scholarly journals A potent liver-mediated mechanism for loss of muscle mass during androgen deprivation therapy

2019 ◽  
Vol 8 (5) ◽  
pp. 605-615 ◽  
Author(s):  
Teresa Lam ◽  
Mark McLean ◽  
Amy Hayden ◽  
Anne Poljak ◽  
Birinder Cheema ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Protein Metabolism ◽  
Exercise Intervention ◽  
Muscular Atrophy ◽  
Androgen Deprivation ◽  
Whole Body ◽  
Protein Loss ◽  
Body Protein ◽  
Urea Production

Context Androgen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism. Objective To investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program. Design A randomized controlled trial. Patients and intervention Twenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT. Main outcome measures The rate of hepatic urea production was measured by the urea turnover technique using 15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated. Results ADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production. Conclusion As early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.

scholarly journals Clinical Utility of miRNA-1, miRNA-29g and miRNA-133s Plasma Levels in Prostate Cancer Patients With High-Intensity Training After Androgen-Deprivation Therapy

2019 ◽  
pp. S139-S147
Author(s):  
A. GAZOVA ◽  
A. SAMAKOVA ◽  
E. LACZO ◽  
D. HAMAR ◽  
M. POLAKOVICOVA ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Body Composition ◽  
Exercise Training ◽  
Androgen Deprivation Therapy ◽  
Plasma Levels ◽  
Exercise Intervention ◽  
Free Testosterone ◽  
Androgen Deprivation ◽  
Control Group ◽  
The Impact

The randomized trials showed that the addition of training resistance program to androgen-deprivation therapy (ADT) had many beneficial effects for prostate cancer (PC) patients (significant protective effect on the volume of muscle mass) and the studies have revealed a panel of miRNAs, which are deregulate in PC and may serve as promising biomarkers of PC risk. The primary aim of our present study was to investigate the effect of exercise training to changes in body composition (muscle strength) and the secondary endpoint was to investigate the impact of an exercise training program on plasma levels of selected myogenic microRNAs (miRNAs) (miRNA-1, miRNA-29b, and miRNA-133) in PC patients undergoing the ADT. Effect of ADT and exercise intervention showed significant increase (experimental group vs. control group) the changes in body composition, free testosterone levels, IL-6 and plasma levels of myogenic miRNAs and significant reduced insulin serum levels. In conclusion, resistance training with ADT in the treatment of PC significantly changed the physical and metabolic function and the plasma levels of specific myogenic miRNAs. Our data support with the other publicized results.

scholarly journals Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

2013 ◽  
Vol 20 (5) ◽  
pp. 621-632 ◽  
Author(s):  
Thine Hvid ◽  
Kamilla Winding ◽  
Anders Rinnov ◽  
Thomas Dejgaard ◽  
Carsten Thomsen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Body Composition ◽  
Insulin Sensitivity ◽  
Endurance Training ◽  
Cancer Patients ◽  
Androgen Deprivation Therapy ◽  
Systemic Inflammation ◽  
Muscle Protein ◽  
Androgen Deprivation ◽  
Whole Body

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic–hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max(ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 andP<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group×time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

scholarly journals Responsiveness to Resistance-Based Multimodal Exercise Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy

2019 ◽  
Vol 17 (10) ◽  
pp. 1211-1220 ◽  
Author(s):  
Dennis R. Taaffe ◽  
Robert U. Newton ◽  
Nigel Spry ◽  
David J. Joseph ◽  
Daniel A. Galvão
Keyword(s):  
Prostate Cancer ◽  
Skeletal Muscle ◽  
Body Composition ◽  
Muscle Strength ◽  
Physical Function ◽  
Androgen Deprivation Therapy ◽  
Lean Mass ◽  
Androgen Deprivation ◽  
Whole Body ◽  
Appendicular Skeletal Muscle

