Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta-analysis
Abstract
Objective:
In this study, we aimed at evaluation of the efficacy of Hypericum perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women
Materials and Methods:
We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (RCT) to explore trials that assessed the effectiveness of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. In this regard, the following terms were used “menopause AND H. perforatum OR flaxseed OR Linum usitatissimum. Only randomized controlled trials were included in the study.
Results:
Nine RCTs were included in this systematic review. Based on the literature, flaxseed showed beneficial effect on hot flash frequency and intensity, which was not statistically significant. According to two trials, flaxseed showed estrogenic effects; however, no conclusion regarding cancer promoting or protecting effects can be made. The evidence of the efficacy of the flaxseed on alleviating vaginal atrophy was also limited due to inconsistent findings in this regard. One trial declared that Vitex agnus-castus and H. perforatum showed comparable decrease in the frequency of hot flashes.
Conclusion:
The results of our systematic review suggest beneficial effect on vasomotor symptom with both of flaxseed and H. perforatum. Consistent conclusion regarding estrogen-dependent cancers and maturation value is limited due to small number of trials related to flaxseed. Further trials are still needed to confirm the results of our systematic review.
Introduction
Menopause is a stage that all women experience in their life time (Ghaderi et al., 2010 ▶). Menopause happens around the age of 50 and is diagnosed by at least 12 months of amenorrhea. Menopause is often accompanied by a clustering of symptoms, including hot flashes, night sweat, vaginal atrophy, anxiety, nervousness and reduced libido (Cramer et al., 2012 ▶). Hormone therapy (HT) has been widely used in menopausal women seeking alleviation of symptoms of menopause (MacLennan et al., 2004 ▶, Loprinzi et al., 2000 ▶, Hidalgo et al., 2005 ▶). However, after publishing the first finding of the Women’s Health Initiative study, concerns was outlined about increased breast cancer risk (Group, 1998). Fear of breast cancer has driven users away from HT and consequently, there has been a sharp decline in the use of HT. Increasingly, many of the previous users of HT are getting interested in the flaxseed, Vitex agnus-castusand and Hypericum perforatum (H. perforatum) as alternatives to HT in the management of menopausal symptoms (Uebelhack et al., 2006 ▶, van Die et al., 2009 ▶, Ghazanfarpour et al., 2013 ▶, Dodin et al., 2005a ▶, Geller et al., 2009 ▶). Indeed, flaxseed is the richest food source of lignans, one of the three major classes of phytoestrogen (Geller et al., 2009 ▶). The aim of this systematic review was to assess the effect of flaxseed and H. perforatum on hot flashes, vaginal atrophy and estrogen-dependent cancers.
Material and Methods
We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials to explore trials that assessed the effect of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. No language restriction was imposed. Here, we searched the terms “menopause AND Hypericum perforatum OR flaxseed OR Linum usitatissimum”. In addition, reference sections of the relevant trials, systematic review and meta-analysis were manually checked to identify further trials missed by electronic search and the authors were contacted by email to obtain additional data. Also, sensitivity analysis was performed to assess the influence of excluding each study on heterogeneity.
Inclusion criteria
The inclusion criteria were limited to randomized controlled trials that used flaxseed or H. perforatum alone or in combination with other herbal medicine.
Important data extraction
Data was independently assessed by two authors and disparities were resolved by discussion with a third researcher. We estimated the differences in means in two ways: difference in means (MD) and standardized difference in means (SMD). The latter was used when studies included in the meta-analysis measured the same outcome by different measurement units. In the included studies, changes in mean at baseline and endpoint were assessed. Average and SD of differences between pre and post-trial variables were extracted, if possible. In other studies, pre and post-trial average and SD of the evaluated variables were extracted. Standardized or non-standardized difference in means was calculated for each study as the effect sizes.
Statistical analyses
We interpreted the results using random effects model (Der-Simonian and Laird method) because of the presence of large heterogeneity among included trials in our meta-analysis. For heterogeneity evaluation, Cochrane Q test (p<0.05 as statistically significant) and I2 index were used. I2 index was use to assess how much of the variance across studies is likely to be real and is not due to sampling errors. All statistical analyses were done by Comprehensive Meta-analysis Version 2 (Biostat, Englewood, NJ, USA). We also included data only from first phase of Baber (Baber et al., 1999 ▶) and Lipovac trials (Lipovac et al., 2012 ▶) to main meta-analysis in order to avoid the carry-over effect.
Results
Out of a total of 143 studies, which were found in the first search, 131 studies were not Randomized Controlled Trials (RCTs) and were excluded from our systematic review. The remaining 12 articles were assessed in detail. Finally, 9 RCTs met the inclusion criteria. Table 1 shows the characteristics of the nine selected RCTs. The process of the search and selection of RCTs is shown in Figure 1.
