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ABSTRACT: In young men (defined as age <50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or testes, testosterone replacement therapy induces a number of beneficial effects, for example, the development of secondary sex characteristics, improvement and maintenance of sexual function, and increases in skeletal muscle mass and BMD. Moreover, testosterone treatment in this patient population is associated with a low frequency of adverse events. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life, owing to defects at all levels of the hypothalamic-pituitary-testicular axis. In cohort studies, testosterone levels are associated weakly but consistently with muscle mass, strength, physical function, anaemia, BMD and bone quality, visceral adiposity, and with the risk of diabetes mellitus, coronary artery disease, falls, fractures and mortality. However, the clinical benefits and long-term risks of testosterone therapy-especially prostate-related and cardiovascular-related adverse events-have not been adequately assessed in large, randomized clinical trials involving older men (defined as age >65 years) with androgen deficiency. Therefore, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified.
Nature Reviews Endocrinology 04/2013; · 9.97 Impact Factor
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Annals of internal medicine 04/2013; 158(7):570-1. · 16.73 Impact Factor
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Wen Guo,
Eric Bachman,
Michelle Li,
Cindy N Roy,
Jerzy Blusztajn,
Siu Wong,
Stephen Y Chan,
Carlo Serra,
Ravi Jasuja, Thomas G Travison,
Martina U Muckenthaler,
Elizabeta Nemeth,
Shalender Bhasin
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ABSTRACT: Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferring saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound (58) Fe, the amount of (58) Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to BMP-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. Conclusion: Testosterone inhibits hepcidin transcription through its interaction with BMP-Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Aging cell 02/2013; · 7.55 Impact Factor
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ABSTRACT: BACKGROUND: Androgen receptor (AR) knockout male mice display hepatic steatosis, suggesting that AR signaling may regulate hepatic fat. However, the effects of testosterone replacement on hepatic fat in men are unknown. The aim of this study was to determine the effects of testosterone administration on hepatic fat in older men with mobility limitation and low testosterone levels who were participating in a randomized trial (the Testosterone in Older Men trial). METHODS: Two hundred and nine men with mobility limitation and low total or free testosterone were randomized in the parent trial to either placebo or 10-g testosterone gel daily for 6 months. Hepatic fat was determined by magnetic resonance imaging in 73 men (36 in placebo and 37 in testosterone group) using the volumetric method. Insulin sensitivity (homeostatic model assessment-insulin resistance) was derived from fasting glucose and insulin. RESULTS: Baseline characteristics were similar between the two groups, including liver volumes (1583±363 in the testosterone group vs 1522±271mL in the placebo group, p = .42). Testosterone concentrations increased from 250±72 to 632±363ng/dL in testosterone group but did not change in placebo group. Changes in liver volume during intervention did not differ significantly between groups (p = .5) and were not related to on-treatment testosterone concentrations. The change in homeostatic model assessment-insulin resistance also did not differ significantly between groups and was not related to either baseline or change in liver fat. CONCLUSION: Testosterone administration in older men with mobility limitation and low testosterone levels was not associated with a reduction in hepatic fat. Larger trials are needed to determine whether testosterone replacement improves liver fat in men with nonalcoholic hepatic steatosis.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 01/2013; · 4.60 Impact Factor
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Matthew Spitzer,
Shehzad Basaria, Thomas G Travison,
Maithili N Davda,
Amanda Paley,
Beth Cohen,
Norman A Mazer,
Philip E Knapp,
Samson Hanka,
Kishore M Lakshman,
Jagadish Ulloor,
Anqi Zhang,
Katie Orwoll,
Richard Eder,
Lauren Collins,
Nurahmed Mohammed,
Raymond C Rosen,
Leonard Derogatis,
Shalender Bhasin
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ABSTRACT: Erectile dysfunction and low testosterone levels frequently occur together.
To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels.
Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707)
Outpatient academic research center.
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).
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.
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.
