Abstract
Phytoestrogens are present in certain edible plants being most abundant in soy; they are structurally and functionally analogous to the estrogens. Phytoestrogens have been applied for compensation of hormone deficiency in the menopause. At the same time, soy products are used in infant food and other foodstuffs. Furthermore, soy is applied as animal fodder, so that residual phytoestrogens and their active metabolites such as equol can remain in meat and influence the hormonal balance of the consumers. There have been only singular reports on modified gender-related behavior or feminization in humans in consequence of soy consumption. In animals, the intake of phytoestrogens was reported to impact fertility, sexual development and behavior. Feminizing effects in humans can be subtle and identifiable only statistically in large populations.
Keywords: phytoestrogens, soy, menopause, nutrition
Zusammenfassung
Phytoöstrogene sind in einigen essbaren Pflanzen enthalten, am reichlichsten in der Soja; sie sind strukturell und funktionell den natürlichen Östrogenen ähnlich. Die Phytoöstrogene werden für den Ausgleich des Hormondefizits in der Menopause verwendet. Gleichzeitig wird die Soja in der Säuglingsnahrung und anderen Lebensmitteln gebraucht. Außerdem wird die Soja als Viehfutter benutzt, sodass die Phytoöstrogene und deren aktive Metaboliten (Equol) im Fleisch verbleiben und die Homöostase der Geschlechtshormone bei den Verbrauchern beeinflussen können. Es gibt nur einzelne Mitteilungen über eine Änderung des geschlechtsassoziierten Verhaltens oder eine feminisierende Wirkung bei Menschen infolge des Sojakonsums. Eine Störung der geschlechtlichen Entwicklung, des Verhaltens und der Fertilität bei Tieren unter der Einwirkung der Phytoöstrogene ist bekannt. Die Feminisierung bei Menschen kann im Einzelfall geringfügig und nur statistisch in größeren Kontingenten nachweisbar sein.
Soy and phytoestrogens
Phytoestrogens are substances of plant origin that are structurally and functionally similar to the estrogens. Among them, isoflavones and coumestans are the most extensively studied groups. Isoflavones are present in different edible plants being most abundant in soy [1], [2], [3]. Consumption of soy products has been associated with favorable health effects; while potential adverse effects can be undervalued [4]. Phytoestrogens are used as a natural alternative to estrogens for replacement therapy in the menopause [1]. Preclinical trials have demonstrated both genomic and non-genomic action of phytoestrogens including selective but weak binding to the estrogen receptors [5]. Some epidemiological studies suggest that dietary intake of phytoestrogens may contribute to the decreased incidence of postmenopausal cardiovascular disease [6] and that phytoestrogens are significantly more effective than placebo in reducing the frequency of hot flashes [7]. Evidence in support of clinically relevant biological effects has, however, been generally rated as insufficient or absent [5], [8], [9], [10], [11], [12], [13], [14]. Recent reviews concluded that in spite of increasing preclinical and clinical studies in the past decade, ‘appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens’ [15], that most good studies show no clear benefit from phytooestrogens and some potential for harm [16]. Menopausal hormone therapy remains the only treatment that consistently has a greater effect than placebo on alleviation of menopause-related vasomotor symptoms [16].
Doubts concerning phytoestrogens have increased recently, when a critical analysis of earlier findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects. Contrasting data have been reported on the potential of phytoestrogens to prevent hormone-dependent cancers (e.g. breast and prostate) and to successfully treat post-menopausal complaints [17]. There is little evidence in support of the hypothesis that phytoestrogens protect against menopausal osteoporosis; published studies had no controls for confounding factors, the observations being generally of short duration [18], [19]. In regard to osteoporosis, the latest review concluded that ‘evidence points to a lack of a protective role of soy isoflavones in the prevention of postmenopausal bone loss’ [20]; although there is also an opinion that in vitro and animal studies show some benefit from isoflavones, which however has not been clearly confirmed by long-term human trials [21]. There might be genetic differences in this regard, as equol producers seem to present a more positive response to isoflavone intervention [21]. Differences have been reported in the prevalence of the equol-producer phenotype among ethnicities, with a higher prevalence in soy-consuming Asian than in Western populations [22]. It is probably related to eons of adaptation of East Asians to soy. In view of this adaptation, supposed beneficial effects of soy, if even reported in East Asians, should not be automatically extrapolated onto Whites and other peoples, who had historically no contact with soy.
