ACE inhibitors for sarcopenia--as good as exercise training? Correlates of low testosterone in men with chronic spinal cord injury Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men Prevalence of symptomatic androgen deficiency in men. Testosterone therapy increases sexual desire in ageing men with low–normal testosterone levels and symptoms of androgen deficiency Addressing Dichotomous Data for Participants Excluded from Trial Analysis: A Guide for Systematic Reviewers Oral testosterone undecanoate (Andriol®) supplement therapy improves the quality of life for men with testosterone deficiency Randomized placebo‐controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status. Cardiorespiratory Fitness in Childhood and Adolescence Affects Future Cardiovascular Risk Factors: A Systematic Review of Longitudinal Studies A conversation with Joseph Lau. Lower endogenous androgens predict central adiposity in men. Effect of vitamin D supplementation on inflammation: protocol for a systematic review Interrelation between plasma testosterone and plasma insulin in healthy adult men: the Telecom Study A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men.
10 . Nair N , Oka RK , Waring LD et al. Vascular compliance versus flow-mediated dilatation : correlation with cardiovascular risk factors . Vasc Med 2005 ; 10 : 275–83 . 11 . Wilkinson IB , MacCallum H , Cockcroft JR et al. Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo . Br J Clin Pharmacol 2002 ; 53 : 189–92 . 12 . Stewart AD , Millasseau SC , Kearney MT et al. Effects of inhibition of basal nitric oxide synthesis on carotid-femoral pulse wave velocity and augmentation index in humans . Hypertension 2003 ; 42 : 915–8 . 13 . Bulpitt CJ , Rajkumar C , Cameron JD . Vascular compliance as a measure of biological age . J Am Geriatr Soc 1999 ; 47 : 657–63 . 14 . Rossouw JE . Risks and benefits of estrogen plus progestin in healthy postmenopausal women : principal results From the Women ’s Health Initiative r and omized controlled trial . JAMA 2002 ; 288 : 321–33 . 15 . Haddad RM , Kennedy CC , Caples SM et al.  Testosterone and cardiovascular risk in men : a systematic review and meta analysis of r and omized placebo-controlled trials . Mayo Clin Proc 2007 ; 82 : 29–39 . 16 . Lane HA , Grace F , Smith JC et al. Impaired vasoreactivity in bodybuilders using and rogenic anabolic steroids . Eur J Clin Invest 2006 ; 36 : 483–8 . 17 . McCredie RJ , McCrohon JA , Turner L et al. Vascular reactivity is impaired in genetic females taking high-dose and rogens . J Am Coll Cardiol 1998 ; 32 : 1331–5 . 18 . Ong PJL , Patrizi G , Chong WCF et al. Testosterone enhances flow-mediated brachial artery reactivity in men with coronary artery disease . Am J Cardiol 2000 ; 85 : 269–72 . 19 . Dockery F , Bulpitt CJ , Agarwal S et al. Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia . Clin Sci 2003 ; 104 : 195–201 . 20 . Swartz CM , Young MA . Low serum testosterone and myocardial infa rct ion in geriatric male in patients . J Am Geriatr Soc 1987 ; 35 : 39–44 . 21 . Phillips GB , Pinkernell BH , Jing TY . The association of hypotestosteronaemia with coronary artery disease in men . Arterioscler Thromb 1994 ; 14 : 701–6 . 22 . Webb CM , Elkington AG , Kraidly MM et al. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease . Am J Cardiol 2008 ; 101 : 618–24 , Epub 2007 Dec 21 . 23 . English KM , Steeds RP , Jones TH et al. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina : a r and omized , double-blind , placebocontrolled study . Circulation 2000 ; 102 : 1906–11 . 24 . Ishihara F , Hiramatsu K , Shigematsu S et al. Role of adrenal and rogens in the development of arteriosclerosis as judged by pulse wave velocity and calcification of the aorta . Cardiology 1992 ; 80 : 332–8 . 25 . Hougaku H , Fleg JL , Najjar SS et al. Relationship between and rogenic hormones and arterial stiffness , based on longitudinal hormone measurements . Am J Physiol Endocrinol Metab 2006 ; 290 : E234–42 . 26 . Perheentupa A , Huhtaniemi I. Does the and ropause exist ? Nat Clin Pract Endocrinol Metab 2007 ; 3 : 670–1 . 27 . Emmelot-Vonk MH , Verhaar HJ , Nakhai Pour HR et al. Effect of testosterone supplementation on functional mobility , cognition , and other parameters in older men : a r and omized controlled trial . JAMA 2008 ; 299 : 39–52 . 28 . Isidori AM , Giannetta E , Greco EA et al. Effects of testosterone on body composition , bone metabolism and serum lipid profile in middle-aged men : a meta- analysis . Clin Endocrinol 2005 ; 63 : 280–93 Although high rates of serum testosterone deficiency have been reported in men with spinal cord injury ( SCI ) , its determinants and attributes are not yet established . The aim of this study was to recognize , among putative determinants and attributes of and rogen deficiency , those significantly associated to low testosterone after adjustment for confounders recognizable in men with chronic SCI . A biochemical and rogen deficiency ( total testosterone < 300 ng/dL ) was exhibited by 18 of 51 patients ( 35.3 % ) . Significant correlates of testosterone levels were as follows : weekly leisure time physical activity ( LTPA )  explored by the LTPA Question naire for people with SCI , body mass index ( BMI ) , homeostatic model assessment of insulin resistance ( HOMA‐IR ) , triglycerides and sexual symptoms , explored by the aging males ' symptom ( AMS ) question naire . At the multiple linear regression analysis , among putative determinants of low testosterone , only weekly LTPA and BMI exhibited a significant association with testosterone levels , explaining 54.2 and 9.0 % of testosterone variability respectively . At the linear regression models , among various putative attributes of and rogen deficiency , only lower sexual