
 the current issam ( international society for study of the aging male ) , eau ( european association of urology ) , and bssm ( british society for sexual medicine association ) definition of late onset hypogonadism [ 1 , 2 ] isa biochemical syndrome associated with advancing age and characterised by a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens .
it may result in significant alterations in the quality of life and adversely affect the function of multiple organ systems  .   
a biochemical syndrome associated with advancing age and characterised by a deficiency in serum androgen levels with or without a decreased genomic sensitivity to androgens .
it may result in significant alterations in the quality of life and adversely affect the function of multiple organ systems  .  
this state of hypogonadism causes a global decrease in energy and a decrease in the feeling of well - being .
it also causes a change in sexual function and has other endocrine and metabolic repercussions . these can affect bones , muscles , and lipids , as well as cognitive function testosterone deficiency syndrome ( tds ) or late onset hypogonadism which is defined on the basis of clinical symptoms associated with abnormal testosterone levels
the european male aging study   ( emas ) studied 3369 men aged 4079 at 8 european centres and concluded that the 3 following cardinal symptoms were most likely to be related to low levels of testosterone . 

other symptoms such as hot flushes , sweats and tiredness , loss of vitality , reduced shaving frequency , gynaecomastia , depressed mood , poor concentration , and sleep disturbance were regarded as less specific .
recent guidelines suggest that a level of total testosterone of < 8  nmol / l or free testosterone of less than 180  pmol / l requires testosterone replacement therapy and total testosterone of > 12  nmol / l or free testosterone of > 225  pmol / l does not . between these levels
a trial of therapy for a minimum of 6 months should be considered based on symptoms [ 1 , 2 ]
total testosterone should be measured between the hours of 7 and 11 am on 2 occasions at least 1 month apart and ideally be assessed by mass spectrometry ( id - gcms ) .
equilibrium dialysis is currently the gold standard for free testosterone as immunoassays based on analogue displacement are currently inaccurate [ 1 , 2 , 4 ] . the endocrine society   recommends that men with the following conditions should be screened for low testosterone routinely : type 2 diabetes , metabolic syndrome , moderate to severe chronic lung disease , osteoporosis , hiv , history of infertility , treatment with steroids , opiates ( even medically prescribed ) , and anticonvulsants , alcohol abuse .
moderate to severe chronic lung disease , history of infertility , treatment with steroids , opiates ( even medically prescribed ) , and anticonvulsants ,
there is increasing evidence from multiple long - term studies that tds is associated with increased cardiovascular and all - cause mortality [ 513 ] .
two recent meta - analyses have looked at a large number of long - term studies linking low testosterone to increased cardiovascular and all - cause mortality [ 14 , 15 ] .
araujo et al .   concluded that the evidence for a link between low testosterone and increased mortality was strong but concluded that most studies involved issues in cohort selection and choice .
they concluded that a decrease of 2.1 standard deviations in total testosterone was associated with a 25% increase in mortality .
. looked at the data in terms of several models and found that even after strict adjustment for comorbidities there was a consistent link between mortality risk and testosterone level throughout the studies but that this did not prove causation ( table 1 ) .
the emas group   recently reported 4.3 year follow - up data on 2599 men aged 4079 and concluded that men with a baseline tt of 8  nmol / l or less and sexual symptoms had a 3-fold increased mortality and a 5-fold increased risk of cancer death .
there authors concluded that there is a small number of men with low testosterone at considerable risk of early death .
a recent 10 year study from western australia involving 3690 men followed up from 20012010 concluded that tt and ft levels in the normal range were associated with decreased all - cause and cardiovascular mortality , for the first time suggesting that both low and dht are associated with all - cause mortality and higher levels of dht reduced cardiovascular risk .
six published studies usually involving small samples have shown that low tt and ft are associated with cad and 4 have shown no association .
four studies have shown inverse associations between low tt or ft ( table 2 ) and the severity of cad .
one involved 803 men assessed by gensini score , based on the location and number of stenotic coronary artery segments and degree of luminal narrowing .
such studies do not establish whether low tt or ft is a cause or a consequence of cad .
the prevalence of hypogonadism was 24% , mortality rates were 21% versus 12% ( p = 0.002 ) for hypogonadal men versus eugonadal , and the study was halted early at 6.9 years . only beta - blocker therapy and left ventricular failure were found to have a greater influence on survival .
muraleedaran   et al . screened a primary care diabetic population of 587 patients and followed them up for 5.8 years .
they found that 475 of men had normal tt levels , 22% were overtly hypogonadal ( < 8 
these percentages were in close agreement with earlier publications by kapoor   et al . and
the mortality rate   over 5 years in the hypogonadal group was 17.2% versus 9% in the normal testosterone cohort .
