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Management of diabetes is a challenge starting in the pre-analytical phase with selecting the most appropriate glycolysis inhibitor. Study goal was to calculate the impact of tubes with different glycolysis inhibitors on the classification of the glycemic control of 157,415 consecutive hospital patients according to current WHO diabetes criteria. METHODS: Glucose and lactate were measured in parallel in samples from 68 healthy subjects collected and stored in different sample tubes from Sarstedt and Greiner. Bias to baseline conditions (fluoride heparin (FH) tubes, centrifugation within 1â¯h) was determined. RESULTS: In baseline samples, glucose concentration in fluoride/EDTA/citrate (FC) plasma was ~13% higher and lactate concentration ~20% lower compared to FH, fluoride oxalate, and fluoride EDTA plasma, and in serum. Glucose recovery after storage up to 48â¯h was 99-101% in the different tubes, but the effectiveness of glycolysis inhibition by FC was inconsistent. Based on the observed mean bias of 12% when FC tubes are used, we estimate an increase of 48.4-55.8% in the frequency of patients with impaired glucose levels using current WHO criteria. CONCLUSION: Using current established decision limits, the number of patients with impaired glucose levels in the hospital would increase substantially with a strong impact on patient treatment and consumption of resources. The unpredictable failure of glycolysis inhibition in FC tubes does not allow to adjust the decision limits by a fixed factor. In the absence of prospective outcome studies with FC tubes, we recommend to measure glucose in samples containing FH.
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PURPOSE: Circulating free testosterone (FT) levels have been used widely in the diagnosis and treatment of hypogonadism in men. Due to experimental complexities in FT measurements, the Endocrine Society has recommended the use of calculated FT (cFT) as an appropriate approach for estimating FT. We show here that the prevailing model of testosterone's binding to SHBG, which assumes that each SHBG dimer binds two testosterone molecules and that the two binding sites on SHBG have similar binding affinity is erroneous and provides FT values that differ substantially from those obtained using equilibrium dialysis. METHODS: We characterized testosterone's binding to SHBG using binding isotherms, ligand depletion curves, and isothermal titration calorimetry (ITC). We derived a new model of testosterone's binding to SHBG from these experimental data and used this model to determine FT concentrations and compare these values with those derived from equilibrium dialysis. RESULTS: Experimental data on testosterone's association with SHBG generated using binding isotherms including equilibrium binding, ligand depletion experiments, and ITC provide evidence of a multi-step dynamic process, encompassing at least two inter-converting microstates in unliganded SHBG, readjustment of equilibria between unliganded states upon binding of the first ligand molecule, and allosteric interaction between two binding sites of SHBG dimer. FT concentrations in men determined using the new multistep dynamic model with complex allostery did not differ from those measured using equilibrium dialysis. Systematic error in calculated FT vales in females using Vermeulen's model was also significantly reduced. In European Male Aging Study, the men deemed to have low FT (<2.5th percentile) by the new model were at increased risk of sexual symptoms and elevated LH. CONCLUSION: Testosterone's binding to SHBG is a multi-step dynamic process that involves complex allostery within SHBG dimer. FT values obtained using the new model have close correspondence with those measured using equilibrium dialysis.
Assuntos
Modelos Químicos , Multimerização Proteica , Globulina de Ligação a Hormônio Sexual/química , Testosterona/química , Regulação Alostérica/fisiologia , Feminino , Humanos , Masculino , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/metabolismoRESUMO
BACKGROUND: Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of cardiovascular events in men randomized to testosterone, resulting in enrollment cessation by trial's Data and Safety Monitoring Board. We evaluated changes in gonadal hormones and markers of inflammation and coagulation to elucidate risk factors associated with cardiovascular events. METHODS: Men aged 65 years or more, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Changes in total and free testosterone, estradiol and estrone, C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor-1, and pro-brain naturetic peptide were compared between groups and within the testosterone group between subjects who experienced cardiovascular events and those who did not. RESULTS: Of 209 men randomized (mean age 74 years), gonadal hormones and biomarkers were available in 179 men. Baseline body mass index, gonadal hormones, lipids, Framingham risk scores, and other biomarkers were similar in the two treatment groups. Within the testosterone group, the 6-month increase in free testosterone was significantly greater in men who experienced cardiovascular events than in those who did not [mean (95% confidence interval), 10.6 (4.6-16.7) vs 5.2 (3.0-7.5) ng/dL, p = .05]. In multivariable logistic regression analysis, the change in the serum levels of free testosterone was associated with cardiovascular events. CONCLUSION: Mobility-limited older men who experienced cardiovascular events had greater increases in serum free testosterone levels than those who did not.
