OnLine First

[Michael Scally MD]

Pokhrel M, Ma E. Synthesis and screening of aromatase inhibitory activity of substituted c19 steroidal 17-oxime analogs. Molecules 2011;16(12):9868-85. Molecules | Free Full-Text | Synthesis and Screening of Aromatase Inhibitory Activity of Substituted C19 Steroidal 17-Oxime Analogs

The synthesis and aromatase inhibitory activity of androst-4-en-, androst-5-en-, 1beta,2beta-epoxy- and/or androsta-4,6-dien-, 4beta,5beta-epoxyandrostane-, and 4-substituted androst-4-en-17-oxime derivatives are described. Inhibition activity of synthesized compounds was assessed using aromatase enzyme and [1beta-3H]androstenedione as substrate. Most of the compounds displayed similar to or more aromatase inhibitory activity than formestane (74.2%). 4-Chloro-3beta-hydroxy-4-androsten-17-one oxime (14, 93.8%) showed the highest activity, while 4-azido-3beta-hydroxy-4-androsten-17-one oxime (17, 32.8%) showed the lowest inhibitory activity for aromatase.

 

[Michael Scally MD]

Yonker JA, Chang V, Roetker NS, Hauser TS, Hauser RM, Atwood CS. Hypothalamic-pituitary-gonadal axis homeostasis predicts longevity. Age (Dordr). http://www.springerlink.com/content/k0641741kx324500/ (SpringerLink - AGE, Online First™)

The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study (n = 5,034), we analyzed the relationship between longevity and menopause, including other factors that impact "ovarian lifespan" such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic-pituitary-gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity.

 

[Michael Scally MD]

Dehydroepiandrosterone Sulfate - Action And Mechanism In The Brain

Dong Y, Zheng P. Dehydroepiandrosterone sulfate: action and mechanism in the brain. J Neuroendocrinol. Dehydroepiandrosterone sulfate: action and mechanism in the brain - Dong - Journal of Neuroendocrinology - Wiley Online Library

Dehydroepiandrosterone sulfate (DHEAS) is synthesized from DHEA by the enzyme sulfotransferase. DHEAS is one of the most important neurosteroids in the brain. The concentration of DHEAS in the brain is sometimes higher than peripheral system. At cellular level, DHEAS has been showed to modulate a variety of synaptic transmission, including cholinergic, GABAergic dopaminergic and glutamatergic synaptic transmission. In addition to the effect on the release of a number of neurotransmitters, DHEAS also could modulate the activity of postsynaptic receptors. DHEAS has been found to have multiple important effects on brain functions such as memory enhancing, antidepressant, anxiolytic effects and may have relationships with many brain diseases.

 

[Michael Scally MD]

Wu C, Zhang H, Gao Y, et al. The Association of Smoking and Erectile Dysfunction: Results from the Fangchenggang Area Male Health and Examination Survey (FAMHES). J Androl:jandrol.110.012542. The Association of Smoking and Erectile Dysfunction: Results from the Fangchenggang Area Male Health and Examination Survey (FAMHES) -- Wu et al., 10.2164/jandrol.110.012542 -- Journal of Andrology

To describe the prevalence of erectile dysfunction (ED) and its association with smoking and other risk factors among a large male population. Data were collected from 2,686 men attending the Fangchenggang Area Male Healthy and Examination Survey (FAMHES) from September 2009 to December 2009. ED was assessed using the five-item International Index of Erectile Function. Self-reported smoking history was obtained from the questionnaire.