desire and , at a lesser extent , higher HOMA‐IR , exhibited significant associations with lower testosterone levels , after adjustment for BMI , age , comorbidities and weekly LTPA . In conclusion , poor LTPA , high BMI and low sexual desire are independent predictors of low testosterone in men with chronic SCI . This is relevant to clinical practice , as all these features are routinely assessed in rehabilitation setting s for SCI . As poor LTPA and high BMI are modifiable life‐style related risk factors , prospect i ve studies could clarify whether life‐style modification could increase the level of testosterone and improve the low sexual desire , relevant clinical attribute of low testosterone in men with SCI Abstract Symptomatic and rogen deficiency is common in patients taking opioid analgesics , as these drugs potently suppress the hypothalamic – pituitary – gonadal axis . However , the efficacy of testosterone replacement in this setting remains unclear . The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other and rogen-dependent outcomes in men with opioid-induced and rogen deficiency . We conducted a r and omized , double-blind , parallel placebo-controlled trial at an outpatient academic research center . Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain , and total testosterone levels were < 350 ng/dL. Participants were r and omly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo . Primary outcomes were changes in self-reported clinical pain and objective ly assessed pain sensitivity . Sexual function , quality of life , and body composition were also assessed . The mean age was 49 years . The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm , respectively . Of the 84 r and omized participants , 65 had follow-up data on efficacy outcomes . Compared with men assigned to the placebo arm , those assigned to testosterone replacement experienced greater improvements in pressure and mechanical hyperalgesia , sexual desire , and role limitation due to emotional problems . Testosterone administration was also associated with an improvement in body composition . There were no between-group differences in changes in self-reported pain . In conclusion , in men with opioid-induced and rogen deficiency , testosterone administration improved pain sensitivity , sexual desire , body composition , and aspects of quality of life The objective of this study was to assess the effects of oral testosterone supplementation therapy on glucose homeostasis , obesity and sexual function in middle-aged men with type 2 diabetes and mild and rogen deficiency . Forty-eight middle-aged men , with type 2 diabetes , ( visceral ) obesity and symptoms of and rogen deficiency , were included in this open-label study . Twenty-four subjects received testosterone undecanoate ( TU ; 120 mg daily , for 3 months ) ; 24 subjects received no treatment .  Body composition was analyzed by bio-impedance . Parameters of metabolic control were determined . Symptoms of and rogen deficiency and erectile dysfunction were scored by self-administered question naires . TU had a positive effect on ( visceral ) obesity : statistically significant reduction in body weight ( 2.66 % ) , waist-hip ratio ( -3.96 % ) and body fat ( -5.65 % ) ; negligible changes were found in the control group . TU significantly improved metabolic control : decrease in blood glucose values and mean glycated hemoglobin ( HbA1c ) ( from 10.4 to 8.6 % ) . TU treatment significantly improved symptoms of and rogen deficiency ( including erectile dysfunction ) , with virtually no change in the control group . There were no adverse effects on blood pressure or hematological , biochemical and lipid parameters , and no adverse events . Oral TU treatment of type 2 diabetic men with and rogen deficiency  improves glucose homeostasis and body composition ( decrease in visceral obesity ) , and improves symptoms of and rogen deficiency ( including erectile dysfunction ) . In these men , the benefit of testosterone supplementation therapy exceeds the correction of symptoms of and rogen deficiency and also includes glucose homeostasis and metabolic control Objective —Because male sex is an independent risk factor for the severity of atherosclerosis , it is possible that and rogens may be proatherogenic . There is evidence that sex hormones , particularly estrogens , regulate ( or modulate ) inflammation , a process integral to atherogenesis . Because levels of serum inflammatory markers predict cardiovascular outcomes , we prospect ively assessed the effects of and rogen therapy on these markers in older men . Methods and Results —Levels of high-sensitivity C-reactive protein ( CRP ) , soluble intracellular adhesion molecule-1 ( sICAM-1 ) , and soluble vascular cell adhesion molecule-1 ( sVCAM-1 ) were measured from sera collected at baseline and at the end of 2 r and omized double-blind placebo-controlled trials evaluating the effects of 3 months of and rogen treatment with either dihydrotestosterone ( DHT ) or recombinant human chorionic gonadotropin ( rhCG ) in healthy men aged > 60 years with partial and rogen deficiency ( serum testosterone levels < 15 nmol/L ) . For the DHT study ( 70 mg transdermally daily ) , 33 men completed 3 months of treatment ( 16 men were treated with DHT , and there were 17 controls ) . For the rhCG ( 250 & mgr;g twice weekly ) study , 20 men were treated with rhCG , and there were 20 controls . In both studies , groups were well matched for age and vascular risk factors . And rogen levels ( DHT and testosterone ) were consistently maintained at eugonadal levels throughout the trials , with estradiol markedly increased by rhCG but not DHT .  