Life Extension Magazine®

Issue: Oct 2010

Testosterone

Effect of glucomannan on obese patients: a clinical study.

An eight-week double-blind trial was conducted to test purified glucomannan fiber as a food supplement in 20 obese subjects. Glucomannan fiber (from konjac root) or placebo was given in 1-g doses (two 500 mg capsules) with 8 oz water, 1 h prior to each of three meals per d. Subjects were instructed not to change their eating or exercise patterns. Results showed a significant mean weight loss (5.5 lbs) using glucomannan over an eight-week period. Serum cholesterol and low-density lipoprotein cholesterol were significantly reduced (21.7 and 15.0 mg/dL respectively) in the glucomannan treated group. No adverse reactions to glucomannan were reported.

Int J Obes. 1984;8(4):289-93

IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation.

BACKGROUND: A recent in vitro study indicates that IGOB131, a novel seed extract of the traditional West African food plant Irvingia gabonensis, favorably impacts adipogenesis through a variety of critical metabolic pathways including PPAR gamma, leptin, adiponectin, and glycerol-3 phosphate dehydrogenase. This study was therefore aimed at evaluating the effects of IGOB131, an extract of Irvingia gabonensis, on body weight and associated metabolic parameters in overweight human volunteers. METHODS: The study participants comprised of 102 healthy, overweight and/or obese volunteers (defined as BMI > 25 kg/m2) randomly divided into two groups. The groups received on a daily basis, either 150 mg of IGOB131 or matching placebo in a double blinded fashion, 30-60 minutes before lunch and dinner. At baseline, 4, 8, and 10 weeks of the study, subjects were evaluated for changes in anthropometrics and metabolic parameters to include fasting lipids, blood glucose, C-reactive protein, adiponectin, and leptin. RESULTS: Significant improvements in body weight, body fat, and waist circumference as well as plasma total cholesterol, LDL cholesterol, blood glucose, C-reactive protein, adiponectin and leptin levels were observed in the IGOB131 group compared with the placebo group. CONCLUSION: Irvingia gabonensis administered 150 mg twice daily before meals to overweight and/or obese human volunteers favorably impacts body weight and a variety of parameters characteristic of the metabolic syndrome. This is the first double blind randomized placebo controlled clinical trial regarding the anti-obesity and lipid profile modulating effects of an Irvingia gabonensis extract. The positive clinical results, together with our previously published mechanisms of gene expression modulation related to key metabolic pathways in lipid metabolism, provide impetus for much larger clinical studies. Irvingia gabonensis extract may prove to be a useful tool in dealing with the emerging global epidemics of obesity, hyperlipidemia, insulin resistance, and their co-morbid conditions.

Lipids Health Dis. 2009 Mar 2;8:7

Chronic use of glucomannan in the dietary treatment of severe obesity.

Two groups of 25 severely obese patients underwent 3 months of hypocaloric diet therapy either alone or associated with a glucomannan-based fibrous diet supplement (approx. 4 g/die in 3 doses). The comparative analysis of the results obtained in both groups showed that the diet + glucomannan group had a more significant weight loss in relation to the fatty mass alone, an overall improvement in lipid status and carbohydrate tolerance, and a greater adherence to the diet in the absence of any relevant side effects. Due to the marked ability to satiate patients and the positive metabolic effects, glucomannan diet supplements have been found to be particularly efficacious and well tolerated even in the long-term treatment of severe obesity.

Minerva Med. 1992 Mar;83(3):135-9

Traditional uses and potential health benefits of Amorphophallus konjac K. Koch ex N.E.Br.

Amorphophallus konjac (konjac) has long been used in China, Japan and South East Asia as a food source and as a traditional medicine. Flour extracted from the corm of this species is used in Far Eastern cuisine to make noodles, tofu and snacks. In traditional Chinese medicine (TCM), a gel prepared from the flour has been used for detoxification, tumour-suppression, blood stasis alleviation and phlegm liquefaction; and for more than 2,000 years has been consumed by the indigenous people of China for the treatment of asthma, cough, hernia, breast pain, burns as well as haematological and skin disorders. Over the past two decades, purified konjac flour, commonly known as konjac glucomannan (KGM) has been introduced on a relatively small scale into the United States and Europe, both as a food additive and a dietary supplement. The latter is available in capsule form or as a drink mix and in food products. Clinical studies have demonstrated that supplementing the diet with KGM significantly lowers plasma cholesterol, improves carbohydrate metabolism, bowel movement and colonic ecology. Standards for the classification of both konjac flour and KGM have been established by the Chinese Ministry of Agriculture, the European Commission and the US Food Chemicals Codex. However, to date, there is no worldwide agreed regulatory standard for konjac flour or KGM. This highlights the need for harmonization of konjac commercial standards to assess and ensure the quality of existing and future KGM products. Despite the widespread consumption of konjac derived products in East and South East Asia, there has been limited research on the biology, processing and cultivation of this species in the West. Most studies performed outside Asia have focussed on the structural characterisation and physicochemical properties of KGM. Therefore, the objective of this monograph is to review the literature covering the ethnic uses, botany and cultivation of konjac corms, together with the health benefits of KGM with the associated requirements for quality control. Possible directions for future research and development and standardisation of production and classification of this versatile natural product will be discussed.

J Ethnopharmacol. 2010 Mar 24;128(2):268-78

Blocking carbohydrate absorption and weight loss: a clinical trial using Phase 2 brand proprietary fractionated white bean extract.