Prevalence of ED was 49.5% among 2,686 Chinese men in Fangchenggang aged 20-79 years. After adjusting for age, alcohol drinking, physical activity, hypertension, diabetes, dyslipidemia and obesity, smokers who smoked 20 cigarettes or more daily had a significantly increased risk of ED than never smokers ( OR=1.23; 95%CI=1.03-1.49; P=0.02). After further adjustment for education, the risk of ED was still significantly higher in men smoking more than 23 years than never smokers (OR=1.60; 95%CI=1.22-2.09; P=0.001). Age and education were statistically signi[fi]cantly associated with erectile dysfunction after adjusting for the other variables. A history of diabetes and hypertension all increased the risk of ED, but statistically significant difference not existed after adjustment for other variables. There was an higher association between smoking and ED risk in men with a habit of alcohol drinking (OR=1.32, 95%CI=1.01-1.74) or physical inactivity (OR=1.33, 95%CI=1.05-1.67), or with a with a history of hypertension 1.71 (95%CI=1.11-2.62), dyslipidemia 1.39 (95%CI=1.06-1.81), and diabetes2.69 (95%CI=1.4-6.98).

Our results show that heavy smoking may cause ED and that the duration of the habit increases the risk of ED. Further, it highlights the potential interaction of smoking with other life habits or medical history on ED risk.

 

[Michael Scally MD]

Fruhbeck G. Gastrointestinal hormones: Uroguanylin - a new gut-derived weapon against obesity? Nat Rev Endocrinol 2012;8(1):5-6. Gastrointestinal hormones: Uroguanylin[mdash]a new gut-derived weapon against obesity? : Article : Nature Reviews Endocrinology

A recent report has identified uroguanylin as an endocrine signal that exerts a physiological role in energy homeostasis, adding another factor to the gut–brain axis. From a clinical point of view, several observations highlight the uroguanylin–guanylyl cyclase C pathway as a potential therapeutic target for the development of antiobesity drugs.

Schematic diagram of currently known and foreseeable effects of uroguanylin

 

[HeadDoc]

Interval training and blood sugar regulation:

[ Back to EurekAlert! ] Public release date: 12-Dec-2011
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Contact: Michelle Donovan
donovam@mcmaster.ca
905-525-9140
McMaster University
Brief, high-intensity workouts show promise in helping diabetics lower blood sugar: Study

Researchers at McMaster University have found that brief high intensity workouts, as little as six sessions over two weeks, rapidly lower blood sugar levels in type 2 diabetics, offering a potential fix for patients who struggle to meet exercise guidelines.

The small proof-of-principle study, conducted on eight diabetics, appears in the latest edition of the Journal of Applied Physiology.

It found that a total of 30 minutes of high-intensity intermittent exercise per week, involving a total time commitment of 75 minutes, lowered 24-hour blood sugar concentrations, reduced blood sugar spikes after meals, and increased skeletal muscle mitochondrial capacity, a marker of metabolic health.

"These findings are intriguing because they suggest that exercising very strenuously for short periods of time, may provide many of the same health benefits as traditional exercise training," says Martin Gibala, professor in the Department of Kinesiology at McMaster and supervising author of the study. "This is the first study to show that intense interval training may be a potent, time-efficient strategy to improve glycemic regulation in people with type 2 diabetes."

Current guidelines from the Canadian Diabetes Association call for 150 minutes of moderate to vigorous exercise per week—twice the training time commitment of study participants—which can be tough to manage for many people including those with diabetes, adds Gibala.

He is quick to point out that larger studies are needed to comprehensively examine the potential benefits of this type of training, especially compared to traditional exercise guidelines.

For the study, researchers gave each volunteer a baseline exam to test blood sugar over a 24-hour period, assess fitness levels and take biopsies of thigh muscle to measure proteins linked to health status.

Each workout involved riding a stationary bike for 10 bouts of 60 seconds at roughly 90 percent of maximal heart rate, with one minute between each burst of exercise. The routine also included a warm up and cool down such that each training session lasted 25 minutes in total.

Participants showed improved blood sugar levels even though they did not lose weight during the short two-week study.

"The improved glycemic control may be linked to changes in the subjects' muscles, such as an improved ability to clear glucose from the blood after meals", says Gibala. "We need to conduct further research to identify the mechanisms behind these results."

###

The research was funded by the Natural Sciences and Engineering Council of Canada and the Canadian Diabetes Association.

