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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Side Effect Management
TRT and erythrocytosis
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<blockquote data-quote="madman" data-source="post: 216323" data-attributes="member: 13851"><p><em><strong>*Despite this, the <u>evidence for secondary polycythemia causing harm during TT is scarce</u>, and the <u>hematocrit-based cutoffs present in multiple guidelines appear to be arbitrarily chosen</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Polycythemia and erythrocytosis have been used interchangeably, though polycythemia implies an increase in all blood cells and so <u>erythrocytosis is more accurate when describing the increased erythrocyte mass related to TT</u> [13]. Erythrocytosis confers an increased blood viscosity and concerns arise from the potential increased risk of thromboembolic events including myocardial infarction and cerebrovascular accidents</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Amongst randomized controlled trials (RCTs), meta-analyses do not support an increased risk of MACE; however, <u>these trials are not designed to detect MACE as their primary outcome and are often underpowered to do so</u>. Unfortunately, none of these aforementioned trials evaluated secondary polycythemia as a potential independent risk factor for these adverse events. Amongst multiple guidelines currently, polycythemia is grounds for TT cessation or modification, <u>without evidence that this actually increases the risk</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Another treatment option includes phlebotomy though the benefits of this practice are not clear in men with secondary erythrocytosis from TT</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Polycythemia can be divided into primary and secondary according to its etiology. <u>Primary polycythemia</u>, also known as polycythemia vera (PCV)</strong>, <strong>is due to an over-production of erythrocytes secondary to intrinsic cellular defects within the bone marrow. PCV is often due to a mutation in JAK2, a tyrosine kinase, leading to the proliferation of erythrocytes independent of cellular control</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The <u>secondary subtype</u> is due to either a physiological response to decreased tissue oxygenation or from inappropriate stimulation of erythropoiesis, such as with TT [18]</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The mechanism behind secondary erythrocytosis from TT is <u>multifactorial</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The marked decrease in hepcidin is <u>hypothesized</u> to increase iron metabolism, systemic absorption of iron, and erythropoiesis</strong></em></p><p></p><p><strong><em>*Another mechanism behind secondary polycythemia involves erythropoietin (EPO) [21].</em></strong><em> <strong>Cellular hypoxia stimulates EPO, a renal cytokine, causing an increase in red blood cell production directly in the bone marrow</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*EPO levels failed to decline after subsequent hemoglobin rises, demonstrating the possibility for uninhibited stimulation</strong></em></p><p></p><p><strong><em>*Estradiol, a breakdown product of testosterone via aromatase, <u>may</u> also play a role in polycythemia</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*The increase in estradiol via increased aromatization in men on <u>TT may increase telomerase activity</u>, resulting in increased hematopoietic stem cell proliferation and survival [23]</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*<em><strong>OSA by itself is believed to cause erythrocytosis via hypoxemia [25]. Combined with TT, it is possible that the effects on erythrocytosis may be compounded, either through higher metabolic requirements with elevated testosterone, changes in response to hypoxia, and physiologic changes to the airways</strong></em></em></strong></p><p></p><p><em><strong>*Erythrocytosis can lead to increased blood viscosity [27, 28]. <u>At the molecular level, it has been shown to impact platelet adhesiveness and bleeding time</u> [29]. Elevated hematocrit levels can also increase thromboxane A2 concentrations thereby activating new platelets and increasing platelet aggregation [16]</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Patients with obstructive sleep apnea, advanced age, obesity, type II diabetes mellitus, elevated baseline hematocrit (>50%), and those who live in high altitudes are at higher risk of developing erythrocytosis after TT [32]</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Testosterone formulation, dose, and pharmacokinetics collectively determine the risk of erythrocytosis [11]. The general hypothesis is that increased duration in supraphysiological testosterone levels results in an increased risk of erythrocytosis</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Secondary erythrocytosis is a predictable side effect of testosterone replacement therapy with objective increases in hematocrit noted after one month of therapy</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The percentage increase in hematocrit continues to increase in a linear dose-dependent fashion [38]. Side effects of secondary