Baseline CRP levels were 0.74 to 1.49 mg/L , sVCAM-1 levels were 847 to 950 ng/mL , and sICAM-1 levels were 256 to 292 ng/mL in all groups . Neither DHT nor rhCG result ed in significant changes in CRP , sVCAM-1 , or sICAM-1 compared with placebo ( P > 0.3 in both studies ) . Conclusions —Exogenous and rogen therapy with or without increased estradiol levels does not alter serum inflammatory markers in older men ; this finding is in contrast to the effects of estrogens on inflammatory markers that have been found in postmenopausal women . These data provide a measure of reassurance concerning potential adverse cardiovascular effects of and rogen therapy in older men CONTEXT Despite recognition that and rogen deficiency in men should be defined according to biochemical and clinical criteria , most prevalence estimates are based on low testosterone levels alone . OBJECTIVE The objective of this study was to examine the association between symptoms of and rogen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic and rogen deficiency in men . DESIGN This study was a population -based , observational survey . PARTICIPANTS A total of 1,475 Black , Hispanic , and white men , between the ages of 30 - 79 yr , with complete data on testosterone , SHBG , and symptoms of and rogen deficiency , and who are not taking medications that impact sex steroid levels were r and omly selected from the Boston Area Community Health Survey . OUTCOME Outcomes were measured as symptomatic and rogen deficiency , defined as low total ( < 300 ng/dl ) and free ( < 5 ng/dl ) testosterone plus presence of low libido , erectile dysfunction , osteoporosis or fracture , or two or more of following symptoms : sleep disturbance , depressed mood , lethargy , or diminished physical performance . RESULTS Mean age of the sample was 47.3 + /- 12.5 yr . Approximately 24 % of subjects had total testosterone less than 300 ng/dl , and 11 % of subjects had free testosterone less than 5 ng/dl . Prevalence of symptoms were as follows : low libido ( 12 % ) , erectile dysfunction ( 16 % ) , osteoporosis/fracture ( 1 % ) , and two or more of the nonspecific symptoms ( 20 % ) . Low testosterone levels were associated with symptoms , but many men with low testosterone levels were asymptomatic ( e.g. in men 50 + yr , 47.6 % ) . Crude prevalence of symptomatic and rogen deficiency was 5.6 % ( 95 % confidence interval : 3.6 % , 8.6 % ) , and was not significantly related to race and ethnic group . Prevalence was low in men less than 70 yr ( 3.1 - 7.0 % ) and increased markedly with age to 18.4 % among 70 yr olds . Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30 - 79 yr with symptomatic and rogen deficiency , an increase of 38 % from 2000 population estimates . CONCLUSIONS Prevalence of symptomatic and rogen deficiency in men 30 and 79 yr of age is 5.6 % and increases substantially with age . The aging of the U.S. male population will cause a large increase in the burden of symptomatic and rogen deficiency . Future work should address the clinical significance of low testosterone levels in asymptomatic men Although decline in sexual function is a common reason for ageing men to seek advice regarding testosterone therapy , placebo-controlled trial data have been unable to show a consistent , beneficial role for testosterone . The objective of this study was to determine the effect of testosterone therapy on sexual function in non-obese ageing men with symptoms of and rogen deficiency and low – normal serum testosterone levels . A total of 60 men aged 55 years or older in good general health with total testosterone ( TT ) levels < 15 nM , and with symptoms suggestive of and rogen deficiency , were r and omized in a double-blinded protocol to transdermal testosterone patches or placebo for 12 months  . Sexual function was assessed using the International Index of Erectile Function at weeks 0 , 26 and 52 . In men receiving testosterone TT levels increased by 30 % ( P=0.01 ) and luteinizing hormone decreased by 50 % ( P<0.001 ) . Relative to placebo , testosterone therapy improved sexual desire ( P=0.04 ) ; however other parameters of sexual function including erectile function were unaffected by the treatment . Ageing men in good general health and with symptoms of and rogen deficiency and low – normal serum testosterone levels receiving 12 months of transdermal testosterone therapy experienced , relative to placebo , improved sexual desire but no effect on other parameters of sexual function Introduction Systematic review er authors intending to include all r and omized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data . Objective The objective of this paper is to provide systematic review er authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of r and omized trials . Methods This guide is based on a review of the Cochrane h and book and published method ological research . The guide deals with participants excluded from the analysis who were considered ‘ non-adherent to the protocol ’ but for whom data are available , and participants with missing data . Results Systematic review er authors should include data from ‘ non-adherent ’ participants excluded from the primary study authors ' analysis but for whom data are available . For missing , unavailable participant data , authors may conduct a complete case analysis ( excluding those with missing data ) as the primary analysis . Alternatively , they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data . When the primary analysis suggests important benefit , sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis . The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta- analysis . The proposed guide does not take into account the uncertainty associated with assumed events . Conclusions This guide proposes methods for h and ling participants excluded