Att. Editors: a high-resolution photo of Martin Gibala can be found at http://dailynews.mcmaster.ca/images/gibala2011.JPG

Video clips of Martin Gibala explaining the research can be found at [ame=http://www.youtube.com/watch?v=aMJbaG-QSPI]Lower blood sugar with high-intensity workouts - YouTube[/ame]

A copy of the study is available at http://bit.ly/szq4D

McMaster University, one of four Canadian universities listed among the Top 100 universities in the world, is renowned for its innovation in both learning and discovery. It has a student population of 23,000, and more than 140,000 alumni in 128 countries.

For more information, please contact:

Michelle Donovan
Public Relations Manager
McMaster University
905-525-9140, ext. 22869
michelle.donovan@mcmaster.ca

 

[Michael Scally MD]

Pan Y, Gerasimov MR, Kvist T, et al. CPP-115, a Potent ?-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction. Journal of Medicinal Chemistry. CPP-115, a Potent ?-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction - Journal of Medicinal Chemistry (ACS Publications)

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (<b>CPP-115</b>) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, <b>CPP-115</b> produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600^th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300^th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with <b>CPP-115</b>, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, <b>CPP-115</b> can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.

 

[Michael Scally MD]

Coss CC, Bauler M, Narayanan R, Miller DD, Dalton JT. Alanine Aminotransferase Regulation by Androgens in Non-hepatic Tissues. Pharm Res. Alanine Aminotransferase Regulation by Androgens i... [Pharm Res. 2011] - PubMed - NCBI

PURPOSE: Alanine amino-transferases (ALTs) play a crucial role in drug development as a surrogate marker of liver injury where elevations in serum ALT activity are used to diagnose drug-induced liver damage. Two ALT isoforms have been characterized with disparate but overlapping tissue expression. ALT1 is primarily expressed in live; ALT2 is found in muscle and prostate tissues. We investigate ALT gene expression in diverse rodent tissues following administration of the steroidal androgen receptor (AR) agonist dihydrotestosterone and a novel tissue selective nonsteroidal agonist S-23.

METHODS: Putative AR regulation of ALT expression was determined in silico by an orthologous promoter androgen response element (ARE) search. Regulation was evaluated by transient transfection of ALT promoter region constructs and qRT-PCR experiments in cultured cells and in tissues following androgen administration.

RESULTS: Several putative AREs were found in the proximal promoter regions of ALT1 and ALT2. AREs in ALT2 but not ALT1 were capable of AR-mediated transcription. ALT2 expression was affected by castration and androgen administration in muscle and prostate but not liver tissues.

CONCLUSIONS: Androgen action in non-hepatic tissues, as opposed to xenobiotic toxicity alone, may contribute to increases in serum ALT activity following androgen administration.

 

[HeadDoc]

Coffee and prostate cancer.

From Journal of the National Cancer Institute
Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study

Kathryn M. Wilson; Julie L. Kasperzyk; Jennifer R. Rider; Stacey Kenfield; Rob M. van Dam; Meir J. Stampfer; Edward Giovannucci; Lorelei A. Mucci

Authors and Disclosures

Posted: 09/05/2011; Journal of the National Cancer Institute. 2011;103(11):876-884. © 2011 Oxford University Press

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Background Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.
Methods We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.
Results The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, P trend = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, P trend = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (?6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.
Conclusions We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.

 

[Michael Scally MD]

Ledergerber C, Dessimoz C. Base-calling for next-generation sequencing platforms. Briefings in Bioinformatics 2011;12(5):489-97. Base-calling for next-generation sequencing platforms

Next-generation sequencing platforms are dramatically reducing the cost of DNA sequencing. With these technologies, bases are inferred from light intensity signals, a process commonly referred to as base-calling. Thus, understanding and improving the quality of sequence data generated using these approaches are of high interest. Recently, a number of papers have characterized the biases associated with base-calling and proposed methodological improvements. In this review, we summarize recent development of base-calling approaches for the Illumina and Roche 454 sequencing platforms.


