The Role of Soy Isoflavones in Menopausal Health
The Role of Soy Isoflavones in Menopausal Health
The most studied of the botanicals for menopause-related conditions are isoflavones, sometimes called "phytoestrogens." They are plant-derived compounds with estrogen-like biologic activity and a chemical structure similar to that of estradiol. See Table 1 for definitions of terminology used in this paper.
Isoflavones are a class of phytochemicals, a broad group of nonsteroidal compounds of diverse structures derived from plants that bind to estrogen receptors (ERs) in animals and human beings. Isoflavones have greater affinity for ER-β than for ER-α and possess both estrogen-agonist and estrogen-antagonist properties. The isoflavones include the biochemicals genistein, daidzein, glycitein, biochanin A, and formononetin. Genistein and daidzein are found in high amounts in soybeans and soy products as well as in red clover, kudzu, and the American groundnut.
Soy is the most widely used isoflavone-containing food. The term soy usually refers to a product derived from the whole soybean (or soya bean). Soy protein refers to a product derived by extracting the protein out of the whole bean. Soy protein is usually a rich source of isoflavones. The primary isoflavones of soybeans are genistein, daidzein, and glycitein. The relative amounts of these isoflavones vary depending on the portion of the soybean from which the material is obtained. The whole soybean contains about equal amounts of genistein and daidzein, with smaller amounts of glycitein. The germ of the soybean, however, is quite different; it has a high concentration of isoflavones, with daidzein being about four times greater than that of genistein and with relatively high concentrations of glycitein. Some soy supplements are made from soy germ. The relative amounts of genistein and daidzein are now thought to be determinants of the therapeutic efficacy of soy supplementation, as will be discussed later in this paper. Also to be discussed later is the possibility that individual isoflavones, such as genistein, have different therapeutic outcomes when administered alone compared with the same amounts administered with all three isoflavones (genistein, daidzein, and glycetin) in the supplement.
About 30% of North American women have the ability to metabolize daidzein to equol. Equol is a nonsteroidal estrogen-like compound that binds to both ERs but with a high affinity for ER-β; thus, it is often designated as an ER-β agonist. Equol is produced from daidzen by intestinal bacteria and is thought to be a stable characteristic that is best revealed by a soy challenge of just a few days. Equol has two isomers, S(-)-equol and R(+)-equol. Only S(-)-equol is detected in the plasma of equol-producing women and thought to have any biological activity. By far the most exciting research opportunities in the area of soy isoflavone menopausal health concern the potential benefits of equol and the unanswered issue of whether equol is merely a marker for some beneficial effect of gut bacteria on steroid metabolism. More research is needed that compares equol producers with equol nonproducers.
Isoflavones are frequently referred to as having pleiotropic properties (ie, many modes of action). It is therefore no surprise that they have been proposed to have important benefits in regard to vasomotor symptoms, the breast and uterus, cardiovascular system, bone, and cognition-all of which have relevance to women approaching and experiencing menopause. Detailed discussions of these effects can be found later in this paper.
Isoflavones were first considered to be phytoestrogens or "plant estrogens" because of early work noting their infertility effects in certain but not all species and because they bind to both of the ERs and because of their infertility effects in certain, but not all, species. However, during the 1980s, they were also demonstrated to be inhibitors of critical protein tyrosine kinases such as the epidermal growth factor receptor-a risk factor for recurrence of breast cancer-and the platelet-derived growth factor receptor. Subsequently, other mechanisms of action were proposed, including as antioxidants, inhibitors of DNA topoisomerases, and many enzyme systems in steroid synthesis and metabolism.
Today, the question of which mechanisms of action of isoflavones and their metabolites are relevant to women's health remains controversial. The dose used in cell culture assays to investigate mechanisms is crucial. It has been proposed that concentrations in excess of 5 μM are unphysiologic, even in situations in which therapeutic doses are administered. Many investigators have reported data from studies that used 25 to 100 μM isoflavones. These studies had to use the solvent dimethylsulfoxide to keep the isoflavones in solution, which may have introduced nonbiological variables into the results.
Another rapidly emerging area for the study of all plant-based and synthetic therapeutics is their impact on microRNA expression. MicroRNAs are targeted inhibitors of the translation of specific proteins. An important aspect of microRNA action is that they inhibit translation of multiple proteins. This may account for their pleiotropic properties. The application of microRNA concepts to the actions of isoflavones is in its infancy.
