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Shalender Bhasin

Publications and source records attributed to Shalender Bhasin.

At least 19 recordsLinked to original sources
PubMed2026

Effects of testosterone-augmented multimodal exercise intervention in spinal cord injury: a randomized controlled trial.

CONTEXT: Spinal cord injury (SCI) leads to profound muscle atrophy, aerobic deconditioning, and metabolic dysfunction. Exercise-based interventions alone produce modest benefits. Whether testosterone can augment physiologic responses to exercise in this population remains untested. OBJECTIVE: To evaluate efficacy and safety of home-based intervention combining functional electrical stimulation-assisted leg cycling (FES-LC), arm ergometry (AE), and testosterone compared with FES-LC, AE plus placebo in adults with SCI. METHODS: This randomized, placebo-controlled, double-blind trial enrolled 84 adults (76 males and 8 females) aged 19-70 years with SCI (neurologic levels C4-T12; AIS grades A-D). Participants were randomized to multimodality intervention (home-based FES-LC, AE and intramuscular testosterone undecanoate) (n = 38) or control intervention (FES-LC, AE plus placebo) (n = 46) for 16 weeks. The primary outcome was change in aerobic capacity (peak VO2) during AE cardiopulmonary exercise testing. Secondary outcomes included lean mass, hemoglobin, cardiometabolic markers, and safety. RESULTS: Mean (SD) age was 44 (13) years and time since injury was 13.9 (13) years). Between-group changes in peak VO2 were not statistically significant. Within-group improvements were larger in multimodality (∼19% increase; 0.10 L/min; 95% CI, 0.02-0.18 L/min) compared to controls (∼6% increase; 0.06 L/min; 95% CI, -0.01-0.13). The multimodality group gained significantly more lean mass (whole-body:1.84 kg, 95% CI: 0.52-3.16, P = .007; lower extremity 0.92 kg, 95% CI: 0.38-1.45, P = .001), and anemia was corrected in a greater proportion of participants. Adverse event rates were similar between groups. CONCLUSION: A home-based multimodality intervention combining FES-LC, AE, and testosterone was safe and associated with greater improvements in lean mass and hemoglobin. Although between-group differences in aerobic capacity were not statistically significant, greater within-group increases were observed in the multimodality group. These findings may inform future studies of testosterone-augmented exercise interventions for individuals living with SCI.

Humans↗
PubMed2006

Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity.

BACKGROUND: Whole body and abdominal obesity are associated with increased risk of diabetes mellitus and heart disease. The effects of testosterone therapy on whole body and visceral fat mass in HIV-infected men with abdominal obesity are unknown. OBJECTIVE: The objective of this study was to determine the effects of testosterone therapy on intraabdominal fat mass and whole body fat distribution in HIV-infected men with abdominal obesity. METHODS: IN this multicenter, randomized, placebo-controlled, double-blind trial, 88 HIV-positive men with abdominal obesity (waist-to-hip ratio > 0.95 or mid-waist circumference > 100 cm) and total testosterone 125-400 ng/dl, or bioavailable testosterone less than 115 ng/dl, or free testosterone less than 50 pg/ml on stable antiretroviral regimen, and HIV RNA less than 10,000 copies per milliliter were randomized to receive 10 g testosterone gel or placebo daily for 24 wk. Fat mass and distribution were determined by abdominal computerized tomography and dual energy x-ray absorptiometry during wk 0, 12, and 24. We used an intention-to-treat approach and nonparametric statistical methods. RESULTS: Baseline characteristics were balanced between groups. In 75 subjects evaluated, median percent change from baseline to wk 24 in visceral fat did not differ significantly between groups (testosterone 0.3%, placebo 3.1%, P = 0.75). Total (testosterone -1.5%, placebo 4.3%, P = 0.04) and sc (testosterone-7.2%, placebo 8.1%, P < 0.001) abdominal fat mass decreased in testosterone-treated men, but increased in placebo group. Testosterone therapy was associated with significant decrease in whole body, trunk, and appendicular fat mass by dual energy x-ray absorptiometry (all P < 0.001), whereas whole body and trunk fat increased significantly in the placebo group. The percent of individuals reporting a decrease in abdomen (P = 0.01), neck (P = 0.08), and breast size (P = 0.01) at wk 24 was significantly greater in testosterone-treated than placebo-treated men. Testosterone-treated men had greater increase in lean body mass than placebo (testosterone 1.3%, placebo -0.3, P = 0.02). Plasma insulin, fasting glucose, and total high-density lipoprotein and low-density lipoprotein cholesterol levels did not change significantly. Testosterone therapy was well tolerated. CONCLUSIONS: Testosterone therapy in HIV-positive men with abdominal obesity and low testosterone was associated with greater decrease in whole body, total, and sc abdominal fat mass and a greater increase in lean mass compared to placebo. However, changes in visceral fat mass were not significantly different between groups. Further studies are needed to determine testosterone effects on insulin sensitivity and cardiovascular risk.

