Anne L. Friedlander

Effects of exercise intensity and training on lipid metabolism in young women

We examined the effects of exercise intensity and training [12 wk, 5 days/wk, 1 h, 75% peak oxygen consumption (V˙o 2 peak)] on lipolysis and plasma free fatty acid (FFA) flux in women ( n = 8; 24.3 ± 1.6 yr). Two pretraining trials (45 and 65% ofV˙o 2 peak) and two posttraining trials [same absolute workload (65% of oldV˙o 2 peak; ABT) and same relative workload (65% of newV˙o 2 peak; RLT)] were performed using infusions of [1,1,2,3,3-2H]glycerol and [1-13C]palmitate. Pretraining rates of FFA appearance (Ra), disappearance (Rd), and oxidation (Rox p) were similar between the 65% (6.8 ± 0.6, 6.2 ± 0.7, 3.1 ± 0.3 μmol ⋅ kg-1 ⋅ min-1, respectively) and the 45% ofV˙o 2 peaktrials. At ABT and RLT training increased FFA Ra to 8.4 ± 1.0 and 9.7 ± 1.1 μmol ⋅ kg-1 ⋅ min-1, Rd to 8.3 ± 1.0 and 9.5 ± 1.1 μmol ⋅ kg-1 ⋅ min-1, and Rox p to 4.8 ± 0.4 and 6.7 ± 0.7 μmol ⋅ kg-1 ⋅ min-1, respectively ( P ≤ 0.05). Total FFA oxidation from respiratory exchange ratio was also elevated after training at ABT and RLT, with all of the increase attributed to plasma FFA sources. Pretraining, glycerol Ra was higher during exercise at 65 than 45% of V˙o 2 peak(6.9 ± 0.9 vs. 4.7 ± 0.6 μmol ⋅ kg-1 ⋅ min-1) but was not changed by training. In young women 1) plasma FFA kinetics and oxidation are not linearly related to exercise intensity before training, 2) training increases FFA Ra, Rd, and Rox p whether measured at given absolute or relative exercise intensities, 3) whole body lipolysis (glycerol Ra) during exercise is not significantly impacted by training, and 4) training-induced increases in plasma FFA oxidation are the main contributor to elevated total FFA oxidation during exercise exertion after training.