Although most of the work on the mechanisms of action of isoflavones has been carried out on genistein and daidzein, recent studies on S(-)- and R(+)-equol have challenged earlier concepts about how this metabolite might alter biological systems. S(-)-equol is a better agonist for the ER-β, with agonist properties comparable to genistein.
Overall, evidence suggests that the biological effects of isoflavones and their metabolites are mediated by many pathways, not just estrogen-dependent events. Future studies may exploit data that have been obtained in DNA microarray experiments. In addition, studies have suggested that some of the benefits of dietary isoflavones observed in other populations may depend on early life exposure, which may involve their impact on gene expression at an epigenetic level.
Puerarin (daidzein 8-C-glucoside) is rapidly absorbed and eliminated with a terminal elimination half-life (t1/2) of approximately 4.3 hours in adult men. It is likely that similar pharmacokinetics occur in women.
An extensive literature exists on the pharmacokinetics of soy isoflavones administered as natural components of soy foods, as isolated isoflavone extracts or supplements, as pure compounds, and also as stable-isotope labeled analogs. Overall, apparent bioavailability of these isoflavones are similar. Nonetheless, the rates of absorption of the isoflavones daidzein and genistein as glycosides are distinctly different from those of daidzein and genistein in their aglycone form and this has recently been suggested to be an important difference that could influence the ultimate efficacy of isoflavones. Aglycones demonstrate rapid absorption and peak plasma concentrations are attained within 1 to 3 hours, depending on whether the isoflavones are taken with a meal or without a meal. The effect of a meal is to delay absorption and shift the Tmax value. In contrast, for the β-glycoside conjugates, peak plasma concentrations of isoflavones typically occur 4 to 10 hours later due to a requirement for prior hydrolysis by intestinal brush border β-glycosidases, which is a rate-limiting and time-dependent process.
The t1/2 of all isoflavones is similar and typically 6 to 12 hours although it is significantly longer in patients with renal disease. The clearance rate of genistein is significantly slower than that of daidzein, explaining why the plasma genistein concentrations are typically 1.5 to 2.0 times higher than daidzein concentrations. For supplements containing soy germ, daidzein and glycitein become the predominant isoflavones in plasma because they are enriched in soy germ. Glycitein has relatively poor affinity for the ERs when compared with daidzein or genistein. The plasma appearance/disappearance concentration profile of glycitein is similar to that of other isoflavones. These differences in plasma profiles of isoflavones indicate that not all soy foods or supplements are created equal and therefore may not be expected to have the same efficacy.
Much interest has focused on S(-)-equol, the intestinal bacterial metabolite and end product of daidzin/daidzein because this biologically active isoflavone is not produced by all adults who consume soy foods. Only 20% to 30% of Western adults will produce S(-)-equol when fed soy isoflavones, which is significantly lower than the 50% to 60% frequency of equol producers reported in adults living in Asia and consuming soy foods. The equol hypothesis of Setchell et al proposed that the ability to produce S(-)-equol may explain the greater efficacy of soy in studies of Asians when compared with those reported for Western adults. S(-)-equol has a high systemic bioavailability and relatively slow plasma clearance. Peak plasma concentrations occur 1 to 2 hours after oral administration, consistent with the behavior of other isoflavone aglycones. High circulating plasma concentrations can be achieved in most adults with low oral doses (5-10 mg). S(-)-equol undergoes little biotransformation, apart from phase II metabolism, and consequently its fractional absorption is high. It is cleared from plasma with a t1/2 of 6 to 8 hours and excreted almost exclusively in urine. The optimal clinical efficacy is more likely to occur with twice-daily administration rather than single-dose administration. This is important to consider when designing clinical studies of isoflavones.
Species differ in the extent of isoflavone conjugation; the athymic mouse and several transgenic species of mice show significantly higher proportions of unconjugated isoflavones in plasma than the rat or human. This may be due to differences in expression of individual UDP-glucuronosyltransferases. While conjugation can take place in both the liver and the enterocyte, it appears that extensive conjugation of isoflavones occurs by intestinal UDP-glucuronyltransferase on first-pass uptake.
Unlike endogenous estrogens, which are extensively bound to sex hormone-binding globulin and albumin, genistein and equol have both been reported to be only 45% to 50% protein bound. In contrast, biochanin A and formononetin exhibit strong protein binding.
