Transformative Insights from the Landmark Traverse Trial: A new era in testosterone therapy
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madman
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Some key takeaways here!
Prostate cancer (PCa)
*Recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [144], should prompt caution in choosing to treat symptomatic hypogonadal men in this setting
Cardiovascular Disease (CVD)
*Current available data from interventional studies suggest that there is no increased risk up to three years of testosterone therapy [167-171]. The currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three year course of testosterone therapy, after which no available study can exclude further or long-term CV events [172,173]
Erythrocytosis
*There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis.
EAU GUIDELINES ON SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE APRIL 2024
3.5 Safety and follow-up in hypogonadism management
3.5.1 Hypogonadism and fertility issues
Pharmacological management of hypogonadism aims to increase testosterone levels to normal levels which resolve or improve symptoms of hypogonadism. The first choice is to administer exogenous testosterone.However, while exogenous testosterone has a beneficial effect on the clinical symptoms of hypogonadism, it temporarily inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis and sperm cell maturation [124]. Therefore, testosterone therapy is contraindicated in hypogonadal men seeking fertility treatment [81]. When secondary hypogonadism is present, gonadotropin therapy may maintain normal testosterone levels and restore sperm production [3].
3.5.2 Male breast cancer
Studies have documented that breast cancer growth is significantly influenced by testosterone and/or by its conversion to oestradiol (E2) through different mechanisms and pathways [125]. Accordingly, the use of SERMs still represents an important therapeutic option in the management of this cancer [125]. No information is available on the role of testosterone therapy in patients successfully treated for male breast cancer; therefore, treated and active male breast cancer should be recognised as absolute contraindications for testosterone therapy.
3.5.3 Lower urinary tract symptoms/benign prostatic hyperplasia (BPH)
A trial of 60 patients undergoing testosterone therapy for six months showed no significant differences on postvoid residual urine and prostate volume, while storage symptoms as measured by IPSS significantly improved, despite an increase in prostate-specific antigen (PSA) level [126]. A larger pre-treatment prostate volume was a predictive factor of improvement in LUTS. Similarly, a placebo-controlled RCT including 120 hypogonadal (total testosterone < 12 nmol/L) men with MetS and listed for BPH surgery, showed that testosterone therapy did not result in a difference in LUTS severity compared to placebo. Conversely, an improvement in ultrasound markers of inflammation in the expression of several pro-inflammatory genes was found in the treatment active arm[127]. A long-term study of 428 men undergoing testosterone therapy for eight years demonstrated significant improvements in IPSS, no changes in max flow rate (Qmax) and residual urine volume, but also a significant increase in prostate volume [128]. Similar data from the Registry of Hypogonadism in Men (RHYME), including 999 patients with a follow-up of three years, did not demonstrate any significant difference in PSA levels or total IPSS in men undergoing testosterone therapy, compared to untreated patients [129]. Similar results were reported in an Italian registry (SIAMO-NOI), collecting data from 432 hypogonadal men from fifteen centres[130]. Meta-analyses have not found significant changes in LUTS between patients treated with testosterone or placebo [131-137]. According to the most recent literature, there are no grounds to discourage testosterone therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration. The only concern is related to patients with severe LUTS (IPSS > 19), as they are usually excluded from RCTs; therefore, limiting the long-term safety data of testosterone therapy in this specific setting[61].
3.5.4 Prostate cancer (PCa)
A considerable number of observational studies have failed to demonstrate any association between circulating higher testosterone levels and PCa [138]. In contrast, studies investigating the relationship between low levels of testosterone and risk of PCa have found that men with very low levels of fT have a reduced risk of developing low-to-intermediate-grade PCa, but have a non-significantly increased chance of developing high-grade PCa[138]. This peculiar pattern was also reported in trials such as the Health Professionals Follow-up Study, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE),with varying magnitudes of significance [139].