Abdominal Fat↗
PubMed2006

Determinants of serum total and free testosterone levels in women over the age of 65 years.

CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age. OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women. DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers. CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.

Age Distribution↗
PubMed2006

Dehydroepiandrosterone secretion in healthy older men and women: effects of testosterone and growth hormone administration in older men.

CONTEXT: Aging is associated with diminished gonadal steroid and GH/IGF-I axis activity; whether these changes contribute to the parallel declines of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) production is unknown, as are the effects of sex steroid and/or GH administration on DHEA and DHEAS production. OBJECTIVE: Our objective was to evaluate morning DHEAS concentrations and nocturnal DHEA secretory dynamics in healthy older men and women, before and after chronic administration of sex steroid(s) alone, GH alone, sex steroid(s) combined with GH, or placebo alone. DESIGN: We compared nocturnal DHEA secretory dynamics (2000 h to 0800 h, sampling every 20 min, analyzed by multiparameter deconvolution and approximate entropy algorithms) in healthy older (65-88 yr) men (n = 68) and women (n = 36), both before and after 26 wk of administration of sex steroid(s) alone [testosterone (T) in men or estrogen/progesterone in women], GH alone, sex steroid(s) combined with GH, or placebo alone. RESULTS: Morning concentrations of DHEAS were lower; nocturnal DHEA pulsatile production rate, burst frequency, and amplitude were higher; and half-life was shorter in women (P < 0.05). Nocturnal integrated DHEA concentrations, total production rate, and approximate entropy did not differ significantly by sex. Because of small treatment group sizes in women, only hormone intervention results in men are presented. In men, T and T plus GH administration significantly decreased nocturnal integrated DHEA but not morning DHEAS concentrations. GH alone exerted no significant effects on nocturnal DHEA secretion or morning DHEAS. CONCLUSIONS: Spontaneous nocturnal DHEA secretion is sexually dimorphic in healthy older individuals, and T administration decreases nocturnal DHEA secretion in older men. The clinical significance of sex steroid modulation of DHEA secretion in older persons remains to be elucidated.

Aged↗
PubMed2006

Serum androgen levels in black, Hispanic, and white men.

CONTEXT: Racial/ethnic differences in androgen levels could account for differences in prostate cancer risk, body composition, and bone loss. OBJECTIVE: The objective of the study was to investigate racial/ethnic variations in testosterone, bioavailable testosterone, dihydrotestosterone (DHT), SHBG, and dehydroepiandrosterone sulfate (DHEAS) levels. DESIGN: The Boston Area Community Health (BACH) Survey was a multistage stratified cluster random sample, recruiting from 2002 to 2005. SETTING: The study was a community-based sample of Boston. PARTICIPANTS: Participants included black, Hispanic, or white individuals, aged 30-79 yr, competent to sign informed consent and literate in English/Spanish. Of 2301 men recruited, 1899 provided blood samples (538 black, 651 Hispanic, 710 white). INTERVENTION: Intervention consisted of data obtained during in-person at-home interview, conducted by a bilingual phlebotomist/interviewer. MAIN OUTCOME MEASURE(S): Testosterone, bioavailable testosterone, DHT, DHT to testosterone ratio, SHBG, and DHEAS were measured. RESULTS: With or without adjustment for covariates, there were no significant differences in testosterone, bioavailable testosterone, or SHBG levels by race/ethnicity. DHEAS levels differed by race/ethnicity before covariate adjustment; after adjustment this difference was attenuated. Before adjustment, DHT and DHT to testosterone ratios did not significantly differ by racial/ethnic group. After adjustment, there was evidence of racial/ethnic differences in DHT (P = 0.047) and DHT to testosterone (P = 0.038) levels. Black men had higher DHT levels and DHT to testosterone ratios than white and Hispanic men. CONCLUSIONS: Because there are no racial/ethnic differences in testosterone levels, normative ranges need not be adjusted by race/ethnicity for androgen deficiency diagnosis for men aged 30-79 yr. Further investigation is needed to determine whether differences in DHT levels and DHT to testosterone ratio can help explain racial/ethnic variations in prostate cancer incidence, body composition, and bone mass.

