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Shalender Bhasin

Publications and source records attributed to Shalender Bhasin.

50 records · Page 3Linked to original sources
PubMed2003

Development of models to predict anabolic response to testosterone administration in healthy young men.

Considerable heterogeneity exists in the anabolic response to androgen administration; however, the factors that contribute to variation in an individual's anabolic response to androgens remain unknown. We investigated whether testosterone dose and/or any combination of baseline variables, including concentrations of hormones, age, body composition, muscle function, and morphometry or polymorphisms in androgen receptor could explain the variability in anabolic response to testosterone. Fifty-four young men were treated with a long-acting gonadotropin-releasing hormone (GnRH) agonist and one of five doses (25, 50, 125, 300, or 600 mg/wk) of testosterone enanthate (TE) for 20 wk. Anabolic response was defined as a change in whole body fat-free mass (FFM) by dual-energy X-ray absorptiometry (DEXA), appendicular FFM (by DEXA), and thigh muscle volume (by magnetic resonance imaging) during TE treatment. We used univariate and multivariate analysis to identify the subset of baseline measures that best explained the variability in anabolic response to testosterone supplementation. The three-variable model of TE dose, age, and baseline prostate-specific antigen (PSA) level explained 67% of the variance in change in whole body FFM. Change in appendicular FFM was best explained (64% of the variance) by the linear combination of TE dose, baseline PSA, and leg press strength, whereas TE dose, log of the ratio of luteinizing hormone to testosterone concentration, and age explained 66% of the variation in change in thigh muscle volume. The models were further validated by using Ridge analysis and cross-validation in data subsets. Only the model using testosterone dose, age, and PSA was a consistent predictor of change in FFM in subset analyses. The length of CAG tract was only a weak predictor of change in thigh muscle volume and lean body mass. Hence, the anabolic response of healthy, young men to exogenous testosterone administration can largely be predicted by the testosterone dose.

Absorptiometry, Photon↗
PubMed2003

Androgen effects on body composition.

Androgens are known to have a role in the body fat, muscle size, muscle performance and physical function differences seen between hypogonadal and eugonadal men. The results of investigations into effects of testosterone on body composition, fat metabolism and muscle anabolism are reviewed here. Testosterone dose-response relationships are presented in studies of the effects of physiologic and supraphysiologic doses with and without exercise in young hypogonadal men, older men with low testosterone levels and in chronic illness states.

Adipose Tissue↗
PubMed2003

Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression.

In spite of the widespread belief that testosterone supplementation increases the risk of atherosclerotic heart disease, evidence to support this premise is lacking. Although supraphysiological doses of testosterone, such as those used by athletes and recreational body builders, decrease plasma high-density lipoprotein (HDL) cholesterol concentrations, replacement doses of testosterone have had only a modest or no effect on plasma HDL in placebo-controlled trials. In epidemiological studies, serum total and free testosterone concentrations have been inversely correlated with intra-abdominal fat mass, risk of coronary artery disease, and type 2 diabetes mellitus. Testosterone administration to middle-aged men is associated with decreased visceral fat and glucose concentrations and increased insulin sensitivity. Testosterone infusion increases coronary blood flow. Similarly, testosterone replacement retards atherogenesis in experimental models of atherosclerosis. However, the long-term risks and benefits of testosterone administration in human immunodeficiency virus-infected men with fat redistribution syndrome have not been studied in randomized clinical trials.

Adipose Tissue↗
PubMed2003

Testosterone supplementation for aging-associated sarcopenia.

Aging of humans is associated with a loss of muscle mass and function, and an increase in fat mass. Epidemiologic studies have demonstrated a correlation between bioavailable testosterone concentrations and fat-free mass and muscle strength. Testosterone replacement in older men with low testosterone levels increases fat-free mass and muscle strength, and decreases fat mass. However, we do not know whether testosterone replacement improves physical function and other health-related outcomes, or reduces the risk of disability, falls, or fractures in older men with low testosterone levels. The long-term risks and benefits of testosterone supplementation in older men are not known.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2003

The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action.

Testosterone supplementation increases muscle mass primarily by inducing muscle fiber hypertrophy; however, the mechanisms by which testosterone exerts its anabolic effects on the muscle are poorly understood. The prevalent view is that testosterone improves net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving the reutilization of amino acids. However, the muscle protein synthesis hypothesis does not adequately explain testosterone-induced changes in fat mass, myonuclear number, and satellite cell number. We postulate that testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage. The hypothesis that the primary site of androgen action is the pluripotent stem cell provides a unifying explanation for the observed reciprocal effects of testosterone on muscle and fat mass.

Adolescent↗
PubMed2003

Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension.