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Doenças Cardiovasculares/etiologia , Limitação da Mobilidade , Testosterona/efeitos adversos , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Estradiol/sangue , Estrona/sangue , Fibrinogênio/metabolismo , Humanos , Interleucina-6/sangue , Masculino , Peptídeo Natriurético Encefálico/sangue , Inibidor 1 de Ativador de Plasminogênio/sangue , Fatores de Risco , Testosterona/administração & dosagem , Testosterona/sangueRESUMO
BACKGROUND: Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. METHODS: In this placebo-controlled study, 76 healthy men (21-50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. RESULTS: LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone-binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. CONCLUSIONS: LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations.
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Androgênios/farmacologia , Androgênios/farmacocinética , Receptores Androgênicos/efeitos dos fármacos , Administração Oral , Adulto , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Hormônios Esteroides Gonadais/sangue , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/biossíntese , Força Muscular/efeitos dos fármacos , Especificidade de Órgãos , Próstata/efeitos dos fármacos , Testosterona/sangue , Adulto JovemRESUMO
BACKGROUND: Erectile dysfunction and low testosterone levels frequently occur together. OBJECTIVE: To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels. DESIGN: Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707) SETTING: Outpatient academic research center. PARTICIPANTS: Men aged 40 to 70 years with scores of 25 or less for the erectile function domain (EFD) of the International Index of Erectile Function, total testosterone levels less than 11.45 nmol/L (<330 ng/dL), or free testosterone levels less than 173.35 pmol/L (<50 pg/mL). INTERVENTION: Sildenafil dose was optimized, and 140 participants were then randomly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants. All participants were included in the primary analysis, although 10 in the testosterone group and 12 in the placebo group did not complete the study. RESULTS: At baseline, the 2 groups had similar EFD scores. Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, -0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups. LIMITATION: Whether testosterone could improve erectile function without sildenafil was not studied. CONCLUSION: Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels. PRIMARY FUNDING SOURCE: National Institute of Child Health and Human Development.
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Androgênios/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Terapia de Reposição Hormonal , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Testosterona/uso terapêutico , Administração Cutânea , Adulto , Idoso , Androgênios/administração & dosagem , Androgênios/efeitos adversos , Coito , Método Duplo-Cego , Quimioterapia Combinada , Disfunção Erétil/sangue , Géis , Humanos , Masculino , Pessoa de Meia-Idade , Orgasmo , Ereção Peniana , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Piperazinas/administração & dosagem , Purinas/administração & dosagem , Purinas/uso terapêutico , Qualidade de Vida , Citrato de Sildenafila , Sulfonas/administração & dosagem , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangueRESUMO
CONTEXT: Steroid 5α-reductase inhibitors are used to treat benign prostatic hyperplasia and androgenic alopecia, but the role of 5α-dihydrotestosterone (DHT) in mediating testosterone's effects on muscle, sexual function, erythropoiesis, and other androgen-dependent processes remains poorly understood. OBJECTIVE: To determine whether testosterone's effects on muscle mass, strength, sexual function, hematocrit level, prostate volume, sebum production, and lipid levels are attenuated when its conversion to DHT is blocked by dutasteride (an inhibitor of 5α-reductase type 1 and 2). DESIGN, SETTING, AND PATIENTS: The 5α-Reductase Trial was a randomized controlled trial of healthy men aged 18 to 50 years comparing placebo plus testosterone enthanate with dutasteride plus testosterone enanthate from May 2005 through June 2010. INTERVENTIONS: Eight treatment groups received 50, 125, 300, or 600 mg/wk of testosterone enanthate for 20 weeks plus placebo (4 groups) or 2.5 mg/d of dutasteride (4 groups). MAIN OUTCOME MEASURES: The primary outcome was change in fat-free mass; secondary outcomes: changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels. RESULTS: A total of 139 men were randomized; 102 completed the 20-week intervention. Men assigned to dutasteride were similar at baseline to those assigned to placebo. The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, -0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, -0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk. The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups. CONCLUSION: Changes in fat-free mass in response to graded testosterone doses did not differ in men in whom DHT was suppressed by dutasteride from those treated with placebo, indicating that conversion of testosterone to DHT is not essential for mediating its anabolic effects on muscle. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00493987.