A meta-analysis, including 27 placebo-controlled, RCTs, found no evidence of increased PSA levels following testosterone therapy for one-year. When considering eleven studies reporting on the occurrence of PCa, the meta-analysis found no evidence of increased risk of PCa. However, a one year follow-up may be considered too short to draw firm conclusions on the risks of developing PCa. Furthermore, the analysis was restricted to studies with > 1-year follow-up, but no significant changes in PSA levels nor increased risk of PCa were found [132]. After five-year of median follow-up in three independent registry studies with > 1,000 patients undergoing testosterone therapy, PCa occurrence always remained below the reported incidence rate in the general population [140]. Similar results were reported by a large observational study including 10,311 mentreated with testosterone therapy and 28,029 controls with a median follow-up of 5.3 years [141]. The same study, also showed that the risk of PCa was decreased for men in the highest tertile of testosterone therapy cumulative dose exposure as compared with controls [141].
Recently, the TRAVERSE study, a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial involving 5246 men aged 45 to 80 years, who had pre-existing or a high risk of CVD and who have been treated because of low testosterone levels (i.e., total T < 10.4 nmol/L) associated with reported symptoms of hypogonadism, did not show any difference in terms of PCa incidence or high-grade PCa rate between arms (testosterone therapy vs. placebo) at a mean follow-up, was 33.0± (SD) 12.1 months. Conversely, the same trial showed a significantly greater increase from baseline of total PSA in the treatment group as compared with the placebo arm [77].
With regards to PCa survivors, safety in terms of the risk of recurrence and progression has not yet been established. Limited data are available in the literature, with most case series not providing sufficient data to draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in study population and treatment regimen, etc.) [142]. A meta-analysis derived from thirteen studies including 608 patients, of whom 109 had a history of high-risk PCa, with follow-up of 1-189.3 months [143], suggested that testosterone therapy did not increase the risk of biochemical recurrence, but the available evidence is poor,limiting data interpretation [143]. Similar considerations can be derived from another, larger meta-analysis of 21 studies [144]. However, it is important to recognise both meta-analyses demonstrated high heterogeneity among the different studies and included a limited number of subjects. An RCT assessing the safety/benefit ratio of testosterone therapy in hypogonadal men successfully treated with prostatectomy for non-aggressive prostate PCa is currently ongoing [145].
In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [144], should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. In particular, patients should receive comprehensive counselling regarding the uncertain long-term effects of testosterone therapy in this context, which necessitates further investigation. Due to the lack of strong evidence-based data on safety, the possible use of testosterone therapy in symptomatic hypogonadal men previously treated for PCa should be fully discussed with patients and limited to low-risk individuals.
3.5.5 Cardiovascular Disease
Evidence suggests that hypogonadal men have an increased risk of CVD [146, 147]. Whether or not LOH is a cause or a consequence of atherosclerosis has not been clearly determined. Late-onset hypogonadism is associated with CV risk factors, including central obesity, insulin resistance and hyperglycaemia, dyslipidaemia, pro-thrombotic tendency and chronic inflammatory state [147]. Atherosclerosis is a chronic inflammatory disease, that releases pro-inflammatory cytokines into the circulation, which are known to suppress testosterone release from the HPG axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and suppression of circulating cytokines [28-30, 35, 147, 148]. However, due to the equivocal nature of these studies, testosterone therapy cannot be recommended for use outside of treatment of specific symptoms.
Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [7, 149-152]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for cardiovascular morbidity [136] and mortality [153]. Importantly, men with low testosterone when compared to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [147]. Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal range have a reduced number of CV events compared to men with testosterone in the lower three quartiles[149]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [154].Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal serum testosterone levels [155, 156]. Erectile dysfunction is independently associated with CVD and may be the first clinical presentation in men with atherosclerosis.
The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension,diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone therapy [83]. If appropriate, patients should be referred to cardiologists for risk stratification and treatment of comorbidity.
