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Key Points

Time-course of effects of testosterone replacement therapy in hypogonadal men as shown in clinical studies:

• Effects on sexual interest appear after 3 weeks and plateau at 6 weeks
• Changes in erections/ejaculations occur within 6 months
• Effects on quality of life evident within 3–4 weeks and continue thereafter
• Effects on depressive mood noted after 3–6 weeks and reach a maximum after 18–30 weeks
• Effects on glycaemic control become evident after 3–12 months, although insulin sensitivity may improve within a few days
• Changes in body composition and muscle strength occur within 12–16 weeks and stabilize at 6–12 months
• Effects on bone mineral density are detectable after 6 months and continue for at least 3 years
• Beneficial effects on lipids appear after 4 weeks and reach a maximum after 6–12 months
• Prostate-specific antigen and prostate volume marginally rise, plateauing at 12 months.

Key Points

• Testosterone (T) deficiency (TD; hypogonadism) is a common and under-diagnosed condition associated with aging and with common medical comorbidities
• Significantly increased risk of TD associated with obesity, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM) and hypertension
• Significant associations exist between T levels and all-cause and cardiovascular death in men ≥40 years
• There is rigorous evidence supporting T replacement therapy (TRT) in reducing fat mass, a key component in treating individuals with MetS or T2DM
• TRT reduces fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and increases high-density lipoprotein cholesterol in patients with TD and MetS
• Consistent support for the benefits of TRT in improving sexual desire, erectile function and performance
• Current commercial formulations for TRT include short-acting IM injections, topical gels or patches, subcutaneous T pellets and long-acting intramuscular T undecanoate
• Current treatment modalities appear relatively safe, and adverse events definitively associated with treatment are reversible on withdrawal of treatment
• Lack of a clearly-defined serum threshold for distinguishing T deficiency –published consensus guidelines recommend arbitrary thresholds, generally ranging from 200 to 350 ng/dL
• Physicians managing patients with TD should use their clinical judgment and experience in determining which patients require diagnosis and treatment, based on low T and the presence of symptoms.

Key Points

In elderly men:

• Testosterone (T) is important as a regulator of body composition and for maintaining bone mineral density
  
  
  • Low T is associated with frailty
• Low T is associated with higher mortality
  
  
  • Increased risk of type 2 diabetes, depression, cardiovascular disease, chronic obstructive pulmonary disease, metabolic syndrome, chronic renal disease, and a higher incidence of mortality
• Low T is common in men with heart failure
  
  
  • Low T and dehydroepiandrosterone level appear to be independent predictors of death in men with heart failure

T replacement therapy has been shown to be beneficial in elderly frail men, including those with cardiac dysfunction and/or heart failure

• Improves lean body mass and reduces fat mass
• Ameliorates a number of cardiovascular risk factors
• Improves strength, physical and metabolic function

Key Points

After 6 and 12 months, IM testosterone undecanoate (TU) significantly:

• Improved metabolic parameters by reducing homeostasis model assessment index of insulin resistance (HOMA-IR) (p
• Improved International Index of Erectile Function (IIEF-5) and Aging Males’ Symptoms (AMS) scores

In contrast 6 months of oral TU did not significantly improve any parameters studied

In patients who crossed over from oral TU, 6 months of IM TU:

• Increased TT and FT (p<0.0001)
• Improved metabolic parameters (p<0.001)
• Improved IIEF-5 and AMS scores (p<0.01)

Haemoglobin and haematocrit values increased with oral and IM TU, but remained stable and within the normal range during treatment.

