Menopause Live (11 February, 2013) From IMS

In 1999 the US Food and Drug Administration approved the health claim that daily consumption of soy is effective in reducing the risk of coronary artery disease, with a subsequent rapid and profound impact on the prevalence of soy products. Concerns related to the risk of hormone therapy (HT) have prompted even more of an increase in the use of natural alternatives to estrogens. About 84% of US consumers perceive soy as healthy and 32% consume soy products at least once a month [1]. Within ten major European countries, the mean total phytoestrogen intake in women was reported to be highest in a UK health-conscious group (21.1 mg/day) and lowest with 1.06 mg in Greece and 1.0 mg in Spain [2].

Phytoestrogens are naturally occurring plant compounds that are structurally and/or functionally similar to mammalian estrogens and their metabolites. Most phytoestrogens are phenolic compounds, of which isoflavones and the coumestans are the most widely investigated. Isoflavones are present in berries, wine, grains and nuts, but are most abundant in soybeans and other legumes. Coumestans are enriched in alfalfa and clover sprouts. The lignans are another major class, constituting components of plant cell walls and found in many fiber-rich foods such as berries, seeds (particularly flaxseeds), grains, nuts and fruits. 

Enzymatic metabolic conversion of these compounds in the gut results in the formation of heterocyclic phenols. Isoflavones generate aglycones, genistein and daidzein, lignans the secoisolariciresinol, and coumestans convert to coumestrol. All of these compounds structurally resemble estrogen and have weak estrogenic activity. Hence the term phytoestrogens, all of which are selective estrogen receptor modulators and have tissue-specific estradiol-agonistic or -antagonistic effects.

In a recent review in the Journal of Steroid Biochemistry and Molecular Biology, Bedell, Nachtigall and Naftolin [3] have extensively elaborated the most current research on the efficacy of phytoestrogens and their specific effects on climacteric symptoms – the vasomotor ones, vaginal atrophy, insomnia and osteoporosis in particular.

After detailed listing of clinical outcomes, the authors arrived at the following conclusions:
1. Regarding hot flushes, more recent publications demonstrate an improvement in symptoms, especially in intensity, with isoflavone use. Most promising are the results of combinations of isoflavones and lignans (Femarelle®), which apparently act synergistically, as isoflavones are absorbed early while the action of lignans is delayed.
2. Femarelle® is similarly promising in terms of vulvovaginal atrophy; isoflavones also have a positive effect on vaginal epithelium after prolonged therapy.
3. Regarding benefits for sleep and cognition, studies are limited but isoflavones appear to have demonstrated moderate benefit.
4. As to bone health, positive effects are seen, although preferentially on lumbar spine.
5. Prolonged use of isoflavones, especially during adolescence, apparently correlates with a decreased risk of breast cancer. Increased risks been not been demonstrated in current breast cancer patients or survivors.
6. Endometrial cancer risk has not been noted to increase during the use of any phytoestrogen. 
7. Recent trials of Femarelle®, unlike HT, demonstrated a lack of hypercoagulability, making phytoestrogens a more appealing option for thrombophilic and older patients.

Comment

All of the authors who performed meta-analyses commented on the heterogeneity of the studies. By focusing on studies that only include women who have entered menopause within 1 year, significant benefit for hot flushes is apparent with a combined isoflavone and lignan combination [4]. While soy-based isoflavones are modestly effective in relieving menopausal symptoms, supplements providing higher proportions of genistein or equol may provide more benefits [5]. More clinical studies are needed to compare the outcomes of women whose intestinal bacteria have the ability to convert daidzein to equol (equol producers) with those of women that lack this ability (equol non-producers) in order to determine whether equol producers have greater benefits from soy supplementation [5]. 

There is evidence in support of the concept that soy might indeed lower the risk of endometrial and ovarian cancer [6] – and perhaps breast cancer? A recent Canadian phytoestrogen database did not reveal any significant association of breast cancer with isoflavones or lignans [7]. A population-based, case–control study in German postmenopausal women evaluated dietary data from about 3000 cases and more than 5000 controls and provided evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans [8].

In conclusion, recent data are in support of the statements in the above review. Its authors point to the way in which future studies may be guided. Hot flushes generally diminish over time in frequency and severity without the aid of therapy. This requires studies that only include women who have entered menopause within a short period of time and, consequently, may clarify on some of the published diversity.

In broad terms, the safety studies on isoflavones are reassuring [6]. In all of the literature reviewed, only a few minor side-effects were reported. A particular point relates to the association of combined isoflavones and lignans with their lack of a hypercoagulability risk [9]. This would indeed make phytoestrogen combinations appealing for certain patients and appear to serve as an alternative to hormone therapy. In order to develop some specific indications for plant estrogens, however, more focused research on the topic is warranted.

Hermann P. G. Schneider
University of Muenster, Germany

References

1. Piotrowska E, Jakobkiewicz-Banecka J, Wegrzyn G. Different amounts of isoflavones in various commercially available soy extracts in the light of gene expression-targeted isoflavone therapy. Phytother Res 2010;24(Suppl 1):S109-13.
http://www.ncbi.nlm.nih.gov/pubmed/19610046
2. Zamora-Ros R, Knaze V, Luján-Barroso L, et al. Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort. Eur J Clin Nutr 2012;66:932-41.
http://www.ncbi.nlm.nih.gov/pubmed/22510793
3. Bedell S, Nachtigall M, Naftolin F. The pros and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol 2012 Dec 25. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/23270754
4. Sammartino A, Tommaselli GA, Gargano V, di Carlo C, Attianese W, Nappi C. Short-term effects of a combination of isoflavones, lignans and Cimicifuga racemosa on climacteric-related symptoms in postmenopausal women: a double-blind, randomized, placebo-controlled trial. Gynecol Endocrinol 2006;22:646-50.
http://www.ncbi.nlm.nih.gov/pubmed/17145651
5. North American Menopause Society. The role of isoflavones in menopausal health: report of the North American Menopause Society. Menopause 2011;18:732-53.
http://www.ncbi.nlm.nih.gov/pubmed/21685820
6. Eden JA. Phytoestrogens for menopausal symptoms: a review. Maturitas 2012;72:157-9.
http://www.ncbi.nlm.nih.gov/pubmed/22516278
7. Cotterchio M, Boucher BA, Kreiger N, Mills CA, Thompson LU. Dietary phytoestrogen intake – lignans and isoflavones – and breast cancer risk (Canada). Cancer Causes Control 2008;19:259-72.
http://www.ncbi.nlm.nih.gov/pubmed/17992574
8. Zaineddin AK, Buck K, Vrieling A, et al. The association between dietary lignans, phytoestrogen-rich foods, and fiber intake and postmenopausal breast cancer risk: a German case-control study. Nutr Cancer 2012;64:652-65.
http://www.ncbi.nlm.nih.gov/pubmed/22591208
9. Nachtigall MJ, Jessel R, Flaumenhaft R, et al. The selective estrogen receptor modulator DT56a (Femarelle) does not affect platelet reactivity in normal or thrombophilic postmenopausal women. Menopause 2011;18:285-8.
http://www.ncbi.nlm.nih.gov/pubmed/21037489