Background: Androgen deprivation therapy (ADT) in the management of prostate cancer (PCa) results in an array of adverse effects, and exercise is one strategy to counter treatment-related musculoskeletal toxicities. This study assessed the prevalence of exercise responsiveness in men with PCa undergoing ADT in terms of body composition, muscle strength, and physical function. Methods: Prospective analyses were performed in 152 men (aged 43–90 years) with PCa receiving ADT who were engaged in resistance exercise combined with aerobic or impact training for 3 to 6 months. Whole-body lean mass and fat mass (FM), trunk FM, and appendicular skeletal muscle were assessed with dual x-ray absorptiometry; upper and lower body muscle strength were assessed with the one-repetition maximum; and physical function was assessed with a battery of tests (6-m usual, fast, and backward walk; 400-m walk; repeated chair rise; stair climb). Results: Significant improvements were seen (P<.01) in lean mass (0.4±1.4 kg [range, −2.8 to +4.1 kg]), appendicular skeletal muscle (0.2±0.8 kg [range, −1.9 to +1.9 kg]), and all measures of muscle strength (chest press, 2.9±5.8 kg [range, −12.5 to +37.5 kg]; leg press, 29.2±27.6 kg [range, −50.0 to +140.0 kg]) and physical function (from −0.1±0.5 s [range, +1.3 to −2.1 s] for the 6-m walk; to −8.6±15.2 s [range, +25.2 to −69.7 s] for the 400-m walk). An increase in FM was also noted (0.6±1.8 kg [range, −3.6 to +7.3 kg]; P<.01). A total of 21 men did not exhibit a favorable response in at least one body composition component, 10 did not experience improved muscle strength, and 2 did not have improved physical function. However, all patients responded in at least one of the areas, and 120 (79%) favorably responded in all 3 areas. Conclusions: Despite considerable heterogeneity, most men with PCa receiving ADT responded to resistance-based multimodal exercise, and therefore our findings indicate that this form of exercise can be confidently prescribed to produce beneficial effects during active treatment.

scholarly journals Detection Rate of 68Ga-PSMA Ligand PET/CT in Patients with Recurrent Prostate Cancer and Androgen Deprivation Therapy

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 511
Author(s):  
Joachim Brumberg ◽  
Melanie Beckl ◽  
Alexander Dierks ◽  
Andreas Schirbel ◽  
Markus Krebs ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Detection Rate ◽  
Androgen Deprivation ◽  
Disease Stage ◽  
Whole Body ◽  
Recurrent Prostate Cancer ◽  
Detection Rates ◽  
Psma Ligand ◽  
Pet Ct

Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of 68Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and 68Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All 68Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7% vs. 72.6%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA (p < 0.01) and PSMA-derived tumor volume (p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.

Prospective study of exercise intervention in prostate cancer patients on androgen deprivation therapy

2013 ◽  
Vol 58 (3) ◽  
pp. 369-376 ◽  
Author(s):  
Nadine Beydoun ◽  
Joseph A. Bucci ◽  
Yaw S. Chin ◽  
Nigel Spry ◽  
Robert Newton ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prospective Study ◽  
Cancer Patients ◽  
Androgen Deprivation Therapy ◽  
Exercise Intervention ◽  
Androgen Deprivation

scholarly journals Impact of Growth Hormone and Dehydroepiandrosterone on Protein Metabolism in Glucocorticoid-Treated Patients

2008 ◽  
Vol 93 (3) ◽  
pp. 688-695 ◽  
Author(s):  
Morton G. Burt ◽  
Gudmundur Johannsson ◽  
A. Margot Umpleby ◽  
Donald J. Chisholm ◽  
Ken K. Y. Ho
Keyword(s):  
Protein Metabolism ◽  
Dose Finding ◽  
Whole Body ◽  
Constant Infusion ◽  
Leucine Incorporation ◽  
Protein Loss ◽  
Body Protein ◽  
Prednisone Dose ◽  
Leucine Oxidation

Abstract Context: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. Objective: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. Design: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). Setting: The studies were performed at a clinical research facility. Patients and Intervention: In study 1, six subjects (age 69 ± 4 yr) treated with long-term (&gt;6 months) GCs (prednisone dose 8.3 ± 0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71 ± 3 yr) treated with long-term GCs (prednisone dose 5.4 ± 0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). Main Outcome Measure: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. Results: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P = 0.03) and 31% (P = 0.02), and increased leucine incorporation into protein by 10% (P = 0.13) and 19% (P = 0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. Conclusion: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.

scholarly journals Testosterone prevents protein loss via the hepatic urea cycle in human

2017 ◽  
Vol 176 (4) ◽  
pp. 489-496 ◽  
Author(s):  
Teresa Lam ◽  
Anne Poljak ◽  
Mark McLean ◽  
Neha Bahl ◽  
Ken K Y Ho ◽  
...  
Keyword(s):  
Urea Cycle ◽  
Nitrogen Loss ◽  
Testosterone Replacement ◽  
Whole Body ◽  
Urea Synthesis ◽  
Protein Loss ◽  
Open Label ◽  
Body Protein ◽  
Urea Production ◽  
Testosterone Administration