Key Points

Key evidence-based recommendations included:

• Clinical and biochemical diagnosis
• Testosterone (T) deficiency (TD) and metabolic diseases
• T and cardiovascular (CV) diseases
• T therapy and CV health
• Questionnaires to screen for TD
• Indications for T treatment
• Age and T treatment
• Indications for T treatment in men with sexual dysfunction
• Combination therapy with T and phosphodiesterase type 5 inhibitors
• Commercial T formulations
• Serum T levels to be achieved with T treatment
• Prostate safety
• Cautions in the use of T therapy
• Monitoring

Key Points

• Testosterone replacement therapy (TRT) significantly increased serum total T and free T by week 12 in Korean men with ED and hypogonadism
• TRT also significantly improved:
  
  
  • total IIEF score and all 5 domain scores
  • total AMS scale and all three domain scores of AMS
• 77% of men reported improved erectile function
• Improvements in lipid profile and some metabolic components were seen
• Serum glucose levels tended to improve with treatment, reaching statistical significance in men with elevated initial glucose levels
• TRT was effective, safe and well tolerated in hypogonadal Asian men.

Key Points

Nine symptoms were confirmed to be significantly related to total or freetestosterone (T) level

• Three sexual symptoms
• Three physical symptoms
• Three psychological symptoms
• The probability of symptoms increased with decreased levels of T and the presence of the three sexual symptoms correlated most closely with low T
• Total T <317 ng/dL (11 nmol/L) + free T levels <64 pg/mL (220 pmol/L) + all 3 sexual symptoms were diagnostic of late-onset hypogonadism.

Key Points

• Total and bioavailable testosterone (T) levels increased significantly following administration of the testosterone gel
• T gel was significantly superior to placebo in improving the Erectile Function Domain score in men with baseline T ≤300 ng/dL (10.4 nmol/L), a widely accepted definition of hypogonadism
• The increase in successful intercourse rate increased correspondingly by 33.1% vs 13.4% (p<0.038)
• The lower the baseline level of T, the lower the improvement in sexual function obtained by tadalafil alone in the placebo group
• Hypogonadal men with baseline T ≤300 ng/dL may benefit from the addition of T replacement therapy to optimal ED therapy with tadalafil.

Key Points

• Men with MetS had significantly lower levels of total plasma testosterone compared with healthy subjects
• This was also true when men with or without erectile dysfunction were analysed separately and when different definitions of MetS were used
• The presence of type 2 diabetes mellitus (T2DM) further enhanced the MetS-related decline in testosterone levels
• Adjusted for age and body mass index, both T2DM and MetS independently predicted low testosterone (p<0.001 and p<0.05, respectively)
• Data from longitudinal studies showed that baseline testosterone was significantly lower among patients with MetS than in controls (mean -2.17 nmol/L; p<0.0001)
• Testosterone replacement therapy significantly reduced metabolic risk factors, including fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and increased HDL-cholesterol.

Key Points

• After 12 months, there was a significant difference in homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT) and high-sensitivity C-reactive protein (hsCRP) between the TU and placebo groups (p<0.01)
• No modification of metabolic factors occurred during treatment with placebo
• Consequently, all patients received TU for the remaining 12 months of the study
• TU markedly improved insulin sensitivity from baseline to 12 months (p<0.0001), and maintained the improvement after 24 months
• HOMA-IR significantly improved in patients shifted from placebo to testosterone undecanoate (p<0.001) due to a reduction in fasting glucose and fasting insulin levels
• TU also significantly reduced hsCRP levels (p<0.0001) and CIMT values (p<0.001)
• Overall at 24 months, only 35% and 58% of patients still met NCEP-ATPIII and IDF criteria, respectively, for a diagnosis of MetS
• The main determinants of improvement in MetS were reduction in waist circumference (p<0.0001), visceral fat mass (p<0.0001) and improvement in HOMA-IR (Figure 1).

Key Points

The nested case-control study showed:

• At baseline, over 20% of men were hypogonadal, according to a widely accepted lower limit for normal total testosterone levels
• Hypogonadism ranged from 5.2% to 13.8% and 22.4% depending on the threshold used (total testosterone less than 8, 10.4 and 12 nmol/L, respectively
• During follow-up, 139 of the patients had a major cardiac event, such as ischaemic heart disease, cerebrovascular events (stroke or transient ischaemic attack) or peripheral artery disease
• MACE were fatal in 15 men
• Although low testosterone in itself was not associated with MACE, those patients with total testosterone levels below 10.4 nmol/L who had a major cardiac event were significantly more likely to die than those with higher testosterone levels
• When adjusted for Chronic Diseases Score (an index of comorbidities) the risk of death was increased by a factor of seven (hazard ratio [HR] 7.1) in men with testosterone below 8 nmol/L
• Of interest, fatal MACE were associated with a higher ANDROTEST score measuring hypogonadal-related symptoms and signs (HR = 1.2 for each ANDROTEST score increment; P = 0.05).