No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial (n=790) conducted in older men [157], the TIMES2 study (n=220) [29], along with the BLAST studies involving men with Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM), as well as the study involving pre-frail and frail elderly men - all of which lasted for one year, and the T4DM study spanning two years - did not show any increase in Major Adverse Cardiovascular Events (MACE) increase in Major Adverse Cardiovascular Events (MACE) [29,32, 33, 157, 158]. Randomised controlled trials, between three and twelve months, in men with known heart disease treated with testosterone have not found an increase in MACE, but have reported improvement in cardiac ischaemia, angina and functional exercise capacity [159-161]. A large cohort study (n=20,4857 men) found that neither transdermal gel or intramuscular testosterone was associated with an increased risk of composite cardiovascular outcome in men with or without prevalent CVD (mean follow-up 4.3 years) [162]. The European Medicines Agency (EMA) has stated that ‘The Co-ordination Group for Mutual recognition and Decentralisation Procedures-Human (CMDh), a regulatory body representing EU Member States, has agreed by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone in men. However, the product information is to be updated in line with the most current available evidence on safety, and with warnings that the lack of testosterone should be confirmed by signs and symptoms and laboratory tests before treating men with these drugs [163].
Data recently released from the TRAVERSE study confirm the findings of the EMA [77]. The latter is the first double-blind, placebo-controlled, non-inferiority RCT with primary CV safety as an end point. The results showed that testosterone therapy was noninferior to placebo with respect to the incidence of MACE. However, a mild higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was observed in the testosterone group [77]. The latter observations, however, need to be confirmed since previous available data do not support an increased risk of venous thromboembolism [78, 164] or major arrhythmias [165] after testosterone therapy. Similarly, the long-term follow-up (median of 5.1 years since last injection) of the T4DM study showed no differences in self-reported rates of new diagnosis of CVD [166].
In conclusion, current available data from interventional studies suggest that there is no increased risk up to three years of testosterone therapy [167-171]. The currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three year course of testosterone therapy, after which no available study can exclude further or long-term CV events [172,173].
3.5.5.1 Cardiac Failure
Testosterone therapy is contraindicated in men with severe chronic cardiac failure because fluid retention may lead to exacerbation of the condition. Some studies have shown that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels [160,174, 175]. An interesting observation is that untreated hypogonadism increased the re-admission and mortality rate in men with heart failure [176]. If a decision is made to treat hypogonadism in men with chronic cardiac failure, it is essential that the patient is followed up carefully with clinical assessment and both testosterone and haematocrit measurements on a regular basis.
3.5.6 Erythrocytosis
An elevated haematocrit level is the most common adverse effect of testosterone therapy. Stimulation of erythropoiesis is a normal biological action that enhances the delivery of oxygen to testosterone-sensitive tissues (e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit usually becomes evident between three and twelve months after testosterone therapy initiation. However,polycythaemia can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral administration and, development of comorbidity, which can be linked to an increase in haematocrit (e.g., respiratory or haematological diseases).
There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis.
As detailed, the TRAVERSE study, which had included symptomatic hypogonadal men aged 45-80 years who had pre-existing or a high risk of CVD, showed a mild higher incidence of pulmonary embolism, a component of the adjudicated tertiary end point of venous thromboembolic events, in the testosterone therapy than in the placebo group (0.9% vs. 0.5%) [77]. However, three previous large studies have not shown any evidence that testosterone therapy is associated with an increased risk of venous thromboembolism [180, 181]. Of those, one study showed that an increased risk peaked at six months after initiation of testosterone therapy, and then declined over the subsequent period [182]. In one study venous thromboembolism was reported in 42 cases and 40 of these had a diagnosis of an underlying congenital thrombophilia (including factor V Leiden deficiency, prothrombin mutations and homocysteinuria) [183]. A meta-analysis of RCTs of testosterone therapy reported that venous thromboembolism was frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders [78]. In an RCT of testosterone therapy in men with chronic stable angina there were no adverse effects on coagulation, by assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme activity or fibrinogen levels [184]. Similarly, another meta-analysis and systematic review of RCTs found that testosterone therapy was not associated with an increased risk of venous thromboembolism [164]. With testosterone therapy elevated haematocrit levels are more likely to occur if the baseline level is toward the upper limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include smoking or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather than topical formulations. Accordingly, a large retrospective two-arm open registry, comparing the effects of long-acting testosterone undecanoate and testosterone gels showed that the former preparation was associated with a higher risk of haematocrit levels > 50%, when compared to testosterone gels [185]. In men with pre-existing CVD extra caution is advised with a definitive diagnosis of hypogonadism before initiating testosterone therapy and monitoring of testosterone as well as haematocrit during treatment.