The use of phytoestrogens as an alternative for hormone replacement therapy is not advocated also because of insufficient information on safety [23]. There have been reports on the adverse effects and interactions with drugs [24]. Moreover, soy is known as allergenic food at least for some populations [2], [25]. Finally, it should be mentioned that soybean-based oil emulsions were identified as one of the major causes of cholestasis related to pediatric parenteral nutrition [26].
The biological action of estrogens is mediated by receptors. The question is justified why the incidental plant analogues must be used for replacement therapy instead of right doses of the natural or synthetic hormones that are complimentary to the receptors. If we have keys for the lock, why should we use a screwdriver? The belief that ‘natural’ medicines have no adverse effect is mistaken [16]. Moreover, commercial preparations often contain a mixture of ingredients of unknown concentrations [27]. It should be remarked about the shotgun remedies containing both phytoestrogens and estrogens [28] that, if phytoestrogens indeed bind selectively to the estrogen receptors [5], they might inhibit the action of the estrogens competing with them for binding sites, which would possibly enhance the required dose or at least make the dose effect more difficult to determine.
Phytoestrogens are used to compensate for hormone deficiency in the menopause; at the same time, their hormonal potential does not prevent from the broad use of soy in infant food, other foodstuff and pediatric parenteral nutrition [26], [29]. Note that consumers are sometimes unable to find out whether a product contains soy, while in some countries e.g. Russia products and their labels correlate poorly, a product with the same label can change its quality etc. Considering extensive use of soy for animal fodder, residual phytoestrogens and their active metabolites such as equol, produced by intestinal bacteria in cattle and domestic fowl [30], [31], can remain in meat and influence the hormonal balance of consumers. Apart from singular reports e.g. on changes of the gender-related behavior in girls [32] or gynecomastia in a man [33] after intake of soy products, no data on modification of gender-related characteristics or feminization in humans in consequence of soy consumption have been found. There was a singular report on an inverse association between soy food intake and sperm concentration in men [34]. Phytoestrogens were reported to exert anti-androgenic effects in patients with castration-resistant prostate cancer [35]. Finally, according to some reports mainly from Asia, reviewed in [36], the phytoestrogens protect against both breast and prostate cancer, which is not readily understandable physiologically and appears to be oversimplification at least. Comparisons were often made between ethnic groups or non-vegetarians vs. vegetarians (assuming that the latter consume more soy) [36], where judgment is probably complicated by confounding factors. If high doses of isoflavones are used for long periods of time, they may stimulate the endometrium and breast; women treated for breast cancer were recommended to avoid them [16]. This topic is however outside the scope of the present letter.
In animals, the intake of phytoestrogens was reported to impact fertility and morphogenesis of ovaries, e.g. ‘clover disease’ in sheep [15], [37], to be associated with derangements of sexual development in male rats [38] etc. Feminizing in humans can be subtle and identifiable only statistically in large populations. It was argued that phytoestrogens are selective receptor modulators thus acting differently from the natural estrogens, not necessarily feminizing [36], [39]. If even it is so, the question remains whether such modulations are desirable for the infants receiving soy nutrition, for children and other consumers of soy products. The words ‘modulation’ and ‘regulation’ are sometimes used to make impression that certain botanicals have beneficial effects, which is groundless. ‘Regulation’ for the benefit of the human organism presupposes consciousness and will. When it is stated, for example, that ‘available knowledge suggests that phytoestrogens can affect a number of physiological and pathological processes related to reproduction, bone remodeling, skin, cardiovascular, nervous, immune systems and metabolism’ [40] it is still not a matter-of-course that ‘due to these effects, phytoestrogens and phytoestrogen-containing diet can be useful for the prevention and treatment of menopausal symptoms, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and metabolic diseases’ [40].