BACKGROUND: Phase 2’ starch neutralizer brand bean extract product (“Phase 2”) is a water-extract of a common white bean (Phaseolus vulgaris) that has been shown in vitro to inhibit the digestive enzyme alpha-amylase. Inhibiting this enzyme may prevent the digestion of complex carbohydrates, thus decreasing the number of carbohydrate calories absorbed and potentially promoting weight loss. METHODS: Fifty obese adults were screened to participate in a randomized, double-blind, placebo-controlled study evaluating the effects of treatment with Phase 2 versus placebo on weight loss. Participants were randomized to receive either 1,500 mg Phase 2 or an identical placebo twice daily with meals. The active study period was eight weeks. Thirty-nine subjects completed the initial screening process and 27 subjects completed the study. RESULTS: The results after eight weeks demonstrated the Phase 2 group lost an average of 3.79 lbs (average of 0.47 lb per week) compared with the placebo group, which lost an average of 1.65 lbs (average of 0.21 lb per week), representing a difference of 129% (p=0.35). Triglyceride levels in the Phase 2 group were reduced an average of 26.3 mg/dL, more than three times greater a reduction than observed in the placebo group (8.2 mg/dL) (p=0.07). No adverse events during the study were attributed to the study medication. CONCLUSION: Clinical trends were identified for weight loss and a decrease in triglycerides, although statistical significance was not reached. Phase 2 shows potential promise as an adjunct therapy in the treatment of obesity and hypertriglyceridemia and further studies with larger numbers of subjects are warranted to conclusively demonstrate effectiveness.

Altern Med Rev. 2004 Mar;9(1):63-9

A Dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women.

BACKGROUND: More than one billion human adults worldwide are overweight and, therefore, are at higher risk of developing cardiovascular diseases, diabetes, and a variety of other chronic perturbations. Many believe that use of natural dietary supplements could aid in the struggle against obesity. So-called “starch blockers” are listed among natural weight loss supplements. Theoretically, they may promote weight loss by interfering with the breakdown of complex carbohydrates thereby reducing, or at least slowing, the digestive availability of carbohydrate-derived calories and/or by providing resistant starches to the lower gastrointestinal tract. AIMS: The present research study examines a dietary supplement containing 445 mg of Phaseolus vulgaris extract derived from the white kidney bean, previously shown to inhibit the activity of the digestive enzyme alpha amylase, on body composition of overweight human subjects. METHODS: A randomized, double-blinded, placebo-controlled study was conducted on 60 pre-selected, slightly overweight volunteers, whose weight had been essentially stable for at least six months. The volunteers were divided into two groups, homogeneous for age, gender, and body weight. The test product containing Phaseolus vulgaris extract and the placebo were taken one tablet per day for 30 consecutive days before a main meal rich in carbohydrates. Each subject’s body weight, fat and non-fat mass, skin fold thickness, and waist/hip/thigh circumferences were measured. RESULTS: After 30 days, subjects receiving Phaseolus vulgaris extract with a carbohydrate-rich, 2,000- to 2,200-calorie diet had significantly (p<0.001) greater reduction of body weight, BMI, fat mass, adipose tissue thickness, and waist,/hip/ thigh circumferences while maintaining lean body mass compared to subjects receiving placebo. CONCLUSION: The results indicate that Phaseolus vulgaris extract produces significant decrements in body weight and suggest decrements in fat mass in the face of maintained lean body mass.

Int J Med Sci. 2007 Jan 24;4(1):45-52

Fat storage in adipocytes requires inactivation of leptin’s paracrine activity: implications for treatment of human obesity.

Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-gamma-coactivator-1alpha, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.

Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18011-6

Weight-reducing effects of the plasma protein encoded by the obese gene.

The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30% after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12% weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7%. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.

Science. 1995 Jul 28;269(5223):543-6

Digestive and hepatic enzymes in streptozotocin-induced diabetic rats fed supplements of dikanut (Irvingia gabonensis) and cellulose.

In a feeding trial involving dikanut (an African viscous fibre) and cellulose (a particulate fibre), diabetic rats were maintained for 4 weeks on each of the test fibres. The levels of digestive and membrane-bound enzymes of the intestine, and hepatic glycolytic enzymes were determined. The effect of the supplements on intestinal morphology was also assessed. The two types of dietary fibre caused a general reduction in the levels of all the intestinal enzymes assayed with the effect of dikanut supplementation resulting in more drastic reductions. Evidence was obtained for a marked alteration in the intestinal morphology. It was concluded that the reduced absorption of glucose resulted in its lowered level in the blood and urine. The disruption of the mucosal membrane may also curtail the absorption of glucose. On the other hand, the activities of hepatic glycolytic enzymes became elevated to efficiently utilize the low substrates reaching the liver. The dietary fibres caused a shift away from the depletion of glycogen by the diabetic rat to synthesis of the storage polysaccharide. The long-term effects of the several adaptive responses resulting in lowered blood glucose from feeding these dietary fibre supplements to the diabetic rat requires further research.

Ann Nutr Metab. 1993;37(1):14-23

Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene.

BACKGROUND: Endeavors to manage obesity have been heavily reliant on controlling energy intake and expenditure equilibrium, but have failed to curtail the overweight and obesity epidemic. This dynamic equilibrium is more complex than originally postulated and is influenced by lifestyle, calorie and nutrient intake, reward cravings and satiation, energy metabolism, stress response capabilities, immune metabolism and genetics. Fat metabolism is an important indicator of how efficiently and to what extent these factors are competently integrating. We investigated whether an Irvingia gabonensis seed extract (IGOB131) would provide a more beneficial comprehensive approach influencing multiple mechanisms and specifically PPAR gamma, leptin and adiponectin gene expressions, important in anti-obesity strategies. METHODS: Using murine 3T3-L1 adipocytes as a model for adipose cell biology research, the effects of IGOB131 were investigated on PPAR gamma, adiponectin, and leptin. These adipocytes were harvested 8 days after the initiation of differentiation and treated with 0 to 250 microM of IGOB131 for 12 and 24 h at 37 degree C in a humidified 5 percent CO2 incubator. The relative expression of PPAR gamma, adiponectin, and leptin in 3T3-L1 adipocytes was quantified densitometrically using the software LabWorks 4.5, and calculated according to the reference bands of beta-actin. RESULTS: The IGOB131 significantly inhibited adipogenesis in adipocytes. The effect appears to be mediated through the down-regulated expression of adipogenic transcription factors (PPAR gamma) [P less than 0.05] and adipocyte-specific proteins (leptin) [P less than 0.05], and by up-regulated expression of adiponectin [P less than 0.05]. CONCLUSION: IGOB131 may play an important multifaceted role in the control of adipogenesis and have further implications in in-vivo anti obesity effects by targeting the PPAR gamma gene, a known contributory factor to obesity in humans.

