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[Michael Scally MD]

Higher Energy Expenditure in Humans Predicts Natural Mortality

Higher energy turnover is associated with shorter lifespan in animals, but evidence for this association in humans is limited. Over a century ago, the German physiologist Max Rubner linked body size and energy turnover with lifespan, and Benedict’s mouse-elephant curve extended these findings by demonstrating that smaller animals expend relatively more energy per body mass and have a shorter life span than larger animals. The physiological underpinnings of the theory that lifespan is determined by a rate of living, however, are not clear. The free radical theory of aging proposes that aging is accelerated by the accumulation of cellular metabolites, in particular toxic free radicals. Free radicals in the form of reactive oxygen species (ROS) accumulate more quickly with higher metabolic rates and are responsible for various types of oxidative damage in the cell. To investigate the hypothesis that higher metabolic rate is associated with aging, researchers examined whether energy expenditure (EE), measured in a metabolic chamber over 24 h and during rest predicts natural mortality in nondiabetic Pima Indians from the Gila River Indian Community.

In this longitudinal study, they found that 24EE and RMR, measured on different days, predict natural mortality in Pima Indians. These results are consistent with previously described data for RMR in an older population . In the present study, EE was measured in a younger population, and two different measures of EE provided consistent results.

Increased EE and ATP turnover increase free radical formation, and this is proposed as a mechanism for accelerated aging and increased mortality. Furthermore, studies in animals indicate that reduced metabolic rate after caloric restriction has beneficial effects on lifespan. However, recent studies using knockout models of key antioxidant genes in the worm Caenorhabditis elegans and data from long-lived mouse models have produced inconsistent results, therefore calling this oxidative damage theory into question.

Importantly, studies in which energy turnover is willfully increased (via physical activity) demonstrate clear metabolic benefits. Therefore, these results do not apply to increased energy turnover due to exercise. This belief is supported by two recent reports showing that 1) excess fat intake (which increases metabolic rates) leads to increased ROS production, which links overnutrition to insulin resistance, whereas 2) transient elevations in ROS induced by physical exercise may be essential for training induced insulin sensitivity. Thus, a transient elevation of ROS, as seen during physical exercise, could have beneficial effects on human health, whereas sustained elevations in ROS due to higher metabolic rates as a consequence of macronutrient excess could be harmful. Recent experiments have shown that transgenic hypermetabolic mice with increased uncoupling from ectopically expressed uncoupling protein 1 live longer than their wild-type counterparts. Despite higher metabolic rates, these mice show substantial reductions in mitochondrial ROS production. Together these data indicate that the effect of elevated metabolic rate on cell/organ damage over a lifespan needs to be viewed against the background of ROS production.


Jumpertz R, Hanson RL, Sievers ML, Bennett PH, Nelson RG, Krakoff J. Higher Energy Expenditure in Humans Predicts Natural Mortality. J Clin Endocrinol Metab:jc.2010-944. Higher Energy Expenditure in Humans Predicts Natural Mortality -- Jumpertz et al., 10.1210/jc.2010-2944 -- Journal of Clinical Endocrinology & Metabolism

Context: Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality.

Objective: Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans.

Design: Nondiabetic healthy Pima Indian volunteers (n = 652) were admitted to an inpatient unit for approximately 7 d as part of a longitudinal study of obesity and diabetes risk factors. Vital status of study participants was determined through December 31, 2006. Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals, and 240 underwent both measurements on separate days. Data for 24EE were collected in a respiratory chamber between 1985 and 2006 with a mean (SD) follow-up time of 11.1(6.5) yr and for RMR using an open-circuit respiratory hood system between 1982 and 2006 with a mean follow-up time of 15.4 (6.3) yr. Cox regression models were used to test the effect of EE on natural mortality, controlled for age, sex, and body weight.

Results: In both groups, 27 natural deaths occurred during the study period. For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 (95% confidence interval = 1.00–1.66; P < 0.05) in the 24EE group and by 1.25 (95% confidence interval = 1.01–1.55; P < 0.05) in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses.

Conclusions: Higher metabolic rates as reflected by 24EE or RMR predict early natural mortality, indicating that higher energy turnover may accelerate aging in humans.

 

[Michael Scally MD]

Diet has been recognized to play an important and influential role in this regard. Many risk factors for cardiovascular and thrombotic diseases are profoundly affected by diet and thus can be managed or prevented with a nutritional approach. Diet is a multicomponent mixture of nutrients that may interact with one another to offer cardioprotection. However, the Western diet contains an imbalance in fatty acid composition, macronutrient composition, and micronutrient density. This diet also contributes to the rising prevalence of obesity and diabetes mellitus, which in turn further enhances the risk of thrombotic disease. This diet and the associated risk factors are present in youth. Therefore, preventive measures must be initiated at an early age to lessen the burden of disease much later in life. Nutrition is a modifiable determinant of disease, with scientific evidence increasingly supporting the view that alterations in diet have both positive and negative effects on cardiovascular health and disease. This article reviews the antithrombotic effects of nutrients, vitamins, minerals, dietary supplements, and nonnutrient bioactive substances.


Phang M, Lazarus S, Wood LG, Garg M. Diet and thrombosis risk: nutrients for prevention of thrombotic disease. Semin Thromb Hemost 2011;37(3):199-208. Diet and thrombosis risk: nutrients for prevention... [Semin Thromb Hemost. 2011] - PubMed result

An increased prothrombotic state is a major risk factor for the development of heart attacks, strokes, and venous thromboembolism. Platelet activation and aggregation play an important role in determining a prothrombotic state. Although pharmaceutical agents such as aspirin, heparin, and warfarin are able to reduce prothrombotic tendency, long-term drug treatment may produce a variety of side effects, including bleeding. Diet is generally recognized to be significantly involved in modifying the individual risk for the development of thrombotic diseases, although its influence during the treatment of these disorders is probably less important. Dietary intervention has proven effective in lowering serum lipid levels, which are otherwise essential elements in the pathogenesis of cardiovascular disease. Likewise, certain dietary components have also been proven effective in decreasing platelet activation through various mechanisms and therefore may contribute to attenuating the future risk of thrombosis. This article provides an up-to-date review of the role of nutrient and nonnutrient supplements on platelet aggregation and risk of thrombosis.

 

[Michael Scally MD]

Neural Correlates of Food Addiction

One-third of American adults are now obese and obesity-related disease is the second leading cause of preventable death. Unfortunately, most obesity treatments do not result in lasting weight loss because most patients regain their lost weight within 5 years.