Berglund EC, Kiialainen A, Syvanen AC. Next generation sequencing technologies and applications for human Genetic History and Forensics. Investig Genet 2011;2(1):23. http://www.investigativegenetics.com/content/pdf/2041-2223-2-23.pdf

The rapid advances in the development of sequencing technologies in recent years enable an increasing number of applications in biology and medicine. Here we review key technical aspects of the preparation of DNA templates for sequencing, the biochemical reaction principles and assay formats underlying next generation sequencing systems, methods for imaging and base calling, quality control, and bioinformatic approaches for sequence alignment, variant calling and assembly. We also discuss some of the most important advances that the new sequencing technologies have brought to the fields of human population genetics, human genetic history and forensic genetics.

 

[Michael Scally MD]

Lee D-c, Sui X, Artero EG, et al. Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in Men / Clinical Perspective. Circulation 2011;124(23):2483-90. Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in MenClinical Perspective / http://newsroom.heart.org/pr/aha/document/Lee_38422_final_proof.pdf

Background—The combined associations of changes in cardiorespiratory fitness and body mass index (BMI) with mortality remain controversial and uncertain.

Methods and Results—We examined the independent and combined associations of changes in fitness and BMI with all-cause and cardiovascular disease (CVD) mortality in 14 345 men (mean age 44 years) with at least 2 medical examinations. Fitness, in metabolic equivalents (METs), was estimated from a maximal treadmill test. BMI was calculated using measured weight and height. Changes in fitness and BMI between the baseline and last examinations over 6.3 years were classified into loss, stable, or gain groups. During 11.4 years of follow-up after the last examination, 914 all-cause and 300 CVD deaths occurred. The hazard ratios (95% confidence intervals) of all-cause and CVD mortality were 0.70 (0.59–0.83) and 0.73 (0.54–0.98) for stable fitness, and 0.61 (0.51–0.73) and 0.58 (0.42–0.80) for fitness gain, respectively, compared with fitness loss in multivariable analyses including BMI change. Every 1-MET improvement was associated with 15% and 19% lower risk of all-cause and CVD mortality, respectively. BMI change was not associated with all-cause or CVD mortality after adjusting for possible confounders and fitness change. In the combined analyses, men who lost fitness had higher all-cause and CVD mortality risks regardless of BMI change.

Conclusions—Maintaining or improving fitness is associated with a lower risk of all-cause and CVD mortality in men. Preventing age-associated fitness loss is important for longevity regardless of BMI change.

 

[Michael Scally MD]

Oyola MG, Portillo W, Reyna A, et al. Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-? (ER?) Activation by a Selective ER? Agonist in Female Mice. Endocrinology. http://endo.endojournals.org/content/early/2011/12/14/en.2011-1674.abstract (Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-? (ER?) Activation by a Selective ER? Agonist in Female Mice)

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ER? and ER?, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ER? and extended and these observations to demonstrate the neuroanatomical targets involved in ER? activation in these behavioral responses.

We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ER? gene (?ERKO).

S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their ?ERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the ?ERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation, we identified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not ?ERKO females.

These studies provide compelling evidence for anxiolytic effects mediated by ER?, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamo-pituitary-adrenal axis function and behaviors.

 

[Michael Scally MD]

Reproduction is arguably the most important event in any animals' life. Thus understanding how reproduction is regulated offers important insights into the evolution of a species. In particular, learning how social and physiological factors collaborate to control reproductive activity is essential for understanding selective pressures that have shaped reproductive control. For example, how does reception of social information reach brain regions responsible for initiating reproductive behaviors, how is gamete (sperm, oocyte) production and steroid hormone release controlled, and, ultimately, how do social interactions influence gene expression to control reproduction? Although there are many studies on regulation of social behaviors from molecular or genomic perspectives, much less is known about how social information directly influences the reproductive genome from the brain to the gonads. Here, we review how social information can influence plasticity in gene expression of the highly conserved vertebrate hypothalamic-pituitary-gonadal (HPG) reproductive control system.