Adult↗
PubMed2006

Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone.

BACKGROUND: Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels. OBJECTIVE: The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T. METHODS: Sixty-one younger (19-35 yr) and 60 older (59-75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot. RESULTS: Older men had lower total (316 +/- 13 vs. 585 +/- 26 ng/dl, P < 0.00001) and free testosterone (4 +/- 0.1 vs. 6 +/- 0.3 ng/dl, P < 0.00001) and higher SHBG (52 +/- 3 vs. 33 +/- 2 nmol/liter, P < 0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 +/- 69 vs. 1821 +/- 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001). CONCLUSIONS: Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.

Adult↗
PubMed2006

Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.

OBJECTIVE: The objective was to provide guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a professional writer. The Task Force received no corporate funding or remuneration. EVIDENCE: The Task Force used systematic reviews of available evidence to inform its key recommendations. The Task Force used consistent language and graphical descriptions of both the strength of recommendation and the quality of evidence, using the recommendations of the Grading of Recommendations, Assessment, Development, and Evaluation group. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during three group meetings, several conference calls, and e-mail communications. The drafts prepared by the panelists with the help of a professional writer were reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Committee, and Council. The version approved by the Council was placed on The Endocrine Society's web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and in some patients by measurement of free or bioavailable testosterone level, using accurate assays. We recommend testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 3 ng/ml without further urological evaluation, erythrocytosis (hematocrit > 50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) greater than 19, or class III or IV heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.

Evidence-Based Medicine↗
PubMed2006

Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men.

OBJECTIVE: In this study, we determined the effects of graded doses of testosterone on muscle fiber cross-sectional area (CSA) and satellite cell number and replication in older men. PARTICIPANTS: Healthy men, 60-75 yr old, received a long-acting GnRH agonist to suppress endogenous testosterone production and 25, 50, 125, 300, or 600 mg testosterone enanthate im weekly for 20 wk. METHODS: Immunohistochemistry, light and confocal microscopy, and electron microscopy were used to perform fiber typing and quantitate myonuclear and satellite cell number in vastus lateralis biopsies, obtained before and after 20 wk of treatment. RESULTS: Testosterone administration in older men was associated with dose-dependent increases in CSA of both types I and II fibers. Satellite cell number increased dose dependently at the three highest doses (3% at baseline vs. 6.2, 9.2, and 13.0% at 125, 300, and 600 mg doses, P < 0.05). Testosterone administration was associated with an increase in the number of proliferating cell nuclear antigen+ satellite cells (1.8% at baseline vs. 3.9, 7.5, and 13% at 125, 300, and 600 mg doses, P < 0.005). The expression of activated Notch, examined only in the 300-mg group (baseline, 2.3 vs. 9.0% after treatment, P < 0.005), increased in satellite cells after testosterone treatment. The expression of myogenin (baseline, 6.2 vs. 20.7% after treatment, P < 0.005), examined only in the 300-mg group, increased significantly in muscle fiber nuclei after testosterone treatment, but Numb expression did not change. CONCLUSIONS: Older men respond to graded doses of testosterone with a dose-dependent increase in muscle fiber CSA and satellite cell number. Testosterone-induced skeletal muscle hypertrophy in older men is associated with increased satellite cell replication and activation.

Aged↗
PubMed2006

Effects of transdermal testosterone administration on insulin sensitivity, fat mass and distribution, and markers of inflammation and thrombolysis in human immunodeficiency virus-infected women with mild to moderate weight loss.