Based on numerous parallels in neural functioning associated with substance dependence (in the current article, the terms substance dependence and addiction are used interchangeably to represent a diagnosis of substance dependence as defined by the DSM-IV-TR) and obesity, theorists have proposed that addictive processes may be involved in the etiology of obesity. Food and drug use both result in dopamine release in mesolimbic regions and the degree of release correlates with subjective reward from both food and drug use. Similar patterns of brain activation in response to food and drug cues have also been found. Individuals with vs without substance dependence show greater activation in brain regions that encode the reward value of stimuli (eg, the orbitofrontal cortex [OFC], amygdala, insula, striatum, anterior cingulate cortex [ACC], and dorsolateral prefrontal cortex [DLPFC]) and greater dopamine release in the dorsal striatum in response to drug cues. Similarly, obese vs lean individuals show greater activation in the OFC, amygdala, ACC, striatum, and mediodorsal thalamus in response to food cues and greater activation in regions associated with cue-related craving for drugs, such as the ACC, striatum, insula, and the DLPFC, in response to anticipated receipt of palatable foods.

Although obese and substance-dependent individuals show hyperresponsivity of reward learning regions to food and substance cues, respectively, actual intake of food and drugs is associated with reduced reward circuitry activation. Obese vs lean individuals show less dorsal striatal and medial OFC activation in response to palatable food intake, echoing evidence that substance-dependent individuals exhibit blunted dopaminergic release during actual drug consumption and report weaker subjective reward relative to healthy controls. Results dovetail with evidence of reduced D2 receptor availability in obese and substance-dependent individuals vs healthy controls. These findings have prompted the theory that individuals who experience less reward from food intake may overeat to compensate for this reward deficit.

Although there are strong parallels in brain regions that encode reward from drugs and palatable foods and in neural abnormalities associated with substance dependence and obesity, these findings may tell us little about true "food addiction" (FA). Obesity is strongly linked to excess food consumption, but other factors contribute to unhealthy weight gain, such as physical inactivity. Additionally, excess consumption is not necessarily indicative of substance dependence; whereas 40% of college students binge drink, only 6% meet criteria for alcohol dependence. Thus, to more directly assess FA, it would be useful to identify participants who may exhibit signs of dependence in their eating behavior. Currently, a diagnosis of substance dependence is given when sufficient behavioral criteria are met. The Yale Food Addiction Scale (YFAS) was developed to operationalize the construct of palatable food dependence based on the DSM-IV-TR substance dependence criteria. The identification of individuals who exhibit FA symptoms would allow for more direct examinations of the neurobiological similarities between substance dependence and compulsive food consumption.

In the present study, researchers examined the relation of FA symptoms, as assessed by the YFAS, with neural activation in response to (1) cues signaling impending delivery of a highly palatable food (chocolate milkshake) vs a tasteless control solution and (2) intake of a chocolate milkshake vs a tasteless solution among healthy young women ranging from lean to obese. Based on previous findings, they hypothesized that participants exhibiting elevated FA symptoms would show greater activation in response to food cues in the amygdala, striatum, OFC, DLPFC, thalamus, midbrain, insula, and anterior cingulate gyrus. Further, they hypothesized that, during consumption of a highly palatable food, the high vs low FA group would demonstrate less activation in the dorsal striatum and OFC, analogous to the reduced activation demonstrated in substance-dependent participants on receipt of a drug.


Gearhardt AN, Yokum S, Orr PT, Stice E, Corbin WR, Brownell KD. Neural Correlates of Food Addiction. Arch Gen Psychiatry:archgenpsychiatry.2011.32. Arch Gen Psychiatry -- Abstract: Neural Correlates of Food Addiction, April 4, 2011, Gearhardt et al. 0 (2011): archgenpsychiatry.2011.32v1

Context Research has implicated an addictive process in the development and maintenance of obesity. Although parallels in neural functioning between obesity and substance dependence have been found, to our knowledge, no studies have examined the neural correlates of addictive-like eating behavior.

Objective To test the hypothesis that elevated "food addiction" scores are associated with similar patterns of neural activation as substance dependence.

Design Between-subjects functional magnetic resonance imaging study.

Setting A university neuroimaging center.

Participants Forty-eight healthy young women ranging from lean to obese recruited for a healthy weight maintenance trial.

Main Outcome Measure The relation between elevated food addiction scores and blood oxygen level-dependent functional magnetic resonance imaging activation in response to receipt and anticipated receipt of palatable food (chocolate milkshake).

Results Food addiction scores (N = 39) correlated with greater activation in the anterior cingulate cortex, medial orbitofrontal cortex, and amygdala in response to anticipated receipt of food (P < .05, false discovery rate corrected for multiple comparisons in small volumes). Participants with higher (n = 15) vs lower (n = 11) food addiction scores showed greater activation in the dorsolateral prefrontal cortex and the caudate in response to anticipated receipt of food but less activation in the lateral orbitofrontal cortex in response to receipt of food (false discovery rate-corrected P < .05).

Conclusions Similar patterns of neural activation are implicated in addictive-like eating behavior and substance dependence: elevated activation in reward circuitry in response to food cues and reduced activation of inhibitory regions in response to food intake.

 

[Michael Scally MD]

This review describes the literature on liver injury because of dietary supplements (DS), delineates patterns and mechanisms of injury, and increases the awareness towards this possible cause of acute and chronic liver damage.


Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int 2011;31(5):595-605. Review of liver injury associated with dietary sup... [Liver Int. 2011] - PubMed result

Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms 'dietary/nutritional supplements', 'adverse hepatic reactions', 'liver injury'; 'hepatitis', 'liver failure', 'vitamin A' and 'retinoids', and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife((R)) and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.

 

[Michael Scally MD]

Growth hormone (GH) is secreted primarily in pulses, which mediate anabolic tissue effects. Pulses of GH secretion are controlled in turn by the hypothalamic peptides, GH-releasing hormone (GHRH) and somatostatin (SS), and by the hypothalamo pituitary-gastro-pancreatic peptide, ghrelin (a GH-releasing peptide: GHRP). Somatostatin inhibits, whereas GHRH and GHRP stimulate, GH release. The complex interplay between inhibition and stimulation is achieved by feedback and feedforward connections. In particular, GH and possibly GHRH itself impose negative feedback by initiating hypothalamic outflow of SS, which transsynaptically quenches neuronal GHRH secretion and transportally inhibits both GHRH and GHRP action at the pituitary gland.