the effect of treatment with trt reduced the mortality rate of treated cohort ( 8.4% ) to that of the eugonadal group whereas the mortality for the untreated remained high at 19.2% , after adjustment for all confounding factors .
decreases in serum total cholesterol ( tc ) have been noted as early as after 4 weeks   but most studies have reported a decrease after 3 months .
the mrfit   study showed that hypogonadal men had slightly increased triglycerides and hdl , leading to the suggestion that trt might be expected to lower triglycerides and hdl .
a recently published 5-year registry involving 230 men treated with long acting testosterone showed highly significant reductions in tc , ldl , and triglycerides with increase in hdl , associated with significant reduction in weight , bmi , and visceral fat .
the decrease in serum triglycerides follows a similar pattern : after 4 weeks with decrease over 9 months   and maximum effect at 12 months .
the decrease in low - density lipoprotein cholesterol seems somewhat slower : after 3 months , after 4044 weeks , or after 12 months   studies have found both an increase and decrease in hdl cholesterol [ 2628 ] dependent on the presence of diabetes or the use of statins .
a decline was noted in il6 and tnf - alpha within 16 weeks   and in another study after 16 weeks . in the moscow study , c - reactive protein was reduced by trt at 30 weeks versus placebo .
several of the above studies have shown reduction in waist circumference , visceral fat , and bmi [ 2628 ] .
preliminary longer term studies suggest that considerable weight loss can be seen for up to 4 years .
placebo controlled studies in untreated hypertension are difficult to conduct for ethical reasons . in some studies , a decline in diastolic blood pressure has been observed , after 39 months [ 24 , 26 ] and in systolic blood pressure [ 24 , 26 ] .
maximum effects were observed after 12 months and up to 5 years [ 24 , 26 ] .
men with angiographically proven cad ( coronary artery disease ) have significantly lower testosterone levels   compared to controls ( p < 0.01 ) and there was a significant inverse relationship between the degree of cad and tt ( total testosterone ) levels ( r = 0.52 , p < 0.01 ) .
nearly 25% of men presenting for coronary angiography had testosterone levels in the low hypogonadal range and some 50% had a tt of less than 11 
studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally   and to produce modest but consistent improvement in exercise - induced angina and reverse associated ecg changes .
the mechanism of action is via blockade of calcium channels with effect of similar magnitude to nifedipine . in men with chronic stable angina pectoris
, the ischaemic threshold increased after 4 weeks of trt and a recent study demonstrates improvement continuing beyond 12 months [ 39 , 40 ] .
exercise capacity in men with chronic heart failure increased after 12 weeks , predominantly through the improvement in skeletal muscle performance .
lower levels of endogenous testosterone have been shown to be associated with longer duration of the qtc interval and trt has been shown to reverse this effect .
carotid artery intimal thickness is associated with low endogenous testosterone suggesting an increased risk of atherosclerosis .
a trial of 209 elderly frail men   over 65 randomised to receive either placebo or 100  g of topical testosterone gel was terminated early as there were 23 cardiac events ( 2 deaths ) in the 106 men in the testosterone group versus 5 in the placebo group , despite positive results in study end points .
the authors conceded that there were more cardiovascular comorbidities in the active treatment group and that the starting dose and escalation were outside the product licence .
the study involved rapid escalation up to 150  mg per day , above the manufacturers recommended dose and many of the events were reported with inadequate validation .
studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels .
both hyperinsulinaemia and low testosterone have been shown to predict the development of type 2 diabetes ( t2d ) [ 42 , 43 ] .
medications such as chronic analgesics , anticonvulsants , 5aris , and androgen ablation therapy are associated with increased risk of testosterone deficiency and insulin resistance [ 1 , 2 ] .
intraabdominal adiposity ( iaa ) drives the progression of multiple risk factors directly , through the secretion of excess free fatty acids , inflammatory adipokines , and decreased secretion of adiponectin .
the important contributions of iaa to dyslipidaemia and insulin resistance provide an indirect , though clinically important , link to the genesis and progression of atherosclerosis and cardiovascular disease .
the interheart study   involving 29,972 participants examined the contributory factors involved in first ami ( acute myocardial infarction ) and found iaa to be an important predictive factor and recommended waist circumference or hip - waist ratio as a standard measurement of cardiovascular risk .
the precise interaction between insulin resistance , visceral adiposity , and hypogonadism is , as yet , unclear but the important mechanisms are through increased aromatase production , raised leptin levels , and increase in inflammatory kinins . in obese males , levels of testosterone
patients should be advised to switch to a low glycaemic diet , providing carbohydrate that does not increase glucose levels that means reducing potatoes and bread and substituting natural rice and full corn .
men with low testosterone levels show less diurnal variation compared with younger men with normal levels .
weight loss will increase levels of testosterone and augment the effects of lifestyle and exercise advice .