OBJECTIVE: To determine the effects of raising serum T levels into the high normal female range by transdermal T administration on insulin sensitivity, fat volume, and markers of inflammation and thrombolysis in HIV-infected women with recent weight loss. DESIGN: Placebo-controlled, randomized clinical trial. SETTING: Academic clinical research center. PATIENT(S): Fifty-two HIV-infected, menstruating women with >5% weight loss over the prior 6 months and current T<33 ng/dL. INTERVENTION(S): Placebo or T patches twice weekly for 24 weeks to achieve nominal delivery of 300 microg T daily. MAIN OUTCOME MEASURE(S): Testosterone by liquid chromatography-tandem mass spectrometry, insulin sensitivity by the frequently sampled intravenous glucose tolerance test (FSIVGT), abdominal and thigh fat volumes by magnetic resonance imaging (MRI), and C-reactive protein (CRP) as a measure of inflammation and plasminogen-activated inhibitor-1 (PAI-1) levels as a marker of thrombolysis. RESULT(S): Serum and free T levels significantly increased into the high normal female range in T-treated but not placebo-treated women. Insulin sensitivity by FSIVGT, whole body, thigh SC, and intra-abdominal fat volumes, and CRP and PAI-1 levels did not change significantly in either group and were not significantly different between the two groups. Fasting insulin increased in the placebo group and fell slightly in the T group, resulting in significant differences in change between groups. CONCLUSION(S): Twenty-four weeks of elevation of serum T levels into the high normal female range in HIV-infected women with mild to moderate weight loss by transdermal T patches did not adversely affect insulin sensitivity, whole-body fat mass or regional fat distribution, or markers of inflammation and thrombolysis. More prolonged and larger studies are needed to determine the effects of higher doses of T on body composition and insulin sensitivity in women.

Administration, Topical↗
PubMed2006

Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging.

Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with beta-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

Aging↗
PubMed2006

Oxandrolone in the treatment of HIV-associated weight loss in men: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of oxandrolone in promoting body weight and body cell mass (BCM) gain in HIV-associated weight loss. METHODS: Randomized, double-blind, placebo-controlled trial. Two hundred sixty-two HIV-infected men with documented 10% to 20% weight loss or body mass index < or =20 kg/m were randomized to placebo or to 20, 40, or 80 mg of oxandrolone daily. After 12 weeks, subjects were allowed to receive open-label oxandrolone at a dose of 20 mg for another 12 weeks. RESULTS: Body weight increased in all groups, including the group receiving placebo, during the double-blind phase (1.1 +/- 2.7, 1.8 +/- 3.9, 2.8 +/- 3.3, and 2.3 +/- 2.9 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively; all P < 0.014 vs. baseline). BCM increased from baseline in all groups (0.45 +/- 1.7, 0.91 +/- 2.2, 1.5 +/- 2.5, and 1.8 +/- 1.8 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively). At 12 weeks, only the gain in weight at the 40-mg dose of oxandrolone and the gain in BCM at the 40- and 80-mg doses of oxandrolone were greater than those in the placebo group, however. Oxandrolone treatment was associated with significant suppression of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and total and free testosterone levels. Treatment was generally well tolerated but accompanied by significant increases in transaminases and low-density lipoprotein as well as decreases in high-density lipoprotein. CONCLUSION: Oxandrolone administration is effective in promoting dose-dependent gains in body weight and BCM in HIV-infected men with weight loss.

Adult↗
PubMed2006

The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study.

OBJECTIVE: Changes in adiposity affecting total testosterone (TT) and free testosterone (FT) levels have not been examined in a population-based survey. We aimed to determine whether changes in adiposity predict follow-up levels and rates of change in TT, FT and sex hormone-binding globulin (SHBG) in men. DESIGN: The Massachusetts Male Aging Study is a randomly sampled, population-based cohort interviewed at baseline (T(1), 1987-1989; n = 1,709; aged 40-70 years) and followed-up approximately 9 years later (T(2), 1995-1997; n = 1,156). Men were categorized as overweight (body mass index (BMI) >or= 25 kg/m(2)) or having obesity (BMI >or= 30 kg/m(2)), waist obesity (waist circumference >or= 102 cm), or waist-to-hip ratio (WHR) obesity (WHR>0.95). For each adiposity group, we constructed four categories to represent changes between T(1) and T(2): overweight (or obese, etc.) at neither wave, T(1) only, T(2) only, or both waves. RESULTS: After adjustment for confounding variables, men who were overweight at T(2) only, or at both waves, had significantly lower mean T(2) TT and SHBG levels than men in the neither group (P<0.05). Mean FT did not differ between any overweight group and the neither group. Men who were obese at both times, had the highest mean BMI, the highest fraction of severely obese men, and significantly greater rate of decline in FT than the neither group. CONCLUSIONS: In men who become overweight, the greater rate of decline in TT, but not FT, is related mostly to a lesser age-related increase in SHBG. Since weight gain is highly prevalent in older men, over-reliance on TT levels in the diagnosis of androgen deficiency could result in substantial misclassification.