from analyses of r and omized trials . These methods can help in establishing the extent to which risk of bias impacts meta- analysis results In a single-blind , placebo-controlled study , the effects of a 3-month oral administration of 160 mg/day testosterone undecanoate ( And riol ® ) on the quality of life of men with testosterone deficiency were evaluated . The subjects included ten men with primary hypogonadism and 29 with and ropause with sexual dysfunction as the most common problem . The changes in subjective symptoms were evaluated by the PNUH QoL scoring system and the St. Louis University Question naire for and rogen deficiency in aging males ( ADAM ) . Digital rectal examination ( DRE ) was performed and serum testosterone , prostate-specific antigen ( PSA ) and liver profile were monitored . Testosterone undecanoate treatment ( n = 33 ) significantly improved sexual dysfunction and symptom scores of metabolic , cardiopulmonary , musculo-skeletal and gastrointestinal functions compared to baseline and to placebo ( n = 6 ) . ADAM score also significantly improved after 3 months of treatment . Serum testosterone was significantly increased compared to pretreatment levels only in the testosterone undecanoate group . In the placebo group , no significant changes compared to baseline were found for testosterone levels and QoL question naires . No abnormal findings were detected on DRE or laboratory findings in either group . Adverse events , such as gastrointestinal problems and fatigue , were mild and self-limiting . It is concluded that and rogen supplement therapy with oral testosterone undecanoate ( And riol ) restores the quality of life through improvement of general body functions in men with testosterone deficiency OBJECTIVE Testosterone deficiency is associated with significant morbidity , and and rogen replacement in overt hypogonadism is clearly beneficial . However , there are few data concerning the response to therapy in young men with mild testosterone deficiency BACKGROUND Testosterone in Older Men with Mobility Limitations Trial found an increased incidence of  cardiovascular events in men r and omized to testosterone  , result ing in enrollment cessation by trial 's Data and Safety Monitoring Board . We evaluated changes in gonadal hormones and markers of inflammation and coagulation to eluci date 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 r and omized 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 r and omized ( 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 National Institutes of Health 's consensus conference ( 1 ) defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture . Bone strength reflects the integration of two main features : bone density and bone quality .Bone quality refers to architecture , turnover , damage accumulation ( e.g. , microfractures ) , and mineralization . Although osteoporosis can affect any bone , the hip , spine , and wrist are most likely to be affected . Osteoporosis affects an estimated 44 million Americans or 55 % of people 50 years of age or older . Another 34 million Americans are estimated to have low bone mass , meaning that they are at an increased risk for osteoporosis . Osteoporosis can be diagnosed by the occurrence of fragility fracture . In patients without fragility fracture , osteoporosis is often diagnosed by low bone density .  Dual x-ray absorptiometry ( DXA ) is the current gold st and ard test for diagnosing osteoporosis in people without an osteoporotic fracture .  Dual x-ray absorptiometry results are scored as st and ard deviations ( SDs ) from a young healthy norm ( usually female ) and reported as T-scores . For example , a T-score of 2 indicates a bone mineral density that is 2 SDs below the comparative norm . The international reference st and ard for the description of osteoporosis in postmenopausal women and in men age 50 years or older is a femoral neck bone mineral density of 2.5 SD or more below the young female adult mean ( 2 ) . Low bone density , as measured by DXA , is an imperfect predictor of fracture risk , identifying fewer than half the people who go on to have an osteoporotic fracture . Screening guidelines for women are well established ( 3 ) , and the American College of Physicians ( ACP ) recently published guidelines on screening for men ( 4 ) . This guideline presents the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis . Medications used to treat osteoporosis may affect different parts of the skeletal system differently , and efficacy for vertebral fractures does not necessarily imply efficacy for nonvertebral fractures . The target audience for this guideline is all clinicians and the target patient population is all adult men and women with low bone density or osteoporosis . These recommendations are based on the systematic evidence review by MacLean and colleagues ( 5 ) and the Agency for Healthcare Research and Quality sponsored Southern California Evidence -Based Practice Center evidence report ( 6 ) . The drugs currently approved for prevention of osteoporosis include alendronate , ib and ronate , risedronate , zoledronic acid , estrogen , and raloxifene . The drugs currently approved for treatment of osteoporosis include alendronate , ib and ronate , risedronate , calcitonin , teriparatide , zoledronic acid ( in postmenopausal women ) , and raloxifene . Testosterone , pamidronate , and etidronate are not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Methods The literature search done by MacLean and colleagues for the systematic review ( 5 ) included studies from MEDLINE ( 1966 to December 2006 ) , the ACP Journal Club data base , the Cochrane Central Register of Controlled Trials ( no date limits ) , the Cochrane Data base of Systematic