Isoflavones and their metabolites are often termed phytoestrogens because they bind to oestrogen receptors, although weakly compared to physiologic oestrogens. Phytoestrogens are present in dietary supplements and marketed as a natural alternative to oestrogen replacement therapy [1]. Soy is the principal plant that produces isoflavones (1-2mg/g); generally, only small amounts are found in other edible plants [2]. Some other plants contain isoflavones: e.g. red clover, in addition to genistein and diadzein present in soybean, contains the methylated forms biochanin and formononetin [3]. Preclinical trials have demonstrated both non-genomic and genomic actions of phytoestrogen including selective, but weak, binding to the oestrogen receptors [4]. Evidence of clinically relevant biological effects from observational studies and randomized trials has, in general, been lacking [4]. Recent systematic and other reviews concluded that there is no evidence of effectiveness in the alleviation of menopausal symptoms by phytoestrogens [5,6], that current evidence does not support their use [7], picture produced by conscientious review being overall bleak [8].
Scepticism has developed recently concerning the true potential of phytoestrogens; in particular, a critical analysis of the early findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects, be it by way of lipid reduction, vasodilation or lipoprotein oxidation [9]. There is little data to support the claim that phytoestrogens protect against bone loss, while published studies have no controls for confounding factors such as exercise, the observations being relatively short term [10,11]. Phytoestrogen use as an alternative for replacement therapy is not advocated also because of insufficient and conflicting data on safety [12]. Even carefully designed studies on herbal treatments for vasomotor menopausal symptoms have not addressed the safety issues specifically. Sporadic reports show adverse effects and interactions between herbal and conventional medications [13], which is not surprising considering that phytoestrogens are in fact xenobiotics. Moreover, soy beans rank among the most allergenic foods; so that for some people avoiding soy is essential [2,14]. With increasing consumption of soy products, the incidence of soy-caused allergies is expected to escalate [14]. It was concluded that physicians should warn their patients about the lack of evidence regarding safety and possible interactions of herbal remedies with concurrent medications [13].
It has been argued that East Asians have lower rates of cardiovascular diseases and postmenopausal symptoms compared to Western populations, which can be explained by traditionally high consumption of soy [15]. This cause-effect relationship is however unproven, the difference being possibly caused by averagely better diagnostics in the West or underreporting of symptoms in the East, rather than by a genuinely lower prevalence [10]. It would be also reasonable to suppose that East Asians have genetically been better adapted to soy, in a similar way as they are less adapted to cows' milk (lactose) than North Europeans [16,17].
Prof. Alan J. Husband stated that “good published evidence shows that phytoestrogens are effective not only for managing acute symptoms of the menopause but also for improving cardiovascular and bone health” [18], however, without mentioning limitations of the referenced studies, e.g. absence of a simultaneously studied control group in [19]. A study [20], which concluded that its “data do not indicate a therapeutic benefit from dietary supplementation with isoflavones in women experiencing menopausal symptoms” [20], was cited in the first place after the phrase “good published evidence shows that phytoestrogens are effective” [18]. Moreover, the first author of [20], Prof. J. Rodney Baber, pointed out in his later review: “Despite many trials there remains little evidence that phytoestrogens, whether dietary or supplemented, significantly relieve menopausal vasomotor symptoms or cognition. Several potential mechanisms for a positive effect on bone and cardiovascular health have been demonstrated however no fracture prevention data or cardiovascular end point benefit has yet been demonstrated. In vitro effects of phytoestrogens on breast cells have been both stimulatory and inhibitory however net effects appear neutral with observational studies finding no change in breast cancer risk. No effect has been seen on endometrial or other cancers” [4].
