Recently, n-3 fatty acids are in the center of attention for their potent anti-inflammatory effects. Osteoporosis as a chronic senile disease is associated with inflammation, and the role of inflammatory mediators has been demonstrated in recent years. The beneficial effects of n-3 fatty acids on bone were proven in many animal studies, while to date, no conclusive data is available in human. The aim of this study was to evaluate the impact of n-3 fatty acids on bone biomarkers in osteoporotic postmenopausal women. Twenty-five osteoporotic postmenopausal women were recruited in the study and randomized in treatment and control groups. The patients received 900 mg n-3 fatty acid capsules or placebo per day for 6 months. Serum levels of osteocalcin, bone alkaline phosphatase (BALP), calcium, vitamin D, and parathormone and urine concentration of pyridinoline (Pyd) were measured at baseline, second month, and sixth month in both groups. In the treatment group, compared with baseline, at the second month, osteocalcin increased slightly; thereafter, it showed decrement trend until the end of the study. In the control group, it decreased all over the study. None of these changes was significant. BALP showed nonsignificant decrease from baseline over the time in both groups. Urine level of Pyd decreased significantly (P < 0.05) in the treatment group, while no significant change was seen in the control group. Serum calcium and vitamin D increased in both groups; however, changes were not significant. No significant changes were seen in calcium clearance and parathormone. In conclusion, n-3 fatty acids can decrease bone resorption; however, it could not affect bone formation significantly after 6 months treatment. Further investigations are recommended.
Osteoporosis; n-3 fatty acids; Osteocalcin; Bone alkaline phosphatase; Pyridinoline
Osteoporosis is characterized by skeletal degeneration with low bone mass and destruction of microarchitecture of bone tissue which is attributed to various factors including inflammation. Women are more likely to develop osteoporosis than men due to reduction in estrogen during menopause which leads to decline in bone-formation and increase in bone-resorption activity. Estrogen is able to suppress production of proinflammatory cytokines such as IL-1, IL-6, IL-7, and TNF-α. This is why these cytokines are elevated in postmenopausal women. Studies have shown that estrogen reduction is able to stimulate focal inflammation in bone. Labisia pumila (LP) which is known to exert phytoestrogenic effect can be used as an alternative to ERT which can produce positive effects on bone without causing side effects. LP contains antioxidant as well as exerting anti-inflammatory effect which can act as free radical scavenger, thus inhibiting TNF-α production and COX-2 expression which leads to decline in RANKL expression, resulting in reduction in osteoclast activity which consequently reduces bone loss. Hence, it is the phytoestrogenic, anti-inflammatory, and antioxidative properties that make LP an effective agent against osteoporosis.
Collagen breakdown, and thus bone resorption, can now be assessed by measuring the urinary excretion of the collagen crosslinks, pyridinoline (Pyd) and deoxypyridinoline (Dpd). In a pilot study we measured Pyd and Dpd in 20 patients with breast cancer, ten with known bone metastases and ten with no recognised metastases in bone or elsewhere after 1 year's subsequent follow up. Eight out of the ten patients with metastases had crosslink excretion values higher than the reference interval, but so did some patients without known metastatic disease. For both crosslinks there was a clear correlation with serum alkaline phosphatase activity measured at about the same time. We consider that measurement of urinary collagen crosslink assays may have a place in the early detection of metastatic spread to bone.
Metabolic syndrome is a cluster of coronary heart disease (CHD) risk factors of which central obesity, insulin resistance, increased triglycerides/decreased HDL cholesterol, and hypertension are major cardiovascular risk factors. The educational objectives of this review are to describe hypocholesteromic effects from soybean foods. Early Italian observations indicated that isolated soy protein lowered total cholesterol, especially the LDL component, in humans with elevated serum lipids. Whole soybeans, with their major phytoestrogen inflavones (genistein, daidzein, and glycetin) intact, are known to decrease both total and LDL cholesterol. Major early reviews, meta-analyses, and clinical trials in hyperlipidemic humans indicate a predictable range of decreases in serum lipids: total cholesterol (10-19%), LDL cholesterol (14-20%), and triglycerides (8-14%). Recent, large, randomized trials in postmenopausal women indicated that a soy protein component induces significant increases in HDL cholesterol. Therapy for metabolic syndrome must first be patient education, especially for predominant U.S. minority groups (Afro-, Latino-, and Native Americans). The four major preventive health educational facts necessary to reduce CHD/metabolic syndrome must now recognize that whole soybeans are abundant sources of: 1) vegetable protein, 2) high soluble fiber content, 3) virtual absence of saturated fat, though high in polyunsaturated fats, and 4) major phytoestrogens.