diabetes specialists have traditionally considered the fall in testosterone level as being a consequence of obesity but studies now clearly show that low testosterone leads to visceral obesity and metabolic syndrome and is also a consequence of obesity .
large long - term studies have shown that baseline levels of testosterone predict the later development of type 2 diabetes [ 25 , 42 , 43 ] . in the case of mmas , a baseline total testosterone of less than 10.4  nmol /
l was associated with a greater than 4-fold incidence of type 2 diabetes over the next 9 years and nhanes - iii followed up men from as young as 20 and found a similar 4 times greater prevalence independent of obesity or ethnicity .
diabetes uk data 2010   showed the prevalence of type 2 diabetes in men aged 3544 to be doubled that of women despite men in that age group having lower levels of obesity and taking more exercise .
a study has recently commenced in australia to establish whether treating young obese men with low testosterone will reduce the incidence of type 2 diabetes .
there is high level evidence that trt improves insulin resistance , as measured by homa - ir [ 4952 ] , and reduces hba1c   by approximately 0.7% by 18 months   and inflammatory markers ( crp , il6 , and tnf - alpha ) in men with type 2 diabetes and metabolic syndrome [ 2628 ] .
there is also high level of evidence for reduction in total cholesterol , weight , bmi [ 2628 ] , and visceral fat ( a significant marker for cv risk ) and improvement of lean muscle mass .
the blast study [ 53 , 54 ] suggested that men with depression ( 23% of the cohort with diabetes ) were markedly less responsive to testosterone and that improvement in metabolic parameters required sustained levels of testosterone above 12 
nmol / l [ 53 , 54 ] ( table 3 ) . a recent 5 year registry of 255 men age 3669   treated with long acting tu has shown mean reductions in waist circumference of 8.5  cm , weight reduction of 15.5  kg , total cholesterol by 2.4  mmol / l , reduction in hdl , and triglycerides with hba1c by 0.9% ( 7.06 to 6.16 ) . a prospective recent study of 587 men with type 2 diabetes   involved 5.8 years follow - up
the mortality rate was 20% in the untreated group and 9.1% in the normal group independent of comorbidities and therapies .
mortality was 8.6% in the treated group ( p = 0.049 ) ( figure 1 ) .
the cumulative mortality was 21% in the untreated group versus 10% ( p = 0.001 ) in the treated group with the greatest effect in younger men and those with type 2 diabetes .
in a recent paper of 145 patients with first ischaemic stroke and diabetes , 66% were found to be hypogonadal , and in the testosterone treated group 7% had a recurrence of stroke in 2 years versus 16.6% in the control group with 28% of the treated men returning to work versus 6% of the control group .
a recent retrospective us study of 8709 men   with baseline tt of 10.4  nmol undergoing coronary angiography involved follow - up for mean 840 days .
in the cohort of 7486 patients not receiving testosterone therapy , 681 died , 420 had mis , and 486 had strokes . among 1223
patients receiving testosterone therapy , 67 died , 23 had mis , and 33 had strokes . at first sight these results would closely agree with the findings in [ 21 , 55 ] , but a complex statistical analysis reversed the trend and concluded that there was a greater risk in the trt group .
there were concerns that 1132 patients experiencing events were excluded because they were prescribed trt after the event when surely these should have been included in the untreated group , increasing the events by 70% .
the baseline tt was 1  nmol / l lower in the treated group and previous studies show that this may increase the mortality by up to 30% , yet this was not considered in the 50 confounders for analysis .
men were likely to be treated with trt on the basis of symptoms if they suffered from erectile dysfunction , and the presence of ed has been shown to be an independent risk factor , particularly in hypogonadal men , increasing the risk of cardiac events by over 50% [ 16 , 58 ] .
therapies used were mainly short acting injection and patches , both with high discontinuation rates .
only 60% had any record of a follow - up testosterone level and in those the mean treatment level was 10.2  nmol / l , suggesting suboptimal therapy .
despite these issues , the paper was given an editorial and a separate paper warning patients about the risks of testosterone was included in the same journal .
the level of criticism of this paper led to an immediate revision of the conclusions shortly after publication .
a recent online publication on ischaemic heart disease mortality in men concluded optimal androgen levels are a biomarker for survival . a recent systematic and meta - analysis of placebo - controlled trials of t therapy lasting more than 12 weeks concluded that testosterone therapy may increase the risk of cardiovascular - related events   but most studies involved small cohorts with a small number of events but once again the nonrandomised studies failed to consider the impact of symptoms as an indication for trt prescribing . a meta - analysis of 1000 patient years   versus placebo suggests a slight reduction in myocardial infarction and cva but a reduction in coronary interventions .
there was a 6% incidence of raised haematocrit ( > 50% ) without significant consequences and no deaths in the active treatment group versus 5 in the placebo cohort .
at least 7 observational studies have reported no association of luts with serum testosterone level and 5 have shown an inverse relationship .
no studies to date show an increase in luts / bph symptoms with higher serum testosterone levels . a recent long - term registry of 5 years trt shows sustained reduction in ipss , postresidual volume , and bladder wall thickness , despite minor increase in prostate volume .
another 5-year study involving a smaller cohort showed no impact on luts / bph parameters .
as trt has been shown to upregulate pde5   and enhance the effect of pde5is ( now an accepted therapy for both ed and luts ) , it no longer seems logical to advice avoidance of trt in men with mild to moderate bph .
