madman
Super Moderator
* TRT does not increase MACE risk in men with confirmed organic hypogonadism when titrated to physiological levels. Non-MACE signals warrant vigilance rather than contraindication. Metabolic optimisation should precede TRT in functional hypogonadism. Individualised monitoring and careful patient selection remain essential.
=========
------lkmk
The TRAVERSE trial: what it established and what it did not
Design and population
TRAVERSE was a double-blind, placebo-controlled, event-driven non-inferiority trial conducted across 316 sites in the United States [5]. It enrolled men aged 45 to 80 years with confirmed hypogonadism (total testosterone <300 ng/dL on two separate morning measurements) and at least one cardiovascular risk factor or established cardiovascular disease.
--
Participants received transdermal testosterone gel, titrated to mid-normal physiological concentrations (350–750 ng/dL), rather than supraphysiological levels. The primary endpoint was a composite of major adverse cardiovascular events (MACE): non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. The trial was event-driven, with a median follow-up of 3.2 years.
--
This design addressed several limitations of earlier studies: the trial was adequately powered, enrolled a population
that closely reflects routine clinical practice, used adjudicated endpoints, and avoided the supraphysiological testosterone levels that had confounded the TOM trial. The choice of transdermal gel as the study formulation was deliberate, it allows more precise titration and avoids the sharp peaks associated with injectable preparations. The main characteristics of TRAVERSE and the other pivotal studies are summarised in Table 1.
--
The experience of the TOM study, where supraphysiological testosterone exposure in a high-risk population led to early trial termination, directly informed the TRAVERSE protocol. By titrating to mid-normal levels and excluding men with very recent cardiovascular events, the trial was designed to test the safety of TRT as it would be used in careful clinical practice, not in an extreme scenario.
==========
Primary endpoint: MACE
The clinical implications are relevant. For many men with confirmed organic hypogonadism who have historically been denied TRT because of cardiovascular safety concerns, TRAVERSE offers a more solid basis for reconsidering treatment, provided that patient selection is appropriate an monitoring is carefully implemented. This interpretation is consistent with the individual patient data meta-analysis by Hudson and colleagues, which did not show an increased risk of cardiovascular mortality or events across 35 trials [8], as well as with the updated meta-analysis by Corona and colleagues that incorporates TRAVERSE data [9].
==========
The non-inferiority margin and its limitations
Before moving to the non-MACE findings, it is important to recognize what TRAVERSE cannot fully answer. Although the trial provides robust reassurance regarding major adverse cardiovascular events, the median follow-up of 3.2 years may still be too short to capture potential late cardiovascular consequences of long-term testosterone exposure. This issue is particularly relevant for outcomes such as atrial fibrillation, which may remain intermittent, asymptomatic, and clinically unrecognized for prolonged periods. In addition, only a small proportion of participants were older than 75 years of age (approximately 8%), limiting the applicability of the findings to the oldest and most vulnerable patients commonly encountered in routine clinical practice. Importantly, demonstrating non-inferiority for MACE should not be interpreted as proof of universal cardiovascular safety across all possible outcomes. While the primary endpoint was reassuring, other cardiovascular and systemic signals emerged during the study and deserve separate consideration. Contemporary guideline documents have appropriately emphasized these nuances, encouraging clinicians to interpret the reassuring MACE data within the broader context of individualized risk assessment and long- term monitoring [10, 11].
========
Cardiovascular safety beyond mace
Erythrocytosis: The most consistent signal
From a practical standpoint, current evidence supports haematocrit monitoring at 3–6 months during the first year of TRT and annually thereafter, with dose reduction or temporary treatment discontinuation when haematocrit exceeds 54% or haemoglobin exceeds 18.5 g/dL [12, 15]. Therapeutic phlebotomy may be considered in selected cases where treatment continuation is clinically important. Importantly, given that more than half of patients reach peak haematocrit after the first year, annual monitoring should not be interpreted as a licence to reduce vigilance. In men with borderline baseline haematocrit, OSA, COPD, or concurrent SGLT-2 inhibitor therapy, we recommend more frequent early monitoring (at one month, then three months) and a lower threshold for formulation change toward transdermal or intranasal preparations. These monitoring recommendations are reflected in Table 2.
==========
Hypertension
The mechanisms underlying this effect are likely multifactorial. Testosterone may promote sodium and water
retention and has complex effects on endothelial function and coronary vasodilation that can be directionally opposite depending on the dose and the vascular bed involved [16]. One particularly well-characterised contributor is the erythrocytosis pathway: as haematocrit rises, blood viscosity increases, augmenting peripheral vascular resistance and amplifying the pressor response to testosterone.