The effect of flaxseed on the severity of hot flashes
Three studies (Colli et al., 2012 ▶; Lewis et al., 2006a ▶; Dodin et al., 2005b ▶) provided complete statistical data for the meta-analysis. Standardized difference in means (SMD) of the severity of hot flash in flaxseed group was lower as compared to control group (–0.203; 95%CI: -0.474 to 0.067; p=0.141; heterogeneity p=0.501; I2=0%; 212 participants; random effects model). The forest plot is shown in Figure 2. Coli et al. compared 3 arms (1 g of flaxseed extract containing 100 mg lignan, 90 g flaxseed meal containing 270 mg lignan and placebo) (Colli et al., 2012 ▶). Inclusion of flaxseed extract arm only into the meta-analysis showed no significant change in the pooled effect size as compared to the main analysis. On the other hand, by inclusion of flaxseed meal arm only, pooled effect size showed a less decrease in hot flash severity as compared to the main analysis (SMD=-0.163, 95%CI: -0.437 to 0.111; p=0.245).
The effect of flaxseed on the frequency of hot flashes
Two studies (Simbalista et al., 2010 ▶; Lewis et al., 2006a ▶) provided sufficient statistical data to be included in the meta-analysis. Difference in means (MD) of frequency of hot flash showed greater decrease in flaxseed group as compared to the control group (MD -0.520[-2.528 to 1.489]; p= 0.150 I2=0%; random effects model). The forest plot is shown in Figure 3. FDA and the European Medicines Agency (EMEA) have considered at least 2 hot flash/day as clinically meaningful (Colli et al., 2012 ▶). The results of our meta-analysis should be interpreted in the light of this recommendation.
Two trials did not provide enough statistical data to be included in the meta-analysis:
Dalais et al. compared 3 arms of soy, flaxseed and wheat diet. The frequency of hot flashes decreased significantly in wheat diet (p<0.009) and flaxseed ( p<0.09) but not in the soy group (Dalais et al., 1998 ▶). In fact, hot flash decreased by 41% in flaxseed, 51% in wheat diet and 22% in soy groups. No statistical comparison between groups was provided.
| Author, Year | Menopausal status | During (wk) | Age | Drop out% | Number patient | Intervention | Randomization technique | Blinding method | Intention-to treat reporting | Side effect |
|---|---|---|---|---|---|---|---|---|---|---|
| Colli , 2012 | Parallel | 24wk | Flaxseed extract /53 Flaxseed meal /54 Placebo/56 | 17% | Flaxseed extract/28 Flaxseed meal/22 Con/25 | Flaxseed extract (containing 100 mg Lignans) Flaxseed meal (containing 270 mg of Lignans) Con= 1000 mg of collagen | No | Unclear | No | No serious |
| Pruthi, 2012 | Parallel | 6WK | Flaxseed/53 Control/53 | 18% | Flaxseed/69 Con/77 | Flaxseed bar( containing 410 mg of lignans Con/ placebo | Yes | Unclear | No | Flaxseed experience more diarrhea placebo experience more bloating |
| Simbalista, 2010 | Parallel | 12 WK | Trea=52 Con=52 | 3% | Treatment=20 Con=18 | Bread containing 25 g of flaxseed (46 mg lignans) Con /wheat bran (,1 mg lignans; control) | Yes | Double blind | No | Both group experience intestinal flow, flatulence |
| Lewis, 2006 | Parallel | 16WK | Soy/53 Flaxseed/53 Placebo/52 | 11% | Flaxseed /24 Placebo /23 Soy/24 | Muffins with 25 g of flaxseed (50 mg of lignans), 25 g soy (42 mg of isoflavones), Con/ wheat | Yes | Double blind | Yes | -------------- |
| Dodin, 2005 | Parallel | 51 l | Flaxssed/54 Calcium /55 | 105% | Flaxseed Control/ wheat | Flaxssed= 196ug total lignans Control= wheat | No | Double blind | No | ------- |
| Dalais. 1998 | Cross over | 2 X 12 weeks with 4 week washout period | Soy/53 Flaxseed= 54 Wheat/53 | 15% | Soy/44 Flaxseed/44 Wheat/44 | Soy/45 mg Flaxseed/45mg Wheat/45 mg | No | Unclear | No | ------------- |
| Ghazanfarpour, 2013 | Parallel | 12 WK | Hypericum perforatum/53 Vitex agnus-castus/52 | 18% | Hypericum perforatum/31 Vitex agnus-castus/33 | Hypericum perforatum/31 Vitex agnus-castus/33 | No | Unclear | No | Hypericum perforatum/ Headache and constipation / vitex agnus-castus / headache and Dizziness in the |
| Chung, 2007 | Parallel | 8WK | Cimicifugae racemosa rhizome +Hypericum perforatum Control/placebo/51.02 P/50.43 | 13% | Treatment/42 Placebo /35 | Treatmen group/.0364 ml of extract from Cimicifugae racemosa rhizome plus84 mg of dried extract from Hypericum perforatum Control/placebo | No | Unclear | No | In placebo group Gastro intestinal complaints/4 Generalized Ache n/1 Weight gain n/1 |
| Diana van, 2009 Australia | Parallel | 8WK | T/52.5 P/51.9 | 7% | T/47 Placebo /46 | Hypericum perforatum (contain 990 Kg of hypericin)+ V. Agnus-castus tablet( contained extract equivalent to500 mg of dry fruit), | No | Double blind | No | Two on isoflavones And one on placebo) had a discreet vaginal bleeding During the study |
Another study by Pruthi et al. showed no significant difference between flaxseed and placebo groups regarding decrease in percentage change of hot flashes. There was a comparable decrease of 29% for flaxseed group and 28% for control group, which was not statistically significant (p=0.90) (Pruthi et al., 2012 ▶).