Another example of potential misunderstanding: it was stressed that findings from a recent metaanalysis and subsequently published studies show that neither isoflavone supplements nor isoflavone-rich soy products affect serum testosterone or estrogen levels in men, which according to the context was meant as a proof for the absence of feminizing effects [36], [39]. In a case report on gynecomastia associated with soy consumption by a man it was noted that after the patient stopped consuming soy products, ‘his breast tenderness resolved and his estradiol concentration slowly returned to normal’ [33]. It should be commented that, being estrogen analogues, phytoestrogens may exert estrogenic effects on their own independently of the levels of endogenous hormones.
The supposition that botanicals are ‘natural’ for the human organism can be misleading. It is known that many substances of plant origin are toxic. Marketing of botanicals with unproven effects in the guise of evidence-based medications was commented previously [41]. In this connection, it is sometimes difficult to distinguish between reliable and unreliable publications. For example, a supposed anti-atherogenic effect of phytoestrogens and other botanicals was reported on the basis of experiments with cell monocultures, where the ability of serum to induce accumulation of lipids in the cultured cells was interpreted as an indicator of serum atherogenicity [42], [43]. Anti-atherogenic action of different drugs and botanicals was measured in the cell cultures [44], [45], [46], [47]. However, as discussed previously [41], the relationship between the uptake of lipids by cultured cells and atherogenesis in vivo must be inverse rather than direct. For example, in familial hypercholesterolemia, a genetic defect of lipoprotein receptors results in a reduced uptake of cholesterol by cells and accelerated atherosclerosis [48], [49]. The function of LDL receptors largely determines the concentration of cholesterol-carrying lipoproteins in blood. In tissue cultures, most cells rely on LDL receptors as a source of cholesterol [49]. Accordingly, if a pharmacological agent lowers the uptake of lipids by cells in a culture, it should be expected to increase the blood cholesterol in vivo [50]. This example shows how a spurious theory was used for marketing of botanicals. Following their concept, the same scientists started blood apheresis through a column with immobilized LDL to remove ‘non-lipid atherogenicity factors’ twice monthly for the period of 7–9 months (Grant 14-15-00112 of the Russian Scientific Foundation) [51]. The studied patients with angina pectoris had normal blood level of cholesterol. In the course of the study, the patients were reported to feel better and endure higher physical loads [51], which could have been caused by a placebo effect. It is known that invasive procedures can be associated with placebo effects [52], [53]. Apheresis is associated with risks [54], although severe side-effects are very rare [55]. Beneficial effect of the apheresis in [51] cannot be excluded a priori, although this procedure is usually aimed at removal of lipoproteins, for example, in patients with severe drug-resistant LDL-hypercholesterolemia or lipoprotein elevation and premature atherosclerosis [56], [57].
Conclusion
Phytoestrogens are present in different edible plants being most abundant in soy; among others, they are used to compensate for estrogen deficiency in menopause. However, the estrogenic potential of phytoestrogens does not prevent from extensive use of soy in infant food and other foodstuffs as well as pediatric parenteral nutrition. Feminizing effect of phytoestrogens and soy products may be subtle, detectable only statistically in large populations; it can be of particular importance for children and adolescents. This matter should be clarified by independent research, which can have implications for the future of soy in the agriculture.
Notes
Competing interests
The author declares that he has no competing interests.