Lipids Health Dis. 2008 Nov 13;7:44

Coupling Vascular and Myocardial Inflammatory Injury into a Common Phenotype of Cardiovascular Dysfunction: Systemic Inflammation and Aging - A Mini-Review.

The rising epidemic of cardiovascular (CV) disease is fuelled by obesity, hypertension and diabetes and, independently and cumulatively, by an aging population. Extensive research identified immunoinflammatory mechanisms as key drivers in the initiation and progression of the disease, from early asymptomatic stages of vascular and myocardial injury leading to the clinically manifest dysfunction and remodeling in advanced stages. Underlying processes include endothelial dysfunction and extracellular matrix restructuration leading to increased vascular stiffness, as well as myocardial remodeling with dilatation and wall thinning. In this, overproduction of tumor necrosis factor-alpha, amongst others, contributes to generalized CV injury and dysfunction. Moreover, recent insights into the involvement of innate and adaptive immunity in atherosclerosis have shed light on many interesting parallels with chronic systemic inflammatory conditions, such as rheumatoid arthritis, with aggravated inflammation-induced vascular and myocardial injury. Besides, chronologic age has been identified as a potent, independent risk for reduced CV capacity and a plethora of heart diseases, with other modifiable risk factors acting as accelerators. We discuss the available evidence and propose that characterization of inflammatory CV responses might reveal a distinctive CV inflammatory phenotype. A comprehensive noninvasive bio-signature, comprising immunomic biomarkers and integrated noninvasive imaging, may serve as a potential tool in the early diagnosis and prognostication of CV risk.

Gerontology. 2010 Jun 11

Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.

AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.

Pharmacogenomics. 2010 May;11(5):675-84

Evaluation of plasma non-enzymatic antioxidants in breast cancer etiology.

OBJECTIVE: Oxidative stress has emerged as a major etiological factor for breast cancer. Diet derived antioxidants play an important role against oxidative stress and the aim of the present study was to examine roles of non-enzymatic antioxidants in breast cancer in India. METHODS: Plasma non-enzymatic antioxidants; beta-carotene, vitamin A, vitamin E and vitamin C were analyzed spectrophotometrically from 70 healthy female controls, 30 patients with benign breast diseases (BBD) and 125 untreated breast cancer patients (BCPT). RESULTS: Plasma vitamin C levels were significantly lower in patients with BBD as compared to the controls (p= 0.043). Plasma beta-carotene, vitamin E and vitamin C levels were significantly lower in BCPT as compared to the controls (p= 0.0001, p= 0.040 and p= 0.0001, respectively). Plasma vitamin A levels were significantly higher in patients with BBD and BCPT as compared to the controls (p= 0.0001 and p= 0.0001; respectively) and in BCPT as compared to patients with BBD (p= 0.030). ROC curve analysis revealed that plasma beta-carotene and vitamin A could significantly discriminate between controls and patients with BBD (p= 0.016 and p= 0.000; respectively). Plasma beta-carotene, vitamin A, vitamin E and vitamin C could significantly discriminate between controls and BCPT (p= 0.000, p= 0.000, p= 0.001and p= 0.001, respectively). Plasma vitamin E levels could significantly discriminate between patients with BBD and BCPT (p= 0.055). Odds ratio analysis revealed that, increasing levels of plasma beta-carotene, vitamin E and vitamin C were significantly associated with decreased risk of breast cancer (p= 0.0001, p= 0.003, and p= 0.0001; respectively), whereas, increased risk was linked to plasma vitamin A (p= 0.001). CONCLUSIONS: The trends of the current study provide interesting clues to the etiology of breast cancer and suggest significance of interplay of non-enzymatic antioxidants in breast cancer. Further in-depth study is warranted to elucidate role of these antioxidants as a preventive measure.

Asian Pac J Cancer Prev. 2009 Jan-Mar;10(1):91-6

Vitamin E: an overview of major research directions.

During the last 90 years since the discovery of vitamin E, research has focused on different properties of this molecule, the focus often depending on the specific techniques and scientific knowledge present at each time. Originally discovered as a dietary factor essential for reproduction in rats, vitamin E has revealed in the meantime many more important molecular properties, such as the scavenging of reactive oxygen and nitrogen species with consequent prevention of oxidative damage associated with many diseases, or the modulation of signal transduction and gene expression in antioxidant and non-antioxidant manners. Research over the last 30 years has also resolved the biosynthesis and occurrence of vitamin E in plants, the proteins involved in the cellular uptake, tissue distribution and metabolism, and defined a congenital recessive neurological disease, ataxia with vitamin E deficiency (AVED), characterized by impaired enrichment of alpha-tocopherol in plasma as a result of mutations in the liver alpha-tocopherol transfer gene. This review is giving a brief introduction about vitamin E by following the major research directions since its discovery with a historical perspective.

Mol Aspects Med. 2007 Oct-Dec;28(5-6):400-22

High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age.

In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer’s disease (AD) among oldest-old individuals in a population-based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94) for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): alpha-tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol: 0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.

J Alzheimers Dis. 2010;20(4):1029-37

Cancer-preventive activities of tocopherols and tocotrienols.