For the purpose of this review, researchers define social behaviors as interactions among members of the same species that influence immediate or future behaviors. Importantly, these interactions include the production, reception, and interpretation of communicative signals that influence individual behaviors in a context-dependent manner. Specifically, they concentrate on how communication signals in a social context produce genomic changes to alter the function of the HPG axis. They focus on key elements in the signaling pathway initiated by gonadotropin-releasing hormone (GnRH) neurons in the brain, their impact on gonadotrope-producing cells [luteinizing hormone (LH); follicle-stimulating hormone (FSH)] of the anterior pituitary gland, and the activation of LH and FSH receptors in the testes that leads to stimulation of steroid biosynthesis and sperm production. In light of the recent evidence showing the RFamides, including kisspeptin and gonadotropin inhibitory hormone, also play critical roles in HPG axis function, they discuss the social influence of these upstream regulators of GnRH neurons as well. They use examples from the social African cichlid fish Astatotilapia (formerly Haplochromis) burtoni as a model to illustrate how rapidly the social environment can influence the genome at every level of the HPG axis. Finally, they discuss how little is actually known about the neural pathways and mechanisms that translate social information into a genomic response that ultimately changes the activity of the reproductive axis. This sociogenomic frontier awaits future comparative research in diverse taxa.

Maruska KP, Fernald RD. Social Regulation of Gene Expression in the Hypothalamic-Pituitary-Gonadal Axis. Physiology 2011;26(6):412-23. http://physiologyonline.physiology.org/content/26/6/412.abstract (Social Regulation of Gene Expression in the Hypothalamic-Pituitary-Gonadal Axis)

 

[Michael Scally MD]

Inverse Associations of Sex Hormones with Biomarkers of Inflammation and Oxidative Stress

It remains to be determined whether sex hormone concentrations in men are associated with biomarkers of inflammation and oxidative stress in the general population. Given the link between low sex hormone concentrations and increased inflammation and oxidative stress in cardiovascular disease (CVD) onset and progression, researchers hypothesized an inverse association of sex hormone concentrations with biomarkers of inflammation and oxidative stress in the present sample of 1,344 men from the population-based cohort Study of Health in Pomerania (SHIP).


Haring R, Baumeister S, Volzke H, et al. Prospective Inverse Associations of Sex Hormone Concentrations in Men with Biomarkers of Inflammation and Oxidative Stress. J Androl. Prospective Inverse Associations of Sex Hormone Concentrations in Men with Biomarkers of Inflammation and Oxidative Stress -- Haring et al., 10.2164/jandrol.111.015065 -- Journal of Andrology

Objective: The suggested associations between sex hormone concentrations and inflammatory biomarkers in men originate from cross-sectional studies and small-scale clinical trials. But prior studies have not addressed longitudinal associations.

Methods: Overall, 1,344 men aged 20-79 years from the population-based cohort Study of Health in Pomerania were followed-up for 5.0 (median) years. We used multivariable regression models to analyze cross-sectional and longitudinal associations of serum sex hormone concentrations (total testosterone [TT], sex hormone-binding globulin [SHBG], calculated free testosterone [free T], and dehydroepiandrosterone sulfate [DHEAS]) with biomarkers of inflammation (fibrinogen, high-sensitive C-reactive protein [hsCRP], and white blood cell count [WBC]) and oxidative stress (gamma-glutamyl transferase [GGT]) using ordinary least square (OLS) regression and Generalized Estimating Equations models, respectively.

Results: Cross-sectional models revealed borderline associations of sex hormone concentrations with hsCRP, WBC, and GGT levels that were not retained after multivariable adjustment. Longitudinal multivariable analyses revealed an inverse association between baseline TT, free T, and DHEAS concentrations with change in fibrinogen levels (per SD decrement in TT: 0.25 [95% confidence interval, 0.04-0.45], free T: 0.30 [0.09-0.51], and DHEAS: 0.23 [0.11-0.36]). Furthermore, baseline DHEAS concentrations were inversely associated with change in WBC levels (per SD decrement: 0.53 [0.24-0.82]). Baseline TT, SHBG, free T, and DHEAS concentrations were also inversely associated with change in GGT after multivariable adjustment.