References
- 1.Patisaul HB, Jefferson W. The pros and cons of phytoestrogens. Front Neuroendocrinol. 2010 Oct;31(4):400–419. doi: 10.1016/j.yfrne.2010.03.003. Available from: http://dx.doi.org/10.1016/j.yfrne.2010.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. Lymphat Res Biol. 2010 Mar;8(1):89–98. doi: 10.1089/lrb.2009.0030. Available from: http://dx.doi.org/10.1089/lrb.2009.0030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Mar;84(3):895–898. doi: 10.1210/jcem.84.3.5561. Available from: http://dx.doi.org/10.1210/jcem.84.3.5561. [DOI] [PubMed] [Google Scholar]
- 4.Cederroth CR, Zimmermann C, Nef S. Soy, phytoestrogens and their impact on reproductive health. Mol Cell Endocrinol. 2012 May;355(2):192–200. doi: 10.1016/j.mce.2011.05.049. Available from: http://dx.doi.org/10.1016/j.mce.2011.05.049. [DOI] [PubMed] [Google Scholar]
- 5.Baber R. Phytoestrogens and post reproductive health. Maturitas. 2010 Aug;66(4):344–349. doi: 10.1016/j.maturitas.2010.03.023. Available from: http://dx.doi.org/10.1016/j.maturitas.2010.03.023. [DOI] [PubMed] [Google Scholar]
- 6.Gencel VB, Benjamin MM, Bahou SN, Khalil RA. Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease. Mini Rev Med Chem. 2012 Feb;12(2):149–174. doi: 10.2174/138955712798995020. Available from: http://dx.doi.org/10.2174/138955712798995020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause. 2012 Jul;19(7):776–790. doi: 10.1097/gme.0b013e3182410159. Available from: http://dx.doi.org/10.1097/gme.0b013e3182410159. [DOI] [PubMed] [Google Scholar]
- 8.Gold EB, Leung K, Crawford SL, Huang MH, Waetjen LE, Greendale GA. Phytoestrogen and fiber intakes in relation to incident vasomotor symptoms: results from the Study of Women's Health Across the Nation. Menopause. 2013 Mar;20(3):305–314. doi: 10.1097/GME.0b013e31826d2f43. Available from: http://dx.doi.org/10.1097/GME.0b013e31826d2f43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev. 2013;12:CD001395. doi: 10.1002/14651858.CD001395.pub4. Available from: http://dx.doi.org/10.1002/14651858.CD001395.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol. 2004 Oct;104(4):824–836. doi: 10.1097/01.AOG.0000140688.71638.d3. Available from: http://dx.doi.org/10.1097/01.AOG.0000140688.71638.d3. [DOI] [PubMed] [Google Scholar]
- 11.Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet. 2007 Nov;276(5):463–469. doi: 10.1007/s00404-007-0390-9. Available from: http://dx.doi.org/10.1007/s00404-007-0390-9. [DOI] [PubMed] [Google Scholar]
- 12.Al-Azzawi F, Wahab M. Effectiveness of phytoestrogens in climacteric medicine. Ann N Y Acad Sci. 2010 Sep;1205:262–267. doi: 10.1111/j.1749-6632.2010.05678.x. Available from: http://dx.doi.org/10.1111/j.1749-6632.2010.05678.x. [DOI] [PubMed] [Google Scholar]
- 13.Villaseca P. Non-estrogen conventional and phytochemical treatments for vasomotor symptoms: what needs to be known for practice. Climacteric. 2012 Apr;15(2):115–124. doi: 10.3109/13697137.2011.624214. Available from: http://dx.doi.org/10.3109/13697137.2011.624214. [DOI] [PubMed] [Google Scholar]
- 14.Speroff L. Alternative therapies for postmenopausal women. Int J Fertil Womens Med. 2005 May-Jun;50(3):101–114. [PubMed] [Google Scholar]