Elevated haematocrit in the absence of comorbidity or acute CV or venous thromboembolism can be managed by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is very high by venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone therapy.
3.5.7 Obstructive Sleep Apnoea
There is no evidence that testosterone therapy can result in the onset or worsening of sleep apnoea. Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP alone in the treatment of obstructive sleep apnoea [186]. In one RCT, testosterone therapy in men with severe sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after seven weeks of therapy compared to placebo, but this change was not evident after eighteen weeks’ treatment and there was n oassociation with baseline testosterone levels [187].
Table 6: Clinical and biochemical parameters to be checked during testosterone therapy
3.5.9 Summary of evidence and recommendations on safety and monitoring in testosterone treatment
Prostate cancer (PCa)
*Recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [144], should prompt caution in choosing to treat symptomatic hypogonadal men in this setting
Cardiovascular Disease (CVD)
*Current available data from interventional studies suggest that there is no increased risk up to three years of testosterone therapy [167-171]. The currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three year course of testosterone therapy, after which no available study can exclude further or long-term CV events [172,173]
Erythrocytosis
*There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis.
EAU GUIDELINES ON SEXUAL AND REPRODUCTIVE HEALTH - LIMITED UPDATE APRIL 2024
3.5 Safety and follow-up in hypogonadism management
3.5.1 Hypogonadism and fertility issues
Pharmacological management of hypogonadism aims to increase testosterone levels to normal levels which resolve or improve symptoms of hypogonadism. The first choice is to administer exogenous testosterone.However, while exogenous testosterone has a beneficial effect on the clinical symptoms of hypogonadism, it temporarily inhibits gonadotropin secretion by the pituitary gland, resulting in impaired spermatogenesis and sperm cell maturation [124]. Therefore, testosterone therapy is contraindicated in hypogonadal men seeking fertility treatment [81]. When secondary hypogonadism is present, gonadotropin therapy may maintain normal testosterone levels and restore sperm production [3].
3.5.2 Male breast cancer
Studies have documented that breast cancer growth is significantly influenced by testosterone and/or by its conversion to oestradiol (E2) through different mechanisms and pathways [125]. Accordingly, the use of SERMs still represents an important therapeutic option in the management of this cancer [125]. No information is available on the role of testosterone therapy in patients successfully treated for male breast cancer; therefore, treated and active male breast cancer should be recognised as absolute contraindications for testosterone therapy.
3.5.3 Lower urinary tract symptoms/benign prostatic hyperplasia (BPH)
A trial of 60 patients undergoing testosterone therapy for six months showed no significant differences on postvoid residual urine and prostate volume, while storage symptoms as measured by IPSS significantly improved, despite an increase in prostate-specific antigen (PSA) level [126]. A larger pre-treatment prostate volume was a predictive factor of improvement in LUTS. Similarly, a placebo-controlled RCT including 120 hypogonadal (total testosterone < 12 nmol/L) men with MetS and listed for BPH surgery, showed that testosterone therapy did not result in a difference in LUTS severity compared to placebo. Conversely, an improvement in ultrasound markers of inflammation in the expression of several pro-inflammatory genes was found in the treatment active arm[127]. A long-term study of 428 men undergoing testosterone therapy for eight years demonstrated significant improvements in IPSS, no changes in max flow rate (Qmax) and residual urine volume, but also a significant increase in prostate volume [128]. Similar data from the Registry of Hypogonadism in Men (RHYME), including 999 patients with a follow-up of three years, did not demonstrate any significant difference in PSA levels or total IPSS in men undergoing testosterone therapy, compared to untreated patients [129]. Similar results were reported in an Italian registry (SIAMO-NOI), collecting data from 432 hypogonadal men from fifteen centres[130]. Meta-analyses have not found significant changes in LUTS between patients treated with testosterone or placebo [131-137]. According to the most recent literature, there are no grounds to discourage testosterone therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration. The only concern is related to patients with severe LUTS (IPSS > 19), as they are usually excluded from RCTs; therefore, limiting the long-term safety data of testosterone therapy in this specific setting[61].
