Phytoestrogens as hormone replacement therapy: an evidence-based approach

Postmenopausal women have sought nonestrogen alternatives to hormone replacement in order to avoid possible risks and side effects of the therapy. Selective estrogen receptor modulators have been developed to tailor therapy to a specific risk/benefit profile that will best fit the patient. More women have looked to phytoestrogens, such as the isoflavones found in the soy plant, to tailor their menopausal therapy in a “natural” way. This review examines the evidence regarding the risks and benefits of isoflavones as hormone replacement therapy. Controlled trials have shown a reduction in postmenopausal hot flashes when subjects’ diets were supplemented with soy. There is less evidence for a benefit in vaginal dryness symptoms. Furthermore, dietary supplementation also appears to lower total and low-density lipoprotein cholesterol in hypercholesterolemic subjects. A synthetic isoflavone, ipriflavone, has been shown in controlled trials to prevent postmenopausal bone loss, though there is much less evidence that soy isoflavones will accomplish this goal. Finally, although unopposed estrogen replacement may promote breast and endometrial cancer, there is no evidence that phytoestrogens will do the same. In contrast, great interest has been taken in the potential cancer-protective effects of phytoestrogens, though prospective evidence in postmenopausal women is not available. Although data regarding the use of isoflavone extracts are incomplete, dietary supplementation with soy foods appears to be a safe and possibly beneficial option for postmenopausal women.     

Phytoestrogens and cardiovascular disease

The most extensively studied class of phytoestrogens, isoflavones, occur in soybeans and other legumes. Six systematic reviews have assessed the effects of soy isoflavones on lipid levels, and suggested that a diet supplemented with soy protein isolate (ISP) containing isoflavones reduces low-density lipoprotein (LDL) cholesterol by around 0.15 mmol/L, but without clear effects on triglycerides or high-density lipoprotein (HDL) cholesterol. However, no review has suggested that purified soy isoflavones or soy protein without isoflavones (where the isoflavones have been removed by an alcohol wash) have statistically significant effects. It remains unclear which are the active components of soy. They may include soy protein which has not been denatured by alcohol wash, interaction of isoflavones within the intact soy matrix, or other compounds removed in the alcohol-extracted fraction. The reduction in total cholesterol may be greater in men than in postmenopausal women. There is little evidence that the effectiveness of soy varies with baseline serum lipid levels, or the amount of isoflavone or soy protein consumed. However, changes in triglycerides may be related to baseline levels. While there is no evidence of beneficial effects of phytoestrogens on blood pressure, arterial compliance or oxidation of LDL cholesterol, there may be beneficial effects on endothelial function in postmenopausal women, and on homocysteine concentrations. There is little suggestion of adverse effects of soy or isoflavones at physiological doses, although those taking soy isoflavone supplements do appear to have higher levels of gastro intestinal and menstrual complaints. There have been no published trials on the effects of phytoestrogens on mortality or cardiovascular events, so studies currently rely on the above bio markers of risk. Most evidence relates to soy isoflavones, but there is some evidence for lignans. Further robust studies assessing the effects of whole soy foods on cardiovascular outcomes are needed.     

Complementary medicine: phytotherapy and soyaisoflavones as phytoestrogens

After a introduction concerning complementary medicine, naturopathy and phytotherapy a general view of soy isoflavones as phytoestrogens will be given. In german speaking countries the term and topic naturopathy has a tradition of 150 years regarding theoretical development and practical use among lay people and health professionals in European culture. In contrary the term complementary medicine has been used for approximately 15 years in englisch speaking countries as a kind of collective name for European and Non-European medical cultures and traditions. Complementay medicine summarizes a huge variety of cultural, medical and qualitywise different medical methods and treatments which can be a contribution to conventional medicine. One of the oldest and intensly researched fields in European and Non-European complementary medicine is the use of herbal drugs (phytotherapy). Soy isoflavones serve as an example to show the differences between phytotherapy based on multicompounds and dietary supplements (neutraceuticals) based on monosubstances. The differing preparations of soy isoflavones are not phytotherapeutic medicine. A review of the experimental and clinical data concerning soy isoflavones as phytoestrogens for the prevention of cancer, menopausal complaints, osteoporosis or cardiovascular diseases indicates that the consumption of food containing phytoestrogens seems to be health protective. Yet, the relevance of supplementation of single phytoestrogens for an additional health effect is not sufficiently proven.     

