RESUMO
BACKGROUND: The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. OBJECTIVES: To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. METHODS: A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). RESULTS: Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. CONCLUSIONS: Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors.
Assuntos
Coração/fisiologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/sangue , Estudos de Coortes , Coração/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
There is substantial inter-individual variability in serum testosterone levels in hypogonadal men treated with testosterone gels. We aimed to elucidate participant-level factors that contribute to inter-individual variability in testosterone levels during testosterone therapy. An exploratory aim was to determine whether polymorphisms in genes encoding testosterone-metabolizing enzymes could explain the variation in on-treatment testosterone concentrations in men who were randomized to testosterone arm in TOM Trial. We used data from three randomized trials that used 1% transdermal testosterone gels and had testosterone levels measured 2-4 weeks after randomization for dose adjustment: Testosterone in Older Men with Mobility Limitation (TOM), Effects of Testosterone on Pain Perception (TAP), and Effects of Testosterone on Atherosclerosis Progression (TEAAM). Forty-seven percent, 38%, and 9% of participants in TAP, TEAAM, and TOM trials, respectively, failed to raise testosterone levels >400 ng/dL; 6, 8, and 30% of participants had on-treatment testosterone levels >1000 ng/dL. Even after dose adjustment, there was substantial variation in on-treatment levels at subsequent study visits. Baseline characteristics (age, height, weight, baseline testosterone, SHBG, hematocrit, and creatinine) accounted for only a small fraction of the variance (<8%). Polymorphisms in SHBG and AKR1C3 genes were suggestively associated with on-treatment testosterone levels. To conclude, baseline participant characteristics account for only a small fraction of the variance in on-treatment testosterone levels investigated. Multiple dose titrations are needed to maintain on-treatment testosterone levels in the target range. The role of SHBG and AKR3C1 polymorphisms as contributors to variations in on-treatment testosterone levels should be investigated.
Assuntos
Androgênios/administração & dosagem , Eunuquismo/tratamento farmacológico , Testosterona/administração & dosagem , Testosterona/sangue , Administração Cutânea , Adulto , Idoso , Membro C3 da Família 1 de alfa-Ceto Redutase/genética , Géis , Terapia de Reposição Hormonal/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Globulina de Ligação a Hormônio Sexual/genéticaRESUMO
In a subset of men, sarcopenia and physical dysfunction occur due to destabilization of the neuromuscular junction (NMJ), which is manifested by elevated serum concentrations of C-terminal agrin fragment (CAF). Testosterone administration improves physical function in some studies; however, its effects on serum circulating CAF concentrations remain unknown. Here we evaluate the effects of testosterone administration on circulating CAF levels in mobility-limited men with low testosterone aged 65 or older participating in the Testosterone in Older Men with Mobility Limitations (TOM) Trial. We analyzed the difference in change in serum CAF levels between testosterone and placebo groups, as well as its association with muscle strength and physical function. Association of change in serum CAF levels with serum total (TT) and free testosterone (FT) was also evaluated. Men randomized to testosterone experienced significant improvement in muscle strength and physical function (assessed by loaded stair-climbing power). However; testosterone administration was not associated with a reduction in serum CAF levels (effect size = -50.3 pm; 95% CI = -162.1 to 61.5 pm; p = 0.374); there was no association between changes in CAF levels with changes in TT (p = 0.670) or FT (p = 0.747). There was no association between changes in serum CAF levels with improvement in either muscle strength or stair-climbing power. In conclusion, testosterone treatment in mobility-limited older men with low to low-normal testosterone levels did not reduce serum CAF levels. Additionally, testosterone-induced improvements in muscle strength and physical function were not associated with changes in serum CAF concentrations. These findings suggest that improvement in physical function with testosterone replacement in older men with mobility limitations and elevated CAF levels is mediated by mechanisms other than stabilization of the NMJ.
Assuntos
Agrina/sangue , Androgênios/uso terapêutico , Limitação da Mobilidade , Fragmentos de Peptídeos/sangue , Sarcopenia/tratamento farmacológico , Testosterona/uso terapêutico , Idoso , Envelhecimento/patologia , Método Duplo-Cego , Humanos , Masculino , Força Muscular/efeitos dos fármacosRESUMO
Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose-response trial. Participants were young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose-dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles, 2.530 cm2 (1.627, 3.434) for total abdominal muscles, 0.455 cm2 (0.233, 0.678) for obturator internus, and 0.082 cm2 (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on-treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction.
