Combined Red Clover isoflavones and probiotics potently reduce menopausal vasomotor 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.

Conflict of interest statement

Competing Interests: ML, AT and PBJ are co-inventors on the patent application “PCT/DK2013/050428” for the production of the Red Clover extract used in the present trial as required by US patent authorities. All rights have been assigned to the company Herrens Mark without any kind of compensation, where ML, AT and PBJ have forgone their rights as stipulated by terms and conditions of Aarhus University. Hence, the authors declare no financial or other interests. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Consort diagram.

In total 122 women were screened, 62 women met the inclusion criteria and were enrolled in the study. One participant dropped out due to personal reasons, two participants were excluded; one post medical examination due to undisclosed information regarding her physiological status and one submitted inadequate SC data due to lack of compliance during SC testing.

Fig 2. A and B: The model, program and SC monitor used for determination of hot flush events.

(A) The Q sensor from Affectiva™ (Waltham, MA, USA) used for ambulatory monitoring and capture of participant electrodermal activity. It is applied to the wrist (in a similar fashion to a watch) allowing integrated dual electrodes contact with the ventral side of the arm. Electrodes detect changes in SC, facilitating the determination of changes in the sweat secretion of participants in micro Siemans (μS). (B) Example of an archetypal hot flush shape detected using SC with a “sharp rise and swishy tail” according to Carpenter et al (1999).

Fig 3. Typical skin conductance data sets.

Examples of 24 hour skin conductance data sets, showing baseline (top) and post 12 week red clover treatment (bottom) data from a symptomatic menopausal participant.

Fig 4. A and B: Change in SC determined 24hr HFF and HFI.

(A) The mean (95% CI) change from baseline to 3 months in HFI (μS s-1) between the placebo and treatment groups. (B) The mean (95% CI) change from baseline to 3 months in 24hr HFF (total number of peaks) in the placebo and treatment groups. In all figures the Placebo group are marked as blue and RCE as red and significance is denoted as:* P

Fig 5. A and B: Self-reported rHFF and rHFS diaries.

(A) The mean (95% CI) change from baseline to 3 months in rHFF in the placebo and RCE groups. (B) The mean (95% CI) change from baseline to 3months in 24hr rHFS in the placebo and treatment groups. In all figures the Placebo group are marked as blue and RCE as red and significance is denoted as:* P