The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.

Carcinogenesis. 2010 Apr;31(4):533-42

Vitamin E forms in Alzheimer’s disease: a review of controversial and clinical experiences.

Vitamin E is a collective term for eight naturally occurring compounds, four tocopherols (alpha-, beta-, gamma-, and delta-) and four tocotrienols (alpha-, beta-, gamma-, and delta-). Although it is the major form of vitamin E in US diets, gamma-tocopherol receives little attention when compared to alpha-tocopherol, which is generally found in supplements and most studied for its effects on progression of cognitive impairment. Many clinical trials had been conducted with vitamin E and neurodegenerative disorders, with controversial results, including a recent study which disproves the benefit of vitamin E for Mild Cognitive Impairment and Alzheimer’s Disease. This study examined the alpha-tocopherol supplement instead of gamma-tocopherol. Gamma-tocopherol has been found to be more effective in scavenging free radicals and nitrogen oxygen species that cause inflammation; both of these are components of neurodegenerative disorders. Secondly, the use of alpha-tocopherol supplements significantly reduces serum gamma-tocopherol, and this may have important biological effects. Therefore, any potential health benefits of alpha-tocopherol supplements may be offset by deleterious changes in the bioavailability of other forms of tocopherols and tocotrienols. This might account for the null effects of alpha tocopherol supplementation in Mild Cognitive Impairment and Alzheimer’s Disease.

Crit Rev Food Sci Nutr. 2010 May;50(5):414-9

Undercarboxylated osteocalcin is a biomarker of carotid calcification in patients with essential hypertension.

The development of vascular calcification is an active, highly regulated process with similarities to bone formation. Osteocalcin (OC), a vitamin K-dependent protein expressed by osteoblasts, contains 3 gamma-carboxyglutamic acid residues derived from the vitamin K-dependent posttranslational modification of glutamic acid residues. Circulating undercarboxylated OC (ucOC) is increased in vitamin K deficiency and serum ucOC is reported to be a clinical marker of vitamin K status. Vitamin K deficiency is associated with vascular calcification as well as osteoporosis. We evaluated the relationship between ucOC and carotid artery calcification in 92 patients with essential hypertension. Ultrasound of the common carotid artery was performed to identify vascular calcification and subjects were divided into 2 groups: a calcification (+) group and a calcification (-) group. Serum creatinine and ucOC levels were higher in the calcification (+) group than in the calcification (-) group and serum ucOC correlated with serum creatinine. To identify the independent determinant factor for carotid artery calcification, we applied both ucOC and estimated glomerular filtration rate as independent factors in logistic regression analysis. Serum ucOC was an independent determinant of carotid calcification, suggesting that circulating ucOC may be an important biomarker of carotid artery calcification.

Kidney Blood Press Res. 2010;33(1):66-71

Efficacy of menatetrenone (vitamin K2) against non-vertebral and hip fractures in patients with neurological diseases: meta-analysis of three randomized, controlled trials.

BACKGROUND AND OBJECTIVE: Patients with neurological diseases such as Alzheimer’s disease, stroke and Parkinson’s disease have been reported to have vitamin K deficiency secondary to malnutrition, which increases the risk of non-vertebral and hip fractures. The purpose of the present study was to clarify the efficacy of menatetrenone (vitamin K(2)) against non-vertebral and hip fractures in patients with neurological diseases. METHODS: A literature search was conducted on PubMed from January 1995 to July 2008 to identify randomized controlled trials (RCTs) of use of menatetrenone against non-vertebral and hip fractures in patients with neurological diseases. A meta-analysis of all RCTs meeting these criteria was then performed. RESULTS: Three RCTs of patients with Alzheimer’s disease (n = 178, mean age 78 years), stroke (n = 99, mean age 66 years) and Parkinson’s disease (n = 110, mean age 72 years) met the criteria for meta-analysis. These RCTs did not include placebo controls but did have non-treatment controls. According to the meta-analysis, the overall relative risks (95% confidence intervals) for non-vertebral and hip fractures with menatetrenone treatment compared with non-treatment were 0.13 (0.05, 0.35) and 0.14 (0.05, 0.43), respectively, in patients with neurological diseases. No severe adverse events were reported with menatetrenone treatment. CONCLUSION: The present meta-analysis of three RCTs suggests that there is efficacy for menatetrenone treatment against non-vertebral and hip fractures among patients with neurological diseases. Further larger placebo-controlled trials are needed to confirm the results of the present study.

Clin Drug Investig. 2009;29(7):471-9

Vitamin K supplementation and progression of coronary artery calcium in older men and women.

BACKGROUND: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.

Am J Clin Nutr. 2009 Jun;89(6):1799-807

Effects of vitamin K on bone mass and bone metabolism.

Vitamin K is involved in blood coagulation and in bone metabolism via the carboxylation of glutamate residues in (hepatic) blood coagulation factors and (osteoblastic) bone proteins. The bioavailability of nutritional vitamin K depends on the type of food, the dietary fat content, the length of the aliphatic side chain in the K-vitamer and probably also the genetically determined polymorphism of apolipoprotein E. Although undercarboxylation of blood coagulation factors is very rare, undercarboxylated osteocalcin (bone Gla-protein) is frequently found in postmenopausal women. Supplementation of these women with extra vitamin K causes the markers for bone formation to increase. In parallel, a decrease of the markers for bone resorption is frequently seen. Insufficient data are available to conclude that the regular administration of vitamin K concentrates will reduce the loss of bone mass in white women at risk for developing postmenopausal osteoporosis.

J Nutr. 1996 Apr;126(4 Suppl):1187S-91S

Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding.

