Isoflavone Therapy Research Articles

The Impact of Soy Isoflavone Supplementation on the Menopausal Symptoms in Perimenopausal and Postmenopausal Women.

Introduction:Approximately one-third of a woman's life is spent in the menopausal phase. The unpleasant menopausal symptoms are unacceptable as a part of routine life. Indications of menopausal hormone therapy (MHT) are for alleviation of vasomotor symptoms, prevention of osteoporosis, and genitourinary symptoms associated with menopause. MHT is associated with an increased risk of breast cancer, cerebrovascular accidents, and coronary heart disease. Soy isoflavones have been extensively used as an alternative treatment in patients who cannot take MHT. The evidence of the efficacy of isoflavones in the literature is equivocal.Aim:The aim of the study was to evaluate the efficacy of soy isoflavone supplementation on menopausal symptoms in perimenopausal and postmenopausal women and to evaluate the effect on blood pressure (BP) and body mass index (BMI).Materials and Methods:A questionnaire-based prospective observational study was undertaken involving 39 perimenopausal and 61 postmenopausal women, who were prescribed 40 mg soy isoflavone supplements twice daily for 12 weeks. Menopause Rating Scale questionnaire was given to the patients before starting soy isoflavone therapy and at the end of the treatment; BP and BMI were also noted.Results:The total score of both the groups was comparable at baseline. Among perimenopausal and postmenopausal women, the highest score was noted in symptoms of somatic domain. At the completion of our study, the total scores improved significantly by 38.6% and 33.3% in perimenopausal and postmenopausal women, respectively. The greatest improvement was seen in somatic subscale (42.5%) and psychological subscale (42.5%) and the least in urogenital subscale (16.1%) for perimenopausal women. For postmenopausal women, the greatest improvement was seen in psychological subscale (40.0%) and the least in urogenital subscale (14.2%).Conclusion:Soy isoflavone supplementation is beneficial in both perimenopausal and postmenopausal women, more so in perimenopausal women. There is no beneficial effect of soy isoflavone supplementation on lowering systolic BP and BMI.

Gene expression-targeted isoflavone therapy for Huntington's and Alzheimer's diseases

Gene expression-targeted isoflavone therapy for Huntington's and Alzheimer's diseases

Soybean isoflavones ameliorate ischemic cardiomyopathy by activating Nrf2-mediated antioxidant responses.

Ischemic cardiomyopathy (IC) is the major cause of heart failure. Conventional medicine has been proved ineffective with adverse effects. Soybean presents exciting adjunctive therapies and shows protective benefits for IC. However, the molecular mechanisms remain unclear. Isoflavones are the main bioactive components of soybean and may be protective against heart disease. Isoflavones were extracted by using an acidic-ethanol method and analyzed by HPLC. All patients with ischemic stroke were randomly and evenly assigned to two groups: the isoflavone group (80 mg day-1, n = 100) and control group (80 mg day-1 placebo, n = 100), and the whole period of the experiment was 24 weeks. The effects of soybean isoflavone on brachial flow-mediated dilatation (FMD) were measured. HPLC fractionation shows that isoflavone extracts are mainly composed of 55% genistein, 23% daidzein, and 14% glycitein. Isoflavone therapy reduced more levels of triglyceride and LDL-c in females than in males. FMD was higher in the isoflavone group than in the control group after 24-week therapy (treatment effect 2.0%, 95% CI 0.18-3.0, P = 0.01). The baseline differences were adjusted in FMD and the isoflavone therapies were closely associated with the reduction of FMD impairment at 24 weeks (odds ratio 0.30, 95% CI 0.14-0.85, P = 0.01). The effects of isoflavone on brachial FMD were negatively associated with base FMD (r = -0.65, P < 0.01). Furthermore, isoflavone therapy caused a significant increase in the levels of erythroid-derived 2-like 2 (Nrf2), superoxide dismutase (SOD) and a significant decrease in serum levels of C-reactive protein, 8-isoprostane, malondialdehyde, interleukin-6 and tumor necrosis factor alpha. In contrast, the isoflavones had no effects on the levels of oxidation-related molecules when Nrf2 was silenced. These results suggest that soybean isoflavones ameliorate IC patients by improving their antioxidant capacities via the upregulation of Nrf2.

The Effect of Soy Isoflavones on the Menopause Rating Scale Scoring in Perimenopausal and Postmenopausal Women: A Pilot Study.