Terminology, Mechanisms, Bioavailability & Pharmacokinetics of Isoflavones
The most studied of the botanicals for menopause-related conditions are isoflavones, sometimes called "phytoestrogens." They are plant-derived compounds with estrogen-like biologic activity and a chemical structure similar to that of estradiol. See Table 1 for definitions of terminology used in this paper.
Terminology
Isoflavones are a class of phytochemicals, a broad group of nonsteroidal compounds of diverse structures derived from plants that bind to estrogen receptors (ERs) in animals and human beings. Isoflavones have greater affinity for ER-β than for ER-α and possess both estrogen-agonist and estrogen-antagonist properties. The isoflavones include the biochemicals genistein, daidzein, glycitein, biochanin A, and formononetin. Genistein and daidzein are found in high amounts in soybeans and soy products as well as in red clover, kudzu, and the American groundnut.
Soy is the most widely used isoflavone-containing food. The term soy usually refers to a product derived from the whole soybean (or soya bean). Soy protein refers to a product derived by extracting the protein out of the whole bean. Soy protein is usually a rich source of isoflavones. The primary isoflavones of soybeans are genistein, daidzein, and glycitein. The relative amounts of these isoflavones vary depending on the portion of the soybean from which the material is obtained. The whole soybean contains about equal amounts of genistein and daidzein, with smaller amounts of glycitein. The germ of the soybean, however, is quite different; it has a high concentration of isoflavones, with daidzein being about four times greater than that of genistein and with relatively high concentrations of glycitein. Some soy supplements are made from soy germ. The relative amounts of genistein and daidzein are now thought to be determinants of the therapeutic efficacy of soy supplementation, as will be discussed later in this paper. Also to be discussed later is the possibility that individual isoflavones, such as genistein, have different therapeutic outcomes when administered alone compared with the same amounts administered with all three isoflavones (genistein, daidzein, and glycetin) in the supplement.
About 30% of North American women have the ability to metabolize daidzein to equol. Equol is a nonsteroidal estrogen-like compound that binds to both ERs but with a high affinity for ER-β; thus, it is often designated as an ER-β agonist. Equol is produced from daidzen by intestinal bacteria and is thought to be a stable characteristic that is best revealed by a soy challenge of just a few days. Equol has two isomers, S(-)-equol and R(+)-equol. Only S(-)-equol is detected in the plasma of equol-producing women and thought to have any biological activity. By far the most exciting research opportunities in the area of soy isoflavone menopausal health concern the potential benefits of equol and the unanswered issue of whether equol is merely a marker for some beneficial effect of gut bacteria on steroid metabolism. More research is needed that compares equol producers with equol nonproducers.
Mechanisms
Isoflavones are frequently referred to as having pleiotropic properties (ie, many modes of action). It is therefore no surprise that they have been proposed to have important benefits in regard to vasomotor symptoms, the breast and uterus, cardiovascular system, bone, and cognition-all of which have relevance to women approaching and experiencing menopause. Detailed discussions of these effects can be found later in this paper.
Isoflavones were first considered to be phytoestrogens or "plant estrogens" because of early work noting their infertility effects in certain but not all species and because they bind to both of the ERs and because of their infertility effects in certain, but not all, species. However, during the 1980s, they were also demonstrated to be inhibitors of critical protein tyrosine kinases such as the epidermal growth factor receptor-a risk factor for recurrence of breast cancer-and the platelet-derived growth factor receptor. Subsequently, other mechanisms of action were proposed, including as antioxidants, inhibitors of DNA topoisomerases, and many enzyme systems in steroid synthesis and metabolism.
Today, the question of which mechanisms of action of isoflavones and their metabolites are relevant to women's health remains controversial. The dose used in cell culture assays to investigate mechanisms is crucial. It has been proposed that concentrations in excess of 5 μM are unphysiologic, even in situations in which therapeutic doses are administered. Many investigators have reported data from studies that used 25 to 100 μM isoflavones. These studies had to use the solvent dimethylsulfoxide to keep the isoflavones in solution, which may have introduced nonbiological variables into the results.
Another rapidly emerging area for the study of all plant-based and synthetic therapeutics is their impact on microRNA expression. MicroRNAs are targeted inhibitors of the translation of specific proteins. An important aspect of microRNA action is that they inhibit translation of multiple proteins. This may account for their pleiotropic properties. The application of microRNA concepts to the actions of isoflavones is in its infancy.