Assuntos
Androgênios/administração & dosagem , Composição Corporal/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Testosterona/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pelve , Tronco , Adulto JovemRESUMO
OBJECTIVES: Nutrition impacts the development of sarcopenia and protein intake is an important modulator of skeletal muscle mass loss in older people. The Optimizing Protein Intake in Older Men with Mobility Limitation (OPTIMEN) Trial was designed to assess the independent and combined effects of higher protein intake and a promyogenic agent, testosterone, on lean body mass, muscle strength and physical function in older men with mobility disability. The purpose of this paper is to describe the experimental design and nutrition intervention, including techniques used by research dietitians to develop and deliver energy and protein-specific meals to the homes of community-dwelling participants. Strategies to enhance long-term dietary compliance are detailed. DESIGN: Randomized, double-blind, placebo-controlled six-month intervention trial. SETTING: Participants were recruited from Boston MA USA and surrounding communities. PARTICIPANTS: Older men who were mobility-limited (Short Physical Performance Battery (SPPB) 3-10) and consuming less protein (<0.83 g/kg/day) were recruited for this study. INTERVENTION: Here we report the successful implementation of a double-blind, placebo-controlled, parallel group, randomized controlled trial with a 6-month intervention period among community-living men, age 65 years and older with a mobility limitation. A controlled feeding plan was used to deliver required energy intakes and prescribed protein quantities of 0.8 or 1.3 grams/kilogram/day (g/kg/d) in three meals plus snacks and supplements. A 2x2 factorial design was used to assess the effects of protein level alone and in combination with testosterone (vs. placebo) on changes in lean body mass (primary outcome), muscle strength, and physical function. RESULTS: A total of 154 men met the eligibility criteria; 112 completed a 2-week run-in period designed to evaluate compliance with the nutrition intervention. Of these, 92 subjects met compliance eligibility criteria and agreed to be randomized; 85% completed the full trial. The study successfully delivered three meals per day to subjects, with a high degree of compliance and subject satisfaction. Overall self-reported compliance rates were 80% and 93% for the meals and supplements, respectively. Details of compliance strategies are discussed. CONCLUSION: This community-based study design may serve as a model for longer-term nutritional interventions requiring monitoring of dietary compliance in a home-based feeding and supplementation trial.
Assuntos
Ingestão de Energia/fisiologia , Limitação da Mobilidade , Estado Nutricional/fisiologia , Sarcopenia/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Humanos , MasculinoRESUMO
Animal data shows that testosterone administration increases the volume of some parenchymal organs. However, the effects of exogenous testosterone on solid abdominal organs in humans remain unknown. The present study evaluated the effects of testosterone administration on the volume of liver, spleen and kidneys in a dose-response trial. Young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone secretion and weekly injections of 50, 125, 300 or 600 mg of testosterone enanthate, and were randomized to receive either 2.5 mg dutasteride (5 α-reductase inhibitor) or placebo daily for 20 weeks. Liver, spleen and kidney volumes were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose-effect of testosterone on changes in the volume of parenchymal organs was evaluated by linear regression model. The association between changes in total testosterone (TT) levels and changes in organ volumes were assessed. Testosterone administration increased liver volume dose-dependently (17.4 cm3 per 100 mg of weekly testosterone enanthate; p = 0.031); the increase in liver volume was positively associated with changes in TT levels (R2 = 0.08, p = 0.024). A dose-dependent, but non-significant, increase in kidney volumes was also seen. Inclusion of dutasteride use into the models showed an independent association of randomization to dutasteride group with liver volume increase. In conclusion, Testosterone administration increased the liver volume in a dose-dependent manner. The potential changes in parenchymal organs should be considered when interpreting apparent changes in lean mass in response to anabolic interventions.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Baço/efeitos dos fármacos , Testosterona/análogos & derivados , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/administração & dosagem , Adulto , Composição Corporal , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Testosterona/administração & dosagem , Testosterona/farmacologia , Adulto JovemRESUMO