Menopause is associated with many unpleasant symptoms which vary in different phases of menopausal transition. Although, Hormone Replacement Therapy (HRT) is considered the most effective mode of treatment for these symptoms, its use is associated with increased risk of breast cancer, endometrial cancer and thromboembolic events. Soy isoflavones are being widely used as a safer alternative to HRT, even though scientific evidence of their efficacy is poor or lacking. To study the effect of soy isoflavone supplementation on the menopausal symptoms in perimenopausal and postmenopausal women. An observational pilot study was done involving 29 perimenopausal and 21 postmenopausal women prescribed 100 mg soy isoflavones for 12 weeks. Menopause Rating Scale (MRS) questionnaire was administered to the patients before starting soy isoflavone therapy and at the end of treatment. Responses were analysed using Statistical Package for Social Sciences (SPSS) software 23.0. Total score of both the groups were comparable at baseline. Among perimenopausal women highest score was given to symptoms of psychological domain. Urogenital symptoms were the worst among postmenopausal women. After 12 weeks of treatment, total scores improved significantly by 19.55% and 12.62% in the perimenopausal and postmenopausal women respectively. The greatest improvement was seen in scores of hot flashes for both the groups and the least improvement was shown by symptoms of urogenital subscale. Soy isoflavone improves the MRS score among both the perimenopausal and postmenopausal women. As they are most effective for somatic and psychological symptoms, their use could be beneficial during perimenopause.

Glycosaminoglycans and mucopolysaccharidosis type III.

Mucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is a lysosomal storage disease in which heparan sulfate is accumulated in lysosomes, as well as outside of cells, as the primary storage material. This disease is a complex of four conditions caused by dysfunctions of one of genes coding for lysosomal enzymes involved in degradation of heparan sulfate: SGSH (coding for heparan N-sulfatase) - causing MPS IIIA, NAGLU (coding for alpha-N-acetylglucosaminidase) - causing MPS IIIB, HGSNAT (coding for acetyl CoA alpha-glucosaminide acetyltransferase) - causing MPS IIIC), and GNS (coding for N-acetylglucosamine-6-sulfatase) - causing MPS IIID. The primary storage is responsible for some disease symptoms, but other arise as a result of secondary storage, including glycosphingolipids, and subsequent processes, like oxidative stress and neuroinflammation. Central nervous system is predominantly affected in all subtypes of MPS III. Heparan sulfate and its derivatives are the most commonly used biomarkers for diagnosis and prediction procedures. Currently, there is no therapy for Sanfilippo syndrome, however, clinical trials are ongoing for enzyme replacement therapy, gene therapy and substrate reduction therapy (particularly gene expression-targeted isoflavone therapy).

Effect of Isoflavone on Balloon Catheter-Induced Neointimal Hyperplasia in Ovariectomised Rabbit Carotid Artery

This study was designed to investigate the effects of phytoestrogen isoflavone on balloon catheter-induced hyperplasia of carotid artery. Forty-eight female New Zealand rabbits were randomly divided into four groups: control (balloon-induced carotid artery injury only); ovariectomy control (ovariectomy and carotid artery injury), oestrogen (ovariectomy, carotid artery injury and nilestriol, 5mg/kg daily for 28 days), and isoflavone (ovariectomy, carotid artery injury and isoflavone 120 mg/kg daily for 28 days). The arterial wall thickness was assessed by coloured ultrasonography, and the oestrogen-α and oestrogen-β receptors in the abdominal aorta were measured by Western blotting. The medial layer thickness in the isoflavone group was less than in the ovariectomy control group (0.28±0.03 vs. 0.35±0.04 mm, p<0.01), and the intimal/medial layer (I/M) ratio is the isoflavone group was also less than in the ovariectomy control group (16.85±3.79 vs. 48.94±8.92, p<0.01). There was no statistically significant difference in the medial layer thickness or I/M ratio between the isoflavone and the oestrogen groups. The optical density of the oestrogen-α receptors in the isoflavone group (0.317±0.002) was less than in the oestrogen (0.633±0.002) or ovariectomy control group (0.590±0.001, p<0.01). The optical density of the oestrogen-β receptors in the isoflavone group (1.350±0.002) and the ovariectomy control group (1.2033±0.002) was less than in the oestrogen group (1.7699±0.003, p<0.01). Isoflavone therapy in the ovariectomised rabbit model attenuated balloon catheter-induced intimal and medial layer hyperplasia in the carotid arteries. Down-regulation of the oestrogen-α receptors may be involved in the hyperplasia-preventative effect.