Phytoestrogens are non-steroidal compounds possessing estrogenic activity present in significant amounts in soy-based pet foods. There is speculation that long-term consumption of phytoestrogen-rich diets could have biological effects but this has never been evaluated in dogs.
Soy-based diets may affect general health, adrenocortical function, thyroid function, behavior and skin/coat quality in adult dogs.
Fifteen normal dogs were divided into two groups and fed either high-isoflavone (HID) or a low-isoflavone (LID) soy-based diet.
In this prospective controlled randomized trial end points of general health were assessed at baseline and up to one-year by evaluating body and dermatological condition, hematology, biochemistry profiles, urine-analysis (UA), serum concentrations of adrenal and thyroid hormones, and behavior. Student’s t-test (2 time points) analysis of variance with repeated measures (3 time points) was used to analyze differences in these parameters from baseline between diets.
No differences were found in measures of skin/coat, body condition, or behavior, in either group. Results of hematology, biochemical profiles and urinalysis showed no differences between the two groups. Analysis of variance in repeated measures was used to analyze differences in hair follicles from baseline between diets when there were 2 time points. No differences were found in the evaluation of the skin, hair follicle and hair diameter size. Most adrenal and thyroid hormones did not change over time nor were they different by diet (P>.1). However, total T4 differences were higher in HI than LI group (15.3 vs −1.4 p=.07) and post-ACTH estradiol concentration differences were also increased in HI compared to LI groups (19 vs −5.6 pg/ml at 1 year, p=.0006).
Conclusions and Clinical Importance
These data suggest long-term ingestion of soy phytoestrogens may influence endocrine function in dogs and this could potentially impact results of studies evaluating endocrine function in dogs although larger studies are needed for confirmation.
Dog; Endocrine; Isoflavones; Skin; Coat
Osteoporosis most commonly affects postmenopausal women, placing them at a significant risk of fractures. In particular, hip fractures are an important cause of mortality and morbidity among postmenopausal women. Anti-resorptive therapies that produce greater decreases in bone turnover markers together with greater increases in bone mineral density (BMD) are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Thus, treatment with potent anti-resorptive drugs like alendronate is a strategy for preventing hip fractures in postmenopausal women with osteoporosis. The purpose of this paper is to discuss the efficacy of alendronate against hip fractures and the mechanism for this anti-fracture efficacy in postmenopausal women with osteoporosis. A meta-analysis of randomized controlled trials has shown that alendronate reduces the risk of hip fractures by 55% in postmenopausal women with osteoporosis. According to the analyses of the Fracture Intervention Trial, each 1 standard deviation reduction in a 1-year change in bone-specific alkaline phosphatase (BSAP) is associated with 39% fewer hip fractures in alendronate-treated postmenopausal women, and those with at least 30% reduction in BSAP have a 74% lower risk of hip fractures relative to those with less than 30%. Alendronate is effective in reducing the risk of hip fractures across a spectrum of ages. The mechanism for this anti-fracture efficacy has been clarified; alendronate strongly suppresses bone turnover and subsequently increases hip BMD, decreases cortical porosity, improves parameters of hip structure geometry (cortical thickness, cross-sectional area, section modulus, and buckling ratio), and produces more uniform mineralization (increases the mean degree of mineralization of bone) in cortical bone. A once-weekly regimen of alendronate administration provides better patient compliance and persistence with the treatment than the once-daily dosing regimen, leading to greater efficacy against hip fractures. Thus, the efficacy of alendronate against hip fractures has been confirmed in postmenopausal women with osteoporosis, especially with a once-weekly dosing regimen.
hip fracture; bone turnover; bone mineral density; cortical porosity; cortical thickness
Following the results of the Women’s Health Initiative, many women now decline estrogen replacement at the time of menopause and seek natural remedies that would treat menopausal symptoms and prevent bone loss and other long-term consequences of estrogen deficiency, but without adverse effects on the breast, uterus, and cardiovascular system. The results of most soy studies in this population have had limitations because of poor design, small sample size, or short duration. This report describes the study rationale, design, and procedures of the Soy Phytoestrogens As Replacement Estrogen (SPARE) study, which was designed to determine the efficacy of soy isoflavones in preventing spinal bone loss and menopausal symptoms in the initial years of menopause.