To sum up, flaxseed had better effect as compared to placebo on decreasing the frequency of hot flashes, although the difference was not statistically significant.
Comparison of the Flaxseed vs. Soy
Two trials (Dalais et al., 1998 ▶; Lewis et al., 2006b ▶) compared the effects of flaxseed and soy regarding hot flash frequency. Dalais et al. trial compared 3 arms: soy, flaxseed and wheat diet (Dalais et al., 1998 ▶). Hot flashes frequency showed a significant decrease of 41% in the flaxseed and a non-significant decrease of 22% in the soy group. No statistical comparison between groups was provided. Another study by Lewis et al. compared 3 arms: soy, flaxseed and placebo (Lewis et al., 2006b ▶). Comparison of all groups did not show any significant difference. In fact, hot flash frequency decreased from 3.06 to 2.88 (-0.5%) in soy group, from 3.30 to 2.90 (-12%) in the placebo group and from 2.89 to 2.35 (-19%) in the flaxseed group.
To sum up, flaxseed seems to be more effective as compared to soy and placebo in decreasing the frequency of hot flashes (Dalais et al., 1998 ▶) .
The effect of flaxseed on night sweating
Dodin et al. assessed the effect of flaxseed on night sweating (Dodin et al., 2005b ▶). Night sweats decreased more efficiently in the flaxseed group as compared to the placebo (-1.11 ±1.48 vs. -0.89 ± 1.20), which was not statistically different.
Hormonal effects of flaxseed
The effect of flaxseed on the follicle stimulating hormone (FSH) levels
Two trials (Colli et al., 2012 ▶; Simbalista et al., 2010 ▶) provided complete statistical data to be included in the meta-analysis. Standardized difference in means of FSH demonstrated greater decrease in flaxseed group as compared to placebo (although not statistically significant) (SMD-0.066; 95% CI: -0.550 to 0.418 p=0.790; heterogeneity p=0.248; I2=25%; random effects model). The forest plot is shown in Figure 4.
The effect of flaxseed on the estradiol levels
Two trials (Simbalista et al., 2010 ▶; Colli et al., 2012 ▶) provided complete statistical data to be included in the meta-analysis. Standardized difference in means of estradiol change showed more increase in flaxseed group as compared to placebo (SMD 0.447 95% CI: 0.028 to 0.867 P=0.037; heterogeneity P=0.643; I2=0%; 90 women random effects model). Overall, based on two trials, flaxseed showed an estrogenic effect. Further trials are needed to confirm this finding. The forest plot is shown in Figure 5.
The effect of flaxseed on endometrial thickness
Two trials (Simbalista et al., 2010 ▶; Colli et al., 2012 ▶) provided complete statistical data to be included in the meta-analysis. Flaxseed group showed greater decrease regarding endometrial thickness as compared to placebo (SMD -0.096; 95% CI: -0.510 to 0.319; p=0.651; heterogeneity p=0.248; I2=25%; random effects model). The forest plot is shown in Figure 6. To sum up, flaxseed led to slight decrease in endometrial thickness as compared to the control group. Further trials are needed to confirm this finding.