Viewed from a regulatory perspective, feedback and feedforward are dynamically counterbalanced processes. According to this concept, disruption of either regulatory limb would impair physiological GH pulsatility. Indeed, in Laron syndrome GH-receptor defects result in massive outpouring of GH due to feedback failure. Conversely, experimentally induced GH excess causes hypothalamic overexpression of SS and underexpression of GHRH genes. Despite these important physiological tenets, the primary factors that regulate feedback-dependent control of pulsatile GH secretion are not well understood. In particular, whereas gender and sex steroids are dominant determinants of GHRH and GHRP feedforward, their impact on feedback regulation remains largely unexplored.

To address this fundamental issue, the present study introduces an experimental paradigm of GH-feedback regulated pulsatile GH secretion, where the principal independent variables are gender, sex steroid supplementation, and attempted rescue from feedback inhibition by dual-peptide (GHRH/GHRP-2) drive.


Veldhuis JD, Erickson D, Miles JM, Bowers CY. Complex Regulation of GH Autofeedback under Dual-Peptide Drive: studies under a pharmacological GH and sex-steroid clamp. American Journal of Physiology - Endocrinology And Metabolism. Complex Regulation of GH Autofeedback under Dual-Peptide Drive: studies under a pharmacological GH and sex-steroid clamp

To test the postulate that gender, sex steroids and peptidyl secretagogues control GH autofeedback, 11 healthy postmenopausal women and 14 older men were each given (i) a single i.v. pulse of GH to enforce negative feedback and (ii) continuous i.v. infusion of saline vs combined GHRH/GHRP-2 to drive feedback escape during pharmacological estradiol (E2, women) or testosterone (T, men) supplementation vs placebo in a double-blind, prospectively randomized crossover design.

By 3-way ANCOVA, gender, sex-hormone treatment, peptide stimulation and placebo/saline responses (covariate) controlled total (integrated) GH recovery during feedback (each P<0.001). Both sex-steroid milieu (P=0.019) and dual-peptide stimulation (P<0.001) determined nadir (maximally feedback-suppressed) GH concentrations. E2/T exposure elevated nadir GH concentrations during saline infusion (P=0.003), whereas dual-peptide infusion did so independently of T/E2 and gender (P=0.001). All three of gender (P=0.001), sex-steroid treatment (P=0.005), and double-peptide stimulation (P<0.001) augmented recovery of peak (maximally feedback-escaped) GH concentrations. Peak GH responses to dual-peptidyl agonists were greater in women than men (P=0.016). E2/T augmented peak GH recovery during saline infusion (P<0.001). Approximate entropy analysis corroborated independent effects of sex-steroid treatment (P=0.012) and peptide infusion (P<0.001) on GH regularity.

In summary, gender, sex-steroid supplementation and combined-peptide drive influence nadir, peak and entropic measures of GH release under controlled negative feedback. To the degree that the pharmacological sex-steroid, GH and dual-peptide clamps provide prephysiological regulatory insights, these outcomes suggest major determinants of pulsatile GH secretion in the feedback domain.

 

[Michael Scally MD]

Nigella sativa (NS) is a plant from Ranunculaceae family, with 30 – 60 cm in height, larger leaves above, and blue or white flower at the end of the branch which can produce black seeds. The seeds contain many chemical substances, mainly sterol and essential fatty acids (?-3 and ?-6). Sterol, which is found in NS, is metabolized in the body, producing testosterone. The aim of this study was to evaluate, for the first time in humans, the efficacy of NS on serum free testosterone and metabolic disturbances in Central Obesity in Men (COM). [IMO, basically worthless!!]


Datau EA, Wardhana, Surachmanto EE, Pandelaki K, Langi JA, Fias. Efficacy of Nigella sativa on serum free testosterone and metabolic disturbances in central obese male. Acta Med Indones 2010;42(3):130-4. http://www.inaactamedica.org/archives/2010/20724766.pdf

AIM: to study the efficacy of Nigella sativa in central obese men on serum free testosterone, body weight, waist circumference, blood sugar, lipid, uric acid, adiponectin, hs-CRP, and side effects in the treatment group compare to control.

METHODS: an experimental, clinical test, double blinded with placebo control, pre-test and post-test design. Subjects are 30-45 years old, divided into the treatment and control groups, and evaluated weekly for 3 months. Data obtained were subjective complaints, body weight, waist circumference, and blood pressure, serum free testosterone, fasting blood sugar, triglyceride, HDL-Cholesterol, uric acid, creatinin, SGOT and SGPT, adiponectin, and hs-CRP. Data collected from March 2007 to June 2007 at Prof.Dr.RD Kandou General Hospital, Manado, North Sulawesi, Indonesia. Statistical analysis was performed using descriptive for subjects characteristic and drug's side effect, t independent to compare between two parametric independent variables, Mann-Whitney U to compare between two non-parametric independent variables, and Wilcoxon Signed Ranks test to compare between two non-parametric dependent variables.

RESULTS: in the treatment group, complaints related to central obesity disappear in first week, very significant reduction of body weight, waist circumference, and systolic blood pressure, insignificant reduction in serum free testosterone, diastolic blood pressure, fasting blood sugar, triglyceride and cholesterol-HDL, uric acid, hs-CRP, and insignificant increase of adiponectin. On comparison between both groups, we found a very significant reduction on body weight and waist circumference, but the insignificant reduction on serum free testosterone, systolic and diastolic blood pressure, and the unsignificant increase of adiponectin, meanwhile the reduction of serum free testosterone in the treatment group was smaller than the control group, that means Nigella sativa could inhibit the decreasing of serum free testosterone. No side effects were detected in the treatment group.

CONCLUSION: although the other variables in the treatment group were not significantly different, we found them better than the control group, which can be a good sign for metabolic restoration in COM. It is suggested that larger dose and longer duration of NS consumption will give better results.

 

[Michael Scally MD]

Kisspeptin Resets the Hypothalamic GnRH Clock in Men [I expect Kisspeptin to become available clinically. The remaining question is for what condition(s)!]

