madman
Super Moderator
* Once a patient is established on therapy, both the AUA and the EAU identify a HCT level of 54%, as the level at which intervention is warranted. Neither framework offers a step-by-step approach for responding should the HCT begins to rise or the sequence and timing of necessary actions.
* Before starting TTh, we use the TTh checklist , 3 which highlights the importance of measuring the pre-treatment HCT level. It is important to note that low T levels should be accompanied by low-normal HCT levels or even unexplained anemia. Conversely, an elevated HCT in the presence of low T raises concerns about an underlying condition associated with erythrocytosis. Since converting a patient from a T deficient to replete state can increase HCT several percentage points, we take a conservative approach. We further evaluate patients if their baseline HCT exceeds 45%, as this level increases the risk of crossing the 50% threshold once TTh begins. Patients with a base-line HCT below 45% may start TTh without need for additional hematologic evaluation. In patients with a baseline HCT of 45% or greater, causes of an elevated HCT should be considered before starting TTh, including OSA, chronic pulmonary disease, residence at altitude, and polycythemia vera, among others
Polycythemia (PCT) is defined as an absolute increase in red blood cell mass, manifested clinically as an elevation in hematocrit (HCT), and is categorized as primary or secondary. Primary PCT refers to polycythemia vera. Secondary PCT is caused by an identifiable external stimulus to erythropoiesis, such as hypoxia, pulmonary disease, living at altitude, increased erythropoietin levels, or the administration of exogenous testosterone (T).
Secondary PCT is one of the most common adverse events of testosterone therapy (TTh). The underlying erythropoietic stimulus is multifactorial, with three principal mechanisms described. (1) TTh suppresses hepatic hepcidin production, thereby increasing duodenal iron absorption, mobilizing stored iron, and augmenting substrate availability for erythropoiesis (2) TTh stimulates erythropoietin production and recalibrates the erythropoietin-hemoglobin set point , such that erythropoietin levels remain inappropriately elevated. (3) Androgens enhance erythropoietic activity within the bone marrow. The net effect is a sustained increase in red cell production. Obstructive sleep apnea (OSA) warrants particular attention in this regard. The intermittent nocturnal hypoxia represents an additional erythropoietic stimulus that compounds the effect of TTh, and a concomitant OSA diagnosis has accordingly been associated with a roughly two-fold higher likelihood of developing secondary PCT in men on TTh.
PCT is a serious medical condition linked to an increased risk of thromboembolic cardiovascular events due to higher blood viscosity. These events include deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. In our clinical practice, we have consistently adopted a highly conservative approach to HCT management , with a level ≥ 50% warranting attention, providing us with a safety margin that allows intervention before reaching the higher-risk HCT level.
Current guidelines only partially address this risk , primarily focusing on the period before treatment begins. Both the American Urological Association (AUA) and the European Association of Urology (EAU) recommend exercising caution when the baseline HCT is elevated. They advise evaluating the underlying cause and, when appropriate, withholding TTh until it has been clarified. 1 , 2 Once a patient is established on therapy, both the AUA and the EAU identify a HCT level of 54%, as the level at which intervention is warranted. Neither framework offers a step-by-step approach for responding should the HCT begins to rise or the sequence and timing of necessary actions.
Therefore, we propose the following clinical care pathway to address this management issue. Before starting TTh, we use the TTh checklist , 3 which highlights the importance of measuring the pre-treatment HCT level. It is important to note that low T levels should be accompanied by low-normal HCT levels or even unexplained anemia. Conversely, an elevated HCT in the presence of low T raises concerns about an underlying condition associated with erythrocytosis. Since converting a patient from a T deficient to replete state can increase HCT several percentage points, we take a conservative approach. We further evaluate patients if their baseline HCT exceeds 45%, as this level increases the risk of crossing the 50% threshold once TTh begins. Patients with a base-line HCT below 45% may start TTh without need for additional hematologic evaluation. In patients with a baseline HCT of 45% or greater, causes of an elevated HCT should be considered before starting TTh, including OSA, chronic pulmonary disease, residence at altitude, and polycythemia vera, among others.
Given that the prevalence of secondary PCT in men with OSA on TTh is increased compared to men without OSA, we screen all TTh candidates for OSA using the STOP-BANG questionnaire (SBQ). The SBQ is a validated screening tool for OSA. For patients with a baseline HCT of 45-50%, those who score at moderate to high risk on the SBQ undergo a home sleep apnea test (HSAT). Patients categorized as low risk may begin TTh, and the HCT must be monitored closely. If the HSAT result is positive, TTh is deferred, and a consultation with a sleep medicine clinician is encouraged to treat OSA before proceeding with TTh. If the HSAT result is negative, TTh may be initiated, and the HCT will be monitored carefully. For patients with a baseline HCT of 50% or higher, we go directly to the HSAT. A positive result leads to a deferral of TTh and a referral to a sleep medicine specialist , while a negative result prompts a referral to a hematologist to investigate other potential causes of the elevated HCT before considering TTh ( Supplementar y Figure S1).