Women ages 45 to 60 without osteoporosis and within five years from menopause were randomized to receive soy isoflavones 200 mg daily or placebo for 2 years. Participants have yearly measurements of spine and hip bone density, urinary phytoestrogens, and serum lipids, thyroid stimulating hormone, and estradiol. Menopausal symptoms, mood changes, depression, and quality of life are assessed annually.
The SPARE study recruited 283 women, 66.1% were Hispanic white. With a large cohort, long duration, and large isoflavone dose, this trial will provide important, relevant, and currently unavailable information on the benefits of purified soy isoflavones in the prevention of bone loss and menopausal symptoms in the first five years of menopause. Given the high proportion of Hispanics participating in the study, the results of this trial will also be applicable to this minority group.
menopause; bone health; osteoporosis; soy; isoflavones
Disorders of the Ras/MAPK pathway have an overlapping skeletal phenotype (eg. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and NF1 individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine derived cross-links of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype.
Methods and Results
Participants: [Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14)]. Pyridinium cross-links from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by High Performance Liquid Chromotography. Three separate analyses of covariance (ANCOVA) were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls.
The Dpd and the Dpd/Pyd ratio were elevated (p<0.0001) in all 3 conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.
bone; cardiofaciocutaneous syndrome; Costello syndrome; Noonan syndrome; pyridinium
Although neurofibromatosis type 1 (NF1) is a neuro-cutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5–19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.
The objective of this study was to examine the association of urinary phytoestrogens with the risk of postmenopausal breast cancer. Participants in the Multiethnic Cohort Study included 36,458 postmenopausal women who provided blood or urine specimens. A nested case-control study of breast cancer with biospecimens was created in which cases diagnosed after specimen collection were matched to two controls. Two hundred fifty-one women with breast cancer and 462 controls had urine available for analysis of urinary phytoestrogens. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using conditional logistic regression. A non-monotonic inverse trend (P = 0.04) in breast cancer risk was associated with increasing urinary excretion of genistein (OR 25th to 75th percentile, 0.88; 95% CI, 0.78 to 0.99) and total isoflavones (OR 25th to 75th percentile, 0.80; 95% CI, 0.65 to 0.99). A significant reduction in breast cancer risk in Japanese-American women was associated with the highest compared with the lowest quartile excretion of urinary daidzein (OR, 0.41; 95% CI, 0.19 to 0.89; P for trend, 0.005). The risk of breast cancer was reduced among white women with the highest compared to the lowest quartile excretion of equol (OR, 0.27; 95% CI, 0.08 to 0.95), although the trend in risk was not significant (P = 0.07). Our results provide some support to the hypothesis that a diet rich in isoflavones from soy products reduces the risk of postmenopausal breast cancer, particularly in populations with comparatively high excretion of phytoestrogens.