Systematic Review: The Effects of Growth Hormone on Athletic Performance

The use of human growth hormone to improve athletic performance has recently received worldwide attention. This practice, often called sports doping, is banned by most professional sports leagues and associations, including the International Olympic Committee, Major League Baseball, and the National Football League (13). However, a wide range of athletes, including those from baseball (46), cycling (7, 8), and track and field (5, 9), have been implicated in or have confessed to illicit growth hormone use. The Mitchell report (10) recently identified 89 Major League Baseball players who allegedly used performance-enhancing drugs, and some of these players have subsequently admitted to using growth hormone (11, 12). Part of the attraction of using growth hormone as a performance enhancer has been that its use is difficult to detect. The World Anti-Doping Agency, whose formation stemmed from the widely publicized doping scandal of the 1998 Tour de France (13), first used a blood test to detect exogenous growth hormone during the 2004 Olympic Games in Athens. However, according to the World Anti-Doping Agency, there have been no test-confirmed positive cases for growth hormone doping in professional or Olympic athletes (14), probably because of the limited availability and implementation of this test. Although growth hormone is reportedly used to enhance athletic performance and has been called the most anabolic substance known (15), its efficacy for this purpose is not well established. Some have suggested that growth hormone is a wonder drug (16) that results in ripped muscle (17) and provides stamina-increasing properties (18). Exogenous growth hormone therapy in growth hormonedeficient adults (that is, those with growth hormone deficiency due to hypothalamic or pituitary defects) results in increased lean mass and decreased fat mass (19), and comparable body composition changes are seen in healthy elderly adults who receive growth hormone (20). Some experts, however, have suggested that the strength-enhancing properties of growth hormone among healthy adults have been exaggerated (15). Serious side effects, including diabetes, hepatitis, and acute renal failure, may occur in athletes using high-dose growth hormone (21). Furthermore, the use of growth hormone for athletic enhancement is not approved by the U.S. Food and Drug Administration, and the distribution of growth hormone for this purpose is illegal in the United States (22). We performed a systematic review of randomized, controlled trials to determine the effects of growth hormone therapy on athletic performance in healthy, physically fit, young adults. Our primary aim was to evaluate the effects of growth hormone on body composition, strength, basal metabolism, and exercise capacity. In addition, we sought to synthesize the evidence on adverse events associated with growth hormone in the healthy young and assess the quality of the published literature. Methods Literature Searches In consultation with 2 research librarians, we developed individual search strategies to identify potentially relevant studies from the MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases. We sought English-language reports indexed through 11 October 2007 with keywords including growth hormone and randomized, controlled trial (Appendix Table 1). We searched bibliographies of retrieved articles for additional studies. Appendix Table 1. Search Strategy Study Selection We sought randomized, controlled trials, including crossover trials, that compared growth hormone therapy with no growth hormone therapy. We included studies that 1) evaluated at least 5 participants, 2) enrolled only community-dwelling participants, 3) assessed participants with a mean or median age between 13 and 45 years, and 4) provided data on at least 1 clinical outcome of interest. We excluded studies that 1) focused solely on evaluating growth hormone secretagogues, 2) explicitly included patients with any comorbid medical condition, or 3) evaluated growth hormone as treatment for a specific illness (for example, adult growth hormone deficiency or fibromyalgia). Data Abstraction One author reviewed the titles and abstracts of articles identified through our search and retrieved potentially relevant studies. An endocrinologist and a physician with training in meta-analytic techniques separately reviewed the retrieved studies and abstracted data independently onto pretested abstraction forms. We resolved abstraction differences by repeated review and consensus. If a study did not present data necessary for analysis or mentioned results but did not present data, we requested additional data from study authors. If data were presented graphically, we used the graph-digitizing program DigitizeIt, version 1.5 (Share It, Braunschweig, Germany), to abstract data from the graph (23). If multiple studies presented findings from the same cohort, we used these data only once in our analysis. We abstracted 4 types of data from each study: participant characteristics (for example, age, sex, body mass index, baseline maximum oxygen uptake [VO2max]), study interventions (for example, dose, route, frequency, and duration of growth hormone therapy), study quality (for example, quality of randomization and blinding) (24, 25), and clinical outcomes. We included studies that provided data on at least 1 of the following clinical outcomes: body composition (for example, body weight, lean body mass, fat mass), strength (for example, biceps or quadriceps strength), basal metabolism (for example, resting energy expenditure, basal metabolic rate, heart rate, respiratory exchange ratio, or respiratory quotient), exercise capacity (for example, exercising lactate levels, exercising respiratory exchange ratio or respiratory quotient, maximum inspiratory pressure, bicycling speed, and VO2max), or adverse events. Because the terms lean body mass and fat-free mass are typically used interchangeably in the literature, we report fat-free mass and lean body mass data as a single category of lean body mass. Similarly, we report resting energy expenditure and basal metabolic rate as a single category of basal metabolic rate. Quantitative Data Synthesis To describe key study characteristics, we computed mean values weighted by the number of participants in the trial. To evaluate the effects of growth hormone on body composition and strength, we computed a change score for each clinical outcome for both the treatment and control groups as the value of the outcome at trial end minus the value of the outcome at trial start. We used these change scores to calculate the weighted mean difference and standard mean difference (26) effect sizes. The weighted mean difference is reported in the same units as the clinical outcome of interest, thereby facilitating clinical interpretation. Because our outcomes were similar for both methods, we present only the outcomes from the weighted mean difference method. For studies that did not report the variance of an outcome at trial end minus the value at trial start, we calculated it as the sum of the trial-start and trial-end variances minus twice the covariance (20, 27). Because trial-start data were not available for most of the studies reporting basal metabolic outcomes, we compared trial-end results between treatment and control groups for these outcomes. We combined studies by using random-effects models (2628) because of potential interstudy heterogeneity. The considerable variability in exercise protocols used in the included studies reporting exercise capacity outcomes made pooling these results inappropriate. Instead, we provide a narrative, qualitative assessment of exercise capacity outcomes and report their associated published P values. The variability in reporting adverse events among included studies also made a quantitative meta-analysis of these outcomes inappropriate. Instead, we calculated the proportions of adverse events among participants who received and did not receive growth hormone in studies that reported or evaluated for each adverse event. We performed sensitivity analyses and assessed interstudy heterogeneity to evaluate the robustness of our results. We removed each study individually to evaluate that studys effect on the summary estimates. We assessed publication bias by constructing funnel plots and calculated the number of unpublished studies required to statistically significantly change our results (28). We assessed heterogeneity among study results for each of the summary effects by calculating the Q statistic (and associated P value) and I 2 statistic (26, 2830). We evaluated heterogeneity through predetermined subgroup analysis that stratified studies by duration of treatment. We performed analyses by using Stata software, version 9.1 (Stata, College Station, Texas); SPSS, version 15.0 (SPSS, Chicago); and Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We considered P values less than 0.05 (2-tailed) to indicate statistically significant differences. Role of the Funding Source The authors were supported in part or fully by the Agency for Healthcare Research and Quality, Santa Clara Valley Medical Center, the U.S. Department of Veteran Affairs, Stanford University Medical Center, Stanford University, Genentech, the National Science Foundation, and the Evidence-Based Medicine Center of Excellence of Pfizer. These funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Results The Figure summarizes the results of our literature searches. We reviewed 7599 titles from the MEDLINE, EMBASE, SPORTDiscus, and the Cochrane Collaboration databases. From our search, we reviewed 252 abstracts in detail and retrieved 56 articles for full-text evaluation.