Once TTh is initiated, HCT is monitored alongside the serum T level, typically 2-4 weeks after TTh initiation. Following any dose adjustment or change in formulation, HCT is rechecked at the corresponding interval. Once T levels are stable within the therapeutic T range, HCT is monitored every 6 months in conjunction with the serum T level. For patients undergoing TTh, our approach follows a stepwise protocol based on HCT thresholds (Supplementary Figure S2). We define secondary PCT as an HCT of 50% or higher, which triggers active management . If a patient on TTh remains stable and has an HCT below 50%, we will continue the therapy as is and conduct laboratory testing every 6 months. An HCT level of 50% or higher requires a careful evaluation. For an HCT elevation between 50% and 52%, dose reduction alone may suffice. In our practice, these cases would complete an SBQ and HSAT, and, in the event of a positive OSA result , a sleep medicine referral is ordered to manage OSA. The T dose remains reduced, and labs are repeated in 4 weeks. However, if the HCT reaches 52% or higher, more immediate intervention is necessary.
Phlebotomy is typically performed to address a critically elevated HCT and should be done alongside the discontinuation of TTh or a significant reduction in TTh dose. The goal during this corrective phase is to reduce the HCT back to ≤45%. The procedure consists of the scheduled withdrawal of approximately 450-500 mL of whole blood from a peripheral vein, performed with or without isovolemic fluid replacement depending on the patient’s tolerance and cardiovascular status. No dedicated phlebotomy protocol exists for TTH-induced secondary PCT—our approach is therefore extrapolated from polycythemiavera management—on a weekly basis until the target HCT is reached, after which the interval is adjusted according to HCT monitoring. Repeated phle botomies carries a risk of iron deficiency, which may produce anemia and paradoxically result in thromboc ytosis, with a potential increase in thrombotic risk
The decision to resume TTh after addressing secondary PCT is tailored to the individual. It is recommended to restart TTh only after the HCT has dropped to ≤45%, following phlebotomy and the management of any other contributing factors, particularly OSA. In any patient who develops polycythemia a HSAT is ordered (if not already done) and follow-up with a sleep medicine specialist to evaluate and potentially treat OSA before TTh is resumed. Upon resuming therapy, consideration should be given to starting with a low-dose T regimen or switching to a formulation associated with lower rates of secondary PCT.
In summary, secondar y PCT is a recognized and clinically significant complication of TTh that requires a systematic, protocol-driven approach. The integration of pre-treatment OSA screening, formulation-conscious prescribing, structured HCT monitoring, and a stepwise management algorithm allows for safe continuation or resumption of TTh.
* Before starting TTh, we use the TTh checklist , 3 which highlights the importance of measuring the pre-treatment HCT level. It is important to note that low T levels should be accompanied by low-normal HCT levels or even unexplained anemia. Conversely, an elevated HCT in the presence of low T raises concerns about an underlying condition associated with erythrocytosis. Since converting a patient from a T deficient to replete state can increase HCT several percentage points, we take a conservative approach. We further evaluate patients if their baseline HCT exceeds 45%, as this level increases the risk of crossing the 50% threshold once TTh begins. Patients with a base-line HCT below 45% may start TTh without need for additional hematologic evaluation. In patients with a baseline HCT of 45% or greater, causes of an elevated HCT should be considered before starting TTh, including OSA, chronic pulmonary disease, residence at altitude, and polycythemia vera, among others
Polycythemia (PCT) is defined as an absolute increase in red blood cell mass, manifested clinically as an elevation in hematocrit (HCT), and is categorized as primary or secondary. Primary PCT refers to polycythemia vera. Secondary PCT is caused by an identifiable external stimulus to erythropoiesis, such as hypoxia, pulmonary disease, living at altitude, increased erythropoietin levels, or the administration of exogenous testosterone (T).
Secondary PCT is one of the most common adverse events of testosterone therapy (TTh). The underlying erythropoietic stimulus is multifactorial, with three principal mechanisms described. (1) TTh suppresses hepatic hepcidin production, thereby increasing duodenal iron absorption, mobilizing stored iron, and augmenting substrate availability for erythropoiesis (2) TTh stimulates erythropoietin production and recalibrates the erythropoietin-hemoglobin set point , such that erythropoietin levels remain inappropriately elevated. (3) Androgens enhance erythropoietic activity within the bone marrow. The net effect is a sustained increase in red cell production. Obstructive sleep apnea (OSA) warrants particular attention in this regard. The intermittent nocturnal hypoxia represents an additional erythropoietic stimulus that compounds the effect of TTh, and a concomitant OSA diagnosis has accordingly been associated with a roughly two-fold higher likelihood of developing secondary PCT in men on TTh.
PCT is a serious medical condition linked to an increased risk of thromboembolic cardiovascular events due to higher blood viscosity. These events include deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. In our clinical practice, we have consistently adopted a highly conservative approach to HCT management , with a level ≥ 50% warranting attention, providing us with a safety margin that allows intervention before reaching the higher-risk HCT level.