Reduced cell proliferation may mediate anticarcinogenic effects of caloric restriction (CR). Using heavy water (2H2O) labeling, we investigated the cell proliferation response to CR in detail, including time course, effect of refeeding, and role of intermittent feeding with 5% CR. In the time-course study, 8-wk-old female C57BL/6J mice were placed on a 33% CR regimen (fed 3 times/wk) for varying durations. Compared with responses in controls fed ad libitum (AL), proliferation rates of keratinocytes, mammary epithelial cells, and T cells were markedly reduced within 2 wk of CR. In mice fed 95% ad libitum (C95, fed 3 times/wk), cell proliferation was also reduced in all tissues so that differences from 33% CR were only significant at 1 mo. In the refeeding study, mice were refed a C95 diet for varying durations after 1 mo of 33% CR. Cell proliferation rebounded to a suprabasal rate in all tissues after 2 wk of refeeding and then normalized after 2 mo, although the C95 group again exhibited lower cell proliferation than the AL group. The role of intermittent feeding was studied by comparing 33% CR and C95 animals (both fed intermittently) with animals fed isocalorically either daily or continuously by pellet dispenser. Intermittent feeding had no additive effect on 33% CR but reduced cell proliferation in all tissues at the 95% caloric intake level. In summary, the CR effect on cell proliferation is potent, rapid, and reversible in several tissues, and an intermittent feeding pattern reproduces much of the effect in the absence of substantial CR.

Am J Physiol Endocrinol Metab. 2005 May;288(5):E965-72

Emotional influences on food choice: sensory, physiological and psychological pathways.

Sensory, physiological and psychological mechanisms are reviewed that underlie emotional influences on food choice. Both moods and emotions are considered. Eating a meal will reliably alter mood and emotional predisposition, typically reducing arousal and irritability, and increasing calmness and positive affect. However, this depends on the meal size and composition being close to the eater’s habit, expectations and needs. Unusual meals--e.g. too small, unhealthy--may negatively affect mood. Sweetness, and sensory cues to high energy density, such as fatty texture, can improve mood and mitigate effects of stress via brain opioidergic and dopaminergic neurotransmission. However, adaptation in these pathways, perhaps enhanced by inherited sensitivity, with chronic exposure to such sensory qualities, could lead to overeating of energy-dense foods and consequent obesity. Sweet, fatty foods low in protein may also provide alleviation from stress in vulnerable people via enhanced function of the serotonergic system. Moreover, in rats, such foods seem to act as part of a feedback loop, via release of glucocorticoid hormones and insulin, to restrain activity of the hypothalamic pituitary adrenal axis during stress. However, this effect is also associated with abdominal obesity. In humans, a number of psychological characteristics predict the tendency to choose such foods when stressed, such as restrained or emotional eating, neuroticism, depression and premenstrual dysphoria, all of which could indicate neurophysiological sensitivity to reinforcing effects of such foods. Greater understanding of such predictive traits and the underlying mechanisms could lead to tailoring of diet to meet personal emotional needs.

Physiol Behav. 2006 Aug 30;89(1):53-61

The relationships among self-esteem, stress, coping, eating behavior, and depressive mood in adolescents.

The prevalence of adolescent overweight is significant, almost 25% in some minorities, and often is associated with depressive symptoms. Psychological and psychosocial factors as well as poor coping skills have been correlated with unhealthy eating and obesity. The purpose of this study was to examine relationships among self-esteem, stress, social support, and coping; and to test a model of their effects on eating behavior and depressive mood in a sample of 102 high school students (87% minority). Results indicate that (a) stress and low self-esteem were related to avoidant coping and depressive mood, and that (b) low self-esteem and avoidant coping were related to unhealthy eating behavior. Results suggest that teaching adolescents skills to reduce stress, build self-esteem, and use more positive approaches to coping may prevent unhealthy eating and subsequent obesity, and lower risk of depressive symptoms.

Res Nurs Health. 2009 Feb;32(1):96-109

Brain serotonin content: physiological regulation by plasma neutral amino acids.

When plasma tryptophan is elevated by the injection of tryptophan or insulin, or by the consumption of carbohydrates, brain tryptophan and serotonin also rise; however, when even larger elevations of plasma tryptophan are produced by the ingestion of protein-containing diets, brain tryptophan and serotonin do not change. The main determinant of brain tryptophan and serotonin concentrations does not appear to be plasma tryptophan alone, but the ratio of this amino acid to other plasma neutral amino acids (that is, tyrosine, phenylalanine, leucine, isoleucine, and valine) that compete with it for uptake into the brain.

Science. 1972 Oct 27;178(59):414-6

The composition of lunch determines afternoon plasma tryptophan ratios in humans.

It is well established that the ratio of the plasma tryptophan concentration to those of the other large neutral amino acids determines the transport of tryptophan into the brain. Brain tryptophan levels, in turn, control production of the neurotransmitter serotonin. Protein-rich meals, when consumed in the morning after an overnight fast, have been shown to decrease the plasma tryptophan ratio, while carbohydrate-rich meals have the opposite effect. We now show that these meals have similar effects when consumed for lunch, even if they are preceded by a small breakfast meal.

J Neural Transm. 1986;65(3-4):211-7

The treatment of obesity by carbohydrate deprivation suppresses plasma tryptophan and its ratio to other large neutral amino acids.

We measured plasma concentrations of tryptophan (Trp) and the other large neutral amino acids (LNAA) in 6 control and 7 obese subjects before and after they consumed a low-carbohydrate “protein-sparing modified fast” (PSMF) diet; LNAA levels in control subjects were also assessed after supplemental oral Trp. Consumption of the PSMF diet by non-obese subjects, or obesity per se, caused major reductions in the ratio of the plasma Trp concentration to the summed plasma concentrations of the other LNAA (i.e., the “plasma Trp ratio”), and may thus have diminished brain serotonin synthesis. Administration of even 2 g of supplemental Trp did not elevate the plasma Trp ratio beyond the normal range observed previously in subjects consuming carbohydrate-containing meals.