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Inibidores de 5-alfa Redutase/farmacologia , Adiposidade/efeitos dos fármacos , Azasteroides/farmacologia , Força Muscular/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Adulto , Índice de Massa Corporal , Método Duplo-Cego , Dutasterida , Hematócrito , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Sebo/efeitos dos fármacos , Sebo/metabolismo , Testosterona/administração & dosagem , Testosterona/fisiologia , Resultado do TratamentoRESUMO
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (nâ=â871) and two de novo replication cohorts (nâ=â4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, pâ=â1.2×10(-41) and rs6258, pâ=â2.3×10(-22)). Subjects with ≥ 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (pâ=â5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
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Proteínas Nucleares/genética , Globulina de Ligação a Hormônio Sexual/genética , Testosterona/sangue , Adulto , Idoso de 80 Anos ou mais , Alelos , Índice de Massa Corporal , Cromossomos Humanos X/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
CONTEXT: Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. METHODS: TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. RESULTS: In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. CONCLUSION: Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.
Assuntos
Química Clínica/normas , Cromatografia Líquida/normas , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiologia , Espectrometria de Massas em Tandem/normas , Testosterona/sangue , Adulto , Estudos de Coortes , Humanos , Masculino , Massachusetts/epidemiologia , Prevalência , Valores de Referência , Características de Residência , Fatores de Risco , Adulto JovemRESUMO
CONTEXT: Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. METHODS: Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. RESULTS: Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. CONCLUSIONS: Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.
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Limitação da Mobilidade , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Testosterona/uso terapêutico , Idoso , Método Duplo-Cego , Teste de Esforço , Humanos , Masculino , PlacebosRESUMO
OBJECTIVE: With the progressive aging of the human population, there is an inexorable decline in muscle mass, strength and function. Anabolic supplementation with testosterone has been shown to effectively restore muscle mass in both young and elderly men. In this study, we were interested in identifying serum factors that change with age in two distinct age groups of healthy men, and whether these factors were affected by testosterone supplementation. METHODS: We measured the protein levels of a number of serum biomarkers using a combination of banked serum samples from older men (60 to 75 years) and younger men (ages 18 to 35), as well as new serum specimens obtained through collaboration. We compared baseline levels of all biomarkers between young and older men. In addition, we evaluated potential changes in these biomarker levels in association with testosterone dose (low dose defined as 125 mg per week or below compared to high dose defined as 300 mg per week or above) in our banked specimens. RESULTS: We identified nine serum biomarkers that differed between the young and older subjects. These age-associated biomarkers included: insulin-like growth factor (IGF1), N-terminal propeptide of type III collagen (PIIINP), monokine induced by gamma interferon (MIG), epithelial-derived neutrophil-activating peptide 78 (ENA78), interleukin 7 (IL-7), p40 subunit of interleukin 12 (IL-12p40), macrophage inflammatory protein 1ß (MIP-1ß), platelet derived growth factor ß (PDGFß) and interferon-inducible protein 10 (IP-10). We further observed testosterone dose-associated changes in some but not all age related markers: IGF1, PIIINP, leptin, MIG and ENA78. Gains in lean mass were confirmed by dual energy X-ray absorptiometry (DEXA). CONCLUSIONS: Results from this study suggest that there are potential phenotypic biomarkers in serum that can be associated with healthy aging and that some but not all of these biomarkers reflect gains in muscle mass upon testosterone administration.