Clocks are ubiquitous in living organisms. They drive an extremely wide range of periodic phenomena in individual cells, tissues, organs, and whole organisms. These scales have a range on the order of 10 billion, from milliseconds at the neuronal level, to seconds in cardiac rhythms, to a day on the circadian scale, to a year for seasonal changes. Within this milieu lies the hypothalamus, which houses not only the well-known circadian clock but also the clocks that drive the rhythmic secretion of GnRH, GH, and other hormones. The pulsatile secretion of GnRH initiates puberty; coordinates ovulation; maintains overall reproductive function; and is influenced by gender, sleep, food intake, photoperiod, and stress. Common reproductive disorders, including polycystic ovarian syndrome, hypothalamic amenorrhea, and delayed puberty, are associated with abnormalities in pulsatile GnRH secretion. Although the importance of pulsatile GnRH secretion has been known for decades, the nature of the hypothalamic clock that generates GnRH pulses has remained an enigma.

The hypothalamic neuropeptide kisspeptin is essential for normal reproduction; mutations in the kisspeptin receptor cause abnormal sexual maturation and hypogonadotropic hypogonadism in humans and mice. Kisspeptin is a potent stimulus for GnRH secretion in all mammalian species tested to date, including humans. The effects of kisspeptin on the GnRH pulse generator have yet to be explored in detail.

Researchers administered kisspeptin to healthy adult men and performed frequent blood sampling to chart the morphology and timing of LH pulses before and after kisspeptin administration. This detailed neuroendocrine characterization allowed them to estimate the duration of GnRH secretion in response to kisspeptin and to examine kisspeptin’s effects on endogenous GnRH pulse generation.


Chan Y-M, Butler JP, Pinnell NE, et al. Kisspeptin Resets the Hypothalamic GnRH Clock in Men. J Clin Endocrinol Metab:jc.2010-3046. Kisspeptin Resets the Hypothalamic GnRH Clock in Men -- Chan et al., 10.1210/jc.2010-3046 -- Journal of Clinical Endocrinology & Metabolism

Context: Reproduction in all mammals is controlled by a hypothalamic clock that produces periodic secretory pulses of GnRH, but how the timing of these pulses is determined is poorly understood.The neuropeptide kisspeptin potently and selectively stimulates the secretion of GnRH. Although this property of kisspeptin is well described, the effects of kisspeptin on endogenous GnRH pulse generation remain largely unexplored.

Objective: The objective of the study was to detail the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in men.

Participants: Thirteen healthy adult men participated in the study.

Intervention: The intervention was the administration of a single iv bolus of the C-terminal decapeptide of kisspeptin (amino acids 112–121 of the parent protein).

Results: Kisspeptin induced an immediate LH pulse, regardless of the timing of the previous endogenous pulse. The kisspeptin-induced pulses were on average larger than endogenous pulses (amplitude 5.0 ± 1.0 vs. 2.1 ± 0.3 mIU/ml, P = 0.02). Comparison of the morphology of kisspeptin-induced LH pulses in healthy men with that of GnRH-induced LH pulses in men with isolated GnRH deficiency suggests that a single iv bolus of kisspeptin triggered sustained GnRH release lasting approximately 17 min. Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval.

Conclusions: As the first known agent capable of resetting the hypothalamic GnRH pulse generator, kisspeptin can be used as a physiological tool for studying GnRH pulse generation and opens a door to understanding the mechanisms of biological clocks in general.

 

[Michael Scally MD]

Jannini EA, Gravina GL, Mortengaler A, Morales A, Incrocci L, Hellstrom WJG. Is Testosterone a Friend or a Foe of the Prostate? The Journal of Sexual Medicine 2011;8(4):946-55. Is Testosterone a Friend or a Foe of the Prostate? - Jannini - 2011 - The Journal of Sexual Medicine - Wiley Online Library

Introduction.? Is there any unequivocal evidence that testosterone (T) can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer (PCa)? This is not a controversial point: the answer is yes. However, this evidence does not imply that PCa is a result of T or therapy with T (TTh) of hypogonadal men. Furthermore, currently adequately powered and optimally designed long-term prostate disease data are not available to determine if there is an additional risk from normal T values in cured patients for PCa.

Methods.? This Controversy is introduced by an endocrinologist, the section editor (E.A.J.) with G.L.G., a fellow urologist and radiotherapist expert in basic research on PCa. Two outstanding urologists, A.M and W.J.G.H., debate clinical data and clinical guidelines, respectively. Finally, other controversial issues are discussed by another leader in the field (A.M.) and a radiation oncologist and sexologist who is actually president of the International Society for Sexuality and Cancer (L.I.).

Main Outcome Measure.? Expert opinion supported by the critical review of the currently available literature.

Result.? The answer to the main question “is the prostate a really T-dependent tissue?” is definitively yes, but T stimulates the prostatic tissue in a dose-dependent fashion only to a saturation point, achieved at low T concentrations. At these low T concentrations, stimulation is near maximal, and T supplementation above this level would not lead to significantly greater stimulation. Furthermore, there is no conclusive evidence that TTh increases the risk of PCa or even prostatic hyperplasia. There is also no evidence that TTh will convert subclinical PCa to clinically detectable PCa. However, there is a limited clinical experience of TTh after successful treatment of PCa. So far, just 48 patients have been studied in the three published articles.

Conclusions.? It is evident that the issue is still controversial and much more research is needed. However, the available data suggest to the expert in sexual medicine that TTh can be cautiously considered in selected hypogonadal men previously treated for curative intent of low-risk PCa and without evidence of active disease.

 

[Michael Scally MD]

 

[Michael Scally MD]

[Note: This occurred in a 50-year-old man known to have chronic hepatitis C. How smart/stupid is it to use AAS with known liver disease!]

Methandrostenolone (Dianabol) was first introduced as an anabolic steroid by Ciba in the 1960s. Methandrostenolone was one of the AAS used to enhance athletic performance by the former East German Olympic program. Methandrostenolone has been reported to cause cholestasis of the intra-hepatic bile ducts resulting in elevated aminotransferases, hyperbilirubinemia and clinical jaundice. In this paper, investigators present a case of pancreatitis, cholestasis of the liver and acute kidney injury associated with the use of methandrostenolone for aesthetic purposes in a 50-year-old, non-athlete man. A brief literature review of Medline and PubMed Central, utilizing the search terms ‘androgenic anabolic steroids’, ‘pancreatitis’ and ‘methandrostenolone’, failed to reveal any other cases of pancreatitis arising from the use of anabolic steroids.