Key Points

• 20.9% of men had biochemical testosterone deficiency defined as bioavailable testosterone <2.6 nmol/L, 16.91% using testosterone <8.1 nmol/L and 24% using either
• There was excess mortality in testosterone-deficient men; 21% versus 12% in those with testosterone levels in the normal range (>2.6 nmol/L), p=0.002 (Figure 1)
• Low serum testosterone was one of only four variables found to influence the time to all-cause mortality in multivariate analysis (hazard ratio [HR] 2.27)
• The other variables significantly influencing time to all-cause mortality were presence of left ventricular dysfunction (HR 3.85), aspirin therapy (HR 0.63) and β-blocker therapy (HR 0.45)
• Low bioavailable testosterone more than doubled adjusted all-cause and vascular mortality (HR 2.2, p<0.0001 for all-cause mortality and HR 2.2, p=0.007 for vascular mortality) compared with those with normal levels of testosterone
• Overall, serum total testosterone was inversely associated with mortality (HR 0.96), with a baseline level of <15.1 nmol/L associated with an all-cause HR of 1.86 and vascular mortality with a HR of 2.5.

Key Points

The nested case-control study showed:

• No difference in Fat Free Mass (FFM) beween the two groups (low and normal T), but Fat Mass (FM) percentage was significantly higher in the low T group (32.2% vs 25.9%; P<0.001) compared with controls – this group also had higher weight, waist circumference, and total abdominal adipose tissue (TAT)
• Muscle strength was similar between the groups, but the control group performed significantly better in two of the three functional tests. Bone Mineral Density (BMD) measured in both the lumbar spine and hip showed no significant difference between the groups
• At the Oral Glucose Tolerance Test men with low T had significantly higher fasting and two hour glucose levels compared with the control group. Likewise, the HbA1c, insulin, C-peptide and triglycerides levels and insulin resistance (HOMA) values were significantly higher in men with subnormal testosterone levels
• Men in the control group reported better overall and somatic Quality of Life (QoL) scores (AMS) although the scores in the sexual domain were not significantly different. In the Beck Depression Inventory the control group reported a significantly better total and second subscale score
• There were no differences between groups in the General Health Questionnaire or World Health Organisation quality of life old score (WHOQOL-OLD)

The intervention study showed that:

• Total and free T increased significantly in the T group. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) decreased in the T group and at the end of the study were significantly lower in the T group compared with placebo
• FFM increased and FM reduced significantly during T treatment compared to the placebo group at the end of the study (FFM: +4.2 kg in T group, +0.4 kg in placebo; FM: -5.3kg in T group, -0.6 kg in placebo) while weight, BMI and waist circumference did not change significantly
• BMD in the hip increased significantly in the T group and there was a significant difference between the groups at the end of the study
• T did not increase strength in knee extension or handgrip strength, but in the placebo group handgrip strength was reduced in both the dominant and non-dominant hand such that at the end of the study there were significant differences between the groups
• There was no significant difference in QoL, cognitive function or emotional function between the groups at the end of the study
• Serum PSA, hematocrit and hemoglobin increased in the T group and by the end of the study were significantly higher than in the placebo group; two men in the T group (and one in the placebo group) had PSA levels >4.0µg/l by the end of the study