Testosterone (T) replacement is being increasingly offered to older men with age-related decline in testosterone levels. The effects of long-term testosterone replacement and aromatase inhibition (AI) on glucose homeostasis and cardiometabolic markers were determine in older non-diabetic men with low testosterone levels. Men ≥65 years, mean age 71 ± 3 years with serum total T < 350 ng/dL were randomized in a double-blind, placebo-controlled, parallel-group, proof-of-concept trial evaluating the effects of 5 g transdermal testosterone gel (TT) (n = 10), 1 mg anastrozole (n = 10) or placebo (n = 9) daily for 12 months. Homeostatic Model Assessment of insulin resistance (HOMAIR ) was the primary outcome. Secondary outcomes included OGIS in response to OGTT, fasting lipids, C-reactive protein (CRP), adipokines, and abdominal and mid-thigh fat by computed tomography. All outcomes were assessed at baseline and 12 months. After 12 months, absolute changes in HOMAIR in both treatment arms (TT group: -0.05 ± 0.21); (AI group: 0.15 ± 0.10) were similar to placebo (-0.11 ± 0.26), as were CRP and fasting lipid levels. Adiponectin levels significantly decreased in the TT group (-1.8 ± 0.9 mg/L, p = 0.02) and abdominal subcutaneous fat (-60.34 ± 3.19 cm2 , p = 0.003) and leptin levels (-1.5 ± 1.2 ng/mL, p = 0.04) were significantly lower with AI. Mid-thigh subcutaneous fat was reduced in both treatment arms (TT group: -4.88 ± 1.24 cm2 , p = 0.008); (AI group: -6.05 ± 0.87 cm2 , p = 0.0002). In summary, in this proof-of-concept trial, changes in HOMAIR AI were similar in all three groups while the effects of intervention on subcutaneous fat distribution and adipokines were variable. Larger efficacy and safety trials are needed before AI pharmacotherapy can be considered as a treatment option for low T levels in older men.
Assuntos
Inibidores da Aromatase/uso terapêutico , Glicemia/metabolismo , Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Resistência à Insulina/fisiologia , Testosterona/uso terapêutico , Gordura Abdominal/diagnóstico por imagem , Adipocinas/sangue , Idoso , Inibidores da Aromatase/farmacologia , Composição Corporal/fisiologia , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Humanos , Hipogonadismo/sangue , Hipogonadismo/diagnóstico por imagem , Insulina/sangue , Lipídeos/sangue , Masculino , Testosterona/deficiência , Testosterona/farmacologia , Resultado do TratamentoRESUMO
Aging in men is associated with loss of bone mass, impaired physical function and altered body composition. The objective of this proof-of-concept randomized, double-blind, placebo-controlled, parallel-group, single-center trial was to determine the relative effects of testosterone (T) and estradiol (E(2)) on bone mineral density, body composition, and physical performance in older men. The primary outcome was lumbar spine bone mineral density (BMD), and secondary outcomes were body composition, muscle strength, gait speed, and sex hormone concentrations. Forty three men (age range, 65-82 years; mean age 71 years) with low total T levels <350 ng/dL were randomized to one of three groups: 5 g transdermal testosterone gel (TT) (N = 16), anastrozole (AI) 1 mg (N = 14) or placebo daily (N = 13) for 12 months. Outcomes were assessed at baseline, 3, 6, and 12 months. Both TT and AI increased serum TT levels (>500 ng/dL, p < 0.05) compared to baseline; T values remained stable throughout the duration of the trial. At 12 months, TT improved the primary outcome of lumbar spine BMD (p < 0.01).Both interventions improved knee strength at 12 months compared to baseline (p < 0.05) while lean body mass significantly increased only in the AI group at 6 and 12 months (1.49 ± 0.38 kg, p < 0.01; 1.24 ± 0.39 kg, p < 0.05, respectively) compared to baseline. Interestingly, TT improved fast gait speed at 3 and 12 months (p < 0.01, p < 0.05, respectively). In summary, this proof-of-concept study confirms that aromatization of T is required for maintaining BMD in older men with low-T levels. The trial also uncovered the novel finding that aromatization of T is required for improvement in fast gait speed, an observation that needs to be verified in future studies.