3.5.4 Prostate cancer (PCa)
A considerable number of observational studies have failed to demonstrate any association between circulating higher testosterone levels and PCa [138]. In contrast, studies investigating the relationship between low levels of testosterone and risk of PCa have found that men with very low levels of fT have a reduced risk of developing low-to-intermediate-grade PCa, but have a non-significantly increased chance of developing high-grade PCa[138]. This peculiar pattern was also reported in trials such as the Health Professionals Follow-up Study, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE),with varying magnitudes of significance [139].
A meta-analysis, including 27 placebo-controlled, RCTs, found no evidence of increased PSA levels following testosterone therapy for one-year. When considering eleven studies reporting on the occurrence of PCa, the meta-analysis found no evidence of increased risk of PCa. However, a one year follow-up may be considered too short to draw firm conclusions on the risks of developing PCa. Furthermore, the analysis was restricted to studies with > 1-year follow-up, but no significant changes in PSA levels nor increased risk of PCa were found [132]. After five-year of median follow-up in three independent registry studies with > 1,000 patients undergoing testosterone therapy, PCa occurrence always remained below the reported incidence rate in the general population [140]. Similar results were reported by a large observational study including 10,311 mentreated with testosterone therapy and 28,029 controls with a median follow-up of 5.3 years [141]. The same study, also showed that the risk of PCa was decreased for men in the highest tertile of testosterone therapy cumulative dose exposure as compared with controls [141].
Recently, the TRAVERSE study, a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial involving 5246 men aged 45 to 80 years, who had pre-existing or a high risk of CVD and who have been treated because of low testosterone levels (i.e., total T < 10.4 nmol/L) associated with reported symptoms of hypogonadism, did not show any difference in terms of PCa incidence or high-grade PCa rate between arms (testosterone therapy vs. placebo) at a mean follow-up, was 33.0± (SD) 12.1 months. Conversely, the same trial showed a significantly greater increase from baseline of total PSA in the treatment group as compared with the placebo arm [77].
With regards to PCa survivors, safety in terms of the risk of recurrence and progression has not yet been established. Limited data are available in the literature, with most case series not providing sufficient data to draw definitive conclusions (e.g., insufficient follow-up, small samples, lack of control arms, heterogeneity in study population and treatment regimen, etc.) [142]. A meta-analysis derived from thirteen studies including 608 patients, of whom 109 had a history of high-risk PCa, with follow-up of 1-189.3 months [143], suggested that testosterone therapy did not increase the risk of biochemical recurrence, but the available evidence is poor,limiting data interpretation [143]. Similar considerations can be derived from another, larger meta-analysis of 21 studies [144]. However, it is important to recognise both meta-analyses demonstrated high heterogeneity among the different studies and included a limited number of subjects. An RCT assessing the safety/benefit ratio of testosterone therapy in hypogonadal men successfully treated with prostatectomy for non-aggressive prostate PCa is currently ongoing [145].
