madman
Super Moderator
Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics
Carola S. König, PhD, Stavroula Balabani, PhD, Geoffrey I. Hackett, MD, Richard C. Strange, PhD, and Sudarshan Ramachandran, PhD, FRC Path
Introduction
Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded.
Aim
To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh.
Methods
We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered.
Main Outcome Measures
The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit.
Results
Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds.
Conclusions
TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups.
CONCLUSION
Although TTh use has increased, with most studies demonstrating benefit, doubts of its safety based on a few controversial reports of increased CVD remain. We have seen that increased hematocrit is the most common adverse effect of TTh, and guidelines regarding action thresholds are based on a population derived level of 0.54. Longitudinal studies suggest that hematocrit influences CVD morbidity and mortality, although the association may not be linear. It is clear that further studies are required, and we propose that, in addition to clinical studies with hard and surrogate endpoints, changes in blood flow characteristics should be evaluated across macro- and microcirculatory vascular beds.
*Advanced computational tools are required to understand the particulate nature of blood in the microcirculation, taking into account the impact of increased hematocrit and altered erythrocyte properties. Although this has been carried out in some pathologies (sickle cell anemia,83 malaria84), only simple vascular geometries rather than networks were considered. Microfluidics has allowed microscale blood flow characteristics to be probed, allowing cell and flow distribution to be resolved and phenomena such as erythrocyte aggregation and deformability on those to be studied in detail.52,53 Thus, concurrent studies of clinical outcomes and evaluation of flow changes after hematocrit change during TTh in different patient groups will allow management guidance based on evidence that allows for patient heterogeneity.
Carola S. König, PhD, Stavroula Balabani, PhD, Geoffrey I. Hackett, MD, Richard C. Strange, PhD, and Sudarshan Ramachandran, PhD, FRC Path
Introduction
Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded.
Aim
To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh.
Methods
We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered.
Main Outcome Measures
The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit.
Results
Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds.
Conclusions
TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups.
CONCLUSION
Although TTh use has increased, with most studies demonstrating benefit, doubts of its safety based on a few controversial reports of increased CVD remain. We have seen that increased hematocrit is the most common adverse effect of TTh, and guidelines regarding action thresholds are based on a population derived level of 0.54. Longitudinal studies suggest that hematocrit influences CVD morbidity and mortality, although the association may not be linear. It is clear that further studies are required, and we propose that, in addition to clinical studies with hard and surrogate endpoints, changes in blood flow characteristics should be evaluated across macro- and microcirculatory vascular beds.
*Advanced computational tools are required to understand the particulate nature of blood in the microcirculation, taking into account the impact of increased hematocrit and altered erythrocyte properties. Although this has been carried out in some pathologies (sickle cell anemia,83 malaria84), only simple vascular geometries rather than networks were considered. Microfluidics has allowed microscale blood flow characteristics to be probed, allowing cell and flow distribution to be resolved and phenomena such as erythrocyte aggregation and deformability on those to be studied in detail.52,53 Thus, concurrent studies of clinical outcomes and evaluation of flow changes after hematocrit change during TTh in different patient groups will allow management guidance based on evidence that allows for patient heterogeneity.