==
From a clinical standpoint, the practical implication is one of careful patient stratification rather than categorical avoidance. In a normotensive man with organic hypogonadism and no metabolic comorbidities, the 1.6 mmHg increment observed in TRAVERSE is unlikely to alter his cardiovascular trajectory meaningfully. In a man with borderline or treated hypertension, chronic kidney disease, or established cardiovascular disease, even a small upward pressure shift may be clinically consequential over time, and blood pressure should be measured at baseline and at each monitoring visit. In men with metabolic syndrome or obesity-related functional hypogonadism, the priority should be metabolic optimisation before TRT initiation, not only because testosterone normalisation may occur spontaneously with weight loss, but because the blood pressure effects of TRT in this group may be genuinely beneficial once the metabolic substrate is adequately addressed.
=========
Non-MACE safety signals: a differentiated assessment
The non-MACE safety signals in TRAVERSE require careful interpretation. The trial data and the observational data tell a subtly different story, and conflating them as has sometimes been done in clinical guidelines and regulatory documents leads to either overestimation or underestimation of risk depending on which source is emphasised.
Atrial fibrillation (AF)
The mechanistic underpinning for a testosterone–arrhythmia relationship is biologically coherent. Testosterone inhibits L-type calcium channels, modulates cardiac potassium currents, and may promote atrial structural remodelling through androgenic receptor-mediated pathways [23].
--
The overall interpretation is one of a plausible but incompletely characterised signal. The trial and observational data are directionally consistent: both point toward a modest relationship between the androgenic milieu and AF risk that is likely mediated through multiple converging pathways, direct electrophysiological effects, haemodynamic consequences of erythrocytosis-driven viscosity increases, and the cardiometabolic substrate of the population most likely to receive TRT. The signal does not currently justify withholding TRT from men with well-established hypogonadism, but it does justify incorporating AF risk into the pre-treatment evaluation. Baseline cardiac rhythm assessment, at minimum a standard 12-lead ECG, should be obtained in men with established cardiovascular disease, hypertension, obesity, or obstructive sleep apnoea before initiating TRT, and the arrhythmic signal should be discussed explicitly during the informed consent process in men with pre-existing conduction abnormalities or a history of paroxysmal AF.
========
Venous thromboembolism (VTE) and pulmonary embolism (PE)
The mechanistic explanation for this early risk window is most plausibly erythrocytosis-driven hyperviscosity. Testosterone stimulates erythropoiesis through increased renal erythropoietin production, direct bone marrow effects, and hepcidin suppression, all of which converge to raise haematocrit within the first months of treatment.
--
From a clinical management standpoint, haematocrit monitoring is the central instrument for VTE risk mitigation. Monitoring should be performed at baseline, at three to six months, and annually thereafter, with temporary treatment interruption and dose adjustment triggered by Hct exceeding 54%, or 50% according to the more conservative AACE and ICSM thresholds [25, 26]. Men with prior VTE or known thrombophilia represent a particularly high-risk phenotype in whom TRT should only be initiated after explicit shared decision-making, with an individualised monitoring plan and specialist input regarding thromboprophylaxis. The pre-treatment evaluation should also encompass obstructive sleep apnoea, chronic kidney disease, and uncontrolled hypertension, all conditions that independently amplify erythrocytosis risk and thromboembolic susceptibility. Patients should be counselled proactively on alarm symptoms, new or unexplained dyspnoea, pleuritic chest pain, or unilateral leg swelling, with a low threshold for diagnostic evaluation during the first six months of therapy. A clinically important gap in current practice is that no widely used VTE risk stratification tool including the Wells criteria, the PERC score, or the YEARS algorithm, currently incorporates testosterone replacement therapy as a contributing risk factor, an omission that warrants attention in future guideline revisions [25, 27].
===
Acute kidney injury (AKI)
The mechanistic basis for TRT-associated AKI is multifactorial. Testosterone promotes sodium and water retention through both direct renal tubular effects and RAAS activation, increasing intraglomerular pressure and fluid loading in a manner that can precipitate AKI in men with reduce renal reserve [25].