In conclusion, recent literature does not support an increased risk of PCa in hypogonadal men undergoing testosterone therapy. Although it is mandatory to avoid testosterone administration in men with advanced PCa, insufficient long-term prospective data on the safety of testosterone therapy in PCa survivors [144], should prompt caution in choosing to treat symptomatic hypogonadal men in this setting. In particular, patients should receive comprehensive counselling regarding the uncertain long-term effects of testosterone therapy in this context, which necessitates further investigation. Due to the lack of strong evidence-based data on safety, the possible use of testosterone therapy in symptomatic hypogonadal men previously treated for PCa should be fully discussed with patients and limited to low-risk individuals.
3.5.5 Cardiovascular Disease
Evidence suggests that hypogonadal men have an increased risk of CVD [146, 147]. Whether or not LOH is a cause or a consequence of atherosclerosis has not been clearly determined. Late-onset hypogonadism is associated with CV risk factors, including central obesity, insulin resistance and hyperglycaemia, dyslipidaemia, pro-thrombotic tendency and chronic inflammatory state [147]. Atherosclerosis is a chronic inflammatory disease, that releases pro-inflammatory cytokines into the circulation, which are known to suppress testosterone release from the HPG axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and suppression of circulating cytokines [28-30, 35, 147, 148]. However, due to the equivocal nature of these studies, testosterone therapy cannot be recommended for use outside of treatment of specific symptoms.
Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [7, 149-152]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for cardiovascular morbidity [136] and mortality [153]. Importantly, men with low testosterone when compared to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [147]. Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal range have a reduced number of CV events compared to men with testosterone in the lower three quartiles[149]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [154].Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal serum testosterone levels [155, 156]. Erectile dysfunction is independently associated with CVD and may be the first clinical presentation in men with atherosclerosis.
The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension,diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone therapy [83]. If appropriate, patients should be referred to cardiologists for risk stratification and treatment of comorbidity.
No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial (n=790) conducted in older men [157], the TIMES2 study (n=220) [29], along with the BLAST studies involving men with Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM), as well as the study involving pre-frail and frail elderly men - all of which lasted for one year, and the T4DM study spanning two years - did not show any increase in Major Adverse Cardiovascular Events (MACE) increase in Major Adverse Cardiovascular Events (MACE) [29,32, 33, 157, 158]. Randomised controlled trials, between three and twelve months, in men with known heart disease treated with testosterone have not found an increase in MACE, but have reported improvement in cardiac ischaemia, angina and functional exercise capacity [159-161]. A large cohort study (n=20,4857 men) found that neither transdermal gel or intramuscular testosterone was associated with an increased risk of composite cardiovascular outcome in men with or without prevalent CVD (mean follow-up 4.3 years) [162]. The European Medicines Agency (EMA) has stated that ‘The Co-ordination Group for Mutual recognition and Decentralisation Procedures-Human (CMDh), a regulatory body representing EU Member States, has agreed by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone in men. However, the product information is to be updated in line with the most current available evidence on safety, and with warnings that the lack of testosterone should be confirmed by signs and symptoms and laboratory tests before treating men with these drugs [163].
Data recently released from the TRAVERSE study confirm the findings of the EMA [77]. The latter is the first double-blind, placebo-controlled, non-inferiority RCT with primary CV safety as an end point. The results showed that testosterone therapy was noninferior to placebo with respect to the incidence of MACE. However, a mild higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism was observed in the testosterone group [77]. The latter observations, however, need to be confirmed since previous available data do not support an increased risk of venous thromboembolism [78, 164] or major arrhythmias [165] after testosterone therapy. Similarly, the long-term follow-up (median of 5.1 years since last injection) of the T4DM study showed no differences in self-reported rates of new diagnosis of CVD [166].
In conclusion, current available data from interventional studies suggest that there is no increased risk up to three years of testosterone therapy [167-171]. The currently published evidence has reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable for at least a three year course of testosterone therapy, after which no available study can exclude further or long-term CV events [172,173].