Theoretically, the use of phytoestrogens for menopausal hormone replacement therapy appears irrational. The biological action of oestrogens is receptor-mediated. The question is therefore, why an incidental vegetable analogue should be used instead of physiological hormones optimally complementary to the receptors. Would we use a picklock having an original key? This question should be added to that already posed in [21]: "Why should soy or red clover products containing isoflavone be recommended, if the positive effects are only negligible but the adverse effects serious?" [21] Moreover, commercial phytoestrogen preparations usually contain a mixture of components of unspecified nature and concentrations. Such mixtures can exert undesirable effects, depending on their qualitative and quantitative composition as well as the physiopathological status of the patient [22]. Accordingly, the concept of phytoestrogens as a "natural and safe" alternative to oestrogens [23] is unfounded: in fact, these substances are less natural for the human body than the endogenous hormones. Obviously, apart from the interests of vendors, there are currently no reasons to use phytoestrogens in lieu of the physiological oestrogens. This issue should be seen within the broader perspective: marketing of placebos under the guise of evidence-based medications. Considering the above discussion, it cannot be completely excluded that isoflavones or isoflavone-containing plants have useful properties for some patients [8]; this matter might be more promising than the cases of placebo promotion described e.g. in [24-27]. It should be clarified by further research, primarily by experiments on large populations of animals, the single most important requirement being freedom of scientists from commercial interests.
References
1. Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol. 2010;31(4):400-19.
2. Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat Res Biol. 2010;8(1):89-98.
3. Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J, Cameron JD, West L. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab. 1999;84(3):895-8.
4. Baber R. Phytoestrogens and post reproductive health. Maturitas. 2010;66(4):344-9.
5. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;(4):CD001395.
6. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104(4):824-36.
7. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet. 2007;276(5):463-9.
8. Speroff L. Alternative therapies for postmenopausal women. Int J Fertil Womens Med. 2005;50(3):101-14.
9. Sirtori CR, Arnoldi A, Johnson SK. Phytoestrogens: end of a tale? Ann Med. 2005;37(6):423-38.
10. Davis SR. Phytoestrogen therapy for menopausal symptoms? BMJ. 2001;323(7309):354-5.
11. Coxam V. Phyto-oestrogens and bone health. Proc Nutr Soc. 2008;67(2):184-95.
12. This P, de Cremoux P, Leclercq G, Jacquot Y. A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk. Maturitas. 2011;70(3):222-6.
13. Haimov-Kochman R, Brzezinski A, Hochner-Celnikier D. Herbal remedies for menopausal symptoms: are we cautious enough? Eur J Contracept Reprod Health Care. 2008;13(2):133-7.
14. Wilson S, Blaschek K, de Mejia E. Allergenic proteins in soybean: processing and reduction of P34 allergenicity. Nutr Rev. 2005;63(2):47-58.
15. Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J. 2006;53(1):7-20.
17. Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol Suppl. 1994;202:7-20.
18. Husband AJ. Phytoestrogens and menopause. Published evidence supports a role for phytoestrogens in menopause. BMJ. 2002;324(7328):52.
19. Clifton-Bligh PB, Baber RJ, Fulcher GR, Nery ML, Moreton T. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause. 2001;8(4):259-65.
20. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomised placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85–92.
21. Wuttke W, Jarry H, Seidlová-Wuttke D. Isoflavones - safe food additives or dangerous drugs? Ageing Res Rev. 2007;6(2):150-88.
22. Leclercq G, de Cremoux P, This P, Jacquot Y. Lack of sufficient information on the specificity and selectivity of commercial phytoestrogens preparations for therapeutic purposes. Maturitas. 2011;68(1):56-64.
23. Al-Azzawi F, Wahab M. Effectiveness of phytoestrogens in climacteric medicine. Ann N Y Acad Sci. 2010;1205:262-7.
24. Jargin SV. Surfactant preparations for tuberculosis and other diseases beyond infancy: a letter from Russia. Tuberculosis (Edinb). 2012;92(3):280-2.
26. Jargin SV. Discussion of Evaluation of cholesterol-lowering and antioxidant properties of sugar cane policosanols in hamsters and humans. Appl Physiol Nutr Metab. 2009;34(1):75; discussion 76-7.
27. Jargin SV. Testing of drugs and dietary supplements in cell cultures or how to make the elderly pay for placebos. Healthy Ageing Meeting sponsored by the Dubbo Study of Australian Elderly on March 30 in Sydney, Australia (Chairman, Prof. Leon Simons).