ContextThe urea cycle is a rate-limiting step for amino acid nitrogen elimination. The rate of urea synthesis is a true indicator of whole-body protein catabolism. Testosterone reduces protein and nitrogen loss. The effect of testosterone on hepatic urea synthesis in humans has not been studied.ObjectiveTo determine whether testosterone reduces hepatic urea production.DesignAn open-label study.Patients and interventionEight hypogonadal men were studied at baseline, and after two weeks of transdermal testosterone replacement (Testogel, 100 mg/day).Main outcomes measuresThe rate of hepatic urea synthesis was measured by the urea turnover technique using stable isotope methodology, with15N2-urea as tracer. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, were calculated.ResultsTestosterone administration significantly reduced the rate of hepatic urea production (from 544.4 ± 71.8 to 431.7 ± 68.3 µmol/min;P < 0.01), which was paralleled by a significant reduction in serum urea concentration. Testosterone treatment significantly reduced net protein loss, as measured by percent Lox/LRa, by 19.3 ± 5.8% (P < 0.05). There was a positive association between Lox and hepatic urea production at baseline (r2 = 0.60,P < 0.05) and after testosterone administration (r2 = 0.59,P < 0.05).ConclusionTestosterone replacement reduces protein loss and hepatic urea synthesis. We conclude that testosterone regulates whole-body protein metabolism by suppressing the urea cycle.

Whole-body urea cycling and protein turnover during hyperphagia and dormancy in growing bears (Ursus americanus and U. arctos)

1997 ◽  
Vol 75 (12) ◽  
pp. 2129-2136 ◽  
Author(s):  
Perry S. Barboza ◽  
Sean D. Farley ◽  
Charles T. Robbins
Keyword(s):  
Protein Turnover ◽  
Whole Body ◽  
Turnover Rates ◽  
Protein Loss ◽  
Plasma Urea ◽  
Body Protein ◽  
Urea Production ◽  
Amino Acid Degradation ◽  
Urea Kinetics ◽  
N Resorption

Subadult bears were studied during their autumn hyperphagia (n = 3) and winter dormancy (n = 6). Urea kinetics were measured with 14C- and 15N-urea, protein turnover was estimated with 15N-glycine, and body composition was assessed with 3H-water. Reduced amino acid degradation in winter was indicated by declines in plasma urea and aminotransferase activities, and lower urea production than in autumn (4.7 vs. 27.5 mmol urea-N∙kg−0.75∙d−1). Only 7.5% of urea produced in hyperphagic bears was degraded and just 1.1% of the degraded N reutilized as amino-N. Dormant bears reutilized 99.7% of urea produced, indicating thorough microbial ureolysis and urea-N resorption. Low rates of body N loss during dormancy suggested losses of non-urea N as creatinine. Protein turnover rates (15.2–21.5 g∙kg−0.75∙d−1) were similar between seasons and reflected the apparent maintenance of hepatic, intestinal, and muscular functions through dormancy. Protein synthesis accounted for 32% of energy expended in dormancy, which was mainly (91.5%) derived from fat oxidation. Consistent organ function and body temperature in dormant bears enables recycling of urea-N, which minimizes body protein loss and conserves mobility. In comparison with heterothermic hibernation, ursid dormancy would provide greater flexibility during winter and facilitate rapid resumption of foraging and growth in spring.

scholarly journals The clinical importance of quantifying body fat distribution during androgen deprivation therapy for prostate cancer

2017 ◽  
Vol 24 (3) ◽  
pp. R35-R48 ◽  
Author(s):  
Stephen J Foulkes ◽  
Robin M Daly ◽  
Steve F Fraser
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Body Fat ◽  
Cardiometabolic Risk ◽  
Locally Advanced ◽  
Fat Distribution ◽  
Androgen Deprivation ◽  
Body Fat Distribution ◽  
Visceral Adiposity ◽  
Whole Body

Androgen deprivation therapy (ADT) is now considered a mainstay in the treatment of metastatic and locally advanced prostate cancer (PCa). Despite well-established benefits of ADT in relation to overall survival, this treatment has been associated with a number of adverse effects, particularly with regard to key cardiometabolic risk factors including the development of insulin resistance, dyslipidemia and increases in total and regional fat mass. In non-ADT populations, increased levels of visceral adipose tissue (VAT) are thought to be a key mediator of the increased cardiometabolic risk associated with weight gain, but this has received limited attention in men treated with ADT. VAT is best assessed using tools such as computed tomography or magnetic resonance imaging; however, these tools are not readily accessible for the majority of researchers or clinicians. Recent advances allow for a method of estimating VAT using a whole-body dual-energy X-ray absorptiometry (DXA) scan that shows promise as a practical tool for researchers to evaluate changes in body fat distribution during ADT. The aim of this narrative review is to (1) review the available evidence with regard to the relationship between ADT and cardiometabolic risk; (2) discuss the role of body fat distribution on cardiometabolic risk in non-ADT populations, with a particular emphasis on the importance of visceral adiposity; (3) examine the potential influence of ADT on body fat distribution and visceral adiposity and (4) provide an overview of current tools used to measure changes in body fat distribution in men treated with ADT, highlighting the potential utility of a recently developed DXA-derived measure of VAT.

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