RESUMO
Androgen receptor (AR) coregulators modulate ligand-induced gene expression in a tissue specific manner. The molecular events that follow coactivator binding to AR and the mechanisms that govern the sequence-specific effects of AR coregulators are poorly understood. Using consensus coactivator sequence D11-FxxLF and biophysical techniques, we show that coactivator association is followed by conformational rearrangement in AR ligand binding domain (AR-LBD) that is enthalpically and entropically favorable with activation energy of 29.8±4.2 kJ/mol. Further characterization of ARA70 and SRC3-1 based consensus sequences reveal that each coactivator induces a distinct conformational state in the dihydrotestosterone:AR-LBD:coactivator complex. Complementary computational modeling revealed that coactivator induced specific alterations in the backbone flexibility of AR-LBD distant from the site of coactivator binding and that the intramolecular rearrangements in AR-LBD backbone induced by the two coactivator peptides were different. These data suggest that coactivators may impart specificity in the transcriptional machinery by changing the steady-state conformation of AR-LBD. These data provide direct evidence that even in the presence of same ligand, AR-LBD can occupy distinct conformational states depending on its interactions with specific coactivators in the tissues. We posit that this coactivator-specific conformational gating may then dictate subsequent binding partners and interaction/affinity for the DNA-response elements.
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Coativadores de Receptor Nuclear/química , Peptídeos/química , Receptores Androgênicos/química , Animais , Sítios de Ligação , Simulação por Computador , Sequência Consenso , Transferência Ressonante de Energia de Fluorescência , Cinética , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Ratos , TermodinâmicaRESUMO
CONTEXT: The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown. OBJECTIVE: The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin. PARTICIPANTS: Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied. METHODS: Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders. RESULTS: High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels. CONCLUSION: Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.
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Peptídeos Catiônicos Antimicrobianos/sangue , Policitemia/induzido quimicamente , Testosterona/farmacologia , Adulto , Idoso , Envelhecimento/sangue , Envelhecimento/fisiologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Esquema de Medicação , Hepcidinas , Humanos , Injeções , Leuprolida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Testosterona/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS: Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS: A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)
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Doenças Cardiovasculares/induzido quimicamente , Testosterona/efeitos adversos , Administração Cutânea , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Teste de Esforço , Géis , Humanos , Hiperlipidemias/complicações , Hipertensão/complicações , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Força Muscular/efeitos dos fármacos , Obesidade/complicações , Fatores de Risco , Testosterona/sangue , Testosterona/deficiência , Testosterona/uso terapêutico , CaminhadaRESUMO
CONTEXT: Mobility limitation is associated with increased morbidity and mortality. The relationship between circulating testosterone and mobility limitation and physical performance is incompletely understood. OBJECTIVE: Our objective was to examine cross-sectional and prospective relations between baseline sex hormones and mobility limitations and physical performance in community-dwelling older men. DESIGN, SETTING, AND PARTICIPANTS: We conducted cross-sectional and longitudinal analyses of 1445 men (mean age 61.0 +/- 9.5 yr) who attended Framingham Offspring Study examinations 7 and 8 (mean 6.6 yr apart). Total testosterone (TT) was measured by liquid chromatography tandem mass spectrometry at examination 7. Cross-sectional and longitudinal analyses of mobility limitation and physical performance were performed with continuous (per SD) and dichotomized [low TT and free testosterone (FT) and high SHBG vs. normal] hormone levels. MAIN OUTCOME MEASURES: Self-reported mobility limitation, subjective health, usual walking speed, and grip strength were assessed at examinations 7 and 8. Short physical performance battery was performed at examination 7. RESULTS: Higher continuous FT was positively associated with short physical performance battery score (beta = 0.13; P = 0.008), usual walking speed (beta = 0.02; P = 0.048), and lower risk of poor subjective health [odds ratio (OR) = 0.72; P = 0.01]. In prospective analysis, 1 SD increase in baseline FT was associated with lower risk of developing mobility limitation (OR = 0.78; 95% confidence interval = 0.62-0.97) and progression of mobility limitation (OR = 0.75; 95% confidence interval = 0.60-0.93). Men with low baseline FT had 57% higher odds of reporting incident mobility limitation (P = 0.03) and 68% higher odds of worsening of mobility limitation (P = 0.007). CONCLUSIONS: Lower levels of baseline FT are associated with a greater risk of incident or worsening mobility limitation in community-dwelling older men. Whether this risk can be reduced with testosterone therapy needs to be determined by randomized trials.
