Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial.

The role of calcifediol in the perception of chronic pain is a widely discussed subject. Low serum levels of calcifediol are especially common in patients with severe pain and fibromyalgia syndrome (FMS). We lack evidence of the role of vitamin D supplementation in these patients. To our knowledge, no randomized controlled trial has been published on the subject. Thirty women with FMS according to the 1990 and 2010 American College of Rheumatology criteria, with serum calcifediol levels <32ng/mL (80nmol/L), were randomized to treatment group (TG) or control group (CG). The goal was to achieve serum calcifediol levels between 32 and 48ng/mL for 20weeks via oral supplementation with cholecalciferol. The CG received placebo medication. Re-evaluation was performed in both groups after a further 24weeks without cholecalciferol supplementation. The main hypothesis was that high levels of serum calcifediol should result in a reduction of pain (visual analog scale score). Additional variables were evaluated using the Short Form Health Survey 36, the Hospital Anxiety and Depression Scale, the Fibromyalgia Impact Questionnaire, and the Somatization subscale of Symptom Checklist-90-Revised. A marked reduction in pain was noted over the treatment period in TG: a 2 (groups)×4 (time points) variance analysis showed a significant group effect in visual analog scale scores. This also was correlated with scores on the physical role functioning scale of the Short Form Health Survey 36. Optimization of calcifediol levels in FMS had a positive effect on the perception of pain. This economical therapy with a low side effect profile may well be considered in patients with FMS. However, further studies with larger patient numbers are needed to prove the hypothesis.

Calcium nutrition and extracellular calcium sensing: relevance for the pathogenesis of osteoporosis, cancer and cardiovascular diseases.

Through a systematic search in Pubmed for literature, on links between calcium malnutrition and risk of chronic diseases, we found the highest degree of evidence for osteoporosis, colorectal and breast cancer, as well as for hypertension, as the only major cardiovascular risk factor. Low calcium intake apparently has some impact also on cardiovascular events and disease outcome. Calcium malnutrition can causally be related to low activity of the extracellular calcium-sensing receptor (CaSR). This member of the family of 7-TM G-protein coupled receptors allows extracellular Ca2+ to function as a "first messenger" for various intracellular signaling cascades. Evidence demonstrates that Ca2+/CaSR signaling in functional linkage with vitamin D receptor (VDR)-activated pathways (i) promotes osteoblast differentiation and formation of mineralized bone; (ii) targets downstream effectors of the canonical and non-canonical Wnt pathway to inhibit proliferation and induce differentiation of colorectal cancer cells; (iii) evokes Ca2+ influx into breast cancer cells, thereby activating pro-apoptotic intracellular signaling. Furthermore, Ca2+/CaSR signaling opens Ca2+-sensitive K+ conductance channels in vascular endothelial cells, and also participates in IP(3)-dependent regulation of cytoplasmic Ca2+, the key intermediate of cardiomyocyte functions. Consequently, impairment of Ca2+/CaSR signaling may contribute to inadequate bone formation, tumor progression, hypertension, vascular calcification and, probably, cardiovascular disease.

Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis.

Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1a-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.

Colonic vitamin D metabolism: implications for the pathogenesis of inflammatory bowel disease and colorectal cancer.

In epidemiological studies serum levels below 30 nM of 25-OHD(3), the precursor of the active vitamin D metabolite 1,25-(OH)(2)D(3), were consistently associated with incidence of colorectal cancer. The active vitamin D metabolite possesses antimitotic, prodifferentiating and proapoptotic capacity in vivo and in vitro. The intestinal autocrine/paracrine vitamin D system, which is the main source of local 1,25-(OH)(2)D(3) plays a critical role in maintaining both mucosal immunity and normal growth of epithelial cells. It has been hypothesized that the VDR-mediated signaling antagonizing TNF-α and IL-6 receptor-activated pro-inflammatory and proliferative intracellular pathways, may prevent development of IBD and colitis-associated colorectal cancer. Conversely, any situation that impairs the efficiency of the 1,25-(OH)(2)D(3)/VDR signaling system at the level of the gut mucosa, e.g. vitamin D insufficiency, may increase risk for the development of IBD and colorectal cancer. Therefore, not only adequate serum levels of the precursor 25-OHD(3) are essential, but also optimal expression of the 1α-hydroxylating enzyme CYP27B1. The 1,25-(OH)(2)D(3) catabolizing hydroxylase CYP24A1 is increasingly expressed during colon cancer progression, indicating that colonocytes are released from normal growth control by the steroid hormone. Securing adequate levels of calcitriol by inhibition of catabolism and support of 1α-hydroxylation by calcium, phytoestrogens and folate could be a valid approach to control, at least in part, IBD and CRC pathogenesis.