J Neural Transm. 1983;57(3):187-95

Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome.

In response to stress, some people lose while others gain weight. This is believed to be due to either increased beta-adrenergic activation, the body’s main fat-burning mechanism, or increased intake of sugar- and fat-rich “comfort foods.” A high-fat, high-sugar (HFS) diet alone, however, cannot account for the epidemic of obesity, and chronic stress alone tends to lower adiposity in mice. Here we discuss how chronic stress, when combined with an HFS diet, leads to abdominal obesity by releasing a sympathetic neurotransmitter, neuropeptide Y (NPY), directly into the adipose tissue. In vitro, when “stressed” with dexamethasone, sympathetic neurons shift toward expressing more NPY, which stimulates endothelial cell (angiogenesis) and preadipocyte proliferation, differentiation, and lipid-filling (adipogenesis) by activating the same NPY-Y2 receptors (Y2Rs). In vivo, chronic stress, consisting of cold water or aggression in HFS-fed mice, stimulates the release of NPY and the expression of Y2Rs in visceral fat, increasing its growth by 50% in 2 weeks. After 3 months, this results in metabolic syndrome-like symptoms with abdominal obesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, and hypertension. Remarkably, local intra-fat Y2R inhibition pharmacologically or via adenoviral Y2R knock-down reverses or prevents fat accumulation and metabolic complications. These studies demonstrated for the first time that chronic stress, via the NPY-Y2R pathway, amplifies and accelerates diet-induced obesity and the metabolic syndrome. Our findings also suggest the use of local administration of Y2R antagonists for treatment of obesity and NPY-Y2 agonists for fat augmentation in other clinical applications.

Ann N Y Acad Sci. 2008 Dec;1148:232-7

Asymmetric prefrontal cortex activation in relation to markers of overeating in obese humans.

Dietary restraint is heavily influenced by affect, which has been independently related to asymmetrical activation in the prefrontal cortex (prefrontal asymmetry) in electroencephalograph (EEG) studies. In normal weight individuals, dietary restraint has been related to prefrontal asymmetry; however, this relationship was not mediated by affect. This study was designed to test the hypotheses that, in an overweight and obese sample, dietary restraint as well as binge eating, disinhibition, hunger, and appetitive responsivity would be related to prefrontal asymmetry independent of affect at the time of assessment. Resting EEG recordings and self-report measures of overeating and affect were collected in 28 overweight and obese adults. Linear regression analyses were used to predict prefrontal asymmetry from appetitive measures while controlling for affect. Cognitive restraint and binge eating were not associated with prefrontal asymmetry. However, disinhibition, hunger, and appetitive responsivity predicted left-, greater than right-, sided prefrontal cortex activation independent of affect. Findings in this study add to a growing literature implicating the prefrontal cortex in the cognitive control of dietary intake. Further research to specify the precise role of prefrontal asymmetry in the motivation toward, and cessation of, feeding in obese individuals is encouraged.

Appetite. 2009 Aug;53(1):44-9

Long-term meditators self-induce high-amplitude gamma synchrony during mental practice.

Practitioners understand “meditation,” or mental training, to be a process of familiarization with one’s own mental life leading to long-lasting changes in cognition and emotion. Little is known about this process and its impact on the brain. Here we find that long-term Buddhist practitioners self-induce sustained electroencephalographic high-amplitude gamma-band oscillations and phase-synchrony during meditation. These electroencephalogram patterns differ from those of controls, in particular over lateral frontoparietal electrodes. In addition, the ratio of gamma-band activity (25-42 Hz) to slow oscillatory activity (4-13 Hz) is initially higher in the resting baseline before meditation for the practitioners than the controls over medial frontoparietal electrodes. This difference increases sharply during meditation over most of the scalp electrodes and remains higher than the initial baseline in the postmeditation baseline. These data suggest that mental training involves temporal integrative mechanisms and may induce short-term and long-term neural changes.

Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16369-73

Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone.

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus, lower urinary tract symptoms and erectile dysfunction (ED), were regarded as distinct diagnostic/therapeutic entities but there is a growing awareness that these entities are not disparate and, to improve the health of the ageing male, require an integral approach. There is an inter-dependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. A new concept of the role of testosterone in male physiology suggests that testosterone plays also a significant role in the development and maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but exerts also essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. Treatment of testosterone deficiency is to become part and parcel of this approach.

Andrologia. 2008 Aug;40(4):259-64

Androgens, insulin resistance and vascular disease in men.

Type 2 diabetes mellitus is increasing globally and is an established risk factor for the development of atherosclerotic vascular disease. Insulin resistance is the hallmark feature of type 2 diabetes and is also an important component of the metabolic syndrome. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men. Observational studies have shown that testosterone levels are low in men with diabetes, visceral obesity (which is strongly associated with insulin resistance), coronary artery disease and metabolic syndrome. Short-term interventional studies have also demonstrated that testosterone replacement therapy produces an improvement in insulin sensitivity in men. Thus hypotestosteronaemia may have a role in the pathogenesis of insulin-resistant states and androgen replacement therapy could be a potential treatment that could be offered for improvements in glycaemic control and reduction in cardiovascular risk, particularly in diabetic men.

Clin Endocrinol (Oxf). 2005 Sep;63(3):239-50

Testosterone in obesity, metabolic syndrome and type 2 diabetes.