Conclusions: The present study is the first to demonstrate prospective inverse associations between sex hormone concentrations and markers of inflammation and oxidative stress in men. Additional studies are warranted to elucidate potential mechanisms underlying the revealed associations.

 

[Michael Scally MD]

Testosterone, SHBG, and Exercise Capacity

Serum free (unbound) and total (free and bound to sex hormone binding globulin or albumin) testosterone falls with increasing age. Lower total testosterone serum levels have been associated with increased morbidity and increased mortality in both middle-aged and old men due to cardiovascular disease and metabolic syndrome. The Massachusetts Male Aging study reported an association between low total testosterone serum concentration and cause specific mortality by respiratory disease.

Patients with chronic bronchitis, which increases the risk of death, have been shown to have lower total testosterone serum levels. In correspondence to the importance of testosterone on its prognostic properties and physical function, cardiopulmonary exercise testing (CPET) provides a number of reliable powerful prognostic tools in general populations as well as for patients effected by cardiovascular or pulmonary diseases. Exercise related parameters such as peak oxygen uptake (V’O2, peak) and maximal power output are powerful predictors of survival in patients with congestive heart failure and correlate with physical performance.

Aging is usually associated with a decline in physical activity and in maximal aerobic capacity. Thus, it is not surprising that numerous investigators found a strong dependency of the level of exercise tolerance – usually assessed as V’O2, peak by CPET, muscle strength or walking speed – and low levels of total serum testosterone.

On the other hand, the anabolic effects of testosterone as characterized by an increase in muscle mass, lead to the assumption of improved skeletal muscle performance and health related outcomes in individuals with high levels of total serum testosterone. Testosterone therapy in men has been shown to increase lean body mass. However, the effects on muscle performance and physical function have been inconsistent across trials. The described associations are usually based on small numbers of volunteers.

The main focus in this study was to investigate the association of testosterone and SHBG levels on exercise capacity, characterized by V’O2, peak, anaerobic threshold (V’O2 at ?L) and maximal power output a large population based study, characterized with health-related variables – the SHIP study.


Koch B, Glaser S, Schaper C, et al. Association Between Serum Testosterone and Sex Hormone Binding Globulin and Exercise Capacity in Men: Results of the Study of Health in Pomerania (SHIP). J Androl:jandrol.110.010074. Association Between Serum Testosterone and Sex Hormone Binding Globulin and Exercise Capacity in Men: Results of the Study of Health in Pomerania (SHIP) -- Koch et al., 10.2164/jandrol.110.010074 -- Journal of Andrology

Background: Testosterone exerts a widespread pattern of effects on metabolism and body composition and is gaining interest due to its correlation with physical fitness.

Objective: The main focus of our study was to investigate the association of total serum testosterone and sex hormone binding globulin (SHBG) levels on exercise capacity and maximal power output in men using a cross-sectional, population-based adult cohort.

Design and Setting: From the Study of Health in Pomerania (SHIP) 624 men aged 25-85 years who underwent a standardised progressive incremental exercise protocol on a cycle ergometer were included in the analyses. Exercise capacity was characterised by oxygen uptake at anaerobic threshold (V'O2 at {Theta}L) and peak exercise (V'O2,peak) as well as maximal power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity and smoking were performed. Further, linear regression analyses with cubic splines as well as sensitivity analyses were undertaken.

Results: At peak exercise performance, testosterone and SHBG levels showed no associations to V'O2,peak, V'O2 at {Theta}L as well as maximal power output, even after controlling for confounding factors including age, body mass index, physical activity, and smoking. An adverse association between the free testosterone index and V'O2 at {Theta}L was found. Linear regression analyses with cubic splines did not change the main results.

Conclusion: In conclusion this is the first study focusing on the association of total serum testosterone and SHBG on exercise capacity and physical performance in healthy volunteers based on a large scale population based study. After adjustment for relevant influencing factors neither total serum testosterone nor SHBG did have any interference with peak exercise capacity, aerobic exercise capacity or maximal power output in men.