Assuntos
Limitação da Mobilidade , Força Muscular/fisiologia , Testosterona/sangue , Adolescente , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Força da Mão/fisiologia , Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Razão de Chances , Equilíbrio Postural/fisiologia , Estudos Prospectivos , Globulina de Ligação a Hormônio Sexual/metabolismo , Espectrometria de Massas em Tandem , Caminhada/fisiologiaRESUMO
Ligand-induced conformational perturbations in androgen receptor (AR) are important in coactivator recruitment and transactivation. However, molecular rearrangements in AR ligand-binding domain (AR-LBD) associated with agonist binding and their kinetic and thermodynamic parameters are poorly understood. We used steady-state second-derivative absorption and emission spectroscopy, pressure and temperature perturbations, and 4,4'-bis-anilinonaphthalene 8-sulfonate (bis-ANS) partitioning to determine the kinetics and thermodynamics of the conformational changes in AR-LBD after dihydrotestosterone (DHT) binding. In presence of DHT, the second-derivative absorption spectrum showed a red shift and a change in peak-to-peak distance. Emission intensity increased upon DHT binding, and center of spectral mass was blue shifted, denoting conformational changes resulting in more hydrophobic environment for tyrosines and tryptophans within a more compact DHT-bound receptor. In pressure perturbation calorimetry, DHT-induced energetic stabilization increased the Gibbs free energy of unfolding to 8.4 +/- 1.3 kcal/mol from 3.5 +/- 1.6 kcal/mol. Bis-ANS partitioning studies revealed that upon DHT binding, AR-LBD underwent biphasic rearrangement with a high activation energy (13.4 kcal/mol). An initial, molten globule-like burst phase (k approximately 30 sec(-1)) with greater solvent accessibility was followed by rearrangement (k approximately 0.01 sec(-1)), leading to a more compact conformation than apo-AR-LBD. Molecular simulations demonstrated unique sensitivity of tyrosine and tryptophan residues during pressure unfolding with rearrangement of residues in the coactivator recruitment surfaces distant from the ligand-binding pocket. In conclusion, DHT binding leads to energetic stabilization of AR-LBD domain and substantial rearrangement of residues distant from the ligand-binding pocket. DHT binding to AR-LBD involves biphasic receptor rearrangement including population of a molten globule-like intermediate state.
Assuntos
Di-Hidrotestosterona/farmacologia , Receptores Androgênicos/química , Naftalenossulfonato de Anilina/farmacologia , Calorimetria/métodos , Humanos , Cinética , Ligantes , Pressão , Conformação Proteica , Estrutura Terciária de Proteína , Solventes/química , Temperatura , Termodinâmica , Fatores de Tempo , Tirosina/químicaRESUMO
CONTEXT: Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat. OBJECTIVES: We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men. DESIGN, SETTING, AND PARTICIPANTS: One hundred twenty-two community-dwelling men 70.8 +/- 4.2 yr of age with body mass index of 27.4 +/- 3.4 kg/m2, testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (< or =167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 microg/kg . d) for 16 wk. MAIN OUTCOME MEASURES: Body composition by dual-energy x-ray absorptiometry, muscle performance, and safety tests were conducted. RESULTS: Total lean body mass increased (1.0 +/- 1.7 to 3.0 +/- 2.2 kg) as did appendicular lean tissue (0.4 +/- 1.4 to 1.5 +/- 1.3 kg), whereas total fat mass decreased by 0.4 +/- 0.9 to 2.3 +/- 1.7 kg as did trunk fat (0.5 +/- 0.9 to 1.5 +/- 1.0 kg) across the six treatment groups and by dose levels for each parameter (P < or = 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 +/- 34 to 35 +/- 31% (P < 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 +/- 137 sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 +/- 14 and 8 +/- 8 mm Hg, respectively. Other predictable adverse events were modest and reversible. CONCLUSIONS: Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation.
Assuntos
Composição Corporal/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Músculos/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Testosterona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Exercício Físico/fisiologia , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Músculos/metabolismo , Músculos/fisiologia , Resistência Física/efeitos dos fármacos , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangueRESUMO
The Endocrine Society guideline on Androgen Deficiency in Men emphasized that accurate measurement of testosterone (T) levels is central to the diagnosis of androgen deficiency. Similarly, accurate measurements of testosterone levels are important in the diagnosis of androgen disorders in women and children. However, the accuracy of direct radioimmunoassays for the measurement of total T levels has been questioned, especially in the low range prevalent in women, children, and androgen deficient men. Furthermore, reference limits for total and free T levels generated in a population-based sample of community-dwelling men, women, and children are not available. In the absence of standardized reference limits, the partitioning of total and free T levels into normal, low, or high values is fraught with substantial risk of misclassification. The recommendations for partitioning of individuals into those with low, normal, or high levels should be based on considerations of statistical distribution of total and free T values and the association of outcomes with varying degree of deviations from the reference limits. Ongoing efforts to generate population-based reference ranges for total and free testosterone levels in men and women will provide a framework for the interpretation of serum T levels and enhance the comprehensibility of circulating T values to practicing clinicians. These steps will facilitate the development of rational criteria for the diagnosis of androgen disorders in men, women, and children.