erythrocytosis resulting from hyperviscosity include paresthesias, blurred vision, fatigue, and headaches [39]</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*<em><strong>There are conflicting reports in the literature regarding the association between secondary erythrocytosis and MACE and VTE. <u>This conflicting evidence in part contributes to the varying definitions of what is a “high” hematocrit while on TT</u></strong></em></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The Endocrine Society uses a hematocrit threshold of <u>>50%</u> as a relative contraindication to initiating TT and <u>>54%</u> as an indication to discontinue treatment [1]. The European Association of Urology (EAU) guidelines on hypogonadism also state that the hematocrit should not exceed <u>54%</u>, while recent Canadian guidelines cite <u>55%</u> as the safe upper limit [15, 40]. The AUA guidelines on testosterone deficiency define polycythemia as a hematocrit of <u>52%</u> and recommend stopping or reducing treatment if the hematocrit reaches 54% [14]</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The upper limit of normal for hematocrit in most laboratory reference ranges in healthy adult males is <u>54%, which is where this value is likely derived</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The major limitation to using these studies is that they involve population sampling, and do not investigate men on testosterone. Regardless, a hematocrit of ≥54% appears to be the consistent threshold to discontinuing or reducing treatment utilized by major urologic governing bodies, <u>while the evidence for this specific cutoff is lacking</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*In a meta-analysis of all randomized controlled trials for TT and cardiovascular risk by Corona et al., they concluded that the <u>existing evidence does not support a causal role between TT and adverse CV events when hypogonadism is appropriately diagnosed and treated</u> [45].</strong> <strong>While there is no convincing evidence that links polycythemia in patients who are on TT and MACE, physicians should be prepared to discuss the risks with their patients in a shared-decision making approach</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Therapeutic phlebotomy is one way in which patients may “treat” erythrocytosis. Phlebotomy is a mainstay of treatment in PCV and there are no absolute contraindications [48]</strong></em></p><p></p><p><strong>*</strong><em><strong>Phlebotomy is effective in the management of erythrocytosis in patients with PV in reducing thromboembolic events and this benefit may be conferred onto patients with secondary erythrocytosis secondary to TT, <u>though there is no high-quality evidence to support this claim</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*There are no <u>evidence-based guidelines</u> that outline the frequency or volume of phlebotomy protocols in patients receiving TT</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Whether or not phlebotomy has a role to play in the management of secondary polycythemia deserves further study</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*At this point, phlebotomy appears to be a safe approach to reducing hematocrit but physicians should be aware that it <u>may not be sufficient in reducing hematocrit levels on a long-term basis</u></strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 216323, member: 13851"] [I][B]*Despite this, the [U]evidence for secondary polycythemia causing harm during TT is scarce[/U], and the [U]hematocrit-based cutoffs present in multiple guidelines appear to be arbitrarily chosen[/U] *Polycythemia and erythrocytosis have been used interchangeably, though polycythemia implies an increase in all blood cells and so [U]erythrocytosis is more accurate when describing the increased erythrocyte mass related to TT[/U] [13]. Erythrocytosis confers an increased blood viscosity and concerns arise from the potential increased risk of thromboembolic events including myocardial infarction and cerebrovascular accidents *Amongst randomized controlled trials (RCTs), meta-analyses do not support an increased risk of MACE; however, [U]these trials are not designed to detect MACE as their primary outcome and are often underpowered to do so[/U]. Unfortunately, none of these aforementioned trials evaluated secondary polycythemia as a potential independent risk factor for these adverse events. Amongst multiple guidelines currently, polycythemia is grounds for TT cessation or modification, [U]without evidence that this actually increases the risk[/U] *Another treatment option includes phlebotomy though the benefits of this practice are not clear in men with secondary erythrocytosis from TT *Polycythemia can be divided into primary and secondary according to its etiology. [U]Primary polycythemia[/U], also known as polycythemia vera (PCV)[/B], [B]is due to an over-production of erythrocytes secondary to intrinsic cellular defects within the bone marrow. PCV is often due to a mutation in JAK2, a tyrosine kinase, leading to the proliferation of erythrocytes independent of cellular control *The [U]secondary subtype[/U] is due to either a physiological response to decreased tissue oxygenation or from inappropriate stimulation of erythropoiesis, such as with TT [18] *The mechanism behind secondary erythrocytosis from TT is [U]multifactorial[/U] *The marked decrease in hepcidin is [U]hypothesized[/U] to increase iron metabolism, systemic absorption of iron, and erythropoiesis[/B][/I] [B][I]*Another mechanism behind secondary polycythemia involves erythropoietin (EPO) [21].