Rosenfeld GA, Chang A, Poulin M, Kwan P, Yoshida E. Cholestatic Jaundice, Acute Kidney Injury and Acute Pancreatitis Secondary to The Recreational Use of Methandrostenolone: a Case Report. J Med Case Reports 2011;5(1):138. http://www.jmedicalcasereports.com/content/pdf/1752-1947-5-138.pdf

ABSTRACT: INTRODUCTION: Over the last few years the use of Anabolic steroids has become increasingly common amongst amateur athletes and for aesthetic purposes. As a result, the adverse events related to their use are being seen more frequently. Methandrostenolone is an anabolic steroid which is widely available and has been used for both performance enhancement and aesthetic purposes. This drug has also been reported to cause cholestasis of the intrahepatic bile ducts resulting in elevated aminotransferases, hyperbilirubinemia and clinical jaundice. However, this agent has not been previously reported to cause pancreatitis or acute kidney injury.

Case Presentation In this paper, we report the case of a fifty year old man of Indian decent who presented with a six week history of diffuse abdominal pain, anorexia and weight loss following an eight week cycle of methandrostenolone use. At initial presentation, his Lipase was 785 U/L, bilirubin was 922 umol/L and creatinine was 200 U/L while has AST and ALT were only mildly elevated at 61U/L and 56 U/L respectively. His lipase peaked on day 9 at >3000 U/L and creatinine was 299 U/L. Imaging was consistent with acute pancreatitis while a liver biopsy was consistent with intrahepatic cholestasis and a kidney biopsy revealed evidence of acute tubular necrosis.

CONCLUSION: Both acute pancreatitis and acute kidney injury have rarely been reported with anabolic steroid use and they have not been previously reported to occur in the same patient. This case demonstrates some potentially new and serious adverse consequences occurring with the use of anabolic steroids of which physicians need to be aware.

 

[Michael Scally MD]

Testosterone & Alcohol

The purpose of the present study was, thus, to examine interactive effects of ethanol and time of day on verbal memory in young men. Specifically, the researchers hypothesized that men in the alcohol condition tested in the afternoon would show better recall of prose material than those in the same condition tested in the morning. This difference was hypothesized to be associated with lower breath alcohol levels expected in the afternoon sessions.


Poltavski DV, Marino JM, Guido JM, Kulland A, Petros TV. Effects of acute alcohol intoxication on verbal memory in young men as a function of time of day. Physiol Behav 2011;102(1):91-5.

This experiment examined whether the time of day of alcohol administration influences alcohol metabolism and the impact of alcohol on verbal memory. It was hypothesized that circadian fluctuations in endogenous levels of testosterone in young men would differentially affect blood alcohol levels, which would consequently impair their memory performance to a different degree. Participants were administered alcohol or placebo drinks either at 8am or 6pm and recall of 4 prose passages was examined. The results indicated that recall declined for subjects administered alcohol but time of day did not moderate these effects. Nevertheless, generally alcohol breath levels changed in the predicted direction as a function of the time of the day with higher levels recorded in the morning and lower levels in the afternoon. The results suggested that observed differences in breath alcohol levels may be influenced by differences in endogenous levels of testosterone, but the effect of this presumed interaction on verbal memory appears inconclusive.

 

[HeadDoc]

Dopamine Controls Neurogenesis in the Adult Salamander Midbrain in Homeostasis and during Regeneration of Dopamine Neurons
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Daniel A. Berg1, Matthew Kirkham1, Heng Wang1, Jonas Frisén1 and András Simon1, Corresponding Author Contact Information, E-mail The Corresponding Author

1 Department of Cell and Molecular Biology and Center of Developmental Biology for Regenerative Medicine (DBRM), Karolinska Institute, SE-171 77 Stockholm, Sweden
Received 15 April 2010;
revised 10 December 2010;
accepted 14 January 2011.
Published: April 7, 2011.
Available online 7 April 2011.

Summary

Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.
Graphical Abstract

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Highlights

? Regeneration of midbrain dopamine neurons depends on decreased dopamine signaling ? L-dopa inhibits ependymoglia cell proliferation during dopamine neuron regeneration ? Proliferation of ependymoglia cells is constantly suppressed by dopamine signaling ? Inhibition of dopamine signaling evokes neurogenesis by quiescent ependymoglia cells

 

[HeadDoc]

Original article requested of author. This parallels in some respects research on mindfulness, as the same brain region is involved.

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Contact: Basil Waugh
basil.waugh@ubc.ca
604-822-2048
University of British Columbia
People control thoughts better when they see their brain activity: UBC study

As humans face increasing distractions in their personal and professional lives, University of British Columbia researchers have discovered that people can gain greater control over their thoughts with real-time brain feedback.

The study is the world's first investigation of how real-time functional Magnetic Resonance Imaging (fMRI) feedback from the brain region responsible for higher-order thoughts, including introspection, affects our ability to control these thoughts. The researchers find that real-time brain feedback significantly improves people's ability to control their thoughts and effectively 'train their brains.'

"Just like athletes in training benefit from a coach's guidance, feedback from our brain can help us to be more aware of our thoughts," says co-author Prof. Kalina Christoff, UBC Dept. of Psychology. "Our findings suggest that the ability to control our thinking improves when we know how the corresponding area in our brain is behaving."

For the study, published the current issue of NeuroImage journal, participants performed tasks that either raised or lowered mental introspection in 30-second intervals over four six-minute sessions. fMRI technology tracked real-time activity in the rostrolateral prefrontal cortex (RLPFC), the region of the brain involved with higher-order thoughts.

Participants with access to real-time fMRI feedback could see their RLPFC activity increase during introspection and decrease during non-introspective thoughts, such as mental tasks that focused on body sensations. These participants used the feedback to guide their thoughts, which significantly improved their ability to control their thoughts and successfully perform the mental tasks. In contrast, participants given inaccurate or no brain feedback did not achieve any improvement in brain regulation.

"When participants saw their brain reacting to their thoughts, they knew whether they were performing the task well or poorly, and they could adjust their thoughts accordingly," says co-author Graeme McCaig, a graduate of UBC's Dept. of Electrical and Computer Engineering's Human Computer Interaction specialization. "As a result, participants who received the real-time feedback were able to focus on the mental task more consistently."

The study points to the possibility of improving our everyday lives through fMRI-assisted advances in our ability to focus our minds on personal or professional matters, according to the research team, which includes Matt Dixon, Kamyar Keramatian and Irene Liu.

The findings also raise hope for clinical treatments of conditions that can benefit from improved awareness and regulation of one's thoughts, including depression, anxiety, and obsessive-compulsive disorders, the researchers says. For example, with increased availability of fMRI technology, real-time brain feedback represents a potentially important complement to feedback provided by a therapist or a patient's own self-monitoring ability.