Current guidelines only partially address this risk , primarily focusing on the period before treatment begins. Both the American Urological Association (AUA) and the European Association of Urology (EAU) recommend exercising caution when the baseline HCT is elevated. They advise evaluating the underlying cause and, when appropriate, withholding TTh until it has been clarified. 1 , 2 Once a patient is established on therapy, both the AUA and the EAU identify a HCT level of 54%, as the level at which intervention is warranted. Neither framework offers a step-by-step approach for responding should the HCT begins to rise or the sequence and timing of necessary actions.
Therefore, we propose the following clinical care pathway to address this management issue. Before starting TTh, we use the TTh checklist , 3 which highlights the importance of measuring the pre-treatment HCT level. It is important to note that low T levels should be accompanied by low-normal HCT levels or even unexplained anemia. Conversely, an elevated HCT in the presence of low T raises concerns about an underlying condition associated with erythrocytosis. Since converting a patient from a T deficient to replete state can increase HCT several percentage points, we take a conservative approach. We further evaluate patients if their baseline HCT exceeds 45%, as this level increases the risk of crossing the 50% threshold once TTh begins. Patients with a base-line HCT below 45% may start TTh without need for additional hematologic evaluation. In patients with a baseline HCT of 45% or greater, causes of an elevated HCT should be considered before starting TTh, including OSA, chronic pulmonary disease, residence at altitude, and polycythemia vera, among others.
Given that the prevalence of secondary PCT in men with OSA on TTh is increased compared to men without OSA, we screen all TTh candidates for OSA using the STOP-BANG questionnaire (SBQ). The SBQ is a validated screening tool for OSA. For patients with a baseline HCT of 45-50%, those who score at moderate to high risk on the SBQ undergo a home sleep apnea test (HSAT). Patients categorized as low risk may begin TTh, and the HCT must be monitored closely. If the HSAT result is positive, TTh is deferred, and a consultation with a sleep medicine clinician is encouraged to treat OSA before proceeding with TTh. If the HSAT result is negative, TTh may be initiated, and the HCT will be monitored carefully. For patients with a baseline HCT of 50% or higher, we go directly to the HSAT. A positive result leads to a deferral of TTh and a referral to a sleep medicine specialist , while a negative result prompts a referral to a hematologist to investigate other potential causes of the elevated HCT before considering TTh ( Supplementar y Figure S1).
Once TTh is initiated, HCT is monitored alongside the serum T level, typically 2-4 weeks after TTh initiation. Following any dose adjustment or change in formulation, HCT is rechecked at the corresponding interval. Once T levels are stable within the therapeutic T range, HCT is monitored every 6 months in conjunction with the serum T level. For patients undergoing TTh, our approach follows a stepwise protocol based on HCT thresholds (Supplementary Figure S2). We define secondary PCT as an HCT of 50% or higher, which triggers active management . If a patient on TTh remains stable and has an HCT below 50%, we will continue the therapy as is and conduct laboratory testing every 6 months. An HCT level of 50% or higher requires a careful evaluation. For an HCT elevation between 50% and 52%, dose reduction alone may suffice. In our practice, these cases would complete an SBQ and HSAT, and, in the event of a positive OSA result , a sleep medicine referral is ordered to manage OSA. The T dose remains reduced, and labs are repeated in 4 weeks. However, if the HCT reaches 52% or higher, more immediate intervention is necessary.
Phlebotomy is typically performed to address a critically elevated HCT and should be done alongside the discontinuation of TTh or a significant reduction in TTh dose. The goal during this corrective phase is to reduce the HCT back to ≤45%. The procedure consists of the scheduled withdrawal of approximately 450-500 mL of whole blood from a peripheral vein, performed with or without isovolemic fluid replacement depending on the patient’s tolerance and cardiovascular status. No dedicated phlebotomy protocol exists for TTH-induced secondary PCT—our approach is therefore extrapolated from polycythemiavera management—on a weekly basis until the target HCT is reached, after which the interval is adjusted according to HCT monitoring. Repeated phle botomies carries a risk of iron deficiency, which may produce anemia and paradoxically result in thromboc ytosis, with a potential increase in thrombotic risk
The decision to resume TTh after addressing secondary PCT is tailored to the individual. It is recommended to restart TTh only after the HCT has dropped to ≤45%, following phlebotomy and the management of any other contributing factors, particularly OSA. In any patient who develops polycythemia a HSAT is ordered (if not already done) and follow-up with a sleep medicine specialist to evaluate and potentially treat OSA before TTh is resumed. Upon resuming therapy, consideration should be given to starting with a low-dose T regimen or switching to a formulation associated with lower rates of secondary PCT.
In summary, secondar y PCT is a recognized and clinically significant complication of TTh that requires a systematic, protocol-driven approach. The integration of pre-treatment OSA screening, formulation-conscious prescribing, structured HCT monitoring, and a stepwise management algorithm allows for safe continuation or resumption of TTh.