Red clover isoflavones and menopausal health

Menopausal symptoms such as hot flushes and night sweats can be very disrupting. While hormone replacement therapy is an effective therapy, concerns about side effects and breast cancer risk have stimulated interest into alternative therapies such as phytoestrogens. These are oestrogen-like compounds made by plants. Two major sources of phytoestrogens are soy and red clover. Data on randomised controlled trials of red clover for the control of menopausal symptoms are presented. The conflicting data are encouraging and suggest that phytoestrogens are a treatment modality that needs pursuing.     

A natural alternative to menopausal hormone replacement therapy. Phytoestrogens

Phytoestrogens are non-steroidal plant molecules whose structure differs from gonadal hormones, but with an estrogen-type bioactivity: they are capable of interacting with estrogen receptors, showing both agonist and antagonist methods of action. The beneficial effects of various classes of phytoestrogens present in nature are now known, but the main isoflavone present in soya, genistein, appears to be particularly effective. Interest in this substance is concentrated in particular on its therapeutic role in menopause. This paper is a review of the main studies published to date on the efficacy of phytoestrogens in reducing the symptoms of menopause. A diet rich in isoflavones is associated with a reduced incidence of vasomotor episodes; the average supplement of genistein is approximately 50 mg/day. After supplementing the diet with phytoestrogens, studies show a reduction in total cholesterol and LDL fraction. This is accompanied by an increase in BMD (Bone mineral density) after taking 90 mg of isoflavones for 6 months. Isoflavones may reduce the risk of developing breast cancer. The data examined confirm the excellent clinical efficacy of supplementing the diet with soy extracts, particularly genistein which is indicated to alleviate both the short-term symptoms of menopause and the long-term effects, although the latter finding requires further subsantiation.     

Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150?mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.     

Endocrine disrupters and menopausal health

Chemicals known to disrupt the endocrine system of animal models are assessed for their potential impact on the health of menopausal and postmenopausal women. These "endocrine disrupters" consist of two groups of compounds - man-made and naturally occurring. There is some evidence to suggest that the naturally occurring phytoestrogens, derived from plant material, may have some beneficial effects on menopausal symptoms and the risk of breast cancer, cardiovascular disease and osteoporosis. Further studies are required to confirm these possibilities. Some man-made environmental pollutants appear to increase the risk of breast cancer, although again the evidence is inconclusive. Mechanistic experiments indicate that these chemicals interact with oestrogen receptors and alter metabolism in a number of different ways, some of which may be important in postmenopausal women. Further investigation of the differences in mode of action between the man-made and the natural endocrine disrupters may lead to important insights into their effects on women's health.     

Phytoestrogens for treatment of menopausal symptoms: a systematic review

OBJECTIVE: To assess the efficacy and tolerability of phytoestrogens for treatment of menopausal symptoms. DATA SOURCES: We searched the Cochrane Library and MEDLINE from 1966 to March 2004, using a detailed list of terms related to phytoestrogens and menopausal symptoms and also hand-searched abstracts from relevant meetings. METHODS OF STUDY SELECTION: Randomized trials were eligible if they involved symptomatic perimenopausal or postmenopausal women, compared phytoestrogen with placebo or control, reported hot flush frequency or menopausal symptom scores, and were at least 4 weeks in duration. TABULATION, INTEGRATION, AND RESULTS: Data were extracted onto standardized forms using a prospectively developed protocol. Twenty-five trials involving 2,348 participants met criteria. At baseline, the mean age was 53.1 years, mean duration of menopause was 4.3 years, and mean daily hot flush frequency was 7.1. Mean study duration was 17 weeks. Trials were grouped into categories according to type of phytoestrogen: soy foods, beverages, or powders (n = 11); soy extracts (n = 9); and red clover extracts (n = 5). Of the 8 soy food trials reporting hot flush frequency outcomes, 7 were negative. Five trials of soy foods provided information to calculate effect sizes; these were in the small-to-medium range, favoring placebo in 3 trials and soy in 2. Of the 5 soy extract trials reporting hot flush frequency, 3 (including the 2 largest trials) were negative. Effect sizes were calculated for 2 soy extract trials: one favored placebo with small effect size and the other favored soy with moderate effect size. Red clover trials showed no improvement in hot flush frequency (weighted mean difference -0.60, 95% confidence interval -1.71 to 0.51). Adverse effects were primarily gastrointestinal and taste intolerance in the soy food and beverage trials. CONCLUSION: The available evidence suggests that phytoestrogens available as soy foods, soy extracts, and red clover extracts do not improve hot flushes or other menopausal symptoms.     