breast cancer; prospective cohort study; phytoestrogens; urinary excretion; multiethnic
Estrogen deficiency is a major risk factor for osteoporosis in postmenopausal women. Although hormone replacement therapy (HRT) has been rampantly used to recompense for the bone loss, but the procedure is coupled with severe adverse effects. Hence, there is a boost in the production of newer synthetic products to ward off the effects of menopause-related osteoporosis. As of today, there are several prescription products available for the treatment of postmenopause osteoporosis; most of these are estrogenic agents and combination products. Nevertheless, in view of the lack of effect and/or toxicity of these products, majority of the postmenopausal women are now fascinated by highly publicized natural products. This is an offshoot of the generalized consensus that these products are more effective and free from any adverse effects. Recently, certain plant-derived natural products, mostly phytoestrogens (isoflavones, lignans, coumestanes, stilbenes, flavonoids) and many more novel estrogen-like compounds in plants have been immensely used to prevent menopause-related depletion in bone mineral density (BMD). Although, a number of papers are published on menopause-related general symptoms, sexual dysfunction, cardiovascular diseases, Alzheimer's disease, diabetes, colon, and breast cancers, there is paucity of literature on the accompanying osteoporosis and its treatment. In view of the controversies on synthetic hormones and drugs and drift of a major population of patients toward natural drugs, it was found worthwhile to investigate if these drugs are suitable to be used in the treatment of postmenopausal osteoporosis. Preparation of this paper is an attempt to review the (a) epidemiology of postmenopausal osteoporosis, (b) treatment modalities of postmenopausal osteoporosis by hormones and synthetic drugs and the associated drawbacks and adverse effects, and (c) prevention and treatment of postmenopausal osteoporosis by phytoestrogens, their drawbacks and toxicity. It is apparent that both the categories of treatment are useful and both have adverse effects, but the plant products are nonscientific and hence are not advised to be used till more studies are undertaken to ensure that the benefits clearly outweigh the risk, in addition to recognition by Food and Drug Administration.
Menopause; osteoporosis; phytoestrogens
Prebiotics and phytoestrogens have sparked great interest because evidence indicates that consumption of these dietary constituents leads to lower cholesterol levels and inhibition of postmenopausal bone loss. The aim of this study was to determine the effect of both a prebiotic (Synergy®) and phytoestrogen (genistein) on bone and blood lipid levels in an animal model of postmenopausal women.
A four week feeding study was conducted in 5 mo old ovariectomized (OVX) Sprague Dawley rats to examine the effect of genistein, Synergy® (prebiotic) and genistein + Synergy® on bone density and strength, calcium metabolism and lipid biomarkers. There were six treatment groups: SHAM Control, OVX Control, OVX rats receiving daily estradiol injections, and OVX rats receiving an AIN 93M diet supplement with either 200 ppm genistein, 5% Synergy®, or 200 ppm genistein + 5% Synergy®.
Rats receiving genistein had significantly lower total serum cholesterol concentration than OVX Control (17%), OVX rats receiving daily estradiol injections (14%), and OVX rats on the 5% Synergy® diet (19%). Synergy® improved calcium absorption efficiency (41%) compared to OVX Control. SHAM Control rats had significantly higher femoral bone density, as determined by underwater weighing, than all OVX groups. Genistein consumption restored total and trabecular BMD at the distal femur similar to levels of SHAM rats.
Genistein supplementation imparts modest heart health benefits and improves bone geometry at the distal femur, and prebiotic consumption (Synergy®) results in improved calcium utilization strength in ovariectomized rats but the combination produced no synergistic effects.
genistein; prebiotics; cholesterol; bone rodents
To test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P< 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P< 0.001), and serum β2-microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P< 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P< 0.001, logrank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM. © 2001 Cancer Research Campaign http://www.bjcancer.com
bone sialoprotein; multiple myeloma; tumour burden; neoplastic bone involvement; prognosis
Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens.
Soy; Isoflavones; Genistein; Equol; Endocrine disruption; Estrogen; ERα; ERβ; Brain; Hypothalamus
The bone mineral density (BMD), the cross- links (PYD, DPD and NTx) and the bone specific alcaline phosphatase (BAP) was investigated in a cross-sectional study in 62 male patients with spinal cord injury (SCI), n = 28 short-term (0–1 year after SCI) and n = 34 long-term SCI patients (> 5 years after SCI). Knowledge about this parameters are necessary to find an adequate therapy for this special kind of osteoporosis. Immobilisation osteoporosis in SCI patients is a well-known problem that may lead to pathological fractures. Little is known regarding the extend of the osteoporosis as well as the causative factors. Measurements of the BMD in the proximal femur and the lumbar spine were performed with dual-energy-X-ray-absorptiometry (DEXA), of the osteoblast marker BAP (bone specific alkaline phosphatase) from serum and the osteoclast markers PYD (pyridinoline), DPD (desoxy-pyridinoline) and NTx (N-telopeptide of collagen type I) from urine. We found a significant decrease of BMD in the proximal femur and no relevant change in the lumbar spine compared to an age- and sex correlated control group (Z-score) in short-term and long-term SCI patients. There was a significant bone loss at the proximal femur between short and long-term SCI patients, whereas at the lumbar spine the BMD even slightly increases. Bone resorption (cross-links) was increased in both groups, though in long-term SCI patients it is significantly decreased compared to short-term SCI patients (DPD from 211.7 u/g creatinine to 118.1 u/g creatinine; NTx from 215.1 nmol/mmol creatinine to 83,6 nmol/mmol creatinine). The bone formation marker BAP is slightly below normal range in both groups (12.3 U/l in short-term, 9.7 U/l in long- term SCI patients). Only the proximal femur is affected by the immobilisation osteoporosis of SCI patients, therefore the BMD measurements in these patients should be performed at the lower limb. The problem of the immobilisation osteoporosis in SCI patients is the striking increase of bone resorption and the missing reaction of the bone formation.