Rapid Response:
Re: Phytoestrogens and menopause
Isoflavones and their metabolites are often termed phytoestrogens because they bind to oestrogen receptors, although weakly compared to physiologic oestrogens. Phytoestrogens are present in dietary supplements and marketed as a natural alternative to oestrogen replacement therapy [1]. Soy is the principal plant that produces isoflavones (1-2mg/g); generally, only small amounts are found in other edible plants [2]. Some other plants contain isoflavones: e.g. red clover, in addition to genistein and diadzein present in soybean, contains the methylated forms biochanin and formononetin [3]. Preclinical trials have demonstrated both non-genomic and genomic actions of phytoestrogen including selective, but weak, binding to the oestrogen receptors [4]. Evidence of clinically relevant biological effects from observational studies and randomized trials has, in general, been lacking [4]. Recent systematic and other reviews concluded that there is no evidence of effectiveness in the alleviation of menopausal symptoms by phytoestrogens [5,6], that current evidence does not support their use [7], picture produced by conscientious review being overall bleak [8].
Scepticism has developed recently concerning the true potential of phytoestrogens; in particular, a critical analysis of the early findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects, be it by way of lipid reduction, vasodilation or lipoprotein oxidation [9]. There is little data to support the claim that phytoestrogens protect against bone loss, while published studies have no controls for confounding factors such as exercise, the observations being relatively short term [10,11]. Phytoestrogen use as an alternative for replacement therapy is not advocated also because of insufficient and conflicting data on safety [12]. Even carefully designed studies on herbal treatments for vasomotor menopausal symptoms have not addressed the safety issues specifically. Sporadic reports show adverse effects and interactions between herbal and conventional medications [13], which is not surprising considering that phytoestrogens are in fact xenobiotics. Moreover, soy beans rank among the most allergenic foods; so that for some people avoiding soy is essential [2,14]. With increasing consumption of soy products, the incidence of soy-caused allergies is expected to escalate [14]. It was concluded that physicians should warn their patients about the lack of evidence regarding safety and possible interactions of herbal remedies with concurrent medications [13].
It has been argued that East Asians have lower rates of cardiovascular diseases and postmenopausal symptoms compared to Western populations, which can be explained by traditionally high consumption of soy [15]. This cause-effect relationship is however unproven, the difference being possibly caused by averagely better diagnostics in the West or underreporting of symptoms in the East, rather than by a genuinely lower prevalence [10]. It would be also reasonable to suppose that East Asians have genetically been better adapted to soy, in a similar way as they are less adapted to cows' milk (lactose) than North Europeans [16,17].
Prof. Alan J. Husband stated that “good published evidence shows that phytoestrogens are effective not only for managing acute symptoms of the menopause but also for improving cardiovascular and bone health” [18], however, without mentioning limitations of the referenced studies, e.g. absence of a simultaneously studied control group in [19]. A study [20], which concluded that its “data do not indicate a therapeutic benefit from dietary supplementation with isoflavones in women experiencing menopausal symptoms” [20], was cited in the first place after the phrase “good published evidence shows that phytoestrogens are effective” [18]. Moreover, the first author of [20], Prof. J. Rodney Baber, pointed out in his later review: “Despite many trials there remains little evidence that phytoestrogens, whether dietary or supplemented, significantly relieve menopausal vasomotor symptoms or cognition. Several potential mechanisms for a positive effect on bone and cardiovascular health have been demonstrated however no fracture prevention data or cardiovascular end point benefit has yet been demonstrated. In vitro effects of phytoestrogens on breast cells have been both stimulatory and inhibitory however net effects appear neutral with observational studies finding no change in breast cancer risk. No effect has been seen on endometrial or other cancers” [4].
Theoretically, the use of phytoestrogens for menopausal hormone replacement therapy appears irrational. The biological action of oestrogens is receptor-mediated. The question is therefore, why an incidental vegetable analogue should be used instead of physiological hormones optimally complementary to the receptors. Would we use a picklock having an original key? This question should be added to that already posed in [21]: "Why should soy or red clover products containing isoflavone be recommended, if the positive effects are only negligible but the adverse effects serious?" [21] Moreover, commercial phytoestrogen preparations usually contain a mixture of components of unspecified nature and concentrations. Such mixtures can exert undesirable effects, depending on their qualitative and quantitative composition as well as the physiopathological status of the patient [22]. Accordingly, the concept of phytoestrogens as a "natural and safe" alternative to oestrogens [23] is unfounded: in fact, these substances are less natural for the human body than the endogenous hormones. Obviously, apart from the interests of vendors, there are currently no reasons to use phytoestrogens in lieu of the physiological oestrogens. This issue should be seen within the broader perspective: marketing of placebos under the guise of evidence-based medications. Considering the above discussion, it cannot be completely excluded that isoflavones or isoflavone-containing plants have useful properties for some patients [8]; this matter might be more promising than the cases of placebo promotion described e.g. in [24-27]. It should be clarified by further research, primarily by experiments on large populations of animals, the single most important requirement being freedom of scientists from commercial interests.