Whether testosterone could improve erectile function without sildenafil was not studied.
Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels.
National Institute of Child Health and Human Development.
Annals of internal medicine 11/2012; 157(10):681-91. · 16.73 Impact Factor
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Guneet Kaur Jasuja, Thomas G Travison,
Maithili Davda,
Joanne M Murabito,
Shehzad Basaria,
Anqi Zhang,
Mark M Kushnir,
Alan L Rockwood,
Wayne Meikle,
Michael J Pencina,
Andrea Coviello,
Adam J Rose,
Ralph D'Agostino,
Ramachandran S Vasan,
Shalender Bhasin
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ABSTRACT: BACKGROUND: Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone-binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study. METHODS: Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation. RESULTS: There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m(2)). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others. CONCLUSIONS: Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 10/2012; · 4.60 Impact Factor
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ABSTRACT: 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.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2012; · 4.60 Impact Factor
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Shalender Bhasin, Thomas G Travison,
Thomas W Storer,
Kishore Lakshman,
Manas Kaushik,
Norman A Mazer,
Ahn-Hoa Ngyuen,
Maithili N Davda,
Hernan Jara,
Adam Aakil, [......],
Anqi Zhang,
Brad Brooks,
Katie Orwoll,
Leife Hede-Brierley,
Richard Eder,
Ayan Elmi,
Geeta Bhasin,
Lauren Collins,
Ravinder Singh,
Shehzad Basaria
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ABSTRACT: 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.
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).
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.
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).
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.
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.
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.
clinicaltrials.gov Identifier: NCT00493987.
JAMA The Journal of the American Medical Association 03/2012; 307(9):931-9. · 30.03 Impact Factor
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ABSTRACT: Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.
Asian Journal of Andrology 03/2012; 14(2):204-21. · 1.52 Impact Factor
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ABSTRACT: Our objective was to investigate cross-sectional and longitudinal associations of sex hormone concentrations with ankle-brachial index (ABI) and peripheral arterial disease (PAD).
We used data from 3034 (1612 women) participants of the Framingham Heart Study. ABI was measured and PAD defined as ABI below 0.90, intermittent claudication, or lower extremity revascularization. Sex hormone concentrations were measured by liquid chromatography-tandem mass spectrometry [total testosterone (T), total estradiol, and estrone], immunofluorometric assay (SHBG), or calculated (free T). Sex-specific multivariable linear and logistic regression models were conducted for each sex hormone separately. Cross-sectional multivariable analyses revealed that men with lower free T and higher estrone (E1) concentrations had a significantly lower ABI [for free T, lowest vs. higher quartiles, β = -0.02, with 95% confidence interval (CI) = -0.04 to -0.001; and for E1, highest vs. lower quartiles, β = -0.02, with 95% CI = -0.04 to -0.002, respectively). Lower total T and SHBG concentrations were also associated with prevalent PAD in age-adjusted [odds ratio (OR) = 2.24, 95% CI = 1.17-4.32; and OR = 2.06; 95% CI = 1.07-3.96, lowest vs. highest quartile, respectively), but not in multivariable logistic regression models. Longitudinal multivariable analyses showed an association of lower SHBG with ABI change (decline ≥ 0.15; n = 69) in men [OR for SHBG quartiles 1, 2, and 3 as compared with quartile 4 were 2.56 (95% CI = 1.01-6.45), 2.28 (95% CI = 0.98-5.32), and 2.93 (95% CI = 1.31-6.52), respectively]. In women, none of the investigated associations yielded statistically significant estimates.
Our investigation of a middle-aged community-based sample suggests that sex hormone concentrations in men but not in women may be associated with PAD and ABI change.
The Journal of clinical endocrinology and metabolism 09/2011; 96(12):3724-32. · 6.50 Impact Factor
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ABSTRACT: The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone-binding globulin (SHBG) is independently associated with the risk of metabolic syndrome.
Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography-tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components.
SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.
Diabetes care 09/2011; 34(11):2464-70. · 8.09 Impact Factor
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ABSTRACT: Erectile dysfunction (ED) is thought to affect some 150 million men worldwide, but many men with ED symptoms do not seek treatment. Existing surveys suggest that men with severe ED and who report support from their partners are more likely to receive treatment than were others. Less is known, however, concerning the influence of sociomedical factors such as income and body composition on receipt of treatment.
The aim of this study was to determine the importance of socioeconomic status, comorbidities, and body composition on receipt of treatment for ED symptoms.
We used data on 638 men enrolled in the Boston Area Community Health (BACH) survey reporting ED symptoms and/or treatment for ED as evidenced by phosphodiesterase type 5 inhibitor (PDE5i) use. Logistic regression was employed to assess the relative strength of association between receipt of treatment and socioeconomic factors, body mass index, and medical factors. A replication of these results was then provided via a parallel model using the 2004 follow-up of the Men's Attitudes to Life Events and Sexuality (MALES).
In BACH, ED was deemed present if a subject scored 16 points or fewer on the five-item International Index of Erectile Function or reported PDE5i use. In MALES, presence of ED was indicated by use of a validated single question querying ED severity.
Controlling for age, body composition and other factors, increased household income, availability of a sexual partner, and provider diagnosis of high blood pressure were positively associated with treatment seeking via the use of PDE5i therapy in BACH. Results on data available in MALES produced similar results for household income and partner availability.
These data provide evidence that financial disadvantage may present a barrier to treatment of ED, an increasingly important sentinel marker of the cardiovascular and overall health among aging men.
Journal of Sexual Medicine 08/2011; 8(11):3051-7. · 3.55 Impact Factor
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Thomas G Travison,
Shehzad Basaria,
Thomas W Storer,
Alan M Jette,
Renee Miciek,
Wildon R Farwell,
Karen Choong,
Kishore Lakshman,
Norman A Mazer,
Andrea D Coviello, [......],
Ayan Elmi,
Erica Appleman,
Leife Hede-Brierley,
Geeta Bhasin,
Ashmeet Bhatia,
Antonio Lazzari,
Samuel Davis,
Pengsheng Ni,
Lauren Collins,
Shalender Bhasin
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ABSTRACT: 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.
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.
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.
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.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2011; 66(10):1090-9. · 4.60 Impact Factor
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Shalender Bhasin,
Michael Pencina,
Guneet Kaur Jasuja, Thomas G Travison,
Andrea Coviello,
Eric Orwoll,
Patty Y Wang,
Carrie Nielson,
Frederick Wu,
Abdelouahid Tajar,
Fernand Labrie,
Hubert Vesper,
Anqi Zhang,
Jagadish Ulloor,
Ravinder Singh,
Ralph D'Agostino,
Ramachandran S Vasan
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ABSTRACT: 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.
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.
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.
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.
The Journal of clinical endocrinology and metabolism 06/2011; 96(8):2430-9. · 6.50 Impact Factor
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ABSTRACT: Using the Massachusetts Male Aging Study (MMAS) data from the years 1987-1995, we previously demonstrated high rates of both progression (33%) and regression (35%) of self-reported severity of erectile dysfunction (ED). These results have not been replicated using more recent data-relevant in light of the introduction of phosphodiesterase type 5 inhibitors (PDE5i) to treat ED-nor compared with those from other populations.
To estimate age-specific progression and regression of ED severity among subjects with at least mild self-reported ED.
We used the two most recent data collection waves from the MMAS (baseline in 1995-1997 and follow-up in 2002-2004, approximately 7 years of follow-up) and data from the Men's Attitudes to Life Events and Sexuality (MALES) study (baseline in 2001 and follow-up in 2004, approximately 3 years of follow-up); 367 MMAS and 617 MALES subjects contributed data. MMAS participants were a population-based sample of men living in Boston, Massachusetts, United States. MALES subjects were obtained from a multinational convenience sample.