Assuntos
Inibidores da Aromatase/uso terapêutico , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Nitrilas/uso terapêutico , Testosterona/sangue , Testosterona/uso terapêutico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Anastrozol , Aromatase/efeitos dos fármacos , Osso e Ossos/fisiologia , Método Duplo-Cego , Estradiol/sangue , Humanos , Masculino , PlacebosRESUMO
PURPOSE: To determine the dose-dependent effects of testosterone administration on cognition in women with low testosterone levels. METHODS: 71 hysterectomized women with or without oophorectomy with total testosterone <31 ng/dl and/or free testosterone <3.5 pg/ml received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly intramuscular injections of placebo, 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks. Total testosterone was measured in serum by LC-MS/MS, and free testosterone levels were measured by equilibrium dialysis. Cognitive function was evaluated using a comprehensive battery of standardized neuropsychological tests at baseline and 24 weeks. RESULTS: 46 women who had baseline and end-of-treatment cognitive function data constituted the analytic sample. The five groups were similar at baseline. Mean on-treatment nadir total testosterone concentrations were 15, 89, 98, 134, and 234 ng/dl in the placebo, 3, 6.25, 12.5, and 25 mg groups, respectively. No significant changes in spatial ability, verbal fluency, verbal memory, or executive function were observed in any treatment arm compared to placebo even after adjustment for baseline cognitive function, age, and education. Multiple regression analysis did not show any significant relation between changes in testosterone concentrations and change in cognitive function scores. CONCLUSION: Short-term testosterone administration over a wide range of doses for 24 weeks in women with low testosterone levels was neither associated with improvements nor worsening of cognitive function.
Assuntos
Cognição/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Histerectomia , Testosterona/metabolismo , Testosterona/farmacologia , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Estradiol/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Ovariectomia , Testosterona/administração & dosagem , Resultado do TratamentoRESUMO
Sex steroid hormones are associated with chronic diseases and mortality with risk associations that differ between racial and ethnic groups. However, it is currently unclear whether sex steroid hormone levels differ between black and white men. The aim of this study was to assess racial variation in circulating testosterone, free testosterone, sex hormone-binding globulin (SHBG) and estradiol levels in men. We searched PubMed for articles comparing circulating hormones in black and white men. A meta-analysis was performed using weighted mean differences (WMD) to compare hormones levels between black and white men. Fifteen eligible studies were identified; three did not report adjusted means. After age adjustment, free testosterone levels were significantly higher in black than in white men (WMD = 4.07 pg/mL, 95% CI 1.26, 6.88). Depending on the free testosterone concentration in white men, this WMD translates into a racial difference ranging from 2.5 to 4.9%. Total testosterone (WMD = 0.10 ng/mL, 95% CI -0.02, 0.22), estradiol (WMD = 0.67 pg/mL, 95% CI -0.04, 1.38) and SHBG (WMD = -0.45 nmol/L, 95% CI -1.75, 0.85) concentrations did not differ comparing blacks with whites. After adjustment for age, black men have a modestly but significantly 2.5 to 4.9% higher free testosterone level than white men. Based on previous studies on effects of sex steroid hormones on risk of chronic diseases or mortality, this modest difference is unlikely to explain racial differences in disease risk.
Assuntos
Negro ou Afro-Americano , Estradiol/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , População Branca , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Phosphodiesterase-5-inhibitors, such as sildenafil, increase intracavernosal cyclic guanosine monophosphate levels, which results in corporal smooth muscle relaxation and penile erection. Here, we determined the effects of sildenafil administration on the hypothalamic-pituitary-gonadal axis in men with erectile dysfunction and low testosterone levels. The Testosterone and Erectile Dysfunction trial (ClinicalTrials.gov # NCT00512707) initially administered an optimized dose of sildenafil to 140 men, aged 40-70 years with erectile dysfunction, low serum total testosterone (<11.4 nmol/L; 330 ng/dL) and/or free testosterone (<173 pmol/L; 50 pg/mL) over 3-7 weeks. Sex steroids and gonadotropins were measured at baseline and after sildenafil optimization in a longitudinal study without a separate control group. Serum testosterone, dihydrotestosterone (DHT) and oestrogens were measured using liquid chromatography-tandem mass spectrometry. Administration of an optimized dose of sildenafil was associated with mean increases of 3.6 nmol/L (103 ng/dL; p < 0.001) and 110 pmol/L (31.7 pg/mL; p < 0.001) in total and free testosterone levels respectively. This was accompanied by parallel increases in serum DHT (0.17 nmol/L; 4.9 ng/dL; p < 0.001) and oestradiol (14 pmol/L; 3.7 pg/mL; p < 0.001) and significant suppression of luteinizing hormone (change -1.3 units/L; p = 0.003) levels, suggesting a direct effect at the testicular level. Androstenedione and oestrone increased by 1.3 nmol/L (38 ng/dL; p = 0.011) and 10.7 pmol/L (2.9 pg/mL; p = 0.012), respectively, supporting a possible effect of sildenafil on adrenal steroidogenesis. In conclusion, sildenafil administration was associated with increased testosterone levels likely ascribable to a direct effect on the testis.