Effects of oligofructose-enriched inulin on intestinal absorption of calcium and magnesium and bone turnover markers in postmenopausal women

Deficiency of oestrogen at menopause decreases intestinal Ca absorption, contributing to a negative Ca balance and bone loss. Mg deficiency has also been associated with bone loss. The purpose of the present investigation was to test the hypothesis that treatment with a spray-dried mixture of chicory oligofructose and long-chain inulin (Synergy1; SYN1) would increase the absorption of both Ca and Mg and alter markers of bone turnover. Fifteen postmenopausal women (72.2 (SD 6.4) years) were treated with SYN1 or placebo for 6 weeks using a double-blind, placebo-controlled, cross-over design. Fractional Ca and Mg absorption were measured using dual-tracer stable isotopes before and after treatment. Bone turnover markers were measured at baseline, 3 and 6 weeks. Fractional absorption of Ca and Mg increased following SYN1 compared with placebo (P < 0.05). Bone resorption (by urinary deoxypyridinoline cross-links) was greater than baseline at 6 weeks of active treatment (P < 0.05). Bone formation (by serum osteocalcin) showed an upward trend at 3 weeks and an increase following 6 weeks of SYN1 (P < 0.05). Closer examination revealed a variation in response, with two-thirds of the subjects showing increased absorption with SYN1. Post hoc analyses demonstrated that positive responders had significantly lower lumbar spine bone mineral density than non-responders (dual X-ray absorptiometry 0.887 +/- 0.102 v. 1.104 +/- 0.121 g/cm2; P < 0.01), and changes in bone turnover markers occurred only in responders. These results suggest that 6 weeks of SYN1 can improve mineral absorption and impact markers of bone turnover in postmenopausal women. Further research is needed to determine why a greater response was found in women with lower initial spine bone mineral density.

Foot Cooling Reduces Exercise-Induced Hyperthermia in Men with Spinal Cord Injury

UNLABELLED The number of individuals with spinal cord injury (SCI) participating in sports at recreational and elite levels is on the rise. However, loss of autonomic nervous system function below the lesion can compromise thermoregulatory capacity and increase the risk of heat stress relative to able-bodied (AB) individuals. PURPOSE To test the hypotheses that exercise in a heated environment would increase tympanic temperature (TTY) more in individuals with SCI than AB individuals, and that foot cooling using a new device would attenuate the rise in TTY during exercise in both groups. METHODS Six subjects with SCI (lesions C5-T5) and six AB controls were tested in a heated environment (means +/- SEM, temperature = 31.8 +/- 0.2 degrees C, humidity = 26 +/- 1%) for 45 min at 66% +/- 5 of arm cranking VO2peak and 30 min of recovery on two separate occasions with foot cooling (FC) or no foot cooling (NC) in randomized order. RESULTS During exercise and recovery in both trials, SCI TTY was elevated above baseline (P < 0.001) but more so in the NC versus FC trial (1.6 +/- 0.2 degrees C vs 1.0 +/- 0.2 degrees C, respectively, P < 0.005). Within the AB group, TTY was elevated above baseline for both trials (P < 0.001) with peak increases of 0.5 +/- 0.2 degrees C and 0.3 +/- 0.2 degrees C for NC and FC, respectively. TTY, face, and back temperature were higher in both SCI trials compared with AB trials (P < 0.05). Heart rate during exercise and recovery was lower in the SCI FC versus SCI NC (P < 0.05). CONCLUSION These results suggest that extraction of heat through the foot may provide an effective way to manipulate tympanic temperature in individuals with SCI, especially during exercise in the heat.