Testosterone supplementation in men increases fat-free mass, but whether measures of muscle performance, such as maximal voluntary strength, power, fatigability, or specific tension, are improved has not been determined. Furthermore, the extent to which these measures of muscle performance are related to testosterone dose or circulating concentration is unknown. To examine the relationship between testosterone dose and muscle performance, 61 healthy, eugonadal young men (aged 18-35 yr) were randomized to 1 of 5 groups, each receiving a long-acting GnRH agonist to suppress endogenous testosterone production plus weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate for 20 wk. These doses produced mean nadir testosterone concentrations of 253, 306, 542, 1345, and 2370 ng/dl, respectively. Maximal voluntary muscle strength and fatigability were determined by a seated leg press exercise. Leg power was measured using a validated leg power instrument. Specific tension was estimated by the ratio of one repetition maximum muscle strength to thigh muscle volume determined by magnetic resonance imaging. Testosterone administration was associated with a dose-dependent increase in leg press strength and leg power, but muscle fatigability did not change significantly during treatment. Changes in leg press strength were significantly correlated with total (r = 0.46; P = 0.0005) and free (r = 0.38; P = 0.006) testosterone as was leg power (total testosterone: r = 0.38; P = 0.007; free testosterone: r = 0.35; P = 0.015), but not muscle fatigability. Serum IGF-I concentrations were not significantly correlated with leg strength, power, or fatigability. Specific tension did not change significantly at any dose. We conclude that the effects of testosterone on muscle performance are specific; it increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. The changes in leg strength and power are dependent on testosterone dose and circulating testosterone concentrations and exhibit a log-linear relationship with serum total and free testosterone. Failure to observe a significant testosterone dose relationship with fatigability suggests that testosterone does not affect this component of muscle performance and that different components of muscle performance are regulated by different mechanisms.

Adolescent↗
PubMed2002

Effects of an oral androgen on muscle and metabolism in older, community-dwelling men.

To determine whether oxymetholone increases lean body mass (LBM) and skeletal muscle strength in older persons, 31 men 65-80 yr of age were randomized to placebo (group 1) or 50 mg (group 2) or 100 mg (group 3) daily for 12 wk. For the three groups, total LBM increased by 0.0 +/- 0.6, 3.3 +/- 1.2 (P < 0.001), and 4.2 +/- 2.4 kg (P < 0.001), respectively. Trunk fat decreased by 0.2 +/- 0.4, 1.7 +/- 1.0 (P = 0.018), and 2.2 +/- 0.9 kg (P = 0.005) in groups 1, 2, and 3, respectively. Relative increases in 1-repetition maximum (1-RM) strength for biaxial chest press of 8.2 +/- 9.2 and 13.9 +/- 8.1% in the two active treatment groups were significantly different from the change (-0.8 +/- 4.3%) for the placebo group (P < 0.03). For lat pull-down, 1-RM changed by -0.6 +/- 8.3, 8.8 +/- 15.1, and 18.4 +/- 21.0% for the groups, respectively (1-way ANOVA, P = 0.019). The pattern of changes among the groups for LBM and upper-body strength suggested that changes might be related to dose. Alanine aminotransferase increased by 72 +/- 67 U/l in group 3 (P < 0.001), and HDL-cholesterol decreased by -19 +/- 9 and -23 +/- 18 mg/dl in groups 2 and 3, respectively (P = 0.04 and P = 0.008). Thus oxymetholone improved LBM and maximal voluntary muscle strength and decreased fat mass in older men.

Absorptiometry, Photon↗
PubMed2002

Endogenous expression and localization of myostatin and its relation to myosin heavy chain distribution in C2C12 skeletal muscle cells.

Myostatin is a negative regulator of skeletal muscle growth. We have previously reported that recombinant myostatin protein inhibits DNA and protein synthesis in C2C12 cells. Our objective was to assess if C2C12 cells express myostatin, determine its sub-cellular localization and the developmental stage of C2C12 cells in which myostatin mRNA and protein are expressed. To study the endogenous expression of myostatin, C2C12 myoblasts were allowed to progress to myotubes, and changes in the levels of endogenous myostatin mRNA expression were determined by RT-PCR. The myostatin protein and the two major myosin heavy chain (MHC) isoforms (MHC-I and -II) were determined by Western blot. Confirmation of the relative MHC expression patterns was obtained by a modified polyacrylamide gel electropheretic (PAGE) procedure. Imunofluorescence staining was employed to localize the site of myostatin expression and the relative distribution of the MHC isoforms. Co-expression of these proteins was studied using a dual staining approach. Expression of myostatin mRNA was found in myotubes but not in myoblasts. Myostatin protein was seen in most but not all, of the nuclei of polynucleated fibers expressing MHC-II, and myostatin was detected in the cytoplasm of myotube. The localization of myostatin protein in myotube nuclei was confirmed by Western blot of isolated nuclear and cytoplasmic fractions. Incubation of C2C12 myotubes with graded doses of dexamethasone dose-dependently increased the intensity of nuclear myostatin immunostaining and also resulted in the appearance of cytoplasmic expression. In conclusion, myostatin was expressed mostly in C2C12 myotubes nuclei expressing MHC-II. Its predominant nuclear localization suggests that it may play a role in transcriptional regulation.

Animals↗
PubMed2002

Androgen supplementation in older women: too much hype, not enough data.