.   also found that patients on testosterone were 12 times more likely to get a prostate biopsy but no more likely to have a positive finding .
several meta - analyses have failed to show a link between trt and development of prostate cancer   but some studies have shown a tendency for more aggressive prostate cancer in men with low testosterone .
one recent study of 279 consecutive patients referred for biopsy on the basis of abnormal dre or raised psa found that low bioavailable testosterone and high shbg were associated with a 4.9- and 3.2-fold risk of positive biopsy .
current eau , issam , and bssm guidance [ 1 , 2 ] is that there is  no evidence trt is associated with increased risk of prostate cancer or activation of subclinical cancer .  despite these conclusions , many patients are deprived of clinical and metabolic benefit because of minor physiological increases in psa and concerns that no long - term study has conclusively proved absolute safety .
men with prostate cancer , treated with androgen deprivation , develop an increase of fat mass with an altered lipid profile .
the risks of diabetes mellitus increase by 44% and mortality of cardiovascular diseases by 16% during a follow - up of up to 10 years .
the authors concluded that before commencing adt , the overall health , comorbidities , and life expectancy of the patient need to be fully assessed .
several studies have clearly shown that trt can be effective as monotherapy for ed [ 26 , 28 ] , in men without other multiple comorbidities . a recent double blind placebo controlled study in men with diabetes showed prompt improvement in iief in men with severe hypogonadism and a secondary improvement with 12 to 18 months of therapy , dependent on obtaining prolonged sustained levels in the normal range .
results from a 5-year registry showed 12.3-point improvements in iief in 260 men treated with long acting tu . a systematic review and meta - analysis of placebo - controlled studies published in the past 30 years aimed to study effects of testosterone on the different domains of sexual life .
this latter study concluded that t treatment might be useful for improving vasculogenic ed in selected subjects with low or low - normal t levels .
erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone .
current guidelines suggest that all patients presenting with ed , irrespective of age , should be screened for low testosterone , as it is a potentially curable cause of ed , especially in men without othercomorbidities [ 1 , 2 ] .
nice guidance   suggests that all men with type 2 diabetes be assessed for ed annually and the gp contract now includes routine assessment for ed , and increased demand for testosterone supplementation will be a natural consequence of this correction of previous underdiagnosis and undertreatment .
men with low testosterone usually present with bothersome symptoms , particularly ed , and require treatment to address those problems , not simply for cardiovascular prevention purposes .
the benefits of conventional cardiovascular risk reduction with exercise and weight reduction are fundamental to management but are frequently unsuccessful .
there is a considerable body of evidence that low testosterone is associated with increased cardiovascular and cancer mortality .
a policy of taking little or no action for these men based on concerns of increased cardiovascular and cancer risk associated with physiological replacement would seem illogical .
there is considerable evidence of modest cardiac and metabolic benefits that are shown to reduce cardiovascular risk plus sexual , mood , and quality of life changes associated with restoring testosterone levels .
these benefits may potentially denied to patients by fears over prostate and cardiac risk that is not currently supported by evidence .
ideally , we need large long - term studies to resolve these issues with certainty but such studies are unlikely to be done for logistic and financial reasons .
 low levels of testosterone are manifested by erectile dysfunction , reduced sexual desire , and loss of morning erections with increasing numbers of men are being diagnosed and require treatment . 
 the prevalence rates of testosterone deficiency vary according to different studies but may be as high as 40% in populations of patients with type 2 diabetes . 
 there is increasing evidence that testosterone deficiency is associated with increased cardiovascular and all - cause mortality . screening for low testosterone 
 is recommended in a number of high risk groups including those with type 2 diabetes and metabolic syndrome . 
 there are recent data to suggest that testosterone replacement therapy may reduce cardiovascular mortality as well as improving multiple surrogate markers for cardiovascular events . 
 specific clinical trials of testosterone replacement therapy are needed in selected populations but in the meantime we must treat patients based on the best current evidence . 
1. Introduction
2. Biochemical Assessment of Hypogonadism
3. Low Testosterone and Increased Mortality
4. Long-Term Safety of Testosterone Therapy on the Prostate
5. Effects of Androgen Ablation Therapy
6. Testosterone and Erectile Dysfunction
7. Conclusions