[/I][/B][I] [B]Cellular hypoxia stimulates EPO, a renal cytokine, causing an increase in red blood cell production directly in the bone marrow *EPO levels failed to decline after subsequent hemoglobin rises, demonstrating the possibility for uninhibited stimulation[/B][/I] [B][I]*Estradiol, a breakdown product of testosterone via aromatase, [U]may[/U] also play a role in polycythemia *The increase in estradiol via increased aromatization in men on [U]TT may increase telomerase activity[/U], resulting in increased hematopoietic stem cell proliferation and survival [23] *[I][B]OSA by itself is believed to cause erythrocytosis via hypoxemia [25]. Combined with TT, it is possible that the effects on erythrocytosis may be compounded, either through higher metabolic requirements with elevated testosterone, changes in response to hypoxia, and physiologic changes to the airways[/B][/I][/I][/B] [I][B]*Erythrocytosis can lead to increased blood viscosity [27, 28]. [U]At the molecular level, it has been shown to impact platelet adhesiveness and bleeding time[/U] [29]. Elevated hematocrit levels can also increase thromboxane A2 concentrations thereby activating new platelets and increasing platelet aggregation [16] *Patients with obstructive sleep apnea, advanced age, obesity, type II diabetes mellitus, elevated baseline hematocrit (>50%), and those who live in high altitudes are at higher risk of developing erythrocytosis after TT [32] *Testosterone formulation, dose, and pharmacokinetics collectively determine the risk of erythrocytosis [11]. The general hypothesis is that increased duration in supraphysiological testosterone levels results in an increased risk of erythrocytosis *Secondary erythrocytosis is a predictable side effect of testosterone replacement therapy with objective increases in hematocrit noted after one month of therapy *The percentage increase in hematocrit continues to increase in a linear dose-dependent fashion [38]. Side effects of secondary erythrocytosis resulting from hyperviscosity include paresthesias, blurred vision, fatigue, and headaches [39] *[I][B]There are conflicting reports in the literature regarding the association between secondary erythrocytosis and MACE and VTE. [U]This conflicting evidence in part contributes to the varying definitions of what is a “high” hematocrit while on TT[/U][/B][/I] *The Endocrine Society uses a hematocrit threshold of [U]>50%[/U] as a relative contraindication to initiating TT and [U]>54%[/U] as an indication to discontinue treatment [1]. The European Association of Urology (EAU) guidelines on hypogonadism also state that the hematocrit should not exceed [U]54%[/U], while recent Canadian guidelines cite [U]55%[/U] as the safe upper limit [15, 40]. The AUA guidelines on testosterone deficiency define polycythemia as a hematocrit of [U]52%[/U] and recommend stopping or reducing treatment if the hematocrit reaches 54% [14] *The upper limit of normal for hematocrit in most laboratory reference ranges in healthy adult males is [U]54%, which is where this value is likely derived[/U] *The major limitation to using these studies is that they involve population sampling, and do not investigate men on testosterone. Regardless, a hematocrit of ≥54% appears to be the consistent threshold to discontinuing or reducing treatment utilized by major urologic governing bodies, [U]while the evidence for this specific cutoff is lacking[/U] *In a meta-analysis of all randomized controlled trials for TT and cardiovascular risk by Corona et al., they concluded that the [U]existing evidence does not support a causal role between TT and adverse CV events when hypogonadism is appropriately diagnosed and treated[/U] [45].[/B] [B]While there is no convincing evidence that links polycythemia in patients who are on TT and MACE, physicians should be prepared to discuss the risks with their patients in a shared-decision making approach *Therapeutic phlebotomy is one way in which patients may “treat” erythrocytosis. Phlebotomy is a mainstay of treatment in PCV and there are no absolute contraindications [48][/B][/I] [B]*[/B][I][B]Phlebotomy is effective in the management of erythrocytosis in patients with PV in reducing thromboembolic events and this benefit may be conferred onto patients with secondary erythrocytosis secondary to TT, [U]though there is no high-quality evidence to support this claim[/U] *There are no [U]evidence-based guidelines[/U] that outline the frequency or volume of phlebotomy protocols in patients receiving TT *Whether or not phlebotomy has a role to play in the management of secondary polycythemia deserves further study *At this point, phlebotomy appears to be a safe approach to reducing hematocrit but physicians should be aware that it [U]may not be sufficient in reducing hematocrit levels on a long-term basis[/U][/B][/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Side Effect Management
TRT and erythrocytosis
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