Immobilisation-osteoporosis; Spinal cord injury; Paraplegia; BMD; Cross-links; Bone formation; Bone resorption
There is evidence that diets which contain high levels of phytoestrogenic isoflavanoids are associated with a low incidence of osteoporosis and menopausal vasomotor symptoms. Plant extracts such as red clover, which contain high levels of isoflavanoids, have been used to reduce menopausal symptoms and have been shown to reduce bone loss in healthy women. A placebo-controlled clinical trial [ISRCTN42940165] of red clover is reported in this issue of Breast Cancer Research and shows that these phytoestrogens do not cause any oestrogenic increase in breast density, which would indicate that they are unlikely to cause an increased risk of breast cancer.
isoflavones; red clover; women's health
This review discusses plant-derived compounds with estrogenic activity. The authors rightly emphasize the need for the intake of foods containing phytoestrogens in view of their positive effects on postmenopausal indications. This is particularly significant in the light of the current wave of enthusiasm for vegetarian food, in general, and phytoestrogens, in particular. Phytoestrogens are plant-derived hormone-like diphenolic compounds of dietary origin. These compounds are weakly estrogenic and could play a role in the prevention of other estrogen-related conditions, namely, cardiovascular diseases, menopausal symptoms, postmenopausal osteoporosis, neuroprotective effects, and hormone-dependent cancers (breast and endometrium cancer).
Menopause; menopausal indications; phytoestrogen
Phytoestrogens are a group of plants derived compounds with weekly estrogen effect that appear to have protective effects on metabolic and hormonal abnormalities of women with polycystic ovary syndrome (PCOS). So the aim of this study was to investigate the effect of soy phytoestrogens on reproductive hormones and lipid profiles in PCOS women.
In this quasi-randomized trial, 146 subjects with PCOS were divided into two groups; the experimental group who received Genistein (Bergamon, Italy) 18 mg twice a day orally and the control group that received similar capsules with cellulose for 3 months. Hormonal features and lipid profiles were measured before and after 3 months of supplement therapy.
After 3 months of supplement therapy there were no statistically significant differences in high density lipoprotein cholesterol (HDL) and follicle stimulating hormone (FSH) serum levels in Genistein and placebo group before and after treatment; however serum levels of luteinizing hormone (LH), triglyceride (TG), low density lipoprotein cholesterol (LDL), dehydroepiandrostrone sulfate (DHEAS) and testosterone were significantly decreased after 3 months therapy in Genistein group.
Genistein consumption may prevent cardiovascular and metabolic disorders in PCOS patients by improving their reproductive hormonal and lipid profiles.
Polycystic Ovary Syndrome; Genistein; Phytoestrogens; Cardiovascular Diseases
Due to symptoms and its complications, menopause influences the mental, psychological and physical health, social performance and familial relationships. Because of the undesirable side effects of hormone replacement therapy, tendency and desire toward alternative treatments in relieving menopausal symptoms have increased. Among the alternative therapies are herbs and among those, herbs with phytoestrogens are more preferable. Red clover is a rich source of phytoestrogens. The present study investigated the effect of red clover on quality of life in post-menopausal women.
Materials and Methods:
In a randomized, triple-blind, placebo-controlled clinical trial, 72 menopausal women who at least obtained 15 scores in Kupperman Menopausal Index, after two weeks of monitoring, were randomly allocated to receive either placebo or 45 mg of red clover isoflavones for eight weeks. Before the treatment and at the end of the study, menopause-specific quality of life questionnaire (MENQOL) was completed in the two groups.