Review s ( no date limits ) , Web sites of the United Kingdom National Institute of Health and Clinical Excellence ( no date limits ) , and the United Kingdom Health Technology Assessment Program ( January 1998 to December 2006 ) . The review ers limited their search to English- language publications and human studies . They derived evidence for comparative benefits of various treatments exclusively from r and omized , controlled trials , whereas they included evidence from other types of studies for short- and long-term harms . Two physicians independently abstract ed data about study population s , interventions , follow-up , and outcome ascertainment by using a structured form . For each group within a r and omized trial , a statistician extracted the sample size and number of persons reporting fractures . Two review ers , under the supervision of the statistician , independently abstract ed information about adverse events . The statistician or the principal investigator resolved disagreements . This guideline is based on an evaluation of 76 r and omized , controlled trials , 4 of which were identified in the up date d search , and 24 meta-analyses that were included in the efficacy analyses . The analyses of adverse events included 491 articles , representing 417 r and omized trials , 25 other controlled clinical trials , 11 open-label trials , 31 large observational studies , and 9 case reports of osteonecrosis among bisphosphonate users . MacLean and colleagues ' background article ( 5 ) includes details about the methods used for the systematic evidence review . The ACP rates the evidence and recommendations by using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) system with minor modifications ( Table 1 ) . In addition , the evidence review ers used predefined criteria to assess the quality of systematic review s and r and omized trials , based on internal and external validity assessment s detailed in the Quality of Reporting of Meta-Analyses ( QUOROM ) statement ( 7 ) . Table 1 . The American College of Physicians ' Guideline Grading System The objective of this guideline is to synthesize the evidence for the following questions : What are the comparative benefits in fracture reduction among and also within the following treatments for low bone density :  bisphosphonates , specifically alendronate , risedronate , etidronate , ib and ronate , pamidronate , and zoledronic acid ; calcitonin ; estrogen for women ; teriparatide ; selective estrogen receptor modulators ( SERMs ) , specifically raloxifene and tamoxifen ; testosterone for men ; vitamins and minerals , specifically vitamin D and calcium ; and the combination of calcium plus vitamin D ? How does fracture reduction result ing from treatments vary among individuals with different risks for fracture as determined by bone mineral density ( borderline , low , or severe ) , previous fractures ( prevention vs. treatment ) , age , sex , glucocorticoid use , and other factors ( such as community-dwelling vs. institutionalized or vitamin Ddeficient vs. not ) ? What are the short- and long-term harms ( adverse effects ) of these therapies , and do these vary by specific sub population s ? Comparative Benefits of Drugs versus Placebo in Fracture Reduction Evidence from 24 meta-analyses ( 830 ) and 35 additional r and omized trials published after the meta-analyses ( 3165 ) described the effect of 9 of the 14 agents ( alendronate , etidronate , risedronate , calcitonin , estrogen , teriparatide , raloxifene , calcium , and vitamin D ) on fracture incidence . For 4 agents ( ib and ronate , pamidronate , zoledronic acid , and tamoxifen ) , the review ers found no meta-analyses and instead gathered the evidence from 14 r and omized trials ( 6679 ) . No studies were found that reported fracture rates for testosterone . Three r and omized trials ( 35 , 80 , 81 ) and 1 meta- analysis ( 82 ) evaluated the combination of calcium plus vitamin D  on fractures .  Bisphosphonates Good- quality evidence showed that alendronate , etidronate , ib and ronate , and risedronate prevent vertebral fractures . In addition , evidence from good- quality studies demonstrated that both alendronate and risedronate prevent nonvertebral and hip fractures . Two large r and omized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk population s and reduces the risk for hip fracture ( 67 , 74 ) . Ib and ronate has not been shown to reduce nonvertebral fractures ( 68 ) . Of the 6 fairly small trials that looked at vertebral fractures , 1 demonstrated a statistically significant reduction in fractures with pamidronate relative to placebo ( 0.14 [ 95 % CI , 0.03 to 0.72 ] ) ( 73 ) . However , after these data were pooled , the pooled risk estimate for fractures for pamidronate relative to placebo was not significant ( 0.52 [ CI , 0.21 to 1.24 ] ) ( 6 ) . Calcitonin Fair- quality evidence shows that calcitonin reduces vertebral fractures ( 83 , 84 ) . Good- quality evidence indicates that calcitonin does not reduce nonvertebral fractures ( 13 , 16 ) . Estrogen Good- quality evidence shows that estrogen reduces the incidence of vertebral ( 29 , 85 ) , nonvertebral ( 86 ) , and hip fractures ( 85 ) . Teriparatide Good- quality evidence shows that teriparatide prevents vertebral fractures . The evidence related to teriparatide preventing nonvertebral fractures is mixed ; 1 large r and omized trial showed a reduction in nonvertebral fractures ( 34 ) but 2 small trials did not ( 87 , 88 ) . SERMs Good- quality evidence shows that raloxifene prevents vertebral fractures , but that tamoxifen has no effect on vertebral fractures ( 8991 ) . In addition , both raloxifene and tamoxifen had no effect on hip fractures ( 91 ) . Tamoxifen is