2012년 7월 17일 화요일

Phytoestrogens for menopausal symptoms: A review


  • John A. Eden

Abstract

Objective

To review the evidence that isoflavones are effective treatments for menopausal symptoms and to present the safety data.

Methods

The databases Scopus, ScienceDirect and Primo Central Index were searched and preference was given to systematic reviews and meta-analyses.

Results

The available evidence suggests that isoflavones do not relieve menopausal vasomotor symptoms any better than placebo. Long-term safety studies suggest that women who consume a diet high in isoflavones may have a lower risk of endometrial and ovarian cancer.

Conclusions

Isoflavones cannot be recommended for the relief of hot flushes.

Keywords

  • Phytoestrogen; 
  • Isoflavone; 
  • Menopause; 
  • Endometrium; 
  • Breast cancer; 
  • Cardiovascular; 
  • Meta-analysis; 
  • Hot flush; 
  • Climacteric; 
  • Vasomotor; 
  • Thrombosis; 
  • Review

1. Introduction

Phytoestrogens are plant-derived chemicals [1] that are structurally or functionally similar to oestradiol (E2). There is a large number of different classes of phytoestrogens, but the main type that have been given therapeutically to menopausal women are isoflavones and so they will be the focus of this review.
Isoflavones are naturally occurring polyphenol flavonoids. In the human diet, they are mostly found in legumes such as soybean, chickpeas, alfalfa and red clover [1] and [2]. The major isoflavones are daidzein and genistein. Daidzein can be formed from formononetin and in the gut is further metabolised to equol and 0-desmethylangolensin (0-DMA). Genistein can be produced from biochanin A. Genistein, daidzein, equol and 0-DMA can all be found in human blood [2].
There have been numerous human clinical trials giving isoflavones as purified extracts and sometimes as food products such as soy-protein. Theoretically, if a phytoestrogen product is given to postmenopausal women, then it might relieve menopausal symptoms such as hot flushes and vaginal dryness. However, they may also be the risk of oestrogenic side effects such as endometrial hyperplasia, breast cancer and thrombosis.

2. Methods

The goal of this review was two-fold. The first aim was to examine the evidence that phytoestrogens are effective treatments for relieving menopausal symptoms (in particular hot flushes). The second goal was to present the available safety data on these compounds. To this end, I used the University of New South Wales Library search engine, Sirius, to seek articles in Scopus, ScienceDirect and Primo Central Index, using the keywords phytoestrogen, isoflavone, menopause, endometrium, breast cancer, cardiovascular,meta-analysis, hot flush, climacteric, vasomotor, thrombosis and review. Preference was given to the most recent meta-analyses and systematic reviews.

3. Results

Five meta-analyses [3], [4], [5], [6], [7] and [8] and one review [9] were found which examined the impact of phytoestrogens on menopausal symptoms. One meta-analysis reviewed side effects of isoflavones [10]; another soy intake and breast cancer risk [11]. The impact of isoflavones on breast density was the subject of a meta-analysis [12] as was one on vascular endothelial function [13].

3.1. Are phytoestrogens efficacious for relieving menopausal symptoms?

Jacobs et al. [3] reviewed 17 soy isoflavone randomised controlled trials (RCTs) of menopausal vasomotor symptoms. The studies were so heterogenous that they did not perform a meta-analysis. They concluded that the RCTs had numerous deficiencies and conflicting results. A systematic review by Howes et al. [4]combined all the available soy and red clover studies. Their meta-analysis favoured isoflavones over placebo but the magnitude of the difference was very small and not likely to be clinically relevant. They did find some evidence that higher doses of isoflavones were more likely to relieve symptoms.
The Nelson systematic review [5] examined a number of non-hormonal therapies including soy isoflavones, red clover extracts, selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs), clonidine and gabapentin. These authors concluded that SSRIs, SNRIs and clonidine did have evidence of efficacy. However, their meta-analysis failed to show efficacy for red clover extracts and even though the statistical analysis did favour soy isoflavones over placebo, the heterogeneity of the studies led them to conclude that the efficacy of soy isoflavones for hot flushes could not be established with certainty. Bolanos et al. [6] and Tempfer et al. [7] came to a similar conclusion.
Williamson-Hughes et al. [8] reviewed soy isoflavone studies and agreed with the previously mentioned studies that the poor standard of the trials and the marked heterogeneity of the RCTs meant that a meaningful meta-analysis could not be performed. They also pointed there was marked variation in the dose and type of isoflavones used.

3.2. Safety profile of phytoestrogens used to treat menopausal women

Tempfer et al. [10] identified 174 RCTs comparing phytoestrogens (n = 5502) with placebo or no treatment (n = 4806). Side effects were reported in 92 studies. In broad terms, the safety studies on isoflavones are reassuring. There appears to be no evidence of increased rates of endometrial or breast cancer but the studies are too small to be definitive.