--
From a clinical management standpoint, pre-treatment renal assessment is mandatory in all men being considered for TRT, and CKD stage 3–5 (eGFR <60 ml/min/1.73 m²), a solitary kidney, rapidly progressive CKD, or a history of recurrent AKI should each be considered high-risk phenotypes requiring intensified monitoring or reconsideration of treatment initiation [25]. Renal function should be reassessed at three to six weeks after initiation, capturing the early haemodynamic response and again at three months, with annual review thereafter in stable patients and more frequent assessment in those with baseline renal impairment. A confirmed eGFR decline of ≥ 20% from baseline should trigger evaluation for intercurrent illness, nephrotoxin exposure, and reversible contributors, with dose reduction, formulation change, or temporary interruption as appropriate; persistent or recurrent renal dysfunction should prompt formal reassessment of the indication for TRT [25]. In men with pre-existing CKD or significant proteinuria, nephrology input before initiation and at the first sign of renal deterioration is a clinically prudent step that the current evidence base supports.
=====
Fractures
The apparent contradiction between BMD benefit and fracture risk increase is reconciled by a possible behavioural–musculoskeletal mismatch hypothesis: TRT-related improvements in muscle strength, energy, and perceived vitality lead to increased physical activity and fall exposure in men who were previously sedentary, before slower connective tissue and bone quality adaptations have had time to fully consolidate [36, 38]. Most fractures in TRAVERSE occurred at traumatic sites (ribs, wrists, ankles) and clustered in the early months after treatment initiation, supporting a behavioural rather than a bone quality mechanism [38].
--
It is important to note that untreated hypogonadism is itself a significant fracture risk factor (OR 1.76, 95% CI 1.37–2.26), accounting for 16–30% of male osteoporosis cases [41]. The fracture signal with TRT therefore does not argue for withholding treatment from hypogonadal men, it argues for careful activity counselling, fall risk assessment, and, where indicated, concurrent osteoporosis-specific therapy. Current Endocrine Society guidelines recommend TRT for symptomatic relief in hypogonadal men but do not endorse it as primary treatment for osteoporosis; in men with both hypogonadism and osteoporosis, TRT should combined with evidence-based antiresorptive therapy [42].
--
In our practice, we have become more cautious about initiating TRT in men over 75 with a history of falls or reduced bone density, and we now routinely assess fall risk and consider DXA scanning in this group before starting therapy. Counselling on gradual activity progression avoiding an abrupt transition from sedentary to physically demanding behaviour is a practical measure that we have found valuable in reducing early injury risk.
=========
------lkmk
The TRAVERSE trial: what it established and what it did not
Design and population
TRAVERSE was a double-blind, placebo-controlled, event-driven non-inferiority trial conducted across 316 sites in the United States [5]. It enrolled men aged 45 to 80 years with confirmed hypogonadism (total testosterone <300 ng/dL on two separate morning measurements) and at least one cardiovascular risk factor or established cardiovascular disease.
--
Participants received transdermal testosterone gel, titrated to mid-normal physiological concentrations (350–750 ng/dL), rather than supraphysiological levels. The primary endpoint was a composite of major adverse cardiovascular events (MACE): non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. The trial was event-driven, with a median follow-up of 3.2 years.
--
This design addressed several limitations of earlier studies: the trial was adequately powered, enrolled a population
that closely reflects routine clinical practice, used adjudicated endpoints, and avoided the supraphysiological testosterone levels that had confounded the TOM trial. The choice of transdermal gel as the study formulation was deliberate, it allows more precise titration and avoids the sharp peaks associated with injectable preparations. The main characteristics of TRAVERSE and the other pivotal studies are summarised in Table 1.
--
The experience of the TOM study, where supraphysiological testosterone exposure in a high-risk population led to early trial termination, directly informed the TRAVERSE protocol. By titrating to mid-normal levels and excluding men with very recent cardiovascular events, the trial was designed to test the safety of TRT as it would be used in careful clinical practice, not in an extreme scenario.
==========
Primary endpoint: MACE
The clinical implications are relevant. For many men with confirmed organic hypogonadism who have historically been denied TRT because of cardiovascular safety concerns, TRAVERSE offers a more solid basis for reconsidering treatment, provided that patient selection is appropriate an monitoring is carefully implemented. This interpretation is consistent with the individual patient data meta-analysis by Hudson and colleagues, which did not show an increased risk of cardiovascular mortality or events across 35 trials [8], as well as with the updated meta-analysis by Corona and colleagues that incorporates TRAVERSE data [9].