Assuntos
Androgênios/deficiência , Doenças do Sistema Endócrino/diagnóstico , Testosterona/sangue , Testosterona/deficiência , Criança , Estudos Transversais , Tomada de Decisões , Feminino , Humanos , Imunoensaio , Masculino , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Experimental studies suggest that adipose inflammation is etiologically linked to obesity-induced systemic disease. Our goal was to characterize the state of inflammation in human fat in relation to vascular function and metabolic parameters in obese individuals. METHODS AND RESULTS: We collected subcutaneous abdominal fat in 77 obese subjects (BMI >or=30 kg/m(2)) and quantified adipose macrophage population using targeted immunohistochemistry. Brachial artery vasodilator function was examined using high-resolution vascular ultrasound. In 50 subjects, an inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures was associated with systemic hyperinsulinemia and insulin resistance (HOMA-IR 5.5+/-4.5 versus 2.6+/-1.9, P=0.002) and impaired endothelium-dependent flow-mediated vasodilation (8.5+/-4.4% versus 10.8+/-3.8%, P<0.05), as compared to subjects with quiescent noninflamed adipose architecture (n=27). Macrophage retention in fat was linked to upregulated tissue CD68 and tumor necrosis factor (TNF)-alpha mRNA expression in addition to increased plasma hs-CRP. CONCLUSIONS: In a cohort of obese subjects, we demonstrate that proinflammatory changes in adipose tissue are associated with systemic arterial dysfunction and insulin resistance. These findings suggest that adipose inflammation may be linked to vascular injury and increased cardiovascular risk in obese subjects.
Assuntos
Gordura Abdominal/imunologia , Endotélio Vascular/fisiopatologia , Resistência à Insulina , Macrófagos/imunologia , Obesidade/imunologia , Paniculite/imunologia , Vasodilatação , Gordura Abdominal/fisiopatologia , Adulto , Antígenos CD/análise , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/análise , Antígenos de Diferenciação Mielomonocítica/genética , Artéria Braquial/fisiopatologia , Proteína C-Reativa/análise , Estudos de Coortes , Endotélio Vascular/diagnóstico por imagem , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/fisiopatologia , Paniculite/diagnóstico por imagem , Paniculite/fisiopatologia , Fenótipo , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , UltrassonografiaRESUMO
Testosterone increases fat-free mass (FFM) in men infected with human immunodeficiency virus (HIV), but its effects on muscle performance, physical function, mood, and quality of life are poorly understood. Sixty-one HIV-infected men with weight loss were randomized to receive weekly intramuscular injections of 300 mg of testosterone enanthate or placebo for 16 wk. The primary outcome of interest was physical function (walking speed, stair-climbing power, and load-carrying ability). Secondary outcome measures included body weight and composition, muscle performance, sexual function, mood, and quality of life. Serum nadir free and total testosterone levels increased (+188.0 +/- 29.6 and +720 +/- 86 ng/dl) in the testosterone, but not placebo, group. Testosterone administration was associated with increased FFM (2.8 +/- 0.5 kg), which was significantly greater than in the placebo group (P < 0.0001). Leg press strength increased significantly in testosterone-treated (P = 0.027), but not placebo-treated, men; the difference between groups was not significant. Other measures of muscle performance and physical function did not change significantly in either group. Men receiving testosterone demonstrated significantly greater improvements in mental health and quality-of-life scores than those receiving placebo and improvements in fatigue/energy and mood scores that were not significantly different from those receiving placebo. Sexual function scores did not change in either group. In HIV-infected men with weight loss, a supraphysiological dose of testosterone significantly increased FFM but did not improve self-reported or performance-based measures of physical function. Improvements in mood, fatigue, and quality-of-life measures in the testosterone group, although clinically important, need further confirmation.