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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Controlling the polycythemia effect associated with TRT
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<blockquote data-quote="madman" data-source="post: 277373" data-attributes="member: 13851"><p><em><strong>*The mechanism behind secondary erythrocytosis from TT is multifactorial</strong></em></p><p></p><p><strong><em>*Estradiol, a breakdown product of testosterone via aromatase, may also play a role in polycythemia</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*Therefore the increase in estradiol via increased aromatization in men on TT may increase telomerase activity, resulting in increased hematopoietic stem cell proliferation and survival</em></strong></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/threads/trt-and-erythrocytosis.24753/[/URL]</p><p></p><p><em><strong><u>The mechanism behind secondary erythrocytosis from TT is multifactorial</u>. </strong>See Fig. 1 for a schematic representation of the current understanding of the pathophysiology.</em></p><p><em></em></p><p><em><strong>Hepcidin is a hepatic protein that acts as a regulator of iron metabolism; increasing levels of hepcidin decrease gut absorption of iron increases intracellular iron storage and thus decreases hemoglobin production.</strong> The role of hepcidin was first proposed by Bachman et al. as a key player in the relationship between testosterone and erythropoiesis [20]. This study followed 109 men for 20 weeks during TT and found that increased testosterone levels inhibited hepcidin by more than 50% in all age groups and in a dose-dependent manner. This suppression was persistent throughout the duration of TT. <strong><u>The marked decrease in hepcidin is hypothesized to increase iron metabolism, systemic absorption of iron, and erythropoiesis</u>.</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> Bachman et al. were also able to demonstrate that TT causes a transient spike in EPO. This results in a new set point for EPO expression, where cytokine release is triggered by a smaller drop in hematocrit [21].<strong> <u>EPO levels failed to decline after subsequent hemoglobin rises, demonstrating the possibility for uninhibited stimulation</u>.</strong></em></p><p></p><p><strong><em>Estradiol, a breakdown product of testosterone via aromatase, may also play a role in polycythemia. </em></strong><em>Calado et al. found that estradiol increased hematopoietic telomerase, an enzyme that prevents the shortening of telomeres during cell division [22].</em><strong><em> <u>Therefore the increase in estradiol via increased aromatization in men on TT may increase telomerase activity, resulting in increased hematopoietic stem cell proliferation and survival </u>[23].</em></strong></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>Take home points from post #1 this thread:</p><p></p><p><strong><em><strong><em>*The data also suggest that the timing of injections, as well as sufficient control of fluctuations in testosterone and estrogen levels, are necessary to control the polycythemia</em></strong></em></strong></p><p><strong><em><strong><em></em></strong></em></strong></p><p><strong><em><strong><em>*Patients frequently experienced acne, mood swings, and elevated hemoglobin levels when they were not consistent with both TC and anastrozole dosing. This reinforced the theory that fluctuations in either testosterone or estradiol levels can cause unwanted side effects, including secondary polycythemia, commonly experienced with TRT.</em></strong></em></strong></p><p><strong><em><strong><em></em></strong></em></strong></p><p><strong><em><strong><em>*<strong>Estrogen control was a vital component of hemoglobin stabilization in this study. Patients who started anastrozole generally saw an increase in their total testosterone level, allowing them to remain at lower TC doses overall. This was expected because TC conversion to E2 was inhibited.</strong></em></strong></em></strong></p><p><strong><em><strong><em></em></strong></em></strong></p><p><strong><em><strong><em>*The side effects observed at higher TT levels included acne, aggression, erectile dysfunction, difficulty losing weight, elevated E2 levels, hair loss, and increased body hair. </em></strong></em></strong></p><p><strong><em><strong><em></em></strong></em></strong></p><p><strong><em><strong><em>*Regardless, maintaining relatively consistent and appropriate TT and E2 levels minimized all side effects and helped patients achieve the best results on treatment</em></strong></em></strong></p><p></p><p></p><p>post #1 (this thread)</p><p></p><p><strong><em><strong>However, the data provided in this study suggest that most of the patients experiencing the polycythemia effect were either being overdosed or incorrectly dosed during treatment. The data also suggest that the <u>timing of