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[Michael Scally MD]

New Journal: Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle
Journal of cachexia, sarcopenia and muscle. - NLM Catalog result

von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachex Sarcopenia Muscle 2010;1(1):7-8.

The principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM) are: all authors listed on the manuscript have approved its submission and publication as provided to JCSM; no person who has a right to be recognized as author has been omitted from the list of authors; each author has made an independent material contribution to the work submitted for publication ;the submitted work is original and is neither under consideration elsewhere nor has it been published previously in whole or in part other than in abstract form; all original research work is approved by the relevant bodies such as institutional review boards or ethics committees; all conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively have been duly declared in the manuscript; the manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true; if any of the aforementioned statements ceases to be true, the authors have a duty to notify the editors of JCSM as soon as possible so that the information available online can be updated and/or the manuscript can be withdrawn.

 

[Michael Scally MD]

Researchers designed this study to evaluate the yield of adding chronic kidney disease (CKD) definitions based on albumin-to-creatinine ratio (ACR) and cystatin C to forecast risk compared with a CKD definition using creatinine-based estimates alone. They hypothesized that cystatin C and albuminuria would add complementary risk information among persons with and without CKD, as defined by creatinine-based estimated GFR (GFRcreatinine).


Peralta CA, Shlipak MG, Judd S, et al. Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality. JAMA: The Journal of the American Medical Association. Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality - — JAMA

Context A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.

Objective To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.

Design, Setting, and Participants Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ?60 mL/min/1.73 m2 and ACR of either <30 or ?30 mg/g.

Main Outcome Measures All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.

Results Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0-5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2-4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9-8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4-1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9-2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4-3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7-40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05-2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (P < .001) and for end-stage renal disease was 6.4% (P < .001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.

Conclusion Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.

 

[Michael Scally MD]

[What can I say? This is another attempt to break into the ever growing and profitable testosterone market. It will NOT work, IMO. Also, the title says it all - "Re-examination." Look at the dose - 400 mg/day, LMAO]

Researchers studied the pharmacokinetics (PK) of a new oral formulation incorporating a Self-Emulsifying Drug Delivery System (SEDDS) in hypogonadal men. This SEDDS promotes solubilization and the intestinal lymphatic absorption of lipophilic T esters thereby reducing first-pass hepatic metabolism. Rapid de-esterification of TU by non-specific esterase in liver, blood, and tissue results in production of T. The liberated undecanoic acid moiety is metabolized via beta-oxidation. Five-alpha-reduction of TU in the gut produces dihydrotestosterone undecanoate (DHTU) and dihydrotestosterone (DHT). In this study, they report the PK of serum T, DHT, TU and DHTU after single-day, seven-day and 28-day oral dosing of TU administered in SEDDS, and demonstrate that serum T levels are achieved within the physiologic range after dosing with TU 200 mg twice per day in most hypogonadal men.


Yin AY, Htun M, Swerdloff RS, et al. Re-Examination of Pharmacokinetics of Oral Testosterone Undecanoate in Hypogonadal Men with a New Self-Emulsifying Formulation. J Androl:jandrol.111.013169. Re-Examination of Pharmacokinetics of Oral Testosterone Undecanoate in Hypogonadal Men with a New Self-Emulsifying Formulation -- Yin et al., 10.2164/jandrol.111.013169 -- Journal of Andrology

Context: Many hypogonadal men prefer oral testosterone (T) treatment. Oral T undecanoate (TU) is available in many countries but not in the United States. Objective: Assess pharmacokinetics of oral TU in a new Self-Emulsifying Drug Delivery System (SEDDS) formulation.

Study Design: Pharmacokinetics studies were conducted in three parts: 12 hypogonadal men were enrolled in two centers for single-day dosing study; 29 subjects from three centers for seven-day dosing study; and 15 subjects from one center for 28-day dosing study. Serial blood samples for serum sex hormones measurements by liquid chromatography-tandem mass spectrometry were drawn for up to 36 h after oral TU administration.

Results: Mean serum T levels (Cavg) after oral dosing of T 200 mg as TU twice daily with food were within the adult male range in most subjects in the single-, seven- and 28-day dosing studies but were much lower in the fasting state. The dose proportional increase in Cavg of serum T after oral T 300 mg twice daily resulted in more subjects with supraphysiologic serum T levels. In the 28-day study, trough serum T reached steady state at day seven. Serum DHT and estradiol levels tracked serum T concentration. DHT/T ratios increased three-fold after oral TU administration.

Conclusion: Oral T 200 mg twice daily as TU in a new SEDDS formulation may be a viable therapy for hypogonadal men.

 

[Michael Scally MD]

Physicians Recommend Different Treatments for Patients Than They Would Choose for Themselves

Most physicians have received requests from patients for clinical recommendations. How should physicians respond to such requests?

Some experts contend that patients ought to be the primary decision makers and that physicians should avoid making treatment recommendations that influence patient choice. These experts point out that physician recommendations can be coercive. Indeed, physician recommendations have been shown to have a strong influence on patient choice and can even pull patients away from the alternatives that are in their best interests.

This disapproval of physician recommendations is based on the assumption that because patients know their own preferences better than their physicians do, the best way to ensure that patients make choices consistent with such preferences is to inform them of their medical alternatives and allow them to make the final choice. According to this assumption, physician recommendations will only serve to draw patients away from their own preferences.

However, others have questioned this disapproval on the basis that recommendations could, in some circumstances, promote patients' best interests. Patients' decisions are susceptible to cognitive biases, which can cause them to make choices that contradict their own best interests. Physician recommendations could potentially help patients overcome these biases. First, physicians may be more dispassionate and thus less susceptible to cognitive biases than patients. Second, the mere act of making a recommendation may alter the psychology of the decision in ways that reduce some biases. Research has shown that when people make decisions for others, for example, they hone in on the most important aspect of the decision and are thus less swayed by extraneous factors that could bias the decision. Studies of toddlers, for instance, have shown that they make less impulsive decisions for others than they do for themselves.

In this article, researchers test whether making a recommendation changes the ways that physicians think about medical decisions. Specifically, they conducted 2 randomized experiments in which they ask physicians to decide which treatment they would choose if they themselves were the patient or which treatment they would recommend to a patient facing the same decision. Both experiments were designed to test for the presence of well-established cognitive biases. Thus, by conducting these randomized experiments, they can determine whether the act of making recommendations changes physicians' decisions.