Key Points

• Serum testosterone, glycosylated haemoglobin (HbA1c), fasting plasma glucose, high-density lipoprotein cholesterol, triglyceride concentrations, and waist circumference improved in both groups after 52 weeks of treatment
• The addition of testosterone significantly further improved these measures compared with D&E alone
• All D&E and testosterone treated patients reached the HbA1c glycemic control goal of less than 7.0%, and 87.5% achieved HbA1c of less than 6.5%. In comparison, only 40.4% of the D&E alone participants reached HbA1c less than 7.0%, and none reached less than 6.5%
• Based on Adult Treatment Panel III criteria, 81.3% of the D&E with testosterone patients no longer met the criteria of MetS compared with 31.3% of those receiving D&E alone
• Testosterone treatment improved insulin sensitivity (HOMA model), adiponectin, and high-sensitivity C-reactive protein
• Serum PSA concentrations did not differ between the two treatment groups indicating that 52 weeks of testosterone replacement does not appear to increase risks of prostate problems.

Key Points

• Restoring plasma testosterone levels to normal alleviated the symptoms of testosterone deficiency
• The percentage of patients who reported “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10% after four TU injection intervals
• At baseline, 67% of patients had moderate, severe or extremely severe erectile dysfunction (ED), this decreased to 19% after TU therapy. 61% of patients with some degree of ED reported a decrease in severity
• TU therapy markedly improved patients ability to concentrate and their reported mood
• 89% of patients were “satisfied” or “very satisfied” with TU therapy
• The mean waist circumference in patients decreased from 100 cm to 96 cm
• Intramuscular TU was well tolerated and safe for treatment of male hypogonadism in daily clinical practice, irrespective of ethnic background: adverse events and adverse drug reactions were recorded for 12% and 6% of patients respectively. These were mostly mild to moderate in severity
• The most commonly reported ADRs were increase in hematocrit, increase in PSA and injection site pain (all <1%)
• No case of prostate cancer was observed

Key Points

• This is the longest term study investigating testosterone in patients with stable chronic angina.
  (Angina is severe chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries)
• In the testosterone group, 'time to ST depression' is significantly prolonged, ie the time during exercise when severe chest pain occurs as a result of ischemia (which also becomes visible on the electrocardiogram). This reflects an increase in exercise capacity
• Peak metabolic equivalents (METS) also increased significantly in the testosterone treated patients indicating an improved exercise capability
• BMI and triglycerides were numerically, though significantly reduced in the treatment group
• There was a non-significant reduction in waist-to-hip ratio (a measure of visceral obesity) in the Nebido® group
• Carotid intima-media thickness (CIMT), a measure of atherosclerosis, improved in the Nebido group and did not change in the placebo group. However, the comparison between groups did not reach statistical significance.

Key Points

• This is the first publication from The Moscow Study, a placebo-controlled study in men with metabolic syndrome with a total duration of three years. The first 30 weeks are placebo-controlled, then all men are switched to Nebido®
• All three questionnaires, the Beck Depression Inventory (BDI-IA), the Aging Males' Symptoms (AMS) scale, and the International Index of Erectile Function 5-item (IIEF-5) scale improved significantly in the testosterone group
• These improvements persisted after correcting for smoking habits, BMI, and the presence or absence of type 2 diabetes
• These improvements correlated with improvements in BMI. This means that patients felt better and functioned better when they lost weight, and the more weight they lost, the more they improved

Key Points

• Testosterone treatment consistently reduces fat mass and increases muscle mass
• Body composition changes were similar between men with low testosterone (<10 nmol/L), intermediate testosterone (10-12 nmol/L) and low-normal testosterone (12-15 nmol/L). This questions the validity of the thresholds for deficiency discussed in current guidelines
• Men >65 years yielded the same benefit from testosterone therapy as those <65 years
• This is the largest placebo-controlled testosterone study to date

Key Points

• Long-acting testosterone treatment (Nebido) for 3 months in frail elderly patients was well tolerated
• Nebido significantly improved skeletal muscle function, cardiorespiratory parameters and metabolic parameters, including insulin resistance
• Patients with lower testosterone at baseline achieved the greatest improvements, but eugonadal patients also benefited

Key Points

• Testosterone treatment consistently reduces fat mass and increases muscle mass. This study confirms these findings in a healthy (non-obese and without hypogonadism) cohort
• Changes in visceral fat were more pronounced than changes in subcutaneous fat