Calcium, vitamin D and cancer.

A low vitamin D status and inadequate calcium intake are important risk factors for various types of cancer. Ecological studies using solar UV-B exposure as an index of vitamin D3 photoproduction in the skin found a highly significant inverse association between UV-B and mortality in fifteen types of cancer. Of these, colon, rectal, breast, gastric, endometrial, renal and ovarian cancer exhibit a significant inverse relationship between incidence and oral intake of calcium. In addition, lung and endometrial cancer as well as multiple myeloma are considered calcium and vitamin D sensitive. Studies on tissue-specific expression of the CYP27B1-encoded 25-hdroxyvitamin D-1alpha-hydroxylase and of the extracellular calcium-sensing receptor (CaR) have led to an understanding how locally produced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and extracellular Ca2+ act jointly as key regulators of cellular proliferation, differentiation and function. Thus, impairment of antimitogenic, proapoptotic and prodifferentiating signaling from the 1,25(OH)2D3-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency has been implicated in the pathogenesis of the aforementioned types of cancer. 1,25(OH)2D3 and calcium interact in modulating cell growth in different ways: (i) Signaling pathways from the VDR and the CaR converge on the same downstream elements, e.g. of the canonical Wnt pathway; (ii) high extracellular calcium modulates extrarenal vitamin D metabolism in favor of higher local steady-state concentrations of 1,25(OH)2D3; (iii) 1,25(OH)2D3 may up-regulate expression of the CaR and thus augment CaR-mediated antiproliferative responses to high extracellular Ca2+. This can explain why combined supplementation is required for optimal chemoprevention of cancer by calcium and vitamin D.

Modulation of vitamin D synthesis and catabolism in colorectal mucosa: a new target for cancer prevention.

Sporadic colorectal cancer is a disease of advancing age and the percentage of the population which reaches an advanced age is strongly increasing. Multiple factors are responsible for the etiology of this cancer since the colorectal mucosa is directly influenced by nutrients reaching the colonic lumen and impacting on mucosal cells. The vitamin D system appears to be central to several preventative molecular pathways. Insufficiency of the serum precursor 25-hydroxyvitamin D3 has been linked by epidemiology to enhanced colon tumor incidence, most likely because it is a major determinant of 1,25-dihydroxyvitamin D3 synthesis in colonic mucosal cells. Bound to its receptor, vitamin D regulates colonic proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy, vitamin D synthesis is enhanced to counteract hyperproliferation, whereas in high-grade tumors catabolism by far surpasses synthesis. The colonic vitamin D system is regulated by several known natural factors. One of the most important ones is nutritional calcium that, if supply is low, will result in enhanced catabolism of colonic 1,25-dihydroxyvitamin D3. Estrogenic compounds can increase expression and activity of the synthesizing 25-hydroxyvitamin D-1alpha-hydroxylase. Due to enhanced synthesis of the active metabolite, this can lead to protection against colorectal tumors in women. During tumor progression, expression of 25-hydroxyvitamin D-1alpha-hydroxylase as well as of the catabolizing 25-hydroxyvitamin D-24-hydroxylase appears to be under epigenetic control as demonstrated by studies with phytoestrogens and folate. It is commonly accepted that sporadic colorectal cancer pathogenesis is multifactorial and these are just a few examples of the regulatory capacity of natural (nutrient) substances for improving the colonic vitamin D system. However, protection by vitamin D might have central importance, with nutrients increasing the efficiency of the vitamin D system in a targeted manner. This could result in prevention of hyperproliferation or retardation of progression to clinically manifest primary colonic tumors.

Mutual associations between malignancy, age, gender, and subsite incidence of colorectal cancer.

