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.
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 [
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 [
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 [
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 [
The Endocrine society [ 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.
There is increasing evidence from multiple long-term studies that TDS is associated with increased cardiovascular and all-cause mortality [
Association of low testosterone levels with all-cause mortality by different cut-offs from recent studies.
Cut-off for the definition of low total testosterone (TT) | MMAS; [ |
Wang; [ |
Rancho Bernardo; [ |
Male veterans study; [ |
HIM; [ |
EPIC; [ |
Age-specific cut-off |
---|---|---|---|---|---|---|---|
Low TT ( |
34 | 69 | 82 | 98 | 241 | 474 | |
Model 1 | 1.59 (0.83; 4.02) | 1.96 (0.93; 3.63) | 2.21 (1.26; 3.89)** | 2.24 (1.41; 3.57)** | 1.33 (0.93; 1.90) | 1.28 (0.95; 1.72) | 2.21 (1.40; 3.49)** |
Model 2 | 2.12 (1.01; 4.46)* | 2.08 (1.12; 3.86)* | 2.33 (1.33; 4.12)** | 2.10 (1.34; 3.29)** | 1.28 (0.89; 1.84) | 1.20 (0.88; 1.62) | 2.26 (1.43; 3.59)** |
Model 3 | 2.50 (1.18; 5.27)* | 2.24 (1.21; 4.17)* | 2.53 (1.43; 4.47)** | 2.32 (1.38; 3.89)** | 1.37 (0.95; 1.99) | 1.28 (1.93; 1.75) | 2.35 (1.47; 3.74)*** |
Model 4 | 2.68 (1.19; 6.04)* | 2.13 (1.06; 4.26)* | 2.56 (1.38; 4.76)** | 1.92 (1.18; 3.14)** | 1.11 (0.72; 1.69) | 1.10 (0.78; 1.56) | 2.25 (1.35; 3.75)** |
Model 1: adjusted for age. Model 2: adjusted for age, and WC. Model 3: adjusted for model 2, smoking (3 categories), high-risk alcohol use, and physical activity. Model 4: adjusted for model 3, renal insufficiency, and DHEAS. HR: hazard ratio; CI: 95% confidence interval; CVD: cardiovascular disease; WC: waist circumference; DHEAS: dehydroepiandrosterone sulfate.
The EMAS group [
A recent 10 year study from Western Australia involving 3690 men followed up from 2001–2010 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 [
Association between testosterone level and severity of coronary artery disease.
Study name | Subfraction of testosterone used for analysis | Method of measuring CAD severity | Main findings | Remarks |
---|---|---|---|---|
Dobrzycki et al. [ |
TT, FT, FAI | Duke index* | Inverse correlation between FT and CAD severity |
|
Rosano et al. [ |
TT | Coronary artery score** | Inverse correlation between TT and CAD severity |
|
Li et al. [ |
TT | Genisi score*** | Inverse correlation between TT and CAD severity |
|
Phillips et al. [ |
TT, FT | Visual estimation of coronary artery occlusion and calculation of mean percent occlusion**** | Inverse correlation between TT and FT levels and CAD severity | TT: |
CAD indicates coronary artery disease; CCS: case-control study; FAI: free androgen index; FT: free testosterone; TT: total testosterone.
Malkin et al. [
Muraleedaran [
Decreases in serum total cholesterol (TC) have been noted as early as after 4 weeks [
The decrease in serum triglycerides follows a similar pattern: after 4 weeks with decrease over 9 months [
Studies have found both an increase and decrease in HDL cholesterol [
Several of the above studies have shown reduction in waist circumference, visceral fat, and BMI [
Men with angiographically proven CAD (coronary artery disease) have significantly lower testosterone levels [
Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally [
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 [
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 [
A trial of 209 elderly frail men [
Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels [
Hypogonadism is a common feature of the metabolic syndrome [
In obese males, levels of testosterone are reduced in proportion to degree of obesity. The first step in reducing visceral fat is diet and lifestyle change [
Men with low testosterone levels show less diurnal variation compared with younger men with normal levels [
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 [
There is high level evidence that TRT improves insulin resistance, as measured by HOMA-IR [
Outcome of therapy with long acting TU in a population of men with type 2 diabetes and hypogonadism (BLAST) Hackett et al. IJCP Dec 2013 [
HbA1c |
Weight |
BMI |
WC |
TC |
EF |
AMS |
HADS-D | GEQ | |
---|---|---|---|---|---|---|---|---|---|
30 weeks | −0.41 | −0.7 | −0.3 | −2.5 | −0.25 | +3.0 | −5.3 | −1.01 | 46 |
|
|
0.13 |
|
|
|
|
0.095 | 0.64 |
|
82 weeks | −0.89 | −2.7 | −1.00 | −4.2 | −0.19 | +4.31 |
−8.1 | −2.18 | 67–70 |
|
|
|
|
|
|
|
|
|
|
A recent 5 year registry of 255 men age 36–69 [
A prospective recent study of 587 men with type 2 diabetes [
Low testosterone predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes (mean follow-up: 5.8 years) Muraleedaran et al. [
A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% (
A recent retrospective US study of 8709 men [
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. Symptoms were not considered, yet these are key to the diagnosis of hypogonadism. 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% [
Therapies used were mainly short acting injection and patches, both with high discontinuation rates. 16% filled only one prescription but were included in the “treatment” group. 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 [
A meta-analysis of 1000 patient years [
At least 7 observational studies have reported no association of LUTS with serum testosterone level and 5 have shown an inverse relationship [
Calof et al. [
Current EAU, ISSAM, and BSSM guidance [
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. Total cholesterol by 9, 7, 11, and 26.5%, respectively. These patients also appear to develop insulin resistance, hyperinsulinemia, and hyperglycaemia. The risks of diabetes mellitus increase by 44% and mortality of cardiovascular diseases by 16% during a follow-up of up to 10 years [
Several studies have clearly shown that TRT can be effective as monotherapy for ED [
Erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone [
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 may add up to substantial benefit to many patients. 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. Until then patients require advice and treatment based on the current best evidence.
The authors declare that there is no conflict of interests regarding the publication of this paper.