==========
The non-inferiority margin and its limitations
Before moving to the non-MACE findings, it is important to recognize what TRAVERSE cannot fully answer. Although the trial provides robust reassurance regarding major adverse cardiovascular events, the median follow-up of 3.2 years may still be too short to capture potential late cardiovascular consequences of long-term testosterone exposure. This issue is particularly relevant for outcomes such as atrial fibrillation, which may remain intermittent, asymptomatic, and clinically unrecognized for prolonged periods. In addition, only a small proportion of participants were older than 75 years of age (approximately 8%), limiting the applicability of the findings to the oldest and most vulnerable patients commonly encountered in routine clinical practice. Importantly, demonstrating non-inferiority for MACE should not be interpreted as proof of universal cardiovascular safety across all possible outcomes. While the primary endpoint was reassuring, other cardiovascular and systemic signals emerged during the study and deserve separate consideration. Contemporary guideline documents have appropriately emphasized these nuances, encouraging clinicians to interpret the reassuring MACE data within the broader context of individualized risk assessment and long- term monitoring [10, 11].
========
Cardiovascular safety beyond mace
Erythrocytosis: The most consistent signal
From a practical standpoint, current evidence supports haematocrit monitoring at 3–6 months during the first year of TRT and annually thereafter, with dose reduction or temporary treatment discontinuation when haematocrit exceeds 54% or haemoglobin exceeds 18.5 g/dL [12, 15]. Therapeutic phlebotomy may be considered in selected cases where treatment continuation is clinically important. Importantly, given that more than half of patients reach peak haematocrit after the first year, annual monitoring should not be interpreted as a licence to reduce vigilance. In men with borderline baseline haematocrit, OSA, COPD, or concurrent SGLT-2 inhibitor therapy, we recommend more frequent early monitoring (at one month, then three months) and a lower threshold for formulation change toward transdermal or intranasal preparations. These monitoring recommendations are reflected in Table 2.
==========
Hypertension
The mechanisms underlying this effect are likely multifactorial. Testosterone may promote sodium and water
retention and has complex effects on endothelial function and coronary vasodilation that can be directionally opposite depending on the dose and the vascular bed involved [16]. One particularly well-characterised contributor is the erythrocytosis pathway: as haematocrit rises, blood viscosity increases, augmenting peripheral vascular resistance and amplifying the pressor response to testosterone.
==
From a clinical standpoint, the practical implication is one of careful patient stratification rather than categorical avoidance. In a normotensive man with organic hypogonadism and no metabolic comorbidities, the 1.6 mmHg increment observed in TRAVERSE is unlikely to alter his cardiovascular trajectory meaningfully. In a man with borderline or treated hypertension, chronic kidney disease, or established cardiovascular disease, even a small upward pressure shift may be clinically consequential over time, and blood pressure should be measured at baseline and at each monitoring visit. In men with metabolic syndrome or obesity-related functional hypogonadism, the priority should be metabolic optimisation before TRT initiation, not only because testosterone normalisation may occur spontaneously with weight loss, but because the blood pressure effects of TRT in this group may be genuinely beneficial once the metabolic substrate is adequately addressed.
=========
Non-MACE safety signals: a differentiated assessment
The non-MACE safety signals in TRAVERSE require careful interpretation. The trial data and the observational data tell a subtly different story, and conflating them as has sometimes been done in clinical guidelines and regulatory documents leads to either overestimation or underestimation of risk depending on which source is emphasised.
Atrial fibrillation (AF)
The mechanistic underpinning for a testosterone–arrhythmia relationship is biologically coherent. Testosterone inhibits L-type calcium channels, modulates cardiac potassium currents, and may promote atrial structural remodelling through androgenic receptor-mediated pathways [23].
--
The overall interpretation is one of a plausible but incompletely characterised signal. The trial and observational data are directionally consistent: both point toward a modest relationship between the androgenic milieu and AF risk that is likely mediated through multiple converging pathways, direct electrophysiological effects, haemodynamic consequences of erythrocytosis-driven viscosity increases, and the cardiometabolic substrate of the population most likely to receive TRT. The signal does not currently justify withholding TRT from men with well-established hypogonadism, but it does justify incorporating AF risk into the pre-treatment evaluation. Baseline cardiac rhythm assessment, at minimum a standard 12-lead ECG, should be obtained in men with established cardiovascular disease, hypertension, obesity, or obstructive sleep apnoea before initiating TRT, and the arrhythmic signal should be discussed explicitly during the informed consent process in men with pre-existing conduction abnormalities or a history of paroxysmal AF.