BACKGROUND: A cross-sectional study was performed on a cohort of colorectal cancer (CRC) patients to reveal any influence of age, gender, and subsite on grades of malignancy. PATIENTS AND METHODS: Data from histopathological grading according to WHO criteria were pooled into groups of low-grade (well and moderately differentiated) and high-grade (poorly and undifferentiated) cancer and analyzed for associations. RESULTS: In general, women with CRC were significantly older than men (p<0.05). In particular, women with high-grade cancer in the proximal and distal colon had a median age of 75 years and were thus 10-15 years older (p<0.01 and p<0.05, respectively) than their male counterparts. In contrast, high-grade rectal cancer developed in both genders around the early age of 60 years. CONCLUSION: Women are protected from more aggressive cancer in the colon though not in the rectum until well after menopause. This likely reflects the differential sensitivity of the mucosa at these sites against the anticancer effects triggered by activation of estrogen receptor-beta.

Parallel elevation of colonic 1,25-dihydroxyvitamin D3 levels and apoptosis in female mice on a calcium-deficient diet.

BACKGROUND: Epidemiology suggests that nutritional calcium and vitamin D together prevent colorectal tumor progression. 1,25(OH)2D3 is synthesized and degraded in colonocytes and, when bound to its receptor, has antiproliferative activity. MATERIALS AND METHODS: 1,25(OH)2D3 levels have been successfully measured in cell culture, but this is technically difficult in tissues. Double extraction coupled to an enzyme immunoassay was used to determine 1,25(OH)2D3 concentration in colon mucosa. RESULTS: In a mouse model fed low (0.04%) nutritional calcium, expression of the vitamin D catabolizing CYP24A1, of the synthesizing CYP27B1 hydroxylase and of the vitamin D receptor was induced in the right colon only. While CYP24A1 mRNA was raised in both genders, raised CYP27B1 and VDR was found in females only. Levels of 1,25(OH)2D3 were significantly higher in the right colon of females fed 0.04% calcium compared with the control group on 0.9% calcium, and with males fed either diet. Parallel to increased 1,25(OH)2D3, the intrinsic apoptotic pathway was enhanced in the right colon of females only. CONCLUSION: This demonstrates the significance of high nutritional calcium for colonic accumulation of 1,25(OH)2D3 and suggests that female sex hormones may protect against mitotic action of low nutritional calcium by inducing 1,25(OH)2D3 synthesis.

Regulation of the colonic vitamin D system for prevention of tumor progression: an update.

A compromised vitamin D status and nutritional calcium deficit are linked with sporadic colorectal cancer incidence. 25(OH)D(3) serum concentration is a major determinant of 1,25-dihydroxyvitamin D3 (1,25[OH](2)D(3)) synthesis in colonic mucosa, which expresses the vitamin D receptor and both the synthesizing (CYP27B1) and catabolic (CYP24A1) hydroxylases. Receptor-bound, 1,25(OH)(2)D(3) regulates proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy 1,25(OH)(2)D(3) synthesis is often enhanced to counteract hyperproliferation. In many advanced tumors, vitamin D catabolism surpasses synthesis. In vivo, expression and activity of CYP27B1 and vitamin D receptor are stimulated by (phyto)estrogens. Conversely, low nutritional calcium and folate enhance vitamin D catabolism. These insights could explain the lower colorectal cancer incidence in females, the chemopreventive potency of vitamin D and calcium against colorectal cancer, and the benefit of nutritional folate as a methyl donor for epigenetic regulation of the vitamin D system.

Estimated benefit of increased vitamin D status in reducing the economic burden of disease in western Europe.

Vitamin D has important benefits in reducing the risk of many conditions and diseases. Those diseases for which the benefits are well supported and that have large economic effects include many types of cancer, cardiovascular diseases, diabetes mellitus, several bacterial and viral infections, and autoimmune diseases such as multiple sclerosis. Europeans generally have low serum 25-hydroxyvitamin D [25(OH)D] levels owing to the high latitudes, largely indoor living, low natural dietary sources of vitamin D such as cold-water ocean fish, and lack of effective vitamin D fortification of food in most countries. Vitamin D dose-disease response relations were estimated from observational studies and randomized controlled trials. The reduction in direct plus indirect economic burden of disease was based on increasing the mean serum 25(OH)D level to 40 ng/mL, which could be achieved by a daily intake of 2000-3000 IU of vitamin D. For 2007, the reduction is estimated at euro187,000 million/year. The estimated cost of 2000-3000 IU of vitamin D3/day along with ancillary costs such as education and testing might be about euro10,000 million/year. Sources of vitamin D could include a combination of food fortification, supplements, and natural and artificial UVB irradiation, if properly acquired. Additional randomized controlled trials are warranted to evaluate the benefits and risks of vitamin D supplementation. However, steps to increase serum 25(OH)D levels can be implemented now based on what is already known.

Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer.

There is a growing body of evidence that disturbed circadian clock gene expression is associated with tumor development and tumor progression. Based on our initial experiments demonstrating decreased period 1 (Per1) expression in colon cancer, we evaluated clock gene and estrogen receptor (ER) alpha/beta expression in colon cancer cells of primary colorectal tumors and adjacent normal colon mucosa (NM) by real-time RT-PCR. Analysis of gene expression in G(2) and G(3) colorectal tumors revealed a decrease of Per1 mRNA compared with paired NM (G(2): 0.52-fold; P = n.s. and G(3): 0.48-fold; P = 0.03). A significant gender specific difference of Per1 expression was observed in G(2) tumors as compared with NM (female: 0.38-fold; P = 0.004 vs. male: 0.73-fold; P = n.s.). Expression of CLOCK was significantly elevated in G(2) tumors of male patients (1.63-fold, P = 0.01). The expression of ER-beta was significantly decreased in G(2) and G(3) tumors (G(2): 0.32-fold; P = 0.003 and 0.27; P = 0.001). No significant gender specific differences of ER-beta reduction in tumors were observed. A significant correlation between the decrease of Per1 and ER-beta in colorectal tumors (r = 0.61; P < 0.001) was found. No changes in gene expression were detected for ER-alpha and Per2. Our data demonstrate a correlated decrease of Per1 and ER-beta in colorectal tumors, mediated probably by epigenetic mechanisms. The observed gender differences in the expression of CLOCK and Per1 in G(2) tumors might suggest a gender-specific, distinctive role of the cellular clock in colorectal tumorigenesis.

Chemoprevention of colorectal neoplasia by estrogen: potential role of vitamin D activity.

Postmenopausal hormone replacement therapy lowers colon cancer incidence. In humans, the mechanism is unknown, but animal models suggest that it may involve activation of the vitamin D receptor (VDR) pathway. The aims of our study were to determine whether estrogen intervention affects global gene expression in rectal mucosal biopsies and whether vitamin D-related genes are affected. Estradiol was given to raise serum estradiol to premenopausal levels in 10 postmenopausal women under close nutritional control. Primary end points were expression of VDR, CYP24A1, CYP27B1, and E-cadherin in rectal mucosa by reverse transcription-PCR and examining response to estradiol by genome-wide arrays. Responses in gene expression in rectal biopsies to estrogen were determined in each subject individually and compared with a human estrogen response gene array database and a custom array in vitro-generated database. Cluster analysis showed that subjects maintained their overall gene expression profile and that interindividual differences were greater than intraindividual differences after intervention. Eight of 10 subjects showed significant enrichment in estrogen-responsive genes. Gene array group analysis showed activation of the VDR pathway and down-regulation of inflammatory and immune signaling pathways. Reverse transcription-PCR analysis showed significant up-regulation of VDR and E-cadherin, a downstream target of vitamin D action. These data suggest that the chemopreventive action of hormone replacement therapy on colon neoplasia results, at least in part, from changes in vitamin D activity. Evaluation of gene arrays is useful in chemopreventive intervention studies in small groups of subjects.

Vitamin D and calcium insufficiency-related chronic diseases: an emerging world-wide public health problem.

Vitamin D and calcium insufficiencies are risk factors for multiple chronic diseases. Data from 46 recent studies from Europe, North America, South-East Asia and the South Pacific area clearly indicate that a low vitamin D status and inadequate calcium nutrition are highly prevalent in the general population (30-80%), affecting both genders. The extent of insufficiencies is particularly high in older populations, and in some geographical areas, also in children and in young women of child-bearing age, in ethnic minorities and immigrants, as well as in people of low socio-economic status. Enrichment of cereal grain products with vitamin D and calcium would be a viable approach to increase consumption and improve health outcomes in the general population worldwide.

Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes.