Although most of the work on the mechanisms of action of isoflavones has been carried out on genistein and daidzein, recent studies on S(-)- and R(+)-equol have challenged earlier concepts about how this metabolite might alter biological systems. S(-)-equol is a better agonist for the ER-β, with agonist properties comparable to genistein.
Overall, evidence suggests that the biological effects of isoflavones and their metabolites are mediated by many pathways, not just estrogen-dependent events. Future studies may exploit data that have been obtained in DNA microarray experiments. In addition, studies have suggested that some of the benefits of dietary isoflavones observed in other populations may depend on early life exposure, which may involve their impact on gene expression at an epigenetic level.
Bioavailability & Pharmacokinetics
Puerarin (daidzein 8-C-glucoside) is rapidly absorbed and eliminated with a terminal elimination half-life (t1/2) of approximately 4.3 hours in adult men. It is likely that similar pharmacokinetics occur in women.
An extensive literature exists on the pharmacokinetics of soy isoflavones administered as natural components of soy foods, as isolated isoflavone extracts or supplements, as pure compounds, and also as stable-isotope labeled analogs. Overall, apparent bioavailability of these isoflavones are similar. Nonetheless, the rates of absorption of the isoflavones daidzein and genistein as glycosides are distinctly different from those of daidzein and genistein in their aglycone form and this has recently been suggested to be an important difference that could influence the ultimate efficacy of isoflavones. Aglycones demonstrate rapid absorption and peak plasma concentrations are attained within 1 to 3 hours, depending on whether the isoflavones are taken with a meal or without a meal. The effect of a meal is to delay absorption and shift the Tmax value. In contrast, for the β-glycoside conjugates, peak plasma concentrations of isoflavones typically occur 4 to 10 hours later due to a requirement for prior hydrolysis by intestinal brush border β-glycosidases, which is a rate-limiting and time-dependent process.
The t1/2 of all isoflavones is similar and typically 6 to 12 hours although it is significantly longer in patients with renal disease. The clearance rate of genistein is significantly slower than that of daidzein, explaining why the plasma genistein concentrations are typically 1.5 to 2.0 times higher than daidzein concentrations. For supplements containing soy germ, daidzein and glycitein become the predominant isoflavones in plasma because they are enriched in soy germ. Glycitein has relatively poor affinity for the ERs when compared with daidzein or genistein. The plasma appearance/disappearance concentration profile of glycitein is similar to that of other isoflavones. These differences in plasma profiles of isoflavones indicate that not all soy foods or supplements are created equal and therefore may not be expected to have the same efficacy.
Much interest has focused on S(-)-equol, the intestinal bacterial metabolite and end product of daidzin/daidzein because this biologically active isoflavone is not produced by all adults who consume soy foods. Only 20% to 30% of Western adults will produce S(-)-equol when fed soy isoflavones, which is significantly lower than the 50% to 60% frequency of equol producers reported in adults living in Asia and consuming soy foods. The equol hypothesis of Setchell et al proposed that the ability to produce S(-)-equol may explain the greater efficacy of soy in studies of Asians when compared with those reported for Western adults. S(-)-equol has a high systemic bioavailability and relatively slow plasma clearance. Peak plasma concentrations occur 1 to 2 hours after oral administration, consistent with the behavior of other isoflavone aglycones. High circulating plasma concentrations can be achieved in most adults with low oral doses (5-10 mg). S(-)-equol undergoes little biotransformation, apart from phase II metabolism, and consequently its fractional absorption is high. It is cleared from plasma with a t1/2 of 6 to 8 hours and excreted almost exclusively in urine. The optimal clinical efficacy is more likely to occur with twice-daily administration rather than single-dose administration. This is important to consider when designing clinical studies of isoflavones.
Species differ in the extent of isoflavone conjugation; the athymic mouse and several transgenic species of mice show significantly higher proportions of unconjugated isoflavones in plasma than the rat or human. This may be due to differences in expression of individual UDP-glucuronosyltransferases. While conjugation can take place in both the liver and the enterocyte, it appears that extensive conjugation of isoflavones occurs by intestinal UDP-glucuronyltransferase on first-pass uptake.
Unlike endogenous estrogens, which are extensively bound to sex hormone-binding globulin and albumin, genistein and equol have both been reported to be only 45% to 50% protein bound. In contrast, biochanin A and formononetin exhibit strong protein binding.
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