The effect of flaxseed on the maturation value
Two trials (Colli et al., 2012 ▶; Dalais et al., 1998 ▶) assessed the effect of flaxseed on maturation value. One trial by Coli et al. compared 3 arms (1 g of flaxseed extract containing 100 mg of lignan, 90 g of flaxseed meal containing 270 mg of lignan and placebo) (Colli et al., 2012 ▶). Unexpectedly, both flaxseed extract and meal groups showed a reverse effect on maturation value. Maturation of vaginal epithelium decreased from 39.8 ±15.1 to 32.4 ± 18.3 (-18%) in the flaxseed extract group, and from 41.6 ±10.9 to 36.9 ± 16.0 (%11) in the flaxseed meal group and from 35.7 ±12.9 to 32.0 ± 19.0 (%10) in the placebo group. Each of intervention groups of flaxseed extract and flaxseed meal showed greater decrease regarding maturation of vaginal epithelium as compared to the placebo; however, difference between each of the interventions and placebo was not statistically significant.
Another trial by Dalais et al. compared 3 arms: soy, linseed diets (flaxseed) and wheat diet. Maturation value increased by 5.5% in the linseed diets and by 11% in the wheat diet but in the soy group the increase was statistically significant (103%, <0.05) (Dalais et al., 1998 ▶).
Vitex agnus-castus vs.H. perforatum
One trial by Ghazanfarpour et al. compared Vitex agnus-castus and H. perforatum. Baseline severity means of hot flashes were 3.67 ± 0.74 for St. John’s Wort and 3.58 ± 0.84 for Vitex agnus-castus group (Ghazanfarpour et al., 2013). There was a comparable decrease of John’s Wort group John’s Wort (-61%) and in Vitex agnus-castusgroup (-57%) hot flashes, which was not statistically significant (P=0.68).
Black cohosh and H. perforatum combination vs. placebo
Chung et al. compared black cohosh and H. perforatum combination with placebo and found a gradual decrease in hot flash intensity in the intervention group (7.52, 3.24 and 1.97) and in control group score (7.43, 6.29 and 3.54) at three time points: baseline, 4, and 8 weeks (Chung et al., 2007 ▶). Comparison between groups showed a statistically significant difference at 4 (p=0.04) and 8 (p=0.02) weeks.
Vitex agnus-castus and H. perforatum combinationvs. placebo
One trial by Diana van Die et al. compared Vitex agnus-castus and H. perforatum combination with placebo (van Die et al., 2009 ▶). After 16 weeks, patients in both groups experienced a statistically significant reduction in hot flashes (p<0.0001). In fact, daily flashes
scores decreased from 16.35 ±1.30 to 9.32±1.36 (42%) in placebo group and from 16.53 ±1.32 to 10.86 ±1.34 (34%) in intervention group. Comparison between groups did not show statistically significant differences (p=0.42).
The effect of flaxseed on vasomotor symptoms
Our results revealed that flaxseed consumption decreased vasomotor symptoms (hot flash frequency and intensity and night sweats) more efficiently as compared to the control group, which was not statistically significant. Our result is consistent with another systematic review which showed beneficial effect of flaxseed on hot flashes, without any statistical significance (Dew and Williamson, 2013 ▶).
Maturation value
Two trials assessed the effect of flaxseed on maturation value (Colli et al., 2012 ▶; Dalais et al., 1998 ▶). One gram of flaxseed extract containing 100 mg lignan and 90 g flaxseed meal containing contain 270 mg lignan cannot prevent progressive post-menopausal changes of vaginal epithelial cell (Colli et al., 2012 ▶) while 45 mg flaxseed (containing unknown levels of isoflavone) slightly increased the maturation value by 5% (Dalais et al., 1998 ▶). Based on the current result, no consistent conclusion can be made in this regard and further trials are still needed.
Risk of breast cancer
Cancer-promoting effects
Current systematic review showed that flaxseed may increase the risk of breast cancer. Meta-analysis of the included data showed that the mean increase in estradiol level was higher in the flaxseed group as compared to the placebo. A meta-analysis including a few prospective studies concluded that increase in circulating estradiol concentration was associated with the increased risk of cancer breast (Hooper et al., 2009 ▶).
Cancer-protecting effects
On the other hand, there is evidence for protective effect of flaxseed on breast cancer. A recent study by Lowcock et al. showed that ingestion of flaxseed with high concentrations of lignans, was associated with a reduced risk of breast cancer (Lowcock et al., 2013 ▶). Another meta-analysis of epidemiological studies concluded that consumption of plants containing lignans was associated with a reduced risk of breast cancer only in postmenopausal period (Buck et al., 2010 ▶).
Another evidence for protective effect for flaxseed is a slight decrease in endometrial thickness (although non-significant) in flaxseed group as compared with the control group. Based on the current result, we need more compelling and larger trials to judge more accurately regarding promoting or protective effect of flaxseed on breast cancer.