Phytoöstrogene

Herbal estrogens are substances found in food, i.e., lignans or isoflavones, that induce biological responses in mammals including the human and can imitate or modulate the activity of endogenous estrogens. Epidemiological studies suggest that high intake of phytoestrogens might be associated with a lower risk of developing breast and prostate cancer. Furthermore, data from clinical studies point to preventive effects in cardiovascular disease, postmenopausal osteoporosis, climacteric symptoms, and neurocognitive disorders. There is no direct evidence as yet for these postulated effects in humans by long-term intervention studies. Most if not all information is based on intake of herbal estrogen-rich food in Asian populations or short-term interventions in Western populations. Until now, however, the postulated protective effects are not definitely associated with the bioavailability of these phytoestrogens. Other substances with biological activity in food products might also be responsible for the postulated protective effects. Causal protection by phytoestrogen activity in humans and mechanisms remain to be proved. There are insufficient data concerning negative side effects of herbal estrogens. Further studies are needed to clarify the preventive and therapeutic potential of these substances and possible endocrine side effects.     

Effects of soy isoflavones on menopausal neurovegetative symptoms

AIM: Dietary soy supplementation may reduce the incidence of hot flushes in postmenopausal women due to the presence of phytoestrogens in soy foods. The aim of this study was to assess the effects of a 3-month administration of different doses of either oral or transdermal soy isoflavones on climacteric complaints in postmenopausal women. METHODS: Sixty postmenopausal women were assigned randomly to one of the following groups: groups A and B received 50 mg/day or 75 mg/day of oral isoflavones respectively, while groups C and D received 6 mg/day or 12 mg/day of transdermal isoflavones. A control group (group E) was composed of 15 patients that did not receive any treatment. Hot flushes, Kupper-man index and vaginal dryness at baseline and then after 5, 9 and 13 weeks were evaluated. RESULTS: The isoflavone treatment led to a progressive significant (p<0.01) reduction of the number of hot flushes in the groups A, B and D with a dose-related effect in group D. At week 13, the Kupperman index and hot flush score decreased significantly in all the treated groups, while vaginal dryness score was reduced only in group B. CONCLUSION: Our findings suggest that both oral and transdermal soy isoflavones are effective to attenuate slight to moderate menopausal neurovegetative symptoms with a dose-related effect.     

Use of alternative and complementary medicine in menopause.

OBJECTIVES: To review the clinical evidence available for the treatment of menopausal symptoms with alternative and complementary medicine. METHODS: The MEDLINE, PREMEDLINE and COCHRANE electronic databases for the years 1980-2002 were searched for articles concerning soy products, black cohosh, dong quai, acupuncture, ginseng and evening primrose oil. Studies pertaining to menopausal vasomotor symptoms, lipid profiles and bone mineral densities of postmenopausal women were included. The data from clinical trials were reviewed. RESULTS: Soy isoflavones slightly decrease total cholesterol and LDL levels. The clinical significance of this small change is yet to be determined. The synthetic isoflavone derivative ipriflavone increases bone mineral density in healthy peri- and postmenopausal women with moderate bone mineral densities. Although earlier reports have claimed that soy is beneficial for the improvement of vasomotor symptoms, recent data do not support this claim. There are insufficient data on the other alternative therapies for treating menopausal symptoms at this time. CONCLUSION: Alternative and complementary medicine may play a role in the management of menopause, however, well-designed large studies are still needed.     

Amniotic fluid and maternal characteristics in Chinese pregnancies dated by early ultrasound biometry.

Phytoestrogens (PEs) are natural compounds, with a biological activity like estrogen, which comprise isoflavones, lignans and coumestans. A traditional Asiatic phytoestrogen-rich diet is associated with a lower incidence of breast cancer and postmenopausal illness, and much evidence indicates that PEs prevent bone resorption, increase bone density and reduce cholesterol. The estrogenic effects of phytoestrogens can be useful in preventing postmenopausal osteoporosis and cardiovascular disease.     

Phytoestrogens and the risk of breast cancer: a review of the literature

BACKGROUND: Over the last decade, interest in the physiological role of bioactive compounds in plants has increased dramatically. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of nonsteroidal estrogens that are widely distributed within the plant kingdom, including isoflavones and lignans. Epidemiological studies suggest that diets rich in phytoestrogens, particularly soy and unrefined grain products, may be associated with low risk of breast cancer. This review presents the studies published so far exploring a link between dietary phytoestrogens and breast cancer risk. METHODS: A Medline search was conducted using the key words below. Further articles were obtained by cross-matching references of relevant articles. Twenty-one case-control and 15 prospective studies were identified since 1978. One meta-analysis and several review articles also were noted. RESULTS: Results from previous studies were analyzed and comparisons were made between each type of study. Controversy exists regarding this subject, and we found conflicting evidence in recent literature regarding this hypothesis. CONCLUSION: There is no clear evidence that phytoestrogen intake influences the risk of developing breast cancer.     