Sildenafil Has Little Influence on Cardiovascular Hemodynamics or 6-km Time Trial Performance in Trained Men and Women at Simulated High Altitude

UNLABELLED Sildenafil improves maximal exercise capacity at high altitudes (∼4350-5800 m) by reducing pulmonary arterial pressure and enhancing oxygen delivery, but the effects on exercise performance at less severe altitudes are less clear. PURPOSE To determine the effects of sildenafil on cardiovascular hemodynamics (heart rate, stroke volume, and cardiac output), arterial oxygen saturation (SaO2), and 6-km time-trial performance of endurance-trained men and women at a simulated altitude of ∼3900 m. METHODS Twenty men and 15 women, endurance-trained, completed one experimental exercise trial (30 min at 55% of altitude-specific capacity +6-km time trial) at sea level (SL) and two trials at simulated high altitude (HA) while breathing hypoxic gas (12.8% FIo2) after ingestion of either placebo or 50 mg sildenafil in double-blind, randomized, and counterbalanced fashion. RESULTS Maximal exercise capacity and SaO2 were significantly reduced at HA compared to SL (18%-23%), but sildenafil did not significantly improve cardiovascular hemodynamics or time-trial performance in either men or women compared to placebo and only improved SaO2 in women (4%). One male subject (5% of male subjects, 2.8% of all subjects) exhibited a meaningful 36-s improvement in time-trial performance with sildenafil compared to placebo. CONCLUSIONS In this group of endurance trained men and women, sildenafil had very little influence on cardiovascular hemodynamics, SaO2, and 6-km time-trial performance at a simulated altitude of ∼3900 m. It appears that a very small percentage of endurance-trained men and women derive meaningful improvements in aerobic performance from sildenafil at a simulated altitude of ∼3900 m.

Effects of growth hormone and pioglitazone in viscerally obese adults with impaired glucose tolerance: a factorial clinical trial.

Objective: Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time. Design: Randomized, double-blind, placebo-controlled, 2 × 2 factorial design. Setting: Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States. Participants: 62 abdominally obese adults aged 40–75 with impaired glucose tolerance. Interventions: GH (8 μg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk. Outcome Measures: Baseline and after 40 wk of treatment, VAT content was quantified by CT scan, glucose tolerance was assessed using a 75-g oral glucose tolerance test, and insulin sensitivity was measured using steady-state plasma glucose levels obtained during insulin suppression test. Results: Baseline: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 ± 7.4 cm2 in GH group, mean difference from placebo: −28.1 cm2 (95% CI −49.9 to −6.3 cm2; p = 0.02). Insulin resistance declined 52 ± 11.8 mg/dl with PIO, mean difference from placebo of −58.8 mg/dl (95% CI −99.7 to −18.0 mg/dl; p = 0.01). VAT and SSPG declined with GH and PIO combined, mean differences from placebo of −31.4 cm2 (95% CI −56.5 cm2 to −6.3 cm2; p = 0.02) and −55.3 mg/dl (95% CI −103.9 to −6.7 mg/dl; p = 0.02), respectively. Fasting plasma glucose increased transiently in GH group. No significant changes in BMI were observed. Conclusions: Addition of PIO to GH attenuated the short-term diabetogenic effect of GH; the drug combination reduced VAT and insulin resistance over time. GH plus PIO may have added benefit on body composition and insulin sensitivity in the metabolic syndrome.

Electrically-stimulated muscle hypertrophy in paraplegia: assessment by quantitative CT.

To identify the magnitude of muscle hypertrophy following electrically stimulated exercise in paraplegic subjects, we used quantitative CT (QCT) of the midthigh prior to and following 6 weeks of bicycle ergometry. Three patients who had suffered acute spinal cord injury were examined in this pilot investigation. Average absolute changes in muscle cross-sectional area by QCT were determined to be 10.6 cm2 (p = 0.042) at a distal site located 100 mm above the tibial plateau and 18.8 cm2 (p = 0.019) at a more proximal site (175 mm). Expressed as a percentage increase, these changes were likewise found to be significant. When the total thigh musculature was segmented into anterior and posterior regions, significant increases were observed only among the anterior muscle groups at both the distal and the proximal sites. Muscle hypertrophy as determined by standard anthropometric techniques at 200 mm above the patella was not found to be significant. We conclude that QCT is a valuable technique for discerning changes in muscle size during fitness training and that, in our population, it was capable of differentiating specific muscle compartment hypertrophy secondary to electrical stimulation.