Assuntos
Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Testículo/efeitos dos fármacos , Testosterona/sangue , Adulto , Idoso , Androstenodiona/sangue , Di-Hidrotestosterona/sangue , Disfunção Erétil/sangue , Disfunção Erétil/tratamento farmacológico , Estradiol/sangue , Estrona/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Purinas/uso terapêutico , Citrato de SildenafilaRESUMO
The relationship between testosterone, well-being and mood is poorly understood. We investigated the effect of testosterone supplementation on mood, well-being, and self-reported health in men with erectile dysfunction (ED) and low serum testosterone levels. This was a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov registration number NCT00512707), in which 140 men, 40-70 years, with ED and low serum testosterone levels were first optimized on sildenafil alone for 3-7 weeks and then randomized to receive either sildenafil plus testosterone gel (n = 70) or sildenafil plus placebo (n = 70) gel for 14 weeks. Using multiple imputations and generalized linear regression, we compared psychological changes in well-being, evaluated by the Psychological General Well-Being Index, and mood, evaluated by Derogatis Affects Balance Scale. Mood and well-being scores were similar between the two groups at baseline and did not substantially change during the administration of sildenafil or after randomization to testosterone. Our findings show that the addition of testosterone to sildenafil in men with ED and low serum testosterone levels was not associated with improvement in either well-being or mood.
Assuntos
Afeto/efeitos dos fármacos , Disfunção Erétil/prevenção & controle , Testosterona/administração & dosagem , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Qualidade de Vida , Testosterona/farmacologiaRESUMO
Prostate cancer (PCa) is the most common malignancy in men. Androgen deprivation therapy (ADT) plays an important role in the management of locally advanced and metastatic PCa. Its use in combination with external beam radiation and as an adjuvant therapy has resulted in improved survival in a subset of patients with locally advanced disease. In men with metastatic disease, ADT results in improvement in pain and overall quality of life. In addition to these two clinical settings where ADT has proven benefits, it is also being increasingly used in patients experiencing biochemical recurrence and those with early stage localized disease, even though no survival advantage has been demonstrated. ADT has significant adverse effects such as sexual dysfunction, decreased lean mass, increased fat mass, decreased quality of life, anemia, and osteoporosis. Recently, insulin resistance, diabetes, and metabolic syndrome have emerged as complications of ADT. Some data also suggests that ADT might be responsible for incident cardiovascular disease. Since the majority of men with PCa die of conditions other than their malignancy, recognition and management of these adverse effects is important. This paper serves as a focused review of recent studies examining the metabolic abnormalities and cardiovascular disease related to ADT.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Qualidade de Vida , Humanos , Masculino , Neoplasias da Próstata/secundárioRESUMO
Classic male hypogonadism is associated with known adverse effects including decreased libido, erectile dysfunction, osteoporosis, and changes in body composition. Recently, we have come to appreciate that reduction in serum testosterone (T) levels resulting from aging or chronic disease or androgen deprivation therapy (ADT) have consequences similar to those seen in classic male hypogonadism which include increased fat mass, decreased lean body mass, decreased muscle strength, and sexual dysfunction. These data suggest that low T levels may represent a newly recognized cardiometabolic risk factor. Therefore, we carried out a careful review of the literature, focusing on major turning points of research and studies which gave more important and controversial contribution to the cardiovascular role of T. Observational studies and clinical trials investigating the relationship between T levels and cardiovascular disease and mortality were identified byMedline search. The results were synthesized, tabulated, and interpreted. The aim of this review is to discuss the association between low T levels and adverse metabolic profile such as insulin resistance, metabolic syndrome, and diabetes. We will also investigate the potential mechanisms by which male hypogonadism, especially age related or induced by ADT, may increase cardio-metabolic risk. Finally we will detail the emerging relationship between low T and mortality in men addressing also the reverse hypothesis that low T has a protective role by turning off T-dependent functions.
Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Hipogonadismo/complicações , Testosterona/deficiência , Adulto , Doenças Cardiovasculares/diagnóstico , Humanos , Hipogonadismo/sangue , Masculino , Fatores de Risco , Taxa de SobrevidaRESUMO
Association between androgens and erythropoiesis has been known for more than seven decades. Androgens stimulate hematopoietic system by various mechanisms. These include stimulation of erythropoietin release, increasing bone marrow activity and iron incorporation into the red cells. Before the discovery of recombinant erythropoietin (rhEpo), androgens were used in the treatment of anemia associated with renal disease, bone marrow suppression, and hypopituitarism. Anabolism is an additional advantage of androgen therapy. Furthermore, in light of recent reports regarding adverse effects of rhEpo, the role of androgen therapy in various types of anemias should be readdressed. Polycythemia remains a known side effect of androgen therapy. In this review, we will briefly discuss the initial animal and human studies which demonstrated the role of androgens in the treatment of anemia, their mechanism of action, a detailed account of the efficacy of androgens in the treatment of various anemias, the erythropoietic side effects of androgens and finally, the relationship between hematocrit levels and cardiovascular disease.
Assuntos
Androgênios/uso terapêutico , Eritropoese/efeitos dos fármacos , Envelhecimento/fisiologia , Androgênios/efeitos adversos , Androgênios/farmacologia , Anemia/tratamento farmacológico , Anemia Aplástica/tratamento farmacológico , Animais , Medula Óssea/efeitos dos fármacos , Doença das Coronárias/induzido quimicamente , Eritrócitos/metabolismo , Eritropoese/fisiologia , Eritropoetina/biossíntese , Feminino , Humanos , Ferro/sangue , Falência Renal Crônica/tratamento farmacológico , MasculinoRESUMO
Male hypogonadism now has a new spectrum of complications. They are mainly cardiometabolic in nature. Low serum testosterone levels are a risk factor for diabetes, metabolic syndrome, inflammation and dyslipidemia. These metabolic and inflammatory complications are not without consequences. Recent studies have shown low serum testosterone levels to be an independent risk factor of cardiovascular and all-cause mortality. It is time to welcome low serum testosterone levels as a cardiovascular risk factor.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Testosterona/sangue , Aterosclerose/sangue , Biomarcadores , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/sangue , Humanos , Hiperlipidemias/sangue , Inflamação/sangue , Masculino , Síndrome Metabólica/sangue , Fatores de Risco , Testosterona/deficiênciaRESUMO
CONTEXT: Recent interventional studies indicate that post-menopausal hormone replacement therapy is associated with an increased risk of cardiovascular mortality and breast cancer. Isoflavones, a class of plant estrogens, have structural similarities to estradiol. Hence, isoflavones may exert beneficial estrogenic health effects in postmenopausal women with fewer adverse effects. OBJECTIVE: To evaluate the effect of high-dose isoflavones on self-reported quality of life (QOL), cognition, lipoproteins and androgen status in post-menopausal women. DESIGN AND SUBJECTS: Double-blind, randomized, placebo-controlled, 12-week trial of 93 healthy, ambulatory, post-menopausal women (mean age 56 yr). The study was conducted at a tertiary care center in the United States. INTERVENTION: Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). Both soy and the placebo were provided in the form of a powder to be mixed with beverages. MAIN OUTCOME MEASURES: QOL was judged by the Menopause-specific Quality of Life (MENQOL) questionnaire while cognitive function was assessed with standard instruments. Total, free, and bioavailable testosterone, gonadotropins, SHBG, and fasting lipids were measured. RESULTS: Eighty-four women (90%) completed the study (active=38, placebo=46). There was a significant improvement in all 4 QOL subscales (vasomotor, psychosexual, physical, and sexual) among the women taking isoflavones, while no changes were seen in the placebo group. No significant changes in cognition, serum androgens or plasma lipids were seen within any of the groups. However, at the end of the study, a group-by-time interaction was observed such that total testosterone and HDL levels were significantly lower in the isoflavones compared to placebo groups. CONCLUSION: High-dose isoflavones is associated with improved QOL among women who have become menopausal recently. Hence, the timing of isoflavone supplementation with regards to the onset of menopause appears to be important. The use of isoflavones, as an alternative to estrogen therapy, may be potentially useful and seemingly safe in this group of women who are looking for relief from menopausal symptoms.