Activity of isoflavones and berberine on vasomotor symptoms and lipid profile in menopausal women

The aim of this study was to evaluate the efficacy of a food supplement combination based on isoflavones and berberine (ISB) in the treatment of menopausal symptoms and dyslipidaemia. Isoflavones are extracted from soy and absorbed in the body after being activated by lactobacillus. Berberine, extracted from the plant Berberis aristata, lowers plasma cholesterol and triglycerides (TG) by increasing low-density lipoprotein (LDL) receptors and reducing hepatic synthesis of TG. One hundred twenty women with a mean age of 54.8?±?0.6 years were enrolled and randomized to treatment with ISB (estromineral lipid [EL]?=?60 cases) or calcium and vitamin D₃ (CaD?=?60 cases). Menopausal symptoms, plasma cholesterol, and TG were evaluated at baseline, and after 4 and 12 weeks. EL treatment significantly lowered plasma total cholesterol (?13.5% ± 0.7 vs ?0.2% ± 0.5), LDL cholesterol (?12.4% ± 1.5 vs + 0.8 % ± 0.7) and TG (?18.9% ± 2.5 vs ?1.3% ± 1.2) and improved menopausal symptoms compared with CaD treatment. Safety parameters were unchanged during the study. The combination of berberine and isoflavones was effective in lowering cardiovascular (CV) risk factors in menopausal women with moderate dyslipidaemia and in improving their quality of life.     

Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review

Background Interest in non-hormonal therapies for the treatment of menopausal symptoms has increased since the publication of adverse effects of estrogen replacement therapy. Objective To provide information on the efficacy of non-hormonal therapies for menopausal vasomotor symptoms based on evidence from published randomised controlled studies. Methods The Cochrane Database of Systematic Reviews (CDSR), MEDLINE, Alternative Therapies in Health and Medicine database (ATHMD) and Allied and Complementary Medicine database (AMED) were searched for randomised controlled trials in the English language reporting data on treatment of menopausal vasomotor symptoms. Trials including cancer breast patients were included. Results Our search identified 58 randomised controlled trials of which 11 involved the use of clonidine, six for SSRIs, four for gabapentin, seven for black cohosh, seven for red clover, 18 for phytoestrogens, two for ginseng, one for evening primrose, one for dong quai and one for vitamin E. Most trials had methodological deficiencies. Conclusion There is evidence that clonidine, paroxetine, venlafaxine, gabapentin and black cohosh may be beneficial in the treatment of menopausal vasomotor symptoms in some women. Current evidence does not support the use of fluoxetine, red clover, phytoestrogens, Ginseng, evening primrose, dong quai and vitamin E. The side effects profile of these therapies should be considered.     

Alternative Therapiemöglichkeiten zur Hormontherapie in der Postmenopause

Despite increasing interest in alternative therapies for menopausal hot flashes that avoid use of estrogens, the efficacy and safety of other options currently are not well supported. In women who need relief for mild vasomotor symptoms isoflavones or black cohosh are recommended. Non-hormonal treatments are not as effective as estrogens in relieving hot flashes. There is a suggestion, but no conclusive evidence, that isoflavones have a beneficial effect on bone health and that there is an association between lifelong soya bean intake und reduced risk of breast cancer. Recommended options for women with contraindications relating to estrogen-containing treatments include serotonin reuptake inhibitors and gabapentin.     

Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women

OBJECTIVE: To evaluate the effects of dietary isoflavones in soy products on menopausal symptoms, lipid profiles, and bone mineral densities in postmenopausal Japanese women. METHODS: We estimated the daily intakes of isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption. We recorded serum values of fasting total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoproteins. Bone mineral density was measured at the lumbar spine (L2-L4) by dual energy x-ray absorptiometry. Women were assigned to two groups according to years since menopause (early and late postmenopausal groups), and each group was subcategorized into four groups according to dietary isoflavone intake. Relationships between isoflavone intake, menopausal symptoms, lipid profiles, and bone mineral density were examined in each group. RESULTS: The mean estimated intake of isoflavones among 478 women was 54.3 mg/day. With stepwise regression analysis we found that weight and years since menopause were significant independent predictors of bone mineral density. Bone mineral densities adjusted to years since menopause and weight were significantly different in the highest intake compared with lowest intake category (P <.001) within the early and late postmenopausal groups. In the early postmenopausal group, significant differences were found in palpitation and backaches between the high and low intake categories but were not significant in the late postmenopausal group. CONCLUSION: High consumption of soy products is associated with increased bone mass in postmenopausal women and might be useful for preventing hypoestrogenic effects.     