Cyclic Hypobaric Hypoxia Improves Markers of Glucose Metabolism in Middle-Aged Men

UNLABELLED Chronic hypoxia increases dependence on glucose in men and increases insulin sensitivity in men and women. Cyclic Variations in Altitude Conditioning (CVAC) is a novel technology that provides exposure to rapidly fluctuating cyclic hypobaric hypoxia (CHH). PURPOSE To test the hypothesis that markers of glucose metabolism would change with CVAC CHH, two groups of middle-aged men were exposed to 10 weeks (40 min/day, 3 day/week) of either CHH or sham (SH) sessions. METHODS CHH subjects (age: 48 ± 6, weight: 86 ± 12 kg, BMI: 27.1 ± 3, n=11) experienced cyclic pressures simulating altitudes ranging from sea level to 3048 m (week 1) and progressing to 6096 m (by week 5 through week 10). SH subjects (age: 50 ± 4, weight: 89 ± 15 kg, BMI: 27.5 ± 3, n=10) were exposed to slowly-fluctuating pressures up to 607 m (all subjects blinded to elevation). Physical function and blood markers of glucose metabolism were measured at baseline, 3, 6, and 10 weeks. RESULTS Two CHH subjects were dropped from analysis for failure to progress past 3048 m (CHH: n=9). Weight and physical activity remained stable for both groups. There was a group-by-time interaction in fasting glucose (CHH: 96 ± 9 to 91 ± 7 mg/dL, SH: 94 ± 7 to 97 ± 9 mg/dL, p<0.05). Reduction in plasma glucose response to oral glucose tolerance test [area under the curve] was greater in CHH compared to SH after 10 weeks of exposure (p<0.03). Neither group experienced changes in fasting insulin, insulin response during the OGTT, or changes in a timed walk test. CONCLUSION Ten weeks of CVAC CHH exposure improves markers of glucose metabolism in middle-aged men at risk for metabolic syndrome.

Evaluating technology that makes physical games for children more engaging

Throwing is an important physical skill that lays the foundation for the ability to participate in many physical activities and sports experiences. We aim to support the development of physical skills through exertion game design; our focus here is on the design of an exertion based throwing game that aims to help children improve their ability to throw. We discuss the results of some initial play testing, and how these observations informed our game design.

Five weeks of insulin-like growth factor-I treatment does not alter glucose kinetics or insulin sensitivity during a hyperglycemic clamp in older women

Insulin sensitivity and the activity of the hypothalamic-growth hormone (GH)- insulin-like growth factor-I (IGF-I) axis both decline with age. Treatment with IGF-I increases insulin sensitivity in healthy young subjects. We hypothesized that increasing plasma IGF-I in postmenopausal women to levels characteristic of young women would enhance insulin sensitivity. To test the hypothesis, fasting glucose kinetics and insulin sensitivity were measured in 24 healthy, normoglycemic, postmenopausal women before and after 5 weeks of treatment with either recombinant human (rh)IGF-I (15 microg/kg body weight/d twice daily) or placebo in a double-blind study. Diet energy content and composition were rigidly controlled to maintain energy balance. A hyperglycemic clamp (8 mmol/L) coupled with stable isotope infusion ([6,6(2)H]glucose) was performed before and after treatment to assess whole-body insulin sensitivity; defined as the glucose rate of disappearance (Rd) or rate of infusion (GRIF) scaled to the steady-state insulin concentration (I). There were no differences in fasting glucose or insulin concentrations, glucose kinetics, or glucose oxidation after either treatment. During the clamps, steady-state insulin concentrations with placebo (pre = 151 +/- 28 pmol/L, post = 173 +/- 31 pmol/L) were slightly different than with IGF-I (pre = 182 +/- 37 pmol/L, post = 163 +/- 33 pmol/L), but the variations were not significant. No significant changes in whole-body insulin sensitivity were observed after treatment with IGF-I, calculated as Rd/I (pre = 17.7 +/- 2.6 microg/kg/min/pmol/L, post = 19.3 +/- 2.0 microg/kg/min/pmol/L for IGF-I v pre = 24.2 +/- 2.5 microg/kg/min/pmol/L, post = 22.8 +/- 3.4 microg/kg/min/pmol/L for placebo) or as GRIF/I (pre = 18.0 +/- 3.9 microg/kg/min/pmol/L, post = 22.3 +/- 3.5 microg/kg/min/pmol/L for IGF-I v pre = 26.4 +/- 6.2 microg/kg/min/pmol/L, post = 26.9 +/- 4.8 microg/kg/min/pmol/L for placebo). Baseline insulin sensitivity in women using hormone replacement therapy (HRT, n = 15) was similar to nonusers (n = 9), but HRT users derived a greater portion of energy expenditure from carbohydrate oxidation compared with nonusers. HRT use had no impact on the response to IGF-I. Overall, we observed subtle, but physiologically insignificant, variations after IGF-I treatment in the direction of enhanced insulin sensitivity. The data suggest that 5 weeks of low-dose rhIGF-I treatment has no material influence on whole-body insulin sensitivity in normoglycemic postmenopausal women.