The effect of the black cohosh and H. perforatumcombination on hot flash intensity
Chung et al. showed significant beneficial effect of black and H. perforatum combination as compared to the control group on the hot flashes (Chung et al., 2007 ▶). One prospective controlled open-label observational study by Briese et al. which was not included in the current systematic review (we only included randomized controlled trials) compared the black cohosh and H. perforatum combination with black cohosh alone (Briese et al., 2007 ▶). Black cohosh and H. perforatum combination had higher efficacy compared to black cohosh alone regarding hot flashes reduction. However, larger trials are still needed to investigate the synergistic effect of black cohosh and H. perforatum.
Limitation
Suboptimal methodological quality of the included trials in the current systematic review is the main limitation of our study. Almost none of the included trials reported randomization technique, blinding assessment and intention-to treat reporting. Further trials should take into consideration the CONSORT checklist to improve methodological quality as well as their reporting.
Conclusion
Our systematic review showed beneficial effect of flaxseed on vasomotor symptoms of post-menopausal women. However no consistent conclusion can be reached regarding estrogen dependent cancer and vaginal maturation value. Further high quality trials are still needed to address these issues.
Conflict of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- 1. Is there an association between menopause status and sexual functioning? Menopause20007297309[PubMed][Google Scholar]
- 2. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women Climacteric199928592[PubMed][Google Scholar]
- 3. Black cohosh with or without St John's wort for symptom-specific climacteric treatment—Results of a large-scale, controlled, observational study Maturitas200757405414[PubMed][Google Scholar]
- 4. Meta-analyses of lignans and enterolignans in relation to breast cancer risk Am J Clin Nutr201092141153[PubMed][Google Scholar]
- 5. Black Cohosh and St John's wort (GYNO-Plus®) for climacteric symptoms Yonsei Med200748289294[Google Scholar]
- 6. Evaluation of the Efficacy of Flaxseed Meal and Flaxseed Extract in Reducing Menopausal Symptoms J Med Food201215840845[PubMed][Google Scholar]
- 7. 2012 Effectiveness of yoga for menopausal symptoms: a systematic review and meta-analysis of randomized controlled trials Evid Based Complement Alternat MedArticle ID 863905[Google Scholar]
- 8. Effects of dietary phytoestrogens in postmenopausal women Climacteric19981124129[PubMed][Google Scholar]
- 9. Controlled flax interventions for the improvement of menopausal symptoms and postmenopausal bone health: a systematic review Menopause20132012071215[PubMed][Google Scholar]
- 10. The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial J Clin Endocrinol Metab20059013901397[PubMed][Google Scholar]
- 11. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial Menopause200916115666[PubMed][Google Scholar]
- 12. Evaluation of menopausal women’s attitudes towards menopause in Shiraz Pak J Med Sci201026698703[Google Scholar]
- 13. Comparison the efficacy of Hypericum perforatum and vitex agnus-castus in hot flashes: A double-blinded randomized controlled trial Chron Dis J201316773[Google Scholar]
- 14. Design of the women’s health initiative clinical trial and observational study Control Clin Trials19981961109[PubMed][Google Scholar]
- 15. The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study Gynecol Endocrinol20052125764[PubMed][Google Scholar]
- 16. Effects of soy protein and isoflavones on circulating hormone concentrations in pre-and post-menopausal women: a systematic review and meta-analysis Hum Reprod Update200915423440[PubMed][Google Scholar]
- 17. A randomized controlled trial of the effect of dietary soy and flaxseed muffins on quality of life and hot flashes during menopause Menopause20061363142[PubMed][Google Scholar]
- 18. The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women Gynecol Endocrinol2012 282037[PubMed][Google Scholar]
- 19. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial Lancet200035620592063[PubMed][Google Scholar]
- 20. Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk Cancer Causes Control2013248136[PubMed][Google Scholar]
- 21. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flashes Cochrane Database Syst Rev20044[Google Scholar]
- 22. A phase III, randomized, placebo-controlled, double-blind trial of flaxseed for the treatment of hot flashes: North Central Cancer Treatment Group N08C7 Menopause2012194853[PubMed][Google Scholar]
- 23. Consumption of a flaxseed-rich food is not more effective than a placebo in alleviating the climacteric symptoms of postmenopausal women J Nutr20101402937[PubMed][Google Scholar]
- 24. Black cohosh and St John's wort for climacteric complaints: a randomized trial Obstet Gynecol2006107247255[PubMed][Google Scholar]
- 25. Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial Menopause200916156163[PubMed][Google Scholar]