Changes in hair morphology as a biomarker in gene expression-targeted isoflavone therapy for Sanfilippo disease

Lack of unequivocal markers for assessment of therapeutic effects of treatment procedures is a common problem, but it is especially pronounced in genetic diseases. One of them is Sanfilippo disease (mucopolysaccharidosis type III, or MPS III). Changes in hair morphology have already been reported as one of characteristic and easily detected symptoms of this disease and other mucopolysaccharidoses. This feature has been used previously to monitor efficacy of gene expression-targeted isoflavone therapy (GET IT) in pilot clinical studies performed with low number of patients. Here, we studied changes in hair morphology, observed by using scanning electron microscopy, in 35 patients subjected to GET IT for one year at doses of 5 and 15mg/kg/day. We have observed statistically significant correction of hair morphology in both groups of patients, corroborating results of earlier studies with low number of patients that suggested easily observable improvement in this parameter during different therapies of MPS. Since the improvement was evident in both previous reports and this study, we propose that analysis of hair morphology may be considered as a non-invasive method in monitoring effects of treatment on somatic symptoms of Sanfilippo disease patients.

Isoflavone-Rich Soy Protein and Cognition in Midlife and Late-Life Women: Randomized, Double-Blind, Placebo-Controlled Trial (P04.196)

Objective: To determine cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets. Background Soy isoflavone therapy is suggested to benefit cognitive health in postmenopausal women, but evidence from adequately powered clinical trials is lacking regarding effect on long-term cognitive functioning. Design/Methods: In the parallel-group randomized double-blind Women9s Isoflavone Soy Health (WISH) trial, healthy postmenopausal women were randomly allocated to receive daily 25 g isoflavone-rich soy protein (91 mg aglycone weight of isoflavones) or milk protein matched placebo (0 mg isoflavones). The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite score constructed as the weighted sum of 14 individual test score changes from a comprehensive neuropsychological battery. Results: 350 women (mean age 61 years) enrolled in the WISH trial. 313 women with baseline and endpoint cognitive test data were included in intent-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% CI -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual episodic memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.05 to 0.60) but no significant between-group differences on three other cognitive factors or differences on individual test scores; there was no significant between-group difference within a subgroup of younger postmenopausal women close to menopause. Conclusions: Long-term daily dietary soy isoflavone supplementation has no effect on global cognition among healthy postmenopausal women but may improve visual episodic memory. (ClinicalTrials.gov NCT00118846). Supported by: National Center of Complementary and Alternative Medicine, the Office of Dietary Supplements, and the Office of Research on Women9s Health (U01AT-001653). Disclosure: Dr. Henderson has received research support from Cambridge University Press. Dr. St. John has nothing to disclose. Dr. Hodis has nothing to disclose. Dr. Kono has nothing to disclose. Dr. McCleary has nothing to disclose. Dr. Franke has nothing to disclose. Dr. Mack has nothing to disclose.

Gene expression‐targeted isoflavone therapy

Lysosomal storage diseases (LSD) form a group of inherited metabolic disorders caused by dysfunction of one of the lysosomal proteins, resulting in the accumulation of certain compounds. Although these disorders are among first genetic diseases for which specific treatments were proposed, there are still serious unsolved problems that require development of novel therapeutic procedures. An example is neuronopathy, which develops in most of LSD and cannot be treated efficiently by currently approved therapies. Recently, a new potential therapy, called gene expression-targeted isoflavone therapy (GET IT), has been proposed for a group of LSD named mucopolysaccharidoses (MPS), in which storage of incompletely degraded glycosaminoglycans (GAGs) results in severe symptoms of virtually all tissues and organs, including central nervous system. The idea of this therapy is to inhibit synthesis of GAGs by modulating expression of genes coding for enzymes involved in synthesis of these compounds. Such a modulation is possible by using isoflavones, particularly genistein, which interfere with a signal transduction process necessary for stimulation of expression of certain genes. Results of in vitro experiments and studies on animal models indicated a high efficiency of GET IT, including correction of behavior of affected mice. However, clinical trials, performed with soy isoflavone extracts, revealed only limited efficacy. This caused a controversy about GET IT as a potential, effective treatment of patients suffering from MPS, especially neuronopathic forms of these diseases. It this critical review, I present possible molecular mechanisms of therapeutic action of isoflavones (particularly genistein) and suggest that efficacy of GET IT might be sufficiently high when using relatively high doses of synthetic genistein (which was employed in experiments on cell cultures and mouse models) rather than low doses of soy isoflavone extracts (which were used in clinical trials). This proposal can be tested in double-blinded, placebo-controlled clinical trials.

Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression‐targeted isoflavone therapy (GET IT)

Mucopolysaccharidosis type II (MPS II, Hunter disease) is an X chromosome-linked inherited metabolic disease caused by mutations resulting in deficiency of activity of iduronate-2-sulfatase (IDS) and accumulation of undegraded glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate. Previous experiments with cell cultures and studies on animal model of MPS II suggested that gene expression-targeted isoflavone therapy (GET IT), based on genistein-mediated reduction of efficiency of GAG synthesis, might be a suitable therapy for this disease. In this report, we demonstrate efficacy of GET IT in connective tissue elasticity, particularly in improving the range of joint motion in seven patients with MPS II after 26 weeks of treatment with an isoflavone extract at the dose corresponding to 5 mg/kg/day of genistein.

The role of soy isoflavones in menopausal health

In Brief Objectives: If and to what extent soy protein, soy isoflavones, and their metabolites, including S(-)-equol, have beneficial effects on women's health is currently unclear. The North American Menopause Society (NAMS)/Utian Translational Science Symposium on Soy and Soy Isoflavones convened October 9-10, 2010, to clarify basic and clinical research findings as they relate to the risk and benefits of soy products for peri- and postmenopausal women. Methods: A working group of faculty and panelists composed of clinical and research experts in the fields of women's health and botanicals met during a 2-day translational symposium to cover the latest evidence-based science on isoflavones as they affect menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition. Full descriptions of the bioavailability and pharmacokinetics of isoflavones were also presented. Subspecialty groups then broke off with the goal of translating the information into a report for general medical practice and identifying further research areas. All faculty and panelists reviewed the final report, which was then approved by the NAMS Board of Trustees. Results: From the hundreds of studies reviewed in this report, there are mixed results of the effects on midlife women. Soy-based isoflavones are modestly effective in relieving menopausal symptoms; supplements providing higher proportions of genistein or increased in S(-)-equol may provide more benefits. Soy food consumption is associated with lower risk of breast and endometrial cancer in observational studies. The efficacy of isoflavones on bone has not been proven, and the clinical picture of whether soy has cardiovascular benefits is still evolving. Preliminary findings on cognitive benefit from isoflavone therapy support a "critical window" hypothesis wherein younger postmenopausal women derive more than older women. Conclusions: Several areas for further research have been identified on soy and midlife women. More clinical studies are needed that compare outcomes among women whose intestinal bacteria have the ability to convert daidzein to equol (equol producers) with those that lack that ability (equol nonproducers) in order to determine if equol producers derive greater benefits from soy supplementation. Larger studies are needed in younger postmenopausal women, and more research is needed to understand the modes of use of soy isoflavone supplements in women. The interrelations of other dietary components on soy isoflavones consumed as a part of diet or by supplement on equol production also require further study, as do potential interactions with prescription and over-the-counter medications. And finally, greater standardization and documentation of clinical trial data of soy are needed. Faculty and panelists composed of clinical and research experts in the fields of women's health and botanicals met during a 2-day translational symposium to cover the latest evidence-based science on isoflavones as they affect menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition.

Effect of estrogen therapy, soy isoflavones, and the combination therapy on the submandibular gland of ovariectomized rats

The objective of this study was to evaluate the effect of estrogen deficiency, estrogen therapy, and soy isoflavones on the salivary glands in female rats. Ninety-six animals were ovariectomized, and 24 were sham-operated. Among the ovariectomized rats, 24 received 17β-estradiol; 24 received isoflavone extract; 24 received a combination therapy of both; and 24 received water as placebo. The submandibular glands were histomorphometrically analyzed. As a result, the ANOVA test revealed that the hormonal deficiency affected the acini and the ducts of ovariectomized rats, reducing their percentage compared to the sham group. All treatments caused an increase in ducts and acini compared to the placebo group. It was concluded that the estrogen deficiency may be related to salivary gland function due to a reduction in the quantity of salivary acini and ducts secondary to ovariectomy. The estrogen therapy, soy isoflavone therapy, and the combination of both are effective in reducing the effects of ovariectomy on the salivary glands.

Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: Assessment of effects on cognitive functions and general status of patients

SummaryBackgroundMucopolysaccharidoses (MPS) are inherited metabolic disorders caused by deficiencies in enzymes involved in degradation of glycosaminoglycans. MPS type III (Sanfilippo disease) is clinically characterized mainly by progressive and severe behavioral disturbances and cognitive dysfunction. Recent 1-year experimental treatment of 10 patients with a genistein (4′, 5, 7-trihydroxyisoflavone)-rich extract resulted in improvement of tested parameters, including cognitive and behavioral functions.Material/MethodsEight pediatric patients with Sanfilippo disease were enrolled into the study. The modified version of the Brief Assessment Examination was used to assess cognitive functions. Moreover, 18 different parameters concerning changes in conditions of patients were assessed by their parents.ResultsDuring the first year of the treatment, an improvement of cognitive functions in 7 patients and stabilization in 1 patient were assessed, while after the third year (2-year follow-up) further improvement was observed in 2 patients, stabilization in 3 patients and some deterioration in 3 patients. Monitoring of general and behavioral symptoms revealed improvement in all patients after the first year of the treatment, further improvement in 5 patients, and deterioration in 3 patients during the next 2 years.ConclusionsWe conclude that the treatment of Sanfilippo patients with a genistein-rich soy isoflavone extract (called gene expression-targeted isoflavone therapy [GET IT]) may be effective in either inhibition (in some patients) or slowing down (in other patients) of behavioral and cognitive problems over a longer period. An increased dose of genistein may improve the efficacy of the treatment.

Different amounts of isoflavones in various commercially available soy extracts in the light of gene expression‐targeted isoflavone therapy

Isoflavones are plant-derived, biologically active compounds that are commonly used as natural drugs or diet supplements in the treatment of menopausal symptoms and as antioxidants. Recently, it was proposed that genistein (4',5,7-trihydroxyisoflavone) may be used in the treatment of patients suffering from Sanfilippo disease (mucopolysaccharidosis type III), a severe genetic disorder for which no therapy is available. A pilot clinical study with this novel therapy, called 'gene expression-targeted isoflavone therapy' (GET IT), indicated that a standardized, genistin-rich soy isoflavone extract is effective in the treatment of such patients. Since various isoflavone-containing products are commercially available, the content of the main isoflavones were measured in such products. Extremely different amounts of isoflavones were determined in various products, from 0.13 to 39 mg per tablet. Only some of these products were found to be effective in inhibition of the synthesis of glycosaminoglycans (compounds whose degradation is severely impaired in mucopolysaccharidoses, including Sanfilippo disease) in cultured fibroblasts. Since in GET IT the dose of genistein is calculated per patient's body weight, the amount of this isoflavone in a tablet is crucial for this therapy. Therefore, the results presented in this report indicate that a careful choice of a proper isoflavone extract is necessary for GET IT.

Activation of endothelial nitric oxide synthase by dietary isoflavones: Role of NO in Nrf2-mediated antioxidant gene expression

The endothelium plays a key role in the maintenance of vascular homeostasis, and increased oxidative stress in vascular disease leads to reduced nitric oxide bioavailability and impaired endothelium-dependent relaxation of resistance vessels. Although epidemiological evidence suggests that diets containing high amounts of natural antioxidants afford protection against coronary heart disease (CHD), antioxidant supplementation trials have largely reported only marginal health benefits. There is controversy concerning the cardiovascular benefits of prolonged estrogen/progestin or soy isoflavone therapy for postmenopausal women and patients with an increased risk of CHD. Research on the potential health benefits of soy isoflavones and other polyphenols contained in red wine, green and black tea and dark chocolate developed rapidly during the 1990's, and recent clinical trials and studies in animal models and cultured endothelial cells provide important and novel insights into the mechanisms by which dietary polyphenols afford protection against oxidative stress. In this review, we highlight that NO and reactive oxygen radicals may mediate dietary polyphenol induced activation of Nrf2, which in turn triggers antioxidant response element (ARE) driven transcription of phase II detoxifying and antioxidant defense enzymes in vascular cells.

Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are inherited, severe, progressive, metabolic disorders caused by deficiencies in different enzymes involved in degradation of glycosaminoglycans (GAGs). Although enzyme replacement therapy (ERT) has recently been available for MPS type I, and clinical trials have been performed in ERT for MPS II and MPS VI, there is little chance that this kind of treatment may be effective for neurodegenerative forms of MPS (due to inefficient delivery of enzymes to central nervous system through the blood-brain barrier), hence currently there is no effective therapy available for them. Therefore, we aim to develop an alternative therapy for these diseases. We found that genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) inhibits synthesis of GAGs considerably in cultures of fibroblasts of MPS patients (types I, II, IIIA and IIIB were tested). Prolonged cultivation of these cells in the presence of genistein resulted in reduction of GAG accumulation and normalization of cells as estimated by biochemical tests and electron microscopic analysis, respectively. As genistein inhibits kinase activity of epidermal growth factor receptor, which is required for full expression of genes coding for enzymes involved in GAG production, we propose to consider a substrate reduction therapy for MPS, which is referred to as 'gene expression-targeted isoflavone therapy'.