Adiposity↗
PubMed2005

Pharmacokinetics of a testosterone gel in healthy postmenopausal women.

BACKGROUND: The paucity of pharmacokinetic data on androgen formulations in women has hindered clinical trials of testosterone supplementation in women. OBJECTIVE: The objective of this study was to determine the time course and profile of serum testosterone concentrations during treatment with different doses of testosterone gel in postmenopausal women and assess whether estrogen treatment affects the pharmacokinetics of testosterone gel. METHODS: Postmenopausal women with total testosterone levels less than 33 ng/dl after baseline 24-h sampling were treated with 4.4, 8.8, or 13.2 mg testosterone gel daily for 7 d each in random order, with a 7-d washout period between doses. We studied 13 women who had not received estrogen therapy (group I) and 13 who had received stable estrogen therapy for 3 months or more (group II). Total and free testosterone concentrations were measured for 48 h on the seventh day of each dose administration. RESULTS: Twenty-six women were randomized; of these, 24 were evaluable, 13 in group I and 11 in group II. The average steady-state concentrations (Cav) of serum total and free testosterone increased with increasing testosterone dose and were highly correlated with the dose (dose effect, P < 0.00001), but were not affected by estrogen therapy (P = 0.43). In both groups, the 4.4-mg dose increased Cav total and free testosterone into the mid- to high-normal range, whereas 8.8- and 13.2-mg doses raised total (Cav: 22.3, 51.6, 80.3, and 92.0 ng/dl in group I; 22.7, 59.8, 82.0, and 114.3 ng/dl in group II at 0, 4.4, 8.8, and 13. 2 mg, respectively) and free testosterone (5.9, 8.4, 11.5,12.8 pg/ml in group I and 5.0,7.6,11.1,10.8 in group II, respectively, at the various doses) above the physiological range. The area under the curve, maximum and minimum concentrations, and the change in Cav for total and free testosterone were dose related and significantly higher during administration of the 13.2-mg dose than during the 0- or 4.4-mg dose; estrogen therapy had no significant effect on these measures. Serum estradiol, LH, FSH, and SHBG levels did not change significantly at any dose. Testosterone gel was well tolerated. CONCLUSIONS: Administration of testosterone gel to postmenopausal women raised total and free testosterone concentrations in proportion to the administered dose without affecting estradiol levels. A 4.4-mg dose raised testosterone levels into the mid- to high-normal range. Previous estrogen therapy had no significant effect on testosterone pharmacokinetics over this short duration.

Administration, Topical↗
PubMed2005

Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors.

Testosterone supplementation in men decreases fat mass; however, the mechanisms by which it inhibits fat mass are unknown. We hypothesized that testosterone inhibits adipogenic differentiation of preadipocytes by activation of androgen receptor (AR)/beta-catenin interaction and subsequent translocation of this complex to the nucleus thereby bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1 cells that differentiate to form fat cells in adipogenic medium. We found that these cells express AR and that testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil Red O staining and down-regulation of CCAAT/enhancer binding protein-alpha and -delta and peroxisome proliferator-activated receptor-gamma2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of beta-catenin and AR. Immunoprecipitation studies demonstrated association of beta-catenin with AR and T-cell factor 4 (TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited adipogenic differentiation, whereas a dominant negative TCF4 cDNA construct induced adipogenesis and blocked testosterone's inhibitory effects. Our gene array analysis indicates that testosterone treatment led to activation of some Wnt target genes. Expression of constitutively activated AR fused with VP-16 did not inhibit the expression of CCAAT/enhancer binding protein-alpha in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of beta-catenin and activation of downstream Wnt signaling. These data provide evidence for a regulatory role for androgens in inhibiting adipogenic differentiation and a mechanistic explanation consistent with the observed reduction in fat mass in men treated with androgens.