A total of 55 women completed the study, 28 subjects in red clover and 27 in placebo group. Mean score of total quality of life (p < 0.001 in both groups), mean score of quality of life in vasomotor domain (p < 0.001 in both groups), psycho-social domain (p < 0.001 in red clover and p = 0.02 in placebo group) and physical domain (p < 0.001 red clover and p = 0.01 placebo group) significantly reduced compared to the baseline values. However, the differences between two groups were significant neither for total quality of life nor for its domains. Red clover had no side effects and all the subjects in the red clover group were satisfied with the prescribed administration
In the present study, the effect of red clover supplementation on menopausal women's quality of life showed no difference with the placebo. Further clinical trials are recommended.
Menopause; phytoestrogens; quality of life; red clover; symptoms
Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERα, ERβ and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERα such as PPT, ERβ such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.
sex hormones; progesterone; testosterone; phytoestrogens; estrogen receptor; endothelium; vascular smooth muscle; hypertension
Increased intake or supplementation of vitamin D is often recommended for normal bone health; however, its preventive effect on osteoporosis has not been fully evaluated. The aim of this review is to gather evidence of the efficacy of the optimization of vitamin D nutrition in preventing osteoporosis and osteoporotic fractures. PubMed was used for searching the relevant literature using the MeSH terms “Bone Density (limited to “human”, “female”, and “English” literature)” or “Fractures (limited to “human”, “age ≥45 years”, and “English” literature)”, and “Vitamin D”. The searches yielded 19 randomized controlled trials (RCTs), nine cohort studies, 19 case-control studies, 19 cross-sectional studies, and one meta-analysis. We attempted to answer three questions: 1) does increased vitamin D intake prevent bone loss in peri- and postmenopausal women?, 2) does increased vitamin D intake prevent osteoporotic fractures in the elderly?, and 3) does increased vitamin D in take positively affect peak bone mass attainment in young women? The answer to questions 1 and 2 is that a vitamin D intake of 10–17.5 μg/day (400–700 IU/day) or more is effective in preventing bone loss in late postmenopausal women and an intake of 17.5–20 μg/day (700–800 IU/day) or more together with a calcium supplement reduces the risk of osteoporotic fractures. For question 3, some lines of evidence support the negative effect of low vitamin D nutrition on the attainment of peak bone mass in young women. Further studies are needed to clarify the effect of vitamin D in this age group.
bone density; fractures; osteoporosis; systematic review; vitamin D
Estrogen or phytoestrogens treatment has been suggested to improve cognitive function of the brain in postmenopausal women. However, there is lack of information on the mechanism of such treatment on the central nervous system. The present study aimed to determine the effects of estradiol and soy germ phytoestrogens on spatial memory performance in ovariectomized rats and to explore the underlying mechanisms affecting the central nervous system.
Ovariectomized Sprague-Dawley rats were fed a basic diet supplemented with soy germ phytoestrogens (0.4 g/kg or 1.6 g/kg) or 17β-estradiol (0.15 g/kg) for 12 weeks. At the end of the experiment, animals were evaluated for their spatial learning and memory performance by the Morris Water Maze task. The expressions of brain-derived neurotrophic factor (BDNF) and synaptic formation proteins in the hippocampal tissue were estimated using RT-PCR and ELISA.
It was found that rats supplemented with soy germ phytoestrogens or estradiol performed significantly better in spatial memory acquisition and retention when compared to the rats fed on the control diet. Estradiol or the high dose of phytoestrogens treatment significantly increased BDNF concentration and the mRNA levels for BDNF and its TrkB receptors as well as the synaptic formation proteins, synaptophysin, spinophilin, synapsin 1 and PSD-95, in the hippocampal tissue of the experimental animals. It was also found that phytoestrogens, in contrast to estradiol, did not show any significant effect on the vaginal and uteri.
Soy germ phytoestrogens, which may be a substitute of estradiol, improved spatial memory performance in ovariectomized rats without significant side-effects on the vaginal and uteri. The memory enhancement effect may relate to the increase in BDNF and the synaptic formation proteins expression in the hippocampus of the brain.