- 15.Poluzzi E, Piccinni C, Raschi E, Rampa A, Recanatini M, De Ponti F. Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective. Curr Med Chem. 2014;21(4):417–436. doi: 10.2174/09298673113206660297. Available from: http://dx.doi.org/10.2174/09298673113206660297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Guidozzi F, Alperstein A, Bagratee JS, Dalmeyer P, Davey M, De Villiers TJ, Hirschowitz S, Kopenhager T, Moodley SP, Roos P, Shaw A, Shimange O, Smith T, Thomas C, Titus J, Van der Spuy Z, Van Waart J. South African Menopause Society revised consensus position statement on menopausal hormone therapy, 2014. S Afr Med J. 2014 Aug;104(8):537–543. doi: 10.7196/samj.8423. Available from: http://dx.doi.org/10.7196/samj.8423. [DOI] [PubMed] [Google Scholar]
- 17.Sirtori CR, Arnoldi A, Johnson SK. Phytoestrogens: end of a tale? Ann Med. 2005;37(6):423–438. doi: 10.1080/07853890510044586. Available from: http://dx.doi.org/10.1080/07853890510044586. [DOI] [PubMed] [Google Scholar]
- 18.Davis SR. Phytoestrogen therapy for menopausal symptoms? BMJ. 2001 Aug;323(7309):354–355. doi: 10.1136/bmj.323.7309.354. Available from: http://dx.doi.org/10.1136/bmj.323.7309.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Coxam V. Phyto-oestrogens and bone health. Proc Nutr Soc. 2008 May;67(2):184–195. doi: 10.1017/S0029665108007027. Available from: http://dx.doi.org/10.1017/S0029665108007027. [DOI] [PubMed] [Google Scholar]
- 20.Lagari VS, Levis S. Phytoestrogens in the prevention of postmenopausal bone loss. J Clin Densitom. 2013 Oct-Dec;16(4):445–449. doi: 10.1016/j.jocd.2013.08.011. Available from: http://dx.doi.org/10.1016/j.jocd.2013.08.011. [DOI] [PubMed] [Google Scholar]
- 21.Castelo-Branco C, Soveral I. Phytoestrogens and bone health at different reproductive stages. Gynecol Endocrinol. 2013 Aug;29(8):735–743. doi: 10.3109/09513590.2013.801441. Available from: http://dx.doi.org/10.3109/09513590.2013.801441. [DOI] [PubMed] [Google Scholar]
- 22.Song KB, Atkinson C, Frankenfeld CL, Jokela T, Wähälä K, Thomas WK, Lampe JW. Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls. J Nutr. 2006 May;136(5):1347–1351. doi: 10.1093/jn/136.5.1347. [DOI] [PubMed] [Google Scholar]
- 23.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 Nov;70(3):222–226. doi: 10.1016/j.maturitas.2011.07.001. Available from: http://dx.doi.org/10.1016/j.maturitas.2011.07.001. [DOI] [PubMed] [Google Scholar]
- 24.Haimov-Kochman R, Brzezinski A, Hochner-Celnikier D. Herbal remedies for menopausal symptoms: are we cautious enough? Eur J Contracept Reprod Health Care. 2008 Jun;13(2):133–137. doi: 10.1080/13625180801920131. Available from: http://dx.doi.org/10.1080/13625180801920131. [DOI] [PubMed] [Google Scholar]
- 25.Wilson S, Blaschek K, de Mejia E. Allergenic proteins in soybean: processing and reduction of P34 allergenicity. Nutr Rev. 2005 Feb;63(2):47–58. doi: 10.1111/j.1753-4887.2005.tb00121.x. Available from: http://dx.doi.org/10.1111/j.1753-4887.2005.tb00121.x. [DOI] [PubMed] [Google Scholar]
- 26.Saayman BD. The use of alternative lipid emulsions in paediatric and neonatal parenteral nutrition. S Afr J Clin Nutr. 2011;24(3):S32–S34. [Google Scholar]
- 27.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 Jan;68(1):56–64. doi: 10.1016/j.maturitas.2010.10.003. Available from: http://dx.doi.org/10.1016/j.maturitas.2010.10.003. [DOI] [PubMed] [Google Scholar]
- 28.Frigo P. News-Screen Menopause. Phytotherapie bei klimakterischen Beschwerden. J Gynakol Endokrinol. 2014;8(3):28–29. [Google Scholar]
- 29.Fusch C, Bauer K, Böhles HJ, Jochum F, Koletzko B, Krawinkel M, Krohn K, Mühlebach S Working group for developing the guidelines for parenteral nutrition of The German Society for Nutritional Medicine. Neonatology/Paediatrics – Guidelines on Parenteral Nutrition, Chapter 13. GMS Ger Med Sci. 2009;7:Doc15. Available from: http://dx.doi.org/10.3205/000074. [Google Scholar]