Low nutritional calcium contributes to disruption of the intestinal epithelial barrier function, to hyperproliferation of colonocytes and increased occurrence of aggressive secondary bile acids in the gut lumen. These mechanisms are also known to be involved in the etiology of colonic inflammation and cancer. We studied in mice and human adenocarcinoma-derived Caco-2 cells the impact of low calcium on markers of inflammation (cyclooxygenase-2; COX-2), of detoxification (pregnane and xenobiotic receptor (PXR)/steroid and xenobiotic receptor (SXR), cytochrome P450 steroid-inducible 3a11 (CYP3A11)), and on expression of the vitamin D system as a protection against tumorigenesis. Caco-2 cells express high COX-2 and low SXR mRNA levels when subconfluent. During differentiation this is reversed, while low calcium enhanced COX-2 protein expression. In vivo low dietary calcium significantly increased the expression of the PXR target gene CYP3A11 in the proximal colon, suggesting compensatory defense mechanisms. In comparison with males, low nutritional calcium elicits a better protective response in females: both the vitamin D synthesizing 25-hydroxyvitamin D(3 )1alpha hydroxylase (CYP27B1) mRNA and the detoxifying CYP3A11 mRNA are augmented more. While it is recognized that colonic vitamin D synthesis may prevent tumor progression, low dietary calcium also elevates the 1,25-(OH)(2)-D(3) catabolic 25-hydroxyvitamin D(3) 24 hydroxylase (CYP24) expression primarily in the proximal colon. Our data suggest the proximal colon as the primary site of response to insufficient calcium intake.

Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells.

BACKGROUND: Many cancer cells produce interleukin-6 (IL-6), a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of IL-6 modulators, i.e. IL-1beta, prostaglandin E2, 17beta-estradiol, and 1,25-dihydroxyvitamin D3, on expression and synthesis of the cytokine at different stages of tumour progression. METHODS: We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the IL-6 gene promoter. RESULTS: IL-6 mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1beta (5 ng/ml) to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17beta-estradiol (10-7 M) reduced basal IL-6 production by one-third, but IL-1beta-inducible IL-6 was unaffected. Search for polymorphisms in the IL-6 promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the IL-6 gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-myc proto-oncogene expression. These effects were inhibited by 10-8 M 1,25-dihydroxyvitamin D3. CONCLUSION: In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally affected, if at all, by PGE2, 1,25-dihydroxyvitamin D3, and 17beta-estradiol. However, IL-6 is highly abundant in undifferentiated tumour cells and is effectively stimulated by IL-1beta. In case of overexpression of an IL-6 gene variant with extreme sensitivity to IL-1beta, massive release of the cytokine from undifferentiated tumour cells may accelerate progression towards malignancy by paracrine action on more differentiated tumour cells with a still functioning proliferative IL-6 signalling pathway.

Regulation of genes of the circadian clock in human colon cancer: reduced period-1 and dihydropyrimidine dehydrogenase transcription correlates in high-grade tumors.

Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells.

Phytoestrogens in clinical practice: a review of the literature.

OBJECTIVE: To review clinical studies assessing the effect of phytoestrogen supplementation on the signs and symptoms of the climacteric syndrome and on the incidence of breast cancer, cardiovascular disease, and skeletal fractures. DESIGN: Literature research using PubMed and the Cochrane controlled trials register. SETTING: None. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Six systematic reviews and meta-analyses of 25 randomized, controlled trials (RCTs) assessing the use of phytoestrogens for the treatment of the climacteric syndrome were identified. Systematic reviews of RCTs show contradictory results, and meta-analyses demonstrate no statistically significant reduction of vasomotor symptoms for phytoestrogens. Individual RCTs report significant reductions in vasomotor symptoms for red clover and soy phytoestrogens. In selected patient populations, such as in women with early natural postmenopause and mild to moderate vasomotor symptoms, a systematic review of five RCTs found a significant reduction of hot flashes in five out of five RCTs. Twenty-two case-control and cohort studies examined the incidence of breast cancer among women with and without a diet high in phytoestrogens. A meta-analysis of 21 studies found a significantly reduced incidence of breast cancer among past phytoestrogen users. RCTs document beneficial effects of phytoestrogens on surrogate parameters such as bone mineral density, vasodilation, platelet aggregation, insulin resistance, and serum concentrations of triglycerides, high-density lipoprotein, and low-density lipoprotein. None of the available RCTs documents a protective effect of phytoestrogens for the clinical end points of breast cancer, bone fracture, or cardiovascular events. CONCLUSION(S): Based on the available evidence, phytoestrogens should only be used in selected women, i.e., those presenting with mild to moderate vasomotor symptoms in early natural postmenopause. None of the compounds investigated so far have been proven to protect against breast cancer, bone fracture, or cardiovascular disease.