Ubel PA, Angott AM, Zikmund-Fisher BJ. Physicians Recommend Different Treatments for Patients Than They Would Choose for Themselves. Arch Intern Med 2011;171(7):630-4. Arch Intern Med -- Abstract: Physicians Recommend Different Treatments for Patients Than They Would Choose for Themselves, April 11, 2011, Ubel et al. 171 (7): 630

Background Patients facing difficult decisions often ask physicians for recommendations. However, little is known regarding the ways that physicians' decisions are influenced by the act of making a recommendation.

Methods We surveyed 2 representative samples of US primary care physicians--general internists and family medicine specialists listed in the American Medical Association Physician Masterfile--and presented each with 1 of 2 clinical scenarios. Both involved 2 treatment alternatives, 1 of which yielded a better chance of surviving a fatal illness but at the cost of potentially experiencing unpleasant adverse effects. We randomized physicians to indicate which treatment they would choose if they were the patient or they were recommending a treatment to a patient.

Results Among those asked to consider our colon cancer scenario (n = 242), 37.8% chose the treatment with a higher death rate for themselves but only 24.5% recommended this treatment to a hypothetical patient ({chi}21 = 4.67, P = .03). Among those receiving our avian influenza scenario (n = 698), 62.9% chose the outcome with the higher death rate for themselves but only 48.5% recommended this for patients ({chi}21 = 14.56, P < .001).

Conclusions The act of making a recommendation changes the ways that physicians think regarding medical choices. Better understanding of this thought process will help determine when or whether recommendations improve decision making.


Shaban E, Guerry R, Quill TE. Reconciling Physician Bias and Recommendations: Comment on "Physicians Recommend Different Treatments for Patients Than They Would Choose for Themselves". Arch Intern Med 2011;171(7):634-5. Arch Intern Med -- Reconciling Physician Bias and Recommendations: Comment on "Physicians Recommend Different Treatments for Patients Than They Would Choose for Themselves", April 11, 2011, Shaban et al. 171 (7): 634

 

[Michael Scally MD]

Evaluation Of Early Biomarkers Of Muscle Anabolic Response To Testosterone

Muscle size and strength deteriorate dramatically with increasing age. Sarcopenia can be defined operationally as muscle mass two standard deviations below that of young healthy controls. The prevalence of sarcopenia in individuals older than 80 years of age exceeds 50%. Exercise training can improve sarcopenia, but there are currently no marketed treatments available for sarcopenia. Loss of muscle mass and function threatens the independence and quality of life of the elderly and may compromise their ability to survive critical illness. Further understanding of the pathophysiology of sarcopenia and the development of more sensitive and specific genotyping and phenotyping tools will enable us to develop targeted therapeutic agents to treat this disorder.

A challenge in developing drug therapies for sarcopenia is the long treatment duration required for assessing clinical efficacy. Currently, researchers assess clinical efficacy by quantifying changes in lean body mass using dual-energy X-ray absorptiometry and changes in muscle function by using bilateral leg maximum voluntary force production, but measurable improvement in these endpoints requires at least 12 weeks of follow-up. Here, they hypothesized that short-term testosterone exposure would induce several candidate early predictive biomarkers of muscle anabolism that could be identified using skeletal muscle gene and protein expression profiling platforms. Testosterone enanthate was used because it is a potent anabolic agent known to improve muscle size and strength. Sarcopenia can affect women, but to minimize heterogeneity, only men were enrolled given there are clear data regarding the effects of testosterone in men.

Several existing candidate biomarkers for muscle anabolism were examined. Collagen type III is the characteristic collagen of parenchymal organs and soft connective tissues such as muscle and skin. Collagen III is synthesized from larger procollagen type III with cleavage of peptide fragments from the N- and C-terminal ends. Procollagen type III N-terminal peptide (P3NP) is released into the circulation during collagen III synthesis and increases when skeletal muscle remodeling is activated. Skeletal muscle protein fractional synthesis rate (FSR) increases with muscle protein anabolism and can be assessed by measuring the rate of incorporation of stable isotope-labeled phenylalanine into skeletal muscle proteins. Muscle RNA microarray and protein expression profiling are newer high-throughput approaches that can be used to examine transcript and protein expression changes and can be useful for discovering new candidate biomarkers for myoanabolism.


Chen F, Lam R, Shaywitz D, et al. Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachex Sarcopenia Muscle 2011;2(1):45-56. Evaluation of early biomarkers of muscle anabolic ... [J Cachex Sarcopenia Muscle. 2011] - PubMed result

BACKGROUND: Early biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty.

METHODS AND RESULTS: We examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60-75 years; study 2, 18-40 years) with low to normal testosterone levels. Men were randomized to lower dose (study 1, 100 mg; study 2, 200 mg) or higher dose (study 1, 300 mg; study 2, 600 mg) single intramuscular testosterone or saline injection. After 1 week, testosterone acutely increased plasma P3NP levels in a dose-dependent manner and altered the expression of several skeletal muscle transcripts and proteins. Though not statistically significant, mixed muscle protein fractional synthesis rate tended to increase (1.08-fold with 100 mg testosterone, 1.12-fold with 300 mg testosterone). Testosterone exposure also increased skeletal muscle expression of the collagen type III gene that encodes P3NP.

CONCLUSION: P3NP is a potentially useful early biomarker for muscle anabolic therapy. Skeletal muscle protein and RNA profiling are useful tools for the discovery of novel muscle anabolic biomarkers.

 

[Michael Scally MD]

[There are alot of abstracts available. It is worth a quick look. Following are examples.]