- 30.Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J. 2006 Feb;53(1):7–20. doi: 10.1507/endocrj.53.7. Available from: http://dx.doi.org/10.1507/endocrj.53.7. [DOI] [PubMed] [Google Scholar]
- 31.Setchell KD, Clerici C. Equol: history, chemistry, and formation. J Nutr. 2010 Jul;140(7):1355S–1362S. doi: 10.3945/jn.109.119776. Available from: http://dx.doi.org/10.3945/jn.109.119776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Adgent MA, Daniels JL, Edwards LJ, Siega-Riz AM, Rogan WJ. Early-life soy exposure and gender-role play behavior in children. Environ Health Perspect. 2011 Dec;119(12):1811–1816. doi: 10.1289/ehp.1103579. Available from: http://dx.doi.org/10.1289/ehp.1103579. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract. 2008 May-Jun;14(4):415–418. doi: 10.4158/EP.14.4.415. Available from: http://dx.doi.org/10.4158/EP.14.4.415. [DOI] [PubMed] [Google Scholar]
- 34.Chavarro JE, Toth TL, Sadio SM, Hauser R. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod. 2008 Nov;23(11):2584–2590. doi: 10.1093/humrep/den243. Available from: http://dx.doi.org/10.1093/humrep/den243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Thelen P, Wuttke W, Seidlová-Wuttke D. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer. J Steroid Biochem Mol Biol. 2014 Jan;139:290–293. doi: 10.1016/j.jsbmb.2013.06.009. Available from: http://dx.doi.org/10.1016/j.jsbmb.2013.06.009. [DOI] [PubMed] [Google Scholar]
- 36.Messina M, Messina V. The role of soy in vegetarian diets. Nutrients. 2010 Aug;2(8):855–888. doi: 10.3390/nu2080855. Available from: http://dx.doi.org/10.3390/nu2080855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Jefferson WN, Williams CJ. Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. Reprod Toxicol. 2011 Apr;31(3):272–279. doi: 10.1016/j.reprotox.2010.10.001. Available from: http://dx.doi.org/10.1016/j.reprotox.2010.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Whitten PL, Lewis C, Russell E, Naftolin F. Potential adverse effects of phytoestrogens. J Nutr. 1995 Mar;125(3 Suppl):771S–776S. doi: 10.1093/jn/125.3_Suppl.771S. [DOI] [PubMed] [Google Scholar]
- 39.Messina M, Melby MK, Kronenberg F, Kurzer MS, Taku K. Letters to the editor. Menopause. 2013 Mar;20(3):359–361. doi: 10.1097/GME.0b013e318284e64a. Available from: http://dx.doi.org/10.1097/GME.0b013e318284e64a. [DOI] [PubMed] [Google Scholar]
- 40.Sirotkin AV, Harrath AH. Phytoestrogens and their effects. Eur J Pharmacol. 2014 Oct 15;741:230–236. doi: 10.1016/j.ejphar.2014.07.057. Available from: http://dx.doi.org/10.1016/j.ejphar.2014.07.057. [DOI] [PubMed] [Google Scholar]
- 41.Jargin SV. Phytoestrogens and other botanicals: on the problems of evidence-based evaluation. Recent Pat Cardiovasc Drug Discov. 2013 Apr;8(1):67–71. doi: 10.2174/18722083113079990009. Available from: http://dx.doi.org/10.2174/18722083113079990009. [DOI] [PubMed] [Google Scholar]
- 42.Nikitina NA, Sobenin IA, Myasoedova VA, Korennaya VV, Mel'nichenko AA, Khalilov EM, Orekhov AN. Antiatherogenic effect of grape flavonoids in an ex vivo model. Bull Exp Biol Med. 2006 Jun;141(6):712–715. doi: 10.1007/s10517-006-0260-7. Available from: http://dx.doi.org/10.1007/s10517-006-0260-7. [DOI] [PubMed] [Google Scholar]
- 43.Orekhov AN, Sobenin IA, Korneev NV, Kirichenko TV, Myasoedova VA, Melnichenko AA, Balcells M, Edelman ER, Bobryshev YV. Anti-atherosclerotic therapy based on botanicals. Recent Pat Cardiovasc Drug Discov. 2013 Apr;8(1):56–66. doi: 10.2174/18722083113079990008. Available from: http://dx.doi.org/10.2174/18722083113079990008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ryong LH, Tertov VV, Vasil’ev AV, Tutel’yan VA, Orekhov AN. Antiatherogenic and antiatherosclerotic effects of mushroom extracts revealed in human aortic intima cell culture. Drug Dev Res. 1989;17:109–117. Available from: http://dx.doi.org/10.1002/ddr.430170203. [Google Scholar]