References
1. Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol. 2010;31(4):400-19.
2. Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat Res Biol. 2010;8(1):89-98.
3. Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J, Cameron JD, West L. Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. J Clin Endocrinol Metab. 1999;84(3):895-8.
4. Baber R. Phytoestrogens and post reproductive health. Maturitas. 2010;66(4):344-9.
5. Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;(4):CD001395.
6. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004;104(4):824-36.
7. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet. 2007;276(5):463-9.
8. Speroff L. Alternative therapies for postmenopausal women. Int J Fertil Womens Med. 2005;50(3):101-14.
9. Sirtori CR, Arnoldi A, Johnson SK. Phytoestrogens: end of a tale? Ann Med. 2005;37(6):423-38.
10. Davis SR. Phytoestrogen therapy for menopausal symptoms? BMJ. 2001;323(7309):354-5.
11. Coxam V. Phyto-oestrogens and bone health. Proc Nutr Soc. 2008;67(2):184-95.
12. This P, de Cremoux P, Leclercq G, Jacquot Y. A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk. Maturitas. 2011;70(3):222-6.
13. Haimov-Kochman R, Brzezinski A, Hochner-Celnikier D. Herbal remedies for menopausal symptoms: are we cautious enough? Eur J Contracept Reprod Health Care. 2008;13(2):133-7.
14. Wilson S, Blaschek K, de Mejia E. Allergenic proteins in soybean: processing and reduction of P34 allergenicity. Nutr Rev. 2005;63(2):47-58.
15. Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J. 2006;53(1):7-20.
16. Solomons NW. Fermentation, fermented foods and lactose intolerance. Eur J Clin Nutr. 2002;56 Suppl 4:S50-5.
17. Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol Suppl. 1994;202:7-20.
18. Husband AJ. Phytoestrogens and menopause. Published evidence supports a role for phytoestrogens in menopause. BMJ. 2002;324(7328):52.
19. Clifton-Bligh PB, Baber RJ, Fulcher GR, Nery ML, Moreton T. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause. 2001;8(4):259-65.
20. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomised placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85–92.
21. Wuttke W, Jarry H, Seidlová-Wuttke D. Isoflavones - safe food additives or dangerous drugs? Ageing Res Rev. 2007;6(2):150-88.
22. Leclercq G, de Cremoux P, This P, Jacquot Y. Lack of sufficient information on the specificity and selectivity of commercial phytoestrogens preparations for therapeutic purposes. Maturitas. 2011;68(1):56-64.
23. Al-Azzawi F, Wahab M. Effectiveness of phytoestrogens in climacteric medicine. Ann N Y Acad Sci. 2010;1205:262-7.
24. Jargin SV. Surfactant preparations for tuberculosis and other diseases beyond infancy: a letter from Russia. Tuberculosis (Edinb). 2012;92(3):280-2.
25. Jargin SV. Radioprotective properties of water with low content of stable isotopes: critical evaluation. Fiziologia-Physiology 2010;20.4(68):30-40. http://revista_fiziologia.umft.ro/archives/fiziologia2010_4.pdf
26. Jargin SV. Discussion of Evaluation of cholesterol-lowering and antioxidant properties of sugar cane policosanols in hamsters and humans. Appl Physiol Nutr Metab. 2009;34(1):75; discussion 76-7.
27. Jargin SV. Testing of drugs and dietary supplements in cell cultures or how to make the elderly pay for placebos. Healthy Ageing Meeting sponsored by the Dubbo Study of Australian Elderly on March 30 in Sydney, Australia (Chairman, Prof. Leon Simons).
Competing interests: No competing interests