Endometrial,breast and liver safety of soy isoflavones plus Lactobacillus sporogenes in post-menopausal women

Objective: To assess the safety of a nutraceutical compound containing soy isoflavones and Lactobacillus sporogenes on endometrium, breast and liver function. Setting: Outpatient Menopausal Clinic. Study Design: 130 healthy postmenopausal women suffering from menopausal symptoms were randomized to receive soy isoflavones 60?mg and Lactobacillus sporogenes 1 billion spores (group E: 65 women) or calcium and vitamin D₃ (group C: 65 women). Safety of the treatment was assessed at baseline and after 1 year taking into account endometrial thickness, mammographic density, serum levels of transaminases, γ-GT and bilirubin. Efficacy of the treatment was evaluated rating the score of menopausal symptoms at baseline and every 3 months. The statistical analysis was carried out with χ², Fisher exact’s test and ANOVA. Results: After 12 months of treatment mammographic density, endometrial thickness and hepatic function did not show significant differences between groups, while menopausal symptoms were progressively and significantly reduced in severity and frequency during treatment with soy isoflavones plus Lactobacillus sporogenes versus calcium plus vitamin D₃. Conclusion: A 12 months treatment with a nutraceutical compound based on isoflavones and Lactobacillus sporogenes at the recommended doses is safe for endometrium, mammary glands and liver function in postmenopausal women.     

Phytoestrogens and bone health at different reproductive stages

Abstract

Background: Isoflavones are an alternative to hormonal therapy for the relief of menopausal symptoms. Since isoflavones interact with estrogen receptors it has been hypothesized that such substances may have an effect on bone health.

Objective: To clarify the effect of isoflavones on bone at experimental and clinical level, and to identify areas that require further clarification and research.

Method: A systematic review of studies involving isoflavones and bone health was performed, and a specific search on isoflavone’s mechanism of action and the importance of equol production was made based on Internet search engines, MEDLINE (1966–October 2012) and the Cochrane Controlled Clinical Trials Register. This search was supplemented by a handsearch of reference lists of selected papers.

Results: In vitro and animal studies show a positive effect of isoflavones on bone which has not been clearly confirmed by long-term human trials. Equol producers seem to present a more positive response to isoflavone intervention. Isoflavone rich diets could help maintain peak bone mass in premenopausal women. The effect of isoflavones in perimenopausal women is insufficiently studied but it seems to attenuate bone loss in the menopausal transition. In postmenopause, isoflavones may present a modest benefit but its clinical relevance in preventing osteoporotic fractures remains to be determined.

Conclusions: The present review suggests that isoflavone increase bone mineral density and decrease the bone turnover resorption markers. The effect of soy isoflavones on BMD is mediated by equol production, reproductive status, supplement type, isoflavone dose and intervention duration.     

The effect of soy-derived isoflavones over hot flushes,menopausal symptoms and mood in climacteric women with increased body mass index

Background.?Risk-benefit issues raised after the WHI have significantly increased the use of alternative treatments for the menopause. Despite this, data regarding the effect of soy isoflavones over mood and menopausal symptoms in high risk populations is still lacking.

Objective.?To evaluate the effect of soy derived isoflavones over hot flushes, menopausal symptoms and mood in climacteric women with increased body mass index (BMI).

Methods.?Fifty symptomatic climacteric women aged 40 to 59 with increased BMI (≥25) were recruited to receive oral 100?mg/day of soy derived isoflavones (Climasoy®) for 3 months. Hot flushes (frequency/intensity), menopausal symptoms (Menopause Rating Scale [MRS]) and mood (Hamilton Depressive Rating Scale [HDRS]) were evaluated at baseline and at 90 days.

Results.?A total of 45 women completed the study. After 3 months of soy isoflavone supplementation hot flushes significantly decreased in percentage, number and severity (100% to 31.1%; 3.9?±?2.3 to 0.4?±?0.8 and 2.6?±?0.9 to 0.4?±?0.8, respectively, p?<?0.001). MRS scores (total and for subscales) reflecting general menopausal symptoms also significantly decreased compared to baseline. Regarding mood, after three months total HDRS scores and the rate of women presenting depressed mood (scores?≥?8) significantly decreased (16.3?±?5.4 to 6.9?±?5.2 and 93.3% to 28.9%, respectively, p?<?0.05). There was no effect on blood pressure levels or BMI values after treatment.

Conclusion.?In this high risk climacteric population, soy derived isoflavone treatment improved mood as well as vasomotor and general menopausal symptoms. More research is required to determine if the positive effect over mood is a direct or an indirect one through hot flush alleviation.