- 45.Orekhov AN, Baldenkov GN, Tertov VV, Ryong LH, Kozlov SG, Lyakishev AA, Tkachuk VA, Ruda MYa, Smirnov VN. Cardiovascular drugs and atherosclerosis: effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells. J Cardiovasc Pharmacol. 1988;12 Suppl 6:S66–S68. [PubMed] [Google Scholar]
- 46.Orekhov AN. Anti-atherosclerotic Drugs from Natural Products. Nat Prod Chem Res. 2013;1:121. Available from: http://dx.doi.org/10.4172/2329-6836.1000121. [Google Scholar]
- 47.Orekhov AN, Pivovarova EM, Sobenin IA, Yakushkin VV, Tertov VV. Use of cell culture for optimisation of direct antiatherogenic therapy with verapamil. Drugs. 1992;44 Suppl 1:105–110. doi: 10.2165/00003495-199200441-00020. Available from: http://dx.doi.org/10.2165/00003495-199200441-00020. [DOI] [PubMed] [Google Scholar]
- 48.Marais AD. Familial hypercholesterolaemia. Clin Biochem Rev. 2004 Feb;25(1):49–68. [PMC free article] [PubMed] [Google Scholar]
- 49.Goldstein JL, Brown MS. Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol. J Lipid Res. 1984 Dec;25(13):1450–1461. [PubMed] [Google Scholar]
- 50.Jargin SV. Testing of serum atherogenicity in cell cultures: questionable data published. GMS Ger Med Sci. 2012;10:Doc02. doi: 10.3205/000153. Available from: http://dx.doi.org/10.3205/000153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Orekhov AN, Melnichenko AA, Sobenin IA. Approach to reduction of blood atherogenicity. Oxid Med Cell Longev. 2014;2014:738679. doi: 10.1155/2014/738679. Available from: http://dx.doi.org/10.1155/2014/738679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ, Rombach I, Brindley D, Savulescu J, Beard DJ, Carr AJ. Use of placebo controls in the evaluation of surgery: systematic review. BMJ. 2014;348:g3253. doi: 10.1136/bmj.g3253. Available from: http://dx.doi.org/10.1136/bmj.g3253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Jargin SV. Invasive procedures with questionable indications. Ann Med Surg. 2014;3(4):126–129. doi: 10.1016/j.amsu.2014.06.003. Available from: http://dx.doi.org/10.1016/j.amsu.2014.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology. 2011 Sep;115(3):635–649. doi: 10.1097/ALN.0b013e31822a22d9. Available from: http://dx.doi.org/10.1097/ALN.0b013e31822a22d9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Bambauer R, Schiel R, Latza R. Low-density lipoprotein apheresis: an overview. Ther Apher Dial. 2003 Aug;7(4):382–390. doi: 10.1046/j.1526-0968.2003.00070.x. Available from: http://dx.doi.org/10.1046/j.1526-0968.2003.00070.x. [DOI] [PubMed] [Google Scholar]
- 56.Parhofer KG. How will new medications affect the lipoprotein apheresis situation in Germany? Atheroscler Suppl. 2013 Jan;14(1):71–72. doi: 10.1016/j.atherosclerosissup.2012.10.022. Available from: http://dx.doi.org/10.1016/j.atherosclerosissup.2012.10.022. [DOI] [PubMed] [Google Scholar]
- 57.Julius U. Updates in apheresis and atherosclerotic research. Ther Apher Dial. 2013 Apr;17(2):124. doi: 10.1111/1744-9987.12029. Available from: http://dx.doi.org/10.1111/1744-9987.12029. [DOI] [PubMed] [Google Scholar]
- 58.Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):431–438. doi: 10.1161/ATVBAHA.108.179564. Available from: http://dx.doi.org/10.1161/ATVBAHA.108.179564. [DOI] [PMC free article] [PubMed] [Google Scholar]