Severe developmental and reproductive disorders in wild animals have been linked to high exposure to persistent environmental chemicals with hormonal activity. These adverse effects of environmental estrogens have raised considerable concern and have received increasing attention. Although numerous chemicals with the capacity to interfere with the estrogen receptor (ER) have been identified, information on their molecular mechanism of action and their relative potency is rather limited. For the endometrium, the lack of information is due to the lack of a suitable experimental model. We investigated the functions of phytoestrogens in an endometrial-derived model, RUCA-I rat endometrial adenocarcinoma cells. The cells were cultured on a reconstituted basement membrane to preserve their functional differentiation and estrogen responsiveness. We assessed the relative binding affinity to the estrogen receptor of the selected phytoestrogens coumestrol, genistein, daidzein, and the putative phytoestrogen mangostin compared to estradiol by a competitive Scatchard analysis. The following affinity ranking was measured: 17beta-estradiol >>> coumestrol > genistein > daidzein >>> mangostin. In addition, we investigated the capacity of these compounds to promote the increased production of complement C3, a well-known estradiol-regulated protein of the rat endometrium. All substances tested increased the production of complement C3, although different concentrations were necessary to achieve equivalent levels of induction compared to estradiol. Mechanistically we were able to demonstrate that the increase of complement C3 production was mediated by primarily increasing its steady-state mRNA level. These findings indicate that RUCA-I cells represent a sensitive model system to elucidate relative potencies and functions of environmental estrogens in an endometrium-derived model.
Resveratrol is a polyphenolic phytoestrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory, and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activities result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis and osteoporosis. Receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study, we investigated the effects of resveratrol on RANKL during bone morphogenesis in high density bone cultures in vitro. Untreated bone-derived cell cultures produced well organized bone-like structures with a bone-specific matrix. Treatment with RANKL induced formation of tartrate-resistant acid phosphatase-positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-κB activation, whereas pretreatment with resveratrol completely inhibited this activation and suppressed the activation of IκBα kinase and IκBα phosphorylation and degradation. RANKL up-regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-κB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-κB in a time- and concentration-dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NF-κB, inhibition of NF-κB transcriptional activation, and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factors Cbfa-1 and Sirt-1 and induced the formation of Sirt-1-Cbfa-1 complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between the osteoclastic versus osteoblastic activity result in bone formation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and rheumatoid arthritis-related bone loss.
NF-kappa B; p300; Resveratrol; SIRT; Stem Cell; Cbfa-1; RANKL; Osteoclastogenesis; Osteogenesis
Interleukin-1 (IL-1), a cytokine produced by bone marrow cells and bone cells, has been implicated in the pathogenesis of postmenopausal osteoporosis because of its potent stimulatory effects on bone resorption in vitro and in vivo. To investigate whether IL-1 plays a direct causal role in post ovariectomy bone loss, 6-mo-old ovariectomized rats were treated with subcutaneous infusions of IL-1 receptor antagonist (IL-1ra), a specific competitor of IL-1, for 4 wk, beginning either at the time of surgery or 4 wk after ovariectomy. The bone density of the distal femur was measured non invasively by dual-energy X-ray absorptiometry. Bone turnover was assessed by bone histomorphometry and by measuring serum osteocalcin, a marker of bone formation, and the urinary excretion of pyridinoline cross-links, a marker of bone resorption. Ovariectomy caused a rapid increase in bone turnover and a marked decrease in bone density which were blocked by treatment with 17 beta estradiol. Ovariectomy also increased the production of IL-1 from cultured bone marrow cells. Ovariectomy induced-bone loss was significantly decreased by IL-1ra treatment started at the time of ovariectomy and completely blocked by IL-1ra treatment begun 4 wk after ovariectomy. In both studies IL-1ra also decreased bone resorption in a manner similar to estrogen, while it had no effect on bone formation. In contrast, treatment with IL-1ra had no effect on the bone density and the bone turnover of sham-operated rats, indicating that IL-1ra specifically blocked estrogen-dependent bone loss. In conclusion, these data indicate that IL-1, or mediators induced by IL-1, play an important causal role in the mechanism by which ovariectomy induces bone loss in rats, especially following the immediate post ovariectomy period.