We are delighted to provide you with details of the Society for Endocrinology BES 2011 meeting, taking place in Birmingham on 11-14 April 2011.
http://www.endocrinology.org/meetings/2011/sfebes2011/prog/prog.aspx
http://www.endocrine-abstracts.org/ea/0025/default.htm


The metamorphosis of testosterone from a sex steroid to a universal health factor
Eberhard Nieschlag
The metamorphosis of testosterone from a sex steroid to a universal health factor

When in the 1930s testosterone was isolated, synthesized and introduced to the clinic, it was considered predominantly a sex steroid to be used for the treatment of erectile dysfunction and hypogonadism. In the 1950s the anabolic effect was ‘discovered’ and triggered the misuse of high doses of testosterone in sports, still prevailing today. Consequently, pharmacologic research concentrated its efforts on anabolic steroids, i.e. testosterone analogues hopefully without sexual effects, thus neglecting the search for badly needed improved forms of testosterone application. Improved modes of application only became the focus of the pharmaceutical industry when in the 1990s, the increasing life expectancy of males and the anticipated parallel increase in late-onset hypogonadism (LOH) precipitated the invention of transdermal testosterone preparations, finally producing the desired physiological testosterone levels. Intensified research on the aging male revealed the role of testosterone in the pathognesis of obesity, diabetes type II and the metabolic syndrome as well as in osteoporosis, sarcopenia, atherosclerosis and coronary heart disease. Indeed, testosterone levels in blood are now considered a general predictor of morbidity and mortality. Thus, while the role of testosterone in erection and sexual function (supplemented by phosphodiesterase-5-inhibitors if needed) remained, its spectrum of action broadened to become a universal health factor.


Low testosterone predicts increased mortality and testosterone replacement therapy improves survival in men with type 2 diabetes
Vakkat Muraleedharan, Hazel Marsh & Hugh Jones
Low testosterone predicts increased mortality and testosterone replacement therapy improves survival in men with type 2 diabetes

Background: Low testosterone in men is associated with increase in all-cause and cardiovascular mortality. There is a high prevalence of hypogonadism in men with type 2 diabetes and testosterone replacement therapy (TRT) improves cardiovascular risk. However there is no published data regarding mortality in these patients in relation to testosterone levels, and the long term effect of TRT on mortality.

Aim: We report a 6 year follow-up study examining the effect of baseline testosterone and TRT in hypogonadal men with type 2 diabetes on all-cause mortality.

Methods: Five hundred eighty-seven patients with type 2 diabetes had total testosterone (TT) performed between 2002 and 2005 and were followed up for 5.8±1.3 years.

Deaths during the first 6 months were excluded. Patients were then analysed in three groups. i) normal TT (>10.4 nmol/l) ii) low TT (?10.4 nmol/l) without TRT. iii) low TT receiving TRT for 2 years or more.

Results: Of 580 patients analysed, 338 had normal TT (58%) and 240 low TT (42%). In the low TT group 58 patients received TRT. Mean age 61±11 S.D. and similarly matched in all three groups. Total deaths 72 (12.4%). Mortality rates – low TT without treatment (36/182-20%), normal TT (31/338-9%) and low TT with TRT (5/58-8.6%). Survival was significantly decreased in patients with low TT without TRT (P=0.001 log rank) compared to normal. The treated group had improved survival (P=0.049 log rank). In the Cox Regression model multi-variate (age, weight, HbA1c, pre existing cardiovascular disease, smoking, statin and ACEi/ARB use) adjusted hazard ratio for all-cause mortality was 2.2 (95% CI 1.3–3.7 P=0.001) for low TT.

Conclusions: This study shows that men with type 2 diabetes and low testosterone have a significant increased mortality. TRT improved survival compared to those untreated, recording a similar mortality rate to the normal TT group.

 

[Michael Scally MD]

A significant proportion of elderly men have a testosterone level which is below the normal range seen in young men. Low testosterone levels in ageing men may result in symptoms of hypoandrogenism and such symptoms may therefore be responsive to testosterone replacement. Furthermore, low testosterone has been reported to be an independent predictor of cardiovascular disease, stroke, mortality and Alzheimer's disease, raising the possibility that there could also be prognostic advantages from testosterone replacement. However, the role of testosterone therapy in the ageing male is controversial and remains the subject of ongoing research. Moreover, defining biochemical hypoandrogenism in ageing men is complex, not only because comparison with testosterone levels in young men may not be appropriate but also because of the recognized effects on testosterone of smoking, poor general health status, and obesity. There is also uncertainty about how best to take obesity into account given recent data that waist circumference (WC) may be a better predictor of the testosterone level than body mass index (BMI). An additional issue is whether previous findings in population studies regarding adiposity and testosterone are relevant to that group of symptomatic ageing men who are most likely to be considered for testosterone replacement.

In this study, researchers have examined the relationships of ageing, adiposity and testosterone levels in a highly select group of ageing men (over the age of 54 years) who were recruited on the basis of having symptoms consistent with hypoandrogenism but who were non-smokers and otherwise in good health. Subjects were also excluded if they had a BMI ?35 kg m?2 because of the documented association of severe obesity with hypogonadotrophic hypogonadism. We investigated whether WC was a better predictor of testosterone than BMI in our cohort and, given increasing evidence of the value of indexing WC to height (Ht) as waist-to-height ratio (WHt ratio), they also examined the utility of WHt ratio for prediction of the testosterone level. Furthermore, given the important regulating effect of sex hormone binding globulin (SHBG) on testosterone levels, and the complex relation of SHBG with age and adiposity, they investigated the relationship of BMI, WC and WHt ratio with testosterone after adjusting for SHBG.


Allan CA, Peverill RE, Strauss BJ, Forbes EA, McLachlan RI. Waist-to-height ratio as a predictor of serum testosterone in ageing men with symptoms of androgen deficiency. Asian J Androl. http://www.nature.com/aja/journal/vaop/ncurrent/pdf/aja201113a.pdf

The decline in serum testosterone in ageing men may be mediated in part by obesity; however, it is uncertain which measure of adiposity is most closely associated with testosterone levels. We have examined the relationships of age, adiposity and testosterone levels in ageing men with symptoms consistent with hypoandrogenism but who were otherwise in good health.

We conducted a cross-sectional study of non-smoking men aged >/=54 years recruited from the community and who were free of cancer or serious medical illness. Height (Ht), weight and waist circumference (WC) were measured, and body mass index (BMI) and waist-to-height (WHt) ratio were calculated. Two morning blood samples were collected for measurement of total testosterone (TT), sex hormone binding globulin (SHBG) and luteinizing hormone (LH). Free testosterone (cFT) was calculated. Multivariate linear regression analysis was performed to assess their relationship with measures of adiposity. Two hundred and seven men aged 54-86 years were studied.

On univariate analysis WHt ratio was more strongly correlated with TT and cFT than either WC or BMI. Furthermore, in models of TT and cFT, the addition of Ht to WC resulted in an increase in the magnitude of the regression coefficients for both WC (inverse correlate) and Ht (positive correlate), with the contributions of both WC and Ht both being significant (P<0.05 for all). In conclusion, WHt ratio is the best anthropometric predictor of both TT and cFT in this group of healthy but symptomatic ageing men.