3.5.5.1 Cardiac Failure
Testosterone therapy is contraindicated in men with severe chronic cardiac failure because fluid retention may lead to exacerbation of the condition. Some studies have shown that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve mid-normal range testosterone levels [160,174, 175]. An interesting observation is that untreated hypogonadism increased the re-admission and mortality rate in men with heart failure [176]. If a decision is made to treat hypogonadism in men with chronic cardiac failure, it is essential that the patient is followed up carefully with clinical assessment and both testosterone and haematocrit measurements on a regular basis.
3.5.6 Erythrocytosis
An elevated haematocrit level is the most common adverse effect of testosterone therapy. Stimulation of erythropoiesis is a normal biological action that enhances the delivery of oxygen to testosterone-sensitive tissues (e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit usually becomes evident between three and twelve months after testosterone therapy initiation. However,polycythaemia can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral administration and, development of comorbidity, which can be linked to an increase in haematocrit (e.g., respiratory or haematological diseases).
There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis.
As detailed, the TRAVERSE study, which had included symptomatic hypogonadal men aged 45-80 years who had pre-existing or a high risk of CVD, showed a mild higher incidence of pulmonary embolism, a component of the adjudicated tertiary end point of venous thromboembolic events, in the testosterone therapy than in the placebo group (0.9% vs. 0.5%) [77]. However, three previous large studies have not shown any evidence that testosterone therapy is associated with an increased risk of venous thromboembolism [180, 181]. Of those, one study showed that an increased risk peaked at six months after initiation of testosterone therapy, and then declined over the subsequent period [182]. In one study venous thromboembolism was reported in 42 cases and 40 of these had a diagnosis of an underlying congenital thrombophilia (including factor V Leiden deficiency, prothrombin mutations and homocysteinuria) [183]. A meta-analysis of RCTs of testosterone therapy reported that venous thromboembolism was frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders [78]. In an RCT of testosterone therapy in men with chronic stable angina there were no adverse effects on coagulation, by assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme activity or fibrinogen levels [184]. Similarly, another meta-analysis and systematic review of RCTs found that testosterone therapy was not associated with an increased risk of venous thromboembolism [164]. With testosterone therapy elevated haematocrit levels are more likely to occur if the baseline level is toward the upper limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include smoking or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather than topical formulations. Accordingly, a large retrospective two-arm open registry, comparing the effects of long-acting testosterone undecanoate and testosterone gels showed that the former preparation was associated with a higher risk of haematocrit levels > 50%, when compared to testosterone gels [185]. In men with pre-existing CVD extra caution is advised with a definitive diagnosis of hypogonadism before initiating testosterone therapy and monitoring of testosterone as well as haematocrit during treatment.
Elevated haematocrit in the absence of comorbidity or acute CV or venous thromboembolism can be managed by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is very high by venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone therapy.
3.5.7 Obstructive Sleep Apnoea
There is no evidence that testosterone therapy can result in the onset or worsening of sleep apnoea. Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective than CPAP alone in the treatment of obstructive sleep apnoea [186]. In one RCT, testosterone therapy in men with severe sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after seven weeks of therapy compared to placebo, but this change was not evident after eighteen weeks’ treatment and there was n oassociation with baseline testosterone levels [187].
Table 6: Clinical and biochemical parameters to be checked during testosterone therapy
3.5.9 Summary of evidence and recommendations on safety and monitoring in testosterone treatment
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Erythrocytosis
*There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis
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*There is no evidence that an increase of haematocrit up to and including 54% causes any adverse effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV events and mortality [79, 177-179]. Any relationship is complex as these studies were based on patients with any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no specific studies in men with only testosterone-induced erythrocytosis
Testosterone Therapy and Erythrocytosis - the most common dose-limiting effect of testosterone therapy
https://www.thebloodproject.com/cases-archive/testosterone-therapy-and-erythrocytosis-2/ Introduction Androgens play a crucial role in the development and maintenance of: Male reproductive and sexual functions Body composition Erythropoiesis Muscle and bone health Cognitive function...
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