========
Venous thromboembolism (VTE) and pulmonary embolism (PE)
The mechanistic explanation for this early risk window is most plausibly erythrocytosis-driven hyperviscosity. Testosterone stimulates erythropoiesis through increased renal erythropoietin production, direct bone marrow effects, and hepcidin suppression, all of which converge to raise haematocrit within the first months of treatment.
--
From a clinical management standpoint, haematocrit monitoring is the central instrument for VTE risk mitigation. Monitoring should be performed at baseline, at three to six months, and annually thereafter, with temporary treatment interruption and dose adjustment triggered by Hct exceeding 54%, or 50% according to the more conservative AACE and ICSM thresholds [25, 26]. Men with prior VTE or known thrombophilia represent a particularly high-risk phenotype in whom TRT should only be initiated after explicit shared decision-making, with an individualised monitoring plan and specialist input regarding thromboprophylaxis. The pre-treatment evaluation should also encompass obstructive sleep apnoea, chronic kidney disease, and uncontrolled hypertension, all conditions that independently amplify erythrocytosis risk and thromboembolic susceptibility. Patients should be counselled proactively on alarm symptoms, new or unexplained dyspnoea, pleuritic chest pain, or unilateral leg swelling, with a low threshold for diagnostic evaluation during the first six months of therapy. A clinically important gap in current practice is that no widely used VTE risk stratification tool including the Wells criteria, the PERC score, or the YEARS algorithm, currently incorporates testosterone replacement therapy as a contributing risk factor, an omission that warrants attention in future guideline revisions [25, 27].
===
Acute kidney injury (AKI)
The mechanistic basis for TRT-associated AKI is multifactorial. Testosterone promotes sodium and water retention through both direct renal tubular effects and RAAS activation, increasing intraglomerular pressure and fluid loading in a manner that can precipitate AKI in men with reduce renal reserve [25].
--
From a clinical management standpoint, pre-treatment renal assessment is mandatory in all men being considered for TRT, and CKD stage 3–5 (eGFR <60 ml/min/1.73 m²), a solitary kidney, rapidly progressive CKD, or a history of recurrent AKI should each be considered high-risk phenotypes requiring intensified monitoring or reconsideration of treatment initiation [25]. Renal function should be reassessed at three to six weeks after initiation, capturing the early haemodynamic response and again at three months, with annual review thereafter in stable patients and more frequent assessment in those with baseline renal impairment. A confirmed eGFR decline of ≥ 20% from baseline should trigger evaluation for intercurrent illness, nephrotoxin exposure, and reversible contributors, with dose reduction, formulation change, or temporary interruption as appropriate; persistent or recurrent renal dysfunction should prompt formal reassessment of the indication for TRT [25]. In men with pre-existing CKD or significant proteinuria, nephrology input before initiation and at the first sign of renal deterioration is a clinically prudent step that the current evidence base supports.
=====
Fractures
The apparent contradiction between BMD benefit and fracture risk increase is reconciled by a possible behavioural–musculoskeletal mismatch hypothesis: TRT-related improvements in muscle strength, energy, and perceived vitality lead to increased physical activity and fall exposure in men who were previously sedentary, before slower connective tissue and bone quality adaptations have had time to fully consolidate [36, 38]. Most fractures in TRAVERSE occurred at traumatic sites (ribs, wrists, ankles) and clustered in the early months after treatment initiation, supporting a behavioural rather than a bone quality mechanism [38].
--
It is important to note that untreated hypogonadism is itself a significant fracture risk factor (OR 1.76, 95% CI 1.37–2.26), accounting for 16–30% of male osteoporosis cases [41]. The fracture signal with TRT therefore does not argue for withholding treatment from hypogonadal men, it argues for careful activity counselling, fall risk assessment, and, where indicated, concurrent osteoporosis-specific therapy. Current Endocrine Society guidelines recommend TRT for symptomatic relief in hypogonadal men but do not endorse it as primary treatment for osteoporosis; in men with both hypogonadism and osteoporosis, TRT should combined with evidence-based antiresorptive therapy [42].
--
In our practice, we have become more cautious about initiating TRT in men over 75 with a history of falls or reduced bone density, and we now routinely assess fall risk and consider DXA scanning in this group before starting therapy. Counselling on gradual activity progression avoiding an abrupt transition from sedentary to physically demanding behaviour is a practical measure that we have found valuable in reducing early injury risk.