3T3 Cells↗
PubMed2005

A randomized, placebo-controlled trial of nandrolone decanoate in human immunodeficiency virus-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment.

OBJECTIVE: We compared the effectiveness of a biweekly regimen of 150 mg nandrolone with placebo in HIV-infected men with mild to moderate weight loss and contrasted its effects against a Food and Drug Administration-approved regimen of recombinant human (rh)GH. METHODS: In this placebo-controlled, randomized, 12-wk trial, placebo and nandrolone (150 mg im biweekly) were administered double blind, and rhGH (6 mg sc daily) was administered in an open-label manner. Participants were HIV-infected men with 5-15% weight loss over 6 months and on stable antiretroviral therapy for more than 12 wk. Lean body mass (LBM), muscle performance, physical function, endurance, hormone levels, insulin sensitivity, sexual function, quality of life, and appetite were assessed at baseline and after 12 wk. RESULTS: Nandrolone administration was associated with a greater increase in LBM (+1.6 +/- 0.3 kg) by dual-energy x-ray absorptiometry scan than placebo (+0.4 +/- 0.3 kg; P < 0.05); however, the change in LBMs with nandrolone was not significantly different from rhGH (+2.5 +/- 0.3 kg). Nandrolone administration was also associated with significantly greater gains in fat-free mass (+1.6 +/- 0.3 kg), body cell mass (+1.0 +/- 0.2 kg), and intracellular water (+0.9 +/- 0.2 kg) than placebo; these changes in the nandrolone group were not significantly different from the rhGH group. rhGH administration was associated with greater loss of whole body fat mass and higher frequency of drug-related adverse effects and treatment discontinuations than nandrolone and placebo and a greater increase in extracellular water than nandrolone. Nandrolone treatment was associated with greater improvements in perception of health than rhGH and sexual function than placebo. The cachexia/anorexia scores, health care resource use, and insulin sensitivity did not significantly change. CONCLUSION: We conclude that nandrolone is superior to placebo and not significantly different from a Food and Drug Administration-approved regimen of rhGH in improving lean body mass in HIV-infected men with mild to moderate weight loss.

Adipose Tissue↗
PubMed2005

Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells.

Inactivating mutations of the mammalian myostatin gene are associated with increased muscle mass and decreased fat mass; conversely, myostatin transgenic mice that overexpress myostatin in the skeletal muscle have decreased muscle mass and increased fat mass. We investigated the effects of recombinant myostatin protein and antimyostatin antibody on myogenic and adipogenic differentiation of mesenchymal multipotent cells. Accordingly, 10T(1/2) cells were incubated with 5'-azacytidine for 3 d to induce differentiation and then treated with a recombinant protein for myostatin (Mst) carboxy terminal 113 amino acids or a polyclonal anti-Mst antibody for 3, 7, and 14 d. Cells were also cotransfected with a Mst cDNA plasmid expressing the full-length 375-amino acid protein (pcDNA-Mst375) and the silencer RNAs for either Mst (pSil-Mst) or a random sequence (pSil-RS) for 3 or 7 d, and Mst expression was determined. Adipogenesis was evaluated by quantitative image analysis of fat cells before and after oil-red-O staining, immunocytochemistry of adiponectin, and Western blot for CCAAT/enhancer binding protein-alpha. Myogenesis was estimated by quantitative image analysis-immunocytochemistry for MyoD (Myo differentiation protein), myogenin, and myosin heavy chain type II, or by Western blot for myogenin. 5'-Azacytidine-mediated differentiation induced endogenous full-length Mst expression. Recombinant Mst carboxy terminal 113 amino acids inhibited both early and late markers of myogenesis and stimulated both early and late markers of adipogenesis, whereas the antibody against Mst exerted the reverse effects. Myogenin levels at 7 d after transfection of pcDNA-Mst375 were reduced as expected and elevated by pSil-Mst, which blocked efficiently Mst375 expression. In conclusion, myostatin promotes the differentiation of multipotent mesenchymal cells into the adipogenic lineage and inhibits myogenesis.

Adipocytes↗