-menopausal women experiencing daily VMS. The participants received twice-daily 34 mg/d isoflavones and probiotics or a placebo for 12 weeks. The data from 59 participants was analysed for the results. This indicated that moderate doses of isoflavones from RC and probiotics, effectively reduce both physiological and reported menopausal symptoms. The authors observed discrepancies between physiological and reported measures, which may have been due to reporting biases and missing data in self-reports. Interestingly, both the placebo and treatment groups showed improved symptoms, highlighting the prevalence of the placebo effect in menopausal women and underscoring the challenges associated with self-report measures in menopausal research. Their isoflavones did not exhibit any effect on lowering blood pressure, which confirmed previous research that dietary isoflavones may only impact hypertensive people but not those with normal blood pressure. Isoflavones also did not impact blood lipids. The study highlights the importance of developing and implementing objective assessment methods for interventions targeting menopausal VMS, acknowledging the influence of the prevalent placebo effect. And further demonstrated that well-formulated probiotic isoflavone compounds can be a helpful tool in reducing VMS, with minimal side effects.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Supplementation with red clover isoflavones with probiotics over 12 weeks reduce peri-menopause related hot flush frequency and intensity as measured by an electrodermal sensor.
- This was a small trial of 62 women in peri-menopause. Larger trials of longer duration are required to confirm the findings.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This randomised, double-blind placebo controlled trial aimed to determine the efficacy of a red clover isoflavone/probiotic supplement in reducing the frequency of peri-menopause related hot flushes compared to placebo. The study also assessed impacts of the supplement on hot flush severity, fasting plasma lipids and blood pressure.
Methods
- The trial was a randomised, double-blind, placebo controlled trial over 12 weeks. 62 peri-menopausal women, aged between 40-65, and with 5 or more hot flushes daily, were randomly assigned to receive 75ml of red clover and probiotic supplement formulation twice daily or equivalent placebo formulation.
- Hot flushes were measured by participants wearing an electrodermal sensor for 24 hours at baseline and endpoint.
- Participants also completed the Green Climacteric Scale questionnaire at week 0 and week 12, to assess self-reported impacts on vasomotor, somatic, psychological and sexual symptoms.
- Blood plasma lipids (total cholesterol, HDL and triglycerides) were assessed at week 0 and week 12.
- Blood pressure measurements were taken at week 0 and week 12 using a 24 hour monitor.
Results
- 59 women completed the trial with no adverse side effects or events reported in either arm.
- A statistically significant (P<0.01) decrease in hot flush frequency from baseline to 12 weeks was found in the treatment group (-4.3 Hot Flushes (HF) /24h; 95%CI -6.8 to -2.3) compared to placebo (0.79 HF/24h; 95%CI -1.56 to 3.15) using the electrodermal sensor.
- Hot flush frequency also reduced over the 12 weeks in the treatment arm compared to placebo using the sensor (P<,0.05).
- A reduction in self-reported hot flush frequency was found in the treatment group (-2.97 HF/24h; 95%CI -4.77 to -1.17) compared to placebo (0.035 HF/24h; 95%CI -2.42 to 2.49; p<0.05)).
- No differences between groups were found from baseline to 12 weeks for blood pressure and lipid profiles.
Conclusion
The authors of this study conclude that 12 weeks of red clover isoflavones with probiotics are effective at reducing hot flush frequency and intensity in symptomatic peri-menopausal women.
Clinical practice applications:
- Healthcare practitioners working with peri-menopausal women with > 5 hot flushes daily may like to consider incorporating red clover isoflavones with probiotics at a dose of 75ml twice daily for 3 months into their protocols.
Considerations for future research:
- The women in this trial were normotensive and non-obese. Future studies of red clover isoflavones with probiotics could focus on women with hypertension and/or hyperlipidiaemia to test for effects on blood pressure and plasma lipids.
- Larger trials of longer duration are required to confirm the findings of this small clinical trial, given the typical duration of peri-menopausal symptoms.
Abstract
BACKGROUND Natural estrogen decline leads to vasomotor symptoms (VMS). Hormone therapy alleviates symptoms but increases cancer risk. Effective treatments against VMS with minimal cancer risks are needed. We investigate the effects of a highly bioavailable aglycone rich Red Clover isoflavone treatment to alleviate existing menopausal VMS, assessed for the first time by 24hour ambulatory skin conductance (SC). METHODS AND RESULTS We conducted a parallel, double blind, randomised control trial of 62 peri-menopausal women aged 40-65, reporting ≥ 5 hot flushes/day and follicle stimulating hormone ≥35 IU/L. Participants received either twice daily treatment with bioavailable RC extract (RCE), providing 34 mg/d isoflavones and probiotics, or masked placebo formulation for 12 weeks. The primary outcome was change in daily hot flush frequency (HFF) from baseline to 12 weeks using 24hr SC. Secondary outcomes were change in SC determined hot flush intensity (HFI), self-reported HFF (rHFF) and hot flush severity (rHFS), blood pressure and plasma lipids. A significant decrease in 24hr HFF (P < 0.01) and HFI (P<0.05) was found when comparing change from baseline to 12 months of the RCE (-4.3 HF/24hr, CI -6.8 to -2.3; -12956 μS s-1, CI -20175 to -5737) with placebo (0.79 HF/24hr, CI -1.56 to 3.15; 515 μS s-1, CI -5465 to 6496). rHFF was also significantly reduced (P <0.05)in the RCE (-2.97 HFs/d, CI -4.77 to -1.17) group compared to placebo (0.036 HFs/d, CI -2.42 to 2.49). Other parameters were non-significant. RCE was well tolerated. CONCLUSION Results suggest that moderate doses of RCE were more effective and superior to placebo in reducing physiological and self-reported VMS. Findings support that objective physiological symptom assessment methods should be used together with self-report measures in future studies on menopausal VMS. TRIAL REGISTRATION ClinicalTrials.gov NCT02028702.