Testosterone levels are reduced in obesity, the metabolic syndrome and type 2 diabetes. Low testosterone levels are now being recognised as an independent risk factors for these conditions. Findings from men undergoing androgen suppression as treatment for prostate cancer confirm that the hypogonadal state increases body fat mass and serum insulin and there is a high rate of developing new diabetes in this population. Clinical trial data are consistent in showing reductions in body fat mass during testosterone replacement therapy. There are also trials showing improvements in insulin resistance and glycaemic control with testosterone. Most of the trials in this area to date have been of small size and the promising results require confirmation in larger trials, which are underway. In the longer term, large trials should be conducted to assess the potentially beneficial effects of testosterone on cardiovascular risk in this and other patient groups. In the meantime physicians involved in the care of men with diabetes should remain vigilant for the symptoms and signs of hypogonadism. Testosterone replacement therapy should be considered for those men with subsequently confirmed hypogonadism.

Front Horm Res. 2009;37:74-90

Men’s health, low testosterone, and diabetes: individualized treatment and a multidisciplinary approach.

Testosterone plays a critical role in male reproductive and metabolic functioning. Serum testosterone levels decrease with age, and low testosterone is associated with a variety of comorbidities, including insulin resistance, type 2 diabetes, obesity, metabolic syndrome, and cardiovascular disease. Men with type 2 diabetes have been shown to have significantly lower testosterone levels than men without diabetes. Several forms of testosterone replacement therapy (eg, oral, injectable, buccal, transdermal preparations) are available for use in the United States. The primary goals of testosterone therapy are to restore physiologic testosterone levels and reduce the symptoms of hypogonadism. Testosterone therapy may be a viable option in some men with diabetes and low testosterone; however, clinicians must be aware of contraindications to therapy (eg, prostate cancer and male breast cancer), implement appropriate monitoring procedures, and ensure that patient expectations are realistic regarding treatment outcome. Data suggest that testosterone therapy may have a positive effect on bones, muscles, erythropoiesis and anemia, libido, mood and cognition, penile erection, cholesterol, fasting blood glucose, glycated hemoglobin, insulin resistance, visceral adiposity, and quality of life. Sexual health may be a window into men’s health; thus, more effective communication strategies are needed between clinicians and men with diabetes to ensure that sexual health topics are adequately addressed. Diabetes educators can play a key role in screening for low testosterone, providing relevant information to patients, and increasing clinician awareness of the need to address men’s sexual health and implement appropriate strategies. Multidisciplinary care and individualized treatment are needed to optimize outcome.

Diabetes Educ. 2008 Nov-Dec;34 Suppl 5:97S-112S

The role of testosterone in type 2 diabetes and metabolic syndrome in men.

Over the last three decades, it has become apparent that testosterone plays a significant role in glucose homeostasis and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, insulin resistance, glucose intolerance, raised blood pressure and dyslipidemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol), and a pro-inflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome. There is evidence that hypotestosteronemia should be an element in the definition of the metabolic syndrome since low levels of testosterone are associated with or predict the development of the metabolic syndrome and of diabetes mellitus. Administration of testosterone to hypogonadal men reverses part of the unfavorable risk profile for the development of diabetes and atherosclerosis. So far, studies on the effects of normalization of testosterone in hypogonadal men on glucose homeostasis are limited, but convincing, and if diabetes mellitus is viewed in the context of the metabolic syndrome, the present results of testosterone treatment are very encouraging.

Arq Bras Endocrinol Metabol. 2009 Nov;53(8):901-7

Lower sex hormone-binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the Health in Men Study.

BACKGROUND: Reduced circulating testosterone and sex hormone-binding globulin (SHBG) are implicated as risk factors for metabolic syndrome. As SHBG increases with age while testosterone declines, we examined the relative contributions of SHBG and testosterone to the risk of metabolic syndrome in older men. METHODS: We conducted a cross-sectional study of 2,502 community-dwelling men aged > or = 70 years without known diabetes. Metabolic syndrome was defined using the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) criteria. Early morning fasting sera were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. RESULTS: There were 602 men with metabolic syndrome (24.1%). The risk of metabolic syndrome increased for total testosterone < 20 nmol/l, SHBG < 50 nmol/l and free testosterone < 300 pmol/l. In univariate analyses SHBG was associated with all five components of metabolic syndrome, total testosterone was associated with all except hypertension, and free testosterone was associated only with waist circumference and triglycerides. In multivariate analysis, both total testosterone and especially SHBG remained associated with metabolic syndrome, with odds ratios of 1.34 (95% confidence interval (CI): 1.18-1.52) and 1.77 (95% CI: 1.53-2.06) respectively. Men with hypogonadotrophic hypogonadism (total testosterone < 8 nmol/l, LH < or = 12 IU/l) had the highest prevalence of metabolic syndrome (53%, P<0.001). CONCLUSIONS: Lower SHBG is more strongly associated with metabolic syndrome than lower total testosterone in community-dwelling older men. SHBG may be the primary driver of these relationships, possibly reflecting its relationship with insulin sensitivity. Further studies should examine whether measures that raise SHBG protect against the development of metabolic syndrome in older men.

Eur J Endocrinol. 2008 Jun;158(6):785-92

Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome.

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Curr Mol Med. 2008 Dec;8(8):816-28

The dark side of testosterone deficiency: III. Cardiovascular disease.

A considerable body of evidence exists suggesting that androgen deficiency contributes to the onset, progression, or both of cardiovascular disease (CVD). The aim of this review is to evaluate the relationships between testosterone (T) deficiency and risk factors of CVD and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. The relationship between androgen deficiency and endothelial function, lipid profiles, inflammatory responses, altered vascular smooth muscle reactivity, and hypertension are discussed with regard to CVD. A comprehensive literature search was carried out with the use of Pub Med from 1980 through 2009, and relevant articles pertinent to androgen deficiency and vascular disease were evaluated and discussed. Low T, whether attributed to hypogonadism or androgen deprivation therapy, in men with prostate carcinoma, produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. Testosterone supplementation restores arterial vasoreactivity; reduces proinflammatory cytokines, total cholesterol, and triglyceride levels; and improves endothelial function but also might reduce high-density lipoprotein levels. Testosterone is an anabolic hormone with a wide range of beneficial effects on men’s health. The therapeutic role of T in men’s health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for CVD, androgen replacement therapy could potentially reduce CVD risk in hypogonadal men. It should be emphasized, however, that androgen replacement therapy should be done with very thorough and careful monitoring for prostate diseases.