ED was measured using the validated single-question self-report of ED severity ("none,"minimal,"moderate," or "complete"). ED progression was defined as worsening of ED over time, whereas regression was defined as a lessening of ED severity. Logistic regression analyses were adjusted for age, body mass index (MMAS only), and use of PDE5i.
In MMAS and MALES, 21% (confidence interval [CI]: 17%, 25%) and 25% (22%, 29%) of subjects, respectively, exhibited regression; 51% (45%, 57%) in MMAS and 28% (23%, 33%) in MALES exhibited ED progression. A minority of subjects (14% in MMAS and 28% in MALES) reported use of PDE5i. The proportion of subjects reporting progression increased with age. The higher rate of progression in MMAS may be due in part to the shorter follow-up time (∼3 years) in MALES.
Among subjects with some level of self-reported ED, progression and regression are common over a several-year period. Strategies for therapy and intervention for ED should acknowledge this basic evolution with time.
Journal of Sexual Medicine 05/2011; 8(7):1917-24. · 3.55 Impact Factor
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Carlo Serra,
Shalender Bhasin,
Frances Tangherlini,
Elisabeth R Barton,
Michelle Ganno,
Anqi Zhang,
Janet Shansky,
Herman H Vandenburgh, Thomas G Travison,
Ravi Jasuja,
Carl Morris
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ABSTRACT: Testosterone (T) supplementation increases skeletal muscle mass, circulating GH, IGF-I, and im IGF-I expression, but the role of GH and IGF-I in mediating T's effects on the skeletal muscle remains poorly understood. Here, we show that T administration increased body weight and the mass of the androgen-dependent levator ani muscle in hypophysectomized as well as castrated plus hypophysectomized adult male rats. T stimulated the proliferation of primary human skeletal muscle cells (hSKMCs) in vitro, an effect blocked by transfecting hSKMCs with small interference RNA targeting human IGF-I receptor (IGF-IR). In differentiation conditions, T promoted the fusion of hSKMCs into larger myotubes, an effect attenuated by small interference RNA targeting human IGF-IR. Notably, MKR mice, which express a dominant negative form of the IGF-IR in skeletal muscle fibers, treated with a GnRH antagonist (acyline) to suppress endogenous T, responded to T administration by an attenuated increase in the levator ani muscle mass. In conclusion, circulating GH and IGF-I are not essential for mediating T's effects on an androgen-responsive skeletal muscle. IGF-I signaling plays an important role in mediating T's effects on skeletal muscle progenitor cell growth and differentiation in vitro. However, IGF-IR signaling in skeletal muscle fibers does not appear to be obligatory for mediating the anabolic effects of T on the mass of androgen-responsive skeletal muscles in mice.
Endocrinology 11/2010; 152(1):193-206. · 4.46 Impact Factor
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ABSTRACT: During testosterone (T) therapy, T is partly converted to 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown.
We evaluated age and dose-related differences in E2 and DHT levels in response to graded doses of testosterone enanthate in young and older men.
Fifty-one young (aged 19-35 yr) and 52 older (aged 59-75 yr) men completed treatment with monthly injections of a GnRH agonist plus randomly assigned weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg) for 5 months.
During testosterone administration, total and free E2 levels increased dose-dependently (dose effect, P<0.001) in both young and older men. Total and free E2 levels and E2:T ratios during T administration were higher in older than young men, but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels, percentage fat mass, and SHBG. DHT levels and DHT:T ratios were dose-related but did not differ between young and older men. Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics. The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase, independent of age. The Vmax parameter for E2 was 40% higher in older men than younger men, but Vmax for DHT was not significantly different between age groups.
During im testosterone administration, E2 and DHT levels exhibit saturable increases with dose. The rate of whole body aromatization is higher in older men, partly related to their higher percentage fat mass, SHBG, and testosterone levels.
The Journal of clinical endocrinology and metabolism 08/2010; 95(8):3955-64. · 6.50 Impact Factor
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Shehzad Basaria,
Andrea D Coviello, Thomas G Travison,
Thomas W Storer,
Wildon R Farwell,
Alan M Jette,
Richard Eder,
Sharon Tennstedt,
Jagadish Ulloor,
Anqi Zhang, [......],
Brad Brooks,
Erica Appleman,
Sheetal Aggarwal,
Geeta Bhasin,
Leif Hede-Brierley,
Ashmeet Bhatia,
Lauren Collins,
Nathan LeBrasseur,
Louis D Fiore,
Shalender Bhasin
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ABSTRACT: 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.
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.
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.
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.)
New England Journal of Medicine 07/2010; 363(2):109-22. · 53.30 Impact Factor
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ABSTRACT: The CAG repeat polymorphism in the androgen receptor, denoted (CAG)n, is thought to (inversely) index androgen sensitivity. We hypothesized that (CAG)n would exhibit a modifying influence on the association between circulating total and calculated free testosterone (TT and FT) and physical frailty in aging men.
The objective of the study was to establish the influence of (CAG)n on the relation between circulating TT, FT, LH, SHBG, and frailty.
This was a prospective cohort study of health and endocrine functioning in randomly selected men, with a baseline (T1: 1987-89) and two follow-up (T2: 1995-1997; T3: 2002-2004) visits.
This was an observational study of men residing in greater Boston, MA.
A total of 624 subjects aged 50-86 yr were retained.
The frailty phenotype was measured at T3. Components included weight loss, exhaustion, low physical activity, weakness, and slowness. Subjects exhibiting two of these five components were considered to be in an intermediate state, and those exhibiting three or more were considered frail.
(CAG)n was positively associated with TT and FT. Multivariable regression analyses revealed no influence of CAG on longitudinal within-subject changes in hormone levels or cross-sectional (T3) associations between hormone concentrations and the prevalence of intermediate frailty or frailty. Models incorporating subjects' history of hormone decline produced similar negative results.
This population-based study does not support the hypothesis that interindividual differences in (CAG)n can account for a lack of association between circulating androgens and the frailty phenotype. Longitudinal analyses are needed to confirm these conclusions.
The Journal of clinical endocrinology and metabolism 06/2010; 95(6):2746-54. · 6.50 Impact Factor
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ABSTRACT: This study was designed to determine whether erectile dysfunction (ED) predicts cardiovascular disease (CVD) beyond traditional risk factors.
Both ED and CVD share pathophysiological mechanisms and often co-occur. It is unknown whether ED improves the prediction of CVD beyond traditional risk factors.
This was a prospective, population-based study of 1,709 men (of 3,258 eligible) age 40 to 70 years. The ED data were measured by self-report. Subjects were followed for CVD for an average follow-up of 11.7 years. The association between ED and CVD was examined using the Cox proportional hazards regression model. The discriminatory capability of ED was examined using C statistics. The reclassification of CVD risk associated with ED was assessed using a method that quantifies net reclassification improvement.
Of the prospective population, 1,057 men with complete risk factor data who were free of CVD and diabetes at baseline were included. During follow-up, 261 new cases of CVD occurred. We found ED was associated with CVD incidence controlling for age (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.05 to 1.90), age and traditional CVD risk factors (HR: 1.41, 95% CI: 1.05 to 1.90), as well as age and Framingham risk score (HR: 1.40, 95% CI: 1.04 to 1.88). Despite these significant findings, ED did not significantly improve the prediction of CVD incidence beyond traditional risk factors.
Independent of established CVD risk factors, ED is significantly associated with increased CVD incidence. Nonetheless, ED does not improve the prediction of who will and will not develop CVD beyond that offered by traditional risk factors.
Journal of the American College of Cardiology 01/2010; 55(4):350-6. · 14.16 Impact Factor