3.3. Endometrial and breast cancer risk

There is some evidence that life-long exposure to soy might lower breast cancer risk [9]. However, this is a completely different situation to a Western woman taking a soy or red clover supplement for a few months or years after menopause. The review by Cassidy concluded that the studies to date were too small to be convincing [9]. Palacios et al. [12] performed a 3 year RCT of 70 mg soy isoflavone extract versus placebo (n = 395). Endometrial biopsies and mammograms were performed at inclusion, year 1 and year 3. Transvaginal ultrasound measurement of endometrial thickness was performed at inclusion and annually. No endometrial or breast cancers were found. No change in breast density nor endometrial thickness was detected over the 3 years. One case of simple endometrial hyperplasia was found. Similar results were found by Steinberg et al. [13] and Reed et al. [14].
Ollberding et al. [15] performed a prospective cohort study of 46,027 women with an intact uterus who were followed up for an average of 13.6 years. Careful dietary histories were obtained and dietary isoflavone intake calculated. They found evidence of an inverse relationship between dietary isoflavones intake and risk of developing endometrial cancer.
Myung et al. [16] published a meta-analysis of soy intake and risk of gynaecological cancers. Like Ollberding, they found that high soy intake was associated with a lowered risk of endometrial cancer. They also showed decreased risk of ovarian cancer amongst those with the highest soy intake.
In the Tempfer et al. review [10], there were 153 (7.8%) gynaecological or urological adverse events (AEs) in the phytoestrogen group compared with 117 (6.6%, p = 0.61). Rates of vaginal bleeding or spotting were similar as was the incidence of endometrial hyperplasia.

3.4. Cardiovascular system

Soy protein, but not purified isoflavones lower cholesterol [17]. Isoflavones given to postmenopausal women improve flow-mediated dilatation but not endothelial function [18]. One RCT of postmenopausal women (n = 350) given 91 mg isoflavone (as soy protein) or placebo were followed for 2.7 years. The main end-point was carotid intimal thickness measured with ultrasound. No differences were found. No human RCTs examining risk of thrombosis could be found.

3.5. Thyroid

Theoretically, isoflavones may interfere with thyroid function. Several studies measured thyroid function as a parameter [12] and [13] and no impact of isoflavones was found.

4. Discussion

After 2 decades of research into isoflavones it is disappointing that their therapeutic effects are still not clear. If there is an impact of isoflavones on menopausal flushing then it is small and not much more than placebo. On the positive side, there are several large RCTs and a couple of very large cohort studies demonstrating that dietary soy and/or purified isoflavones do not increase the risk of uterine nor breast cancer. There is evidence supporting the concept that soy might lower the risk of endometrial and ovarian cancer. Isoflavones appear to have minor positive effects on blood vessels and soy protein (and not purified isoflavones) has been shown to have a cholesterol lowering effect. More studies are needed into the impact of soy and purified isoflavones on thrombosis.
All the authors who performed meta-analyses commented on the heterogeneity of the studies. Another issue was the great variety of products with differing composition of isoflavones. The lack of studies on thrombosis was surprising considering the well-known effects of oral oestrogen on the clotting system.
In conclusion, it is difficult to recommend isoflavones as a treatment for menopausal flushing. Studies to date suggest that they are safe to the endometrium and breast. Further studies into the clotting system are recommended.

Practice points

•
Meta-analyses of RCTs of isoflavones given to relieve menopausal flushing have consistently failed to show a therapeutic effect.
•
Isoflavones may lower the risk of endometrial and ovarian cancer.
•
Soy protein (and not purified isoflavones) lower cholesterol.

Research agenda

•
New phytoestrogenic substances need to be identified and tested.
•
The safety of isoflavones on the clotting system needs to be established.

Contributors

There were no contributors.

Competing interest

None.

Provenance and peer review

Commissioned and externally peer reviewed.

References

    • [2]
    • J. Vacek, B. Klejdus, L. Lojkova, V. Kuban
    • Current trends in isolation, separation, determination and identification of isoflavones: a review
    • J Sep Sci, 31 (2008), pp. 2054–2067
    • Full Text via CrossRef
    • [5]
    • H.D. Nelson, K.K. Vesco, E. Haney et al.
    • Non hormonal therapies for menopausal hot flashes systematic review and meta-analysis
    • JAMA, 295 (2006), pp. 2057–2207
    • [6]
    • R. Bolanos, A. Del Castillo, J. Francia
    • Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms: systematic review and meta-analysis
    • Menopause: J North Am Menopause Soc, 17 (3) (2010), pp. 660–666
    • View Record in Scopus
       | Cited By in Scopus (19)
    • [10]
    • C.B. Tempfer, G. Froese, G. Heinze, E.K. Bentz, L.A. Hefler, J.C. Huber
    • Side effects of phytoestrogens: a meta-analysis of randomized trials
    • Am J Med, 122 (2009), pp. 939–946
    • [14]
    • S.D. Reed, K.M. Newton, A.Z. LaCroix, L.C. Grothaus, V.S. Grieco, K. Ehrlich
    • Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal alternatives for menopause (HALT) study
    • Menopause: J North Am Menopause Soc, 15 (1) (2008), pp. 51–58
    • View Record in Scopus
       | 
      Full Text via CrossRef
       | Cited By in Scopus (35)
    • [17]
    • A. Dewell, P.L.W. Hollenbeck, C.B. Hollenbeck
    • Clinical review: a critical evaluation of the Role of soy protein and Isoflavone supplementation in the control of plasma cholesterol concentrations
    • J Clin Endocrinol Metab, 91 (2006), pp. 772–780
    • View Record in Scopus
       | Cited By in Scopus (33)


갱년기 증상(특히 안면홍조)에 대해서 PE는 명확한 효과를 보이지 않음. 
자궁내막암, 난소암, 유방암 발생위험도를 낮춰주는 효과는 보임.
자궁내막증식증이나 유방암 발생을 높이는 부작용은 없는 것으로 보임.
내피기능과는 관련없이 혈관이완을 돕고, 콜레스테롤을 낮추는 효과는 인정됨.
혈전형성과 관련된 보고는 없음.
-> 안면홍조를 치료하는데 이소플라본을 권장하기는 어렵다.
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