Assuntos
Androgênios/sangue , Cognição/efeitos dos fármacos , Isoflavonas/farmacologia , Lipoproteínas/sangue , Qualidade de Vida , Idoso , Método Duplo-Cego , Feminino , Humanos , Isoflavonas/administração & dosagem , Isoflavonas/efeitos adversos , Pessoa de Meia-Idade , Pós-Menopausa/efeitos dos fármacos , Proteínas de Soja/administração & dosagemRESUMO
SHBG is a major carrier of androgens. In men, SHBG levels increase with age, while in women data are scant. There is evidence that body mass index (BMI) and fasting insulin influence SHBG concentration. Since low SHBG levels are predictors of insulin resistance and diabetes, understanding the relationship of SHBG with age, insulin, and BMI is important to gain insight into the role of SHBG as a cardiovascular risk factor in women. Differences in SHBG across adult life span and their relationship with insulin and BMI were evaluated in a representative cohort of 616 Italian women free of diabetes and not on hormone replacement therapy enrolled in the InCHIANTI Study. The relationship of SHBG with age, BMI, and fasting insulin levels was analyzed using linear regression and by loess smoother. Serum SHBG levels showed a U-shaped trajectory with age, declining from the 2nd to the 6th decade of life and increasing after the 6th decade (p<0.0001). Age-related trends for BMI and fasting insulin mirrored the trend observed for SHBG. After adjusting for fasting insulin, the relationship between log (SHBG) and age square was attenuated (beta coefficient from 0.00044 to 0.00039) and was further reduced after adjustment for BMI (from 0.00039 to 0.00028). SHBG levels show an age-related U-shaped trajectory. These changes mirror the age-related changes in BMI and fasting insulin, suggesting that BMI and insulin negatively influence SHBG concentration.
Assuntos
Envelhecimento/fisiologia , Índice de Massa Corporal , Insulina/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Adulto JovemRESUMO
Sex steroids are known to modulate serum lipoproteins. Studies have suggested that serum testosterone levels are associated with a beneficial lipid profile. Androgen deprivation therapy (ADT) is employed in the treatment of recurrent and metastatic prostate cancer (PCa), resulting in profound hypogonadism. As male hypogonadism unfavorably influences lipid profile and men with PCa have high cardiovascular mortality, we evaluated the effects of long-term ADT on fasting lipids. This Cross-sectional study was conducted in a university-based research institution. We evaluated 44 men, 16 undergoing ADT for at least 12 months before the study (ADT group), 14 age-matched eugonadal men with non-metastatic PCa who were status post prostatectomy and/or radiotherapy and not on ADT (non-ADT group) and 14 age-matched eugonadal controls (Control group). None of the men had known history of diabetes or dyslipidemia. Mean age was similar in the three groups (P = 0.37). Serum total (P < 0.01) and free (P < 0.01) testosterone levels were lower in the ADT group compared to the other groups. Men on ADT had higher body mass index (BMI) compared to the other groups (P < 0.01). Men in the ADT group had significantly higher levels of total cholesterol compared to the other two groups (P = 0.03). After adjustment for BMI, men on ADT continued to have significantly higher fasting levels of total cholesterol (P = 0.02), LDL cholesterol (P = 0.04) and non-HDL cholesterol (P = 0.03) compared to the control group. No significant differences were seen in the levels of other lipoproteins between the three groups. These data show that men undergoing long-term ADT have higher total and LDL cholesterol than age-matched controls. Long-term prospective studies are needed to determine the time of onset of changes in these lipoproteins while on ADT and the influence of these changes on cardiovascular mortality.