J Androl. 2009 Sep-Oct;30(5):477-94

The relationship between androgens concentrations (testosterone and dehydroepiandrosterone sulfate) and metabolic syndrome in non-obese elderly men.

INTRODUCTION: The metabolic syndrome characterized by central obesity, insulin and lipid dysregulation, and hypertension, is a precursor state for atherosclerotic process and, in consequence, cardiovascular disease. Decline of both testicular and adrenal function with aging causes a decrease in androgen concentration in men. It has been postulated that low levels of total testosterone and dehydroepiandrosterone sulfate (DHEA-S) are associated with unfavorable levels of several strong cardiovascular disease risk factors, such as lipids and blood pleasure, which are components of the metabolic syndrome, and insulin levels. Both testosterone and DHEA-S deficiency are risk factors of obesity and insulin resistance, but it is not clear, whether this possible influence is independent. The aim of this study was to determined whether lower androgens (testosterone and DHEA-S) levels are associated with the development of metabolic syndrome in non-obese elderly men as well as analysis, whether these sex hormones influents on measured parameters separately. MATERIAL AND METHODS: Together 85 men age from 60 to 70 years (mean 66.3 +/- 1.5 years; mean +/- SEM) were analyzed. Testosterone levels < 4 ng/ml or DHEA levels < 2000 ng/ml and BMI < 30 kg/m(2) were including criteria. Patients were divided into three groups: 52 with testosterone deficiency (L-T), 32 with DHEA deficiency (L-DHEA-S) and 67 with deficiency of both sex hormones (L-T/DHEA-S). The influence of sex hormones deficiency in these groups on blood pressure, lipids, visceral obesity and fasting glucose were measured (according to metabolic syndrome definition NCEP III/IDF). RESULTS: Testosterone levels in L-T, L-DHEA and L-T/DHEA-S groups were respectively 3.19 +/- 0.23 ng/ml, 4.89 +/- 0.45 ng/ml and 3.25 +/- 0.34 g/ml (p < 0.002). While DHEA-S levels were respectively 2498 +/- 98 ng/ml, 1435 +/- 1010 ng/ml and 1501 +/- +/- 89 ng/ml). BMI values do not differ between groups. Waist circumference was significantly higher in L-T/DHEA-S group than in L-T i L-DHEA-S groups (respectively: 99.9 +/- 6,1 cm, 97.1 +/- 7.1 cm i 96.2 +/- 6.4 cm; mean +/- SD, p < 0.05 vs. L-T and L-DHEA-S groups). Mean triglycerides concentration in L-T/DHEA-S group was significantly higher than in L-T and L-DHEA-S groups (respectively: 188.2 +/- 13.3 mg/dl, 161.7 +/- 14.7 mg/dl and 152.2 +/- 12.8 mg/dl (mean +/- SD; p < 0.02 vs. L-T and L-DHEA-S groups). Analysis of prevalence of risk factors showed, that in L-T/DHEA-S group they were more frequent than in other groups. The most significant percentage difference was observed for triglycerides: concentration > or = 150 mg/dl was measured in 31% men in L-T group, 28% men in L-DHEA-S group and 42% men in L-T/DHEA-S group. According metabolic syndrome definition NCEP III/IDF prevalence of this syndrome was: 71% patients in L-T/DHEA-S group, 67% patients in L-T group and 64% patients in L-DHEA-S group. CONCLUSIONS: The DHEA-S and testosterone deficiency was a significant and independent risk factor of the metabolic syndrome in non-obese elderly men. It seems, that triglycerides concentration and waist circumference are more sensitive then others parameters to reflect the influence of sex hormones deficiency on risk of the metabolic syndrome in elderly men.

Endokrynol Pol. 2007 Nov-Dec;58(6):496-504

Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome.

BACKGROUND: Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short- and long-term effects of weight loss on sex steroids in abdominally obese men, however. OBJECTIVES: We assessed the effect of rapid weight loss and sustained weight maintenance on the plasma concentrations of testosterone and other sex hormones in 58 abdominally obese men (age, 46.3 +/- 7.5 years; body mass index, 36.1 +/- 3.8 kg/m(2); waist girth, 121 +/- 10 cm) with the metabolic syndrome. RESULTS: The men lost on average 16.3 +/- 4.5 kg during a 9-week very low-calorie diet (VLCD) and maintained 14.3 +/- 9.1 kg weight loss after a 12-month maintenance period (vs. baseline, p < 0.001). Sex hormone-binding globulin (SHBG) increased from 27.6 +/- 11.9 to 48.1 +/- 23.5 nmol/l during the VLCD but decreased to 32.6 +/- 12.9 nmol/l during weight maintenance, which was still higher than at baseline (p < 0.001). Free testosterone (fT) increased from 185 +/- 66 to 208 +/- 70 pmol/l (p = 0.002) during the VLCD and remained high after 1 year of weight maintenance (212 +/- 84 pmol/l, p = 0.002). Total testosterone levels followed a pattern intermediate between fT and SHBG. Plasma estradiol and dehydroepiandrosterone sulphate concentrations changed only transiently or not at all. CONCLUSIONS: Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome brings about a sustained increase in fT levels. The dramatic increase in SHBG attenuated initially during weight maintenance but remained elevated. These findings may be important with regard to prevention of progressive metabolic decompensation and cardiovascular disease associated with obesity and the metabolic syndrome.

Diabetes Obes Metab. 2004 May;6(3):208-15

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