 

[Michael Scally MD]

Wu Y, Zhao J, Zhao W, Pan J, Bauman WA, Cardozo C. Nandrolone normalizes determinants of muscle mass and fiber type after SCI. J Neurotrauma. Nandrolone normalizes determinants of muscle m... [J Neurotrauma. 2011] - PubMed - NCBI

Spinal cord injury (SCI) results in atrophy of skeletal muscle and changes from slow oxidative to fast glycolytic fibers which may reflect reduced levels of PGC-1alpha, increased myostatin signaling, or both. In animals, testosterone reduces loss of muscle fiber cross sectional area and activity of enzymes of energy metabolism. To identify the molecular mechanisms of the benefits of androgens on paralyzed muscle, male rats were spinal cord transected and treated for 8 weeks with vehicle, testosterone at a physiological replacement dose, or testosterone plus nandrolone, an anabolic steroid. Treatments were initiated immediately after SCI and continued until the day animals were euthanized. In the SCI animals, gastrocnemius muscle mass was significantly increased by testosterone plus nandrolone but not by testosterone alone. Both treatments significantly reduced nuclear content of Smad2/3 and mRNA levels of Activin receptor IIB and follistatin-like 3. Testosterone alone or with nandrolone reversed SCI-induced declines in cellular and nuclear levels of PGC-1alpha protein and PGC-1alpha mRNA levels. For PGC-1alpha target genes, testosterone plus nandrolone partially reversed SCI-induced decreases in levels of proteins without corresponding increases in their mRNA levels. Thus, the findings demonstrate that following SCI, signaling through Activin receptors and Smad2/3 is increased, and that androgens suppress activation of this signaling pathway. The findings also indicate that androgens upregulate PGC-1alpha in paralyzed muscle and promote its nuclear localization, but that these effects are insufficient to fully activate transcription of PGC-1alpha target genes. Furthermore, the transcription of these genes is not tightly coupled with their translation.

 

[Michael Scally MD]

Effects Of Glucagon-Like Peptide-1 Receptor Agonists On Weight Loss

Glucagon-like peptide-1 (GLP-1) is a gut hormone that is secreted from the intestine in response to meal ingestion. GLP-1 based therapy was recently introduced as a new treatment for patients with type 2 diabetes mellitus. Treatment with GLP-1 enhances the endogenous secretion of insulin induced by meal ingestion and inhibits glucagon secretion, thereby improving glucose homoeostasis. Notably, it also suppresses food intake and appetite. Trials of patients with type 2 diabetes suggest that agonists of GLP-1 receptor (GLP-1R) have beneficial effects on metabolic regulation and could lead to weight loss. Researchers did a systematic review and meta-analysis to provide an up to date overview of the beneficial and harmful effects of GLP-1R agonists in patients who are overweight or obese.

The present meta-analyses include data from randomised controlled trials assessing clinically relevant doses of GLP-1R agonists given for at least 20 weeks. The results indicate that treatment with GLP-1R agonists help reduce body weight in patients who are overweight or obese. Three of the included trials assessed the effect of GLP-1R agonists on patients without type 2 diabetes and 22 assessed patients with type 2 diabetes. GLP-1R agonists also had beneficial effects on systolic and diastolic blood pressure. In subgroup and sensitivity analyses, the liver enzyme activity was lower in the GLP-1R agonist groups than in the control groups. However, the overall effect of GLP-1R agonists on liver enzymes was not clear. For patients with type 2 diabetes, GLP-1R agonists improved glycaemic control (as assessed by HbA1c percentage and fasting plasma glucose) and increased the proportion of patients who achieved the target haemoglobin.


Tina Vl, Mikkel C, Anders EJ, Filip KK, Lise Lotte G. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012;344. http://www.bmj.com/content/344/bmj.d7771

Objective To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Design Systematic review with meta-analyses.

Data sources Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011).

Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.

Data extraction Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.

Results 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference ?2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.