not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Testosterone No studies reported fracture rates for testosterone . Calcium and Vitamin D In the studies evaluated by MacLean and colleagues ( 5 ) , the evidence for the effect of calcium alone on reduction of fractures is complex . Most studies of pharmacologic agents for osteoporosis include calcium and vitamin D as part of the treatment regimen . Evidence from 1 meta- analysis ( 27 ) and several r and omized trials ( 35 , 48 , 51 , 92 ) showed no significant difference between calcium and placebo in preventing vertebral , nonvertebral , and hip fractures in postmenopausal women . However , nonadherence to therapy may influence this result , and 1 trial with a prespecified analysis of adherent patients found a reduction in fracture risk ( 48 ) . A recent meta- analysis ( 82 ) concluded that the relative risk ( RR ) for fracture with calcium alone was 0.90 ( CI , 0.80 to 1.00 ) , but it did not include a modestly large trial with negative results ( 35 ) . MacLean and colleagues ( 5 ) CONTEXT Risk factors for low testosterone and symptomatic and rogen deficiency ( AD ) may be modifiable . OBJECTIVE Our objective was to examine demographic , anthropometric , and medical correlates of low testosterone and symptomatic AD . DESIGN Data were used from the Boston Area Community Health Survey , an epidemiological study conducted from 2002 - 2005 . SETTING Data were obtained from a community-based r and om sample of racially and ethnically diverse men . PATIENTS OR OTHER PARTICIPANTS Data were available for 1822 men . MAIN OUTCOME MEASURES Multivariate logistic regression  was used to estimate odds ratios ( OR ) and 95 % confidence intervals ( CI ) for associations of covariates with 1 ) low testosterone and 2 ) symptomatic AD . The operational definition of low testosterone was serum total testosterone less than 300 ng/dl and free testosterone less than 5 ng/dl ; symptomatic AD was defined as the additional presence of symptoms : any of low libido , erectile dysfunction , or osteoporosis or two or more of sleep disturbance , depressed mood , lethargy , or diminished physical performance . RESULTS Factors associated with low testosterone included age ( OR = 1.36 ; 95 % CI= 1.11 - 1.66 , per decade ) , low per-capita income ( $ 6000 or less per household member vs. more than $ 30,000 ; OR = 2.86 ; 95 % CI = 1.39 - 5.87 ) , and waist circumference ( per 10-cm increase ; OR = 1.75 ; 95 % CI = 1.45 - 2.12 ) . Only age ( OR = 1.36 ; 95 % CI = 1.04 - 1.77 ) , waist circumference ( OR = 1.88 ; 95 % CI = 1.44 - 2.47 ) , and health status ( OR = 0.21 ; 95 % CI = 0.05 - 0.92 , excellent vs. fair/poor ) were associated with our construct of symptomatic AD . Of all variables , waist circumference was the most important contributor in both models . CONCLUSIONS Waist circumference is a potentially modifiable risk factor for low testosterone and symptomatic AD . Manifestation of symptoms may be a consequence of generally poor health status Testosterone has immune-modulating properties , and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha , IL-1beta , and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10 . We report a r and omized , single-blind , placebo-controlled , crossover study of testosterone replacement ( Sustanon 100 ) vs. placebo in 27 men ( age , 62 + /- 9 yr ) with symptomatic and rogen deficiency ( total testosterone , 4.4 + /- 1.2 nmol/liter ; bioavailable testosterone , 2.4 + /- 1.1 nmol/liter ) . Compared with placebo , testosterone induced reductions in TNFalpha ( -3.1 + /- 8.3 vs. 1.3 + /- 5.2 pg/ml ; P = 0.01 ) and IL-1beta ( -0.14 + /- 0.32 vs. 0.18 + /- 0.55 pg/ml ; P = 0.08 ) and an increase in IL-10 ( 0.33 + /- 1.8 vs. -1.1 + /- 3.0 pg/ml ; P = 0.01 ) ; the reductions of TNFalpha and IL-1beta were positively correlated ( r(S ) = 0.588 ; P = 0.003 ) . In addition , a significant reduction in total cholesterol was recorded with testosterone therapy ( -0.25 + /- 0.4 vs. -0.004 + /- 0.4 mmol/liter ; P = 0.04 ) . In conclusion , testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol .  Twenty of these men had established coronary disease , and because total cholesterol is a cardiovascular risk factor , and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque , these properties may have particular relevance in men with overt vascular disease BACKGROUND Relative and rogen deficiency in ageing males is assumed to have adverse health effects . This study assessed the effect of 12 months ' st and ard dose , oral testosterone , on symptoms attributed to testosterone deficiency in older men with plasma testosterone levels in the low-normal range for young men . METHODS Testosterone undecanoate ( TU , 80 mg bid ) or placebo was administered for one year to 76 healthy men , 60 years or older , with a free testosterone index ( FTI ) of 0.3 - 0.5 and significant symptoms on a question naire design ed to evaluate and rogen deficiency ( ADAM ) . The ADAM was completed at baseline , 6 and 12 months . Hormone and safety data were collected at baseline , 1 , 3 , 6 and 12 months . RESULTS After 12 months , plasma total testosterone was unchanged in both groups and sex hormone binding globulin decreased in the testosterone group ( P = 0.01 ) . FTI and calculated bioavailable testosterone ( cBT ) were greater in the testosterone group as compared with the placebo group ( P = 0.021 and 0.025 , respectively ) . There was no significant difference in total symptom score between testosterone and placebo groups after 12 months of oral TU . However , there were trends toward improvements in sadness/grumpiness ( P = 0.063 ) , reduced erection strength ( P = 0.059 ) and decreased work performance symptoms ( P = 0.077 ) , particularly in men with baseline cBT levels below 3.1 nmol/l . CONCLUSIONS This study concludes that 80 mg bid oral TU does not improve overall ADAM question naire scores  in older men with low-normal gonadal status . Oral TU may preserve mood and erectile function , as assessed by this question naire , particularly in men with the lowest testosterone levels Background Although cardiorespiratory fitness ( CRF ) in childhood and adolescence may be linked to future cardiovascular health , there is currently limited evidence for a longitudinal association . Objectives To provide a systematic review on the prospect i ve association between CRF in childhood and adolescence and cardiovascular disease ( CVD ) risk factors at least 2 years later . Methods Using a systematic search of Medline , Embase , and SPORTD iscus , relevant articles were identified by the following criteria : generally healthy children and adolescents between 3 and 18 years of age with CRF assessed at baseline , and a follow-up period of ≥ 2 years . The outcome measures were CVD risk factors . We appraised quality of the included articles with STROBE and QUIPS checklists . Results After screening 7524 titles and abstract s , we included 38 articles , assessing 44,169 children and adolescents followed up for a median of 6 years . Eleven articles were of high quality . There was considerable heterogeneity in methodology , measurement of CRF , and outcomes , which hampered meta- analysis . In approximately half of the included articles higher CRF in childhood and adolescence was associated with lower body mass index ( BMI ) , waist circumference , body fatness and lower prevalence of metabolic syndrome in later life . No associations between CRF in childhood and adolescence and future waist-to-hip ratio , blood pressure , lipid profile , and glucose homeostasis were observed . Conclusion Although about half of the included articles reported inverse associations between CRF in childhood and adolescence and future BMI , body fatness , and metabolic syndrome , evidence for other CVD risk factors was unconvincing . Many articles did not account for important confounding factors such as adiposity . Recommendations for future research include st and ardizing the measurement of CRF , i.e. by reporting VO2max , using st and ardized outcome assessment s , and performing individual patient data meta-analyses Dr. Joseph Lau is a world-leading expert in meta- analysis and systematic review s. Currently a professor in the Department of Health Services , Policy and Practice and co-director of the Center for Evidence -based Medicine at Brown University , Professor Lau has applied evidence -based methods to a variety of clinical , biomedical and healthcare topics ; has developed reliable and efficient methods and tools to conduct systematic review s and meta-analyses ; and has advanced an underst and ing on the impact of factors that may contribute to differences of results in scientific studies . His past research includes cumulative meta- analysis of r and omized controlled trials , comparison of results from large trials and meta-analyses of small trials , effect of baseline risk in the interpretation of clinical trial results , and empirical evaluation of existing methods of combining data . His current focus is on a Web-based repository of systematic review data , review s of diagnostic tests , nutrition , clinical practice guidelines , and dissemination of evidence -based methods to varied health-care disciplines . This report is a conversation from an adapted version of an interview , more or less chronologically arranged , between Joseph C. Cappelleri as interviewer and Joseph Lau as interviewee , with Meghan Ingerick recording and transcribing the interview Central adiposity , sometimes described as male pattern fat distribution , is adversely related to cardiovascular risk and mortality independent of other measures of obesity . In a cohort of 511 men aged 30 to 79 years in 1972 to 1974 , levels of and rostenedione , testosterone , and sex hormone-binding globulin measured at baseline were inversely related to subsequent central adiposity , estimated 12 years later using the waist-hip circumference ratio . The observed differences in waist-hip ratio between top and bottom tertiles of these hormones and sex hormone-binding globulin were similar to mean waist-hip ratio differences between men with stroke or ischemic heart disease and those without in another prospect i ve study . These findings , consistent with studies suggesting that testosterone seems to mobilize the abdominal depot on males , suggest that " male pattern " fat distribution may be a misleading description for central adiposity , at least , in men . Degree of maleness as indicated by total and rogen levels is , in fact , negatively associated with central adiposity . However , the role of sex hormone-binding globulin in regulating and rogenic activity warrants further investigation Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 Summary Plasma insulin is a risk factor for diabetes mellitus and cardiovascular disease in men . We investigated the association between  plasma testosterone and plasma insulin  in an occupational sample of 1292 healthy adult men .  