Androgen supplementation in women has received enormous attention in the scientific and lay communities. That it enhances some aspects of cognitive function, sexual function, muscle mass, strength, and sense of well-being is not in question. What is not known is whether physiological testosterone replacement can improve health-related outcome in older women without its virilizing side effects. Although it is assumed that the testosterone dose-response relationship is different in women than in men and that clinically relevant outcomes on the above-mentioned effects can be achieved at lower testosterone doses, these assumptions have not been tested rigorously. Androgen deficiency has no clear-cut definition. Clinical features may include impaired sexual function, low energy, depression, and a total testosterone level of less than 15 ng/dL, the lower end of the normal range. Measurement of free testosterone is ideal, because it provides a better estimate of the biologically relevant fraction. It is not widely used in clinical practice, because some methods of measuring free testosterone assay are hampered by methodological difficulties. In marked contrast to the abrupt decline in estrogen and progesterone production at menopause, serum testosterone is lower in older women than in menstruating women, with the decline becoming apparent a decade before menopause. This article reviews testosterone's effects on sexual function, cognitive function, muscle mass, body composition, and immune function in postmenopausal women.

Aged↗
PubMed2002

Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy.

Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 +/- 186 vs. 4,201 +/- 252 microm(2), P < 0.05 at 300-mg dose, and 3,347 +/- 253 vs. 4,984 +/- 374 microm(2), P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 +/- 401 vs. 5,526 +/- 544 microm(2), P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy.

Adolescent↗
PubMed2002

The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men.

The effects of T supplementation on insulin sensitivity, inflammation-sensitive markers, and apolipoproteins remain poorly understood. We do not know whether T's effects on plasma lipids, apolipoproteins, and insulin sensitivity are dose dependent, or whether significant anabolic effects can be achieved at T doses that do not adversely affect these cardiovascular risk factors. To determine the effects of different doses of T, 61 eugonadal men, 18-35 yr of age, were randomly assigned to 1 of 5 groups to receive monthly injections of long-acting GnRH agonist to suppress endogenous T secretion and weekly injections of 25, 50, 125, 300, or 600 mg T enanthate for 20 wk. Dietary energy and protein intakes were standardized. Combined administration of GnRH agonist and graded doses of T enanthate resulted in nadir T concentrations of 253, 306, 542, 1345, and 2370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Plasma high density lipoprotein cholesterol and apolipoprotein A-I concentrations were inversely correlated with total and free T concentrations and were significantly decreased only in the 600 mg/wk group (change in high density lipoprotein cholesterol: -8 +/- 2 mg/dl; P = 0.0005; change in apolipoprotein A-I: -16 +/- 2 mg/dl; P = 0.0001). Serum total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, and apolipoprotein C-III were not significantly correlated with T dose or concentration. There was no significant change in total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, or apolipoprotein C-III levels at any dose. The insulin sensitivity index, glucose effectiveness, and acute insulin response to glucose, derived from the insulin-modified, frequently sampled, iv glucose tolerance test using the Bergman minimal model, did not change significantly at any dose. Circulating levels of C-reactive protein were not correlated with T concentrations and did not change with treatment in any group. Significant increments in fat-free mass, muscle size, and strength were observed at doses that did not affect cardiovascular risk factors. Over a wide range of doses, including those associated with significant gains in fat-free mass and muscle size, T had no adverse effect on insulin sensitivity, plasma lipids, apolipoproteins, or C-reactive protein. Only the highest dose of T (600 mg/wk) was associated with a reduction in plasma high density lipoprotein cholesterol and apolipoprotein A-I. Long-term studies are needed to determine whether T supplementation of older men with low T levels affects atherosclerosis progression.

Adult↗
PubMed2002

Alteration of gene expression profiles in skeletal muscle of rats exposed to microgravity during a spaceflight.

To clarify the mechanism of skeletal muscle wasting during spaceflights, we investigated whether intramuscular gene expression profiles are affected, by using DNA microarray methods. Male rats sent on the 17-day NASA STS-90 Neurolab spaceflight were sacrificed 24 hours after return to earth (MG group). Ground control rats were maintained for 17 days in flight-simulated cages (CS group). Spaceflight induced a 19% and 23% loss of tibialis anterior and gastrocnemius muscle mass, respectively, as compared to ground controls. Muscle RNA was analyzed by the Clontech Atlas DNA expression array in four rats, with two MG/ CS pairs for the tibialis anterior, and one pair for the gastrocnemius. Alterations in gene expression were verified for selected genes by reverse-transcription PCR. In both muscles of MG rats, mRNAs for 12 genes were up-regulated by over 2-fold, and 38 were down-regulated compared to controls. There was inhibition of genes for cell proliferation and growth factor cascades, including cell cycle genes and signal transduction proteins, such as p21 Cip1, retinoblastoma (Rb), cyclins G1/S, -E and -D3, MAP kinase 3, MAD3, and ras related protein RAB2. These data indicate that following exposure to microgravity, there is downregulation of genes involved in regulation of muscle satellite cell replication.

Animals↗