Conclusions The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

 

[Michael Scally MD]

Drug Induced Liver Injury

Inhibiting Gap Junctions In Hepatic Cells Effectively Prevents Drug Induced Liver Injury
GEN | News Highlights:Inhibiting Gap Junctions In Hepatic Cells Effectively Prevents Drug-Induced Liver Injury

Inhibiting gap junctions in liver cells could provide a feasible strategy to preventing drug-induced liver injury (DILI), investigators claim. A team at the Massachusetts General Hospital (MGH) and the Shriners Burns Hospital, the Massachusetts Institute of Technology (MIT), and Rutgers University, demonstrated that the progression of DILI is gap-junction dependent. Their experiments demonstrated that treating mice with a small molecule inhibitor that specifically target the hepatic gap junction protein connexion 32 (Cx32) provides significant protection against liver damage and death resulting from subsequent or simultaneous challenge with known hepatotoxic drugs such as acetaminophen. Mice deficient in Cx32 were similarly protected.


Patel SJ, Milwid JM, King KR, et al. Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat Biotech;advance online publication. http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2089.html

Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety.

 

[Michael Scally MD]

Goldstein I, McCullough AR, Jones LA, et al. A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Avanafil in Subjects with Erectile Dysfunction. The Journal of Sexual Medicine. A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Avanafil in Subjects with Erectile Dysfunction - Goldstein - 2012 - The Journal of Sexual Medicine - Wiley Online Library

Introduction.? Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED).

Aim.? To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED.

Methods.? In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake.

Main Outcome Measures.? Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire.

Results.? Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P ? 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil-treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events.

Conclusion.? Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED.

 

[Michael Scally MD]

Steffensen C, Maegbaek ML, Laurberg P, et al. Heart Valve Disease among Patients with Hyperprolactinaemia: A Nationwide Population-Based Cohort Study. Journal of Clinical Endocrinology & Metabolism. http://jcem.endojournals.org/content/early/2012/03/09/jc.2011-3257.abstract (Heart Valve Disease among Patients with Hyperprolactinaemia: A Nationwide Population-Based Cohort Study)

Background: Increased risk of heart valve disease during treatment with certain dopamine agonists, such as cabergoline, has been observed in patients with Parkinson's disease. The same compound is used to treat hyperprolactinemia, but it is unknown whether this also associates with heart valve disease.

Objectives: The objective of the study was to assess the incidence of diagnosed heart valve disease and cardiac valve surgery among patients with hyperprolactinemia, compared with a general population cohort in Denmark.

Design: This was a nationwide, population-based, cohort study based on a nationwide hospital registry.

Methods: We identified 2381 hyperprolactinemia patients with a first-time diagnosis recorded from 1994 through 2010 in the registry, with no previous hospital diagnosis of heart valve disease. Each patient was compared with 10 age- and gender-matched comparison cohort members from the general population. The association between hyperprolactinemia and heart valve disease was analyzed with Cox's proportional hazards regression, controlling for potential confounding factors. To assess the risk of cardiac valve surgery and avoid ascertainment bias, a subanalysis was made in a cohort of 2,387 hyperprolactinemia patients with no previous cardiac valve surgery and 23,870 comparison cohort members.

Results: Nineteen hyperprolactinemic patients (0.80%) were diagnosed with heart valve disease during a total of 17,759.8 yr of follow-up, compared with 75 persons (0.31%) in the comparison cohort during 179,940.6 yr of follow-up [adjusted hazard ratio 2.27 (95% confidence interval 1.35–3.82)]. Seven of the 10 patients treated with cabergoline and diagnosed with heart valve disease were asymptomatic and diagnosed on the basis of an echocardiography performed as a safety measure. However, only two patients with hyperprolactinemia (0.08%) underwent surgery, compared with 28 persons in the general population cohort (0.12%) [adjusted hazard ratio 0.55 (95% confidence interval 0.13–2.42)].

Conclusions: Data from the present register-based study do not support that hyperprolactinemia or its treatment is associated with an increased risk of clinically significant heart valve disease.