Total plasma testosterone  decreased with each decade of age and insulin increased with each decade of age . In these cross-sectional data , this significant grade d inverse association between testosterone and insulin was independent of age . The association was reduced but not explained by the addition of obesity and subscapular skinfold to the model . Adjustment for alcohol consumption , cigarette smoking and plasma glucose did not material ly alter the association . These results are the reverse of the positive association of and rogens with insulin in women and suggest alternative possible explanations for the effect of hyperinsulinaemia on cardiovascular disease risk . Prospect i ve studies will be necessary to determine the direction and causal nature of this association The efficacy and safety of and rogen supplementation in older men remains controversial . Despite biochemical evidence of partial and rogen deficiency in older men , controlled studies using T demonstrate equivocal benefits . Furthermore , the importance of aromatization and 5alpha reduction in and rogen actions among older men remains unclear . Dihydrotestosterone is the highest potency natural and rogen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction . Therefore , the effects of dihydrotestosterone may differ from those of T in older men . This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength , mobility , and quality of life in ambulant , community-dwelling men aged 60 yr or older . Eligible men ( plasma T < or = 15 nmol/liter ) were r and omized to undergo daily dermal application of 70 mg dihydrotestosterone gel ( n = 18 ) or vehicle ( n = 19 ) and were studied before , monthly during , and 1 month after treatment . Among 33 ( 17 dihydrotestosterone , 16 placebo ) men completing the study with a high degree of compliance , dihydrotestosterone had significant effects on circulating hormones ( increased dihydrotestosterone ; decreased total and free testosterone , LH , and FSH ; unchanged SHBG and estradiol ) , lipid profiles ( decreased total and low-density lipoprotein cholesterols ; unchanged high-density lipoprotein cholesterol and triglycerides ) , hematopoiesis ( increased hemoglobin , hematocrit , and red cell counts ) , and body composition ( decreased skinfold thickness and fat mass ; unchanged lean mass and waist to hip ratio ) . Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction , nor was there any significant change in gait , balance , or mobility tests , in cognitive function , or in quality of life scales .  Dihydrotestosterone treatment had no adverse effects on prostate ( unchanged prostate volumes and prostate-specific antigen ) and cardiovascular ( no adverse change in vascular reactivity or lipids ) safety markers . We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected and rogenic effects , short-term safety , and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function PURPOSE Because the effects of and rogen replacement on lipoprotein levels are uncertain , we sought to determine the effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in elderly men . SUBJECTS AND METHODS One hundred and eight healthy men more than 65 years of age who had serum testosterone concentrations > 1 SD below the mean for young men were r and omly assigned to receive either testosterone ( 54 men ; 6 mg/day ) or placebo ( 54 men ) transdermally in a double-blind fashion for 36 months . Serum concentrations of lipids and apolipoproteins were measured , and cardiovascular events recorded . RESULTS Serum total cholesterol concentrations decreased in both the testosterone-treated men and placebo-treated men , but the 3-year mean ( + /- SD ) decreases in the two groups ( testosterone treated , -17 + /- 29 mg/dL ; placebo treated , -12 + /- 38 mg/dL ) were not significantly different from each other ( P = 0.4 ) . Similarly , serum low-density lipoprotein ( LDL ) cholesterol levels decreased in both treatment groups , but the decreases in the two groups ( testosterone treated , -16 + /- 24 mg/dL ; placebo treated , -16 + /- 33 mg/dL ) were similar ( P = 1.0 ) . Levels of high-density lipoprotein ( HDL ) cholesterol , triglycerides , and apolipoproteins A-I and B did not change . Lipoprotein(a ) levels increased in both groups by similar amounts ( testosterone treated , 3 + /- 9 mg/dL ; placebo treated , 4 + /- 6 mg/dL ; P = 1.0 ) . The number of cardiovascular events was small and did not differ significantly between the  testosterone-treated  men ( 9 events ) and the placebo-treated men ( 5 events ) during the 3-year study ( relative risk = 1.8 ; 95 % confidence interval : 0.7 to 5.0 ) . CONCLUSIONS As compared with placebo , transdermal testosterone treatment of healthy elderly men for 3 years did not affect any of the lipid or apolipoprotein parameters that we measured . The effect of testosterone treatment on cardiovascular events was unclear , because the number of events was small The relation between sex hormone levels and subsequent risk of a major coronary event was studied in a nested case-control study among 163 men in the Multiple Risk Factor Intervention Trial who later had a major coronary event and in 163 controls . Cases and controls were matched for age , serum cholesterol level , r and omization group , r and omization date and clinic . Blood sample s were collected at baseline before r and omization and frozen at -70 degrees C. Follow-up extended over 6 to 8 years . Sixty-one patients had a nonfatal acute myocardial infa rct ion and 102 fatal infa rct ion .  Total and free testosterone , total and free estradiol , and rostenedione and estrone concentrations were measured . There were no significant differences between cases and controls for any sex hormone level . There was also no difference in the ratio of testosterone to estradiol . Controlling for other cardiovascular risk factors did not change these results . These results do not support previous case-control studies of a relation between sex hormone levels and risk of heart attack among men
Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects .
OBJECTIVE To conduct a systematic review and meta- analysis of r and omized trials that assessed the effect of testosterone use on  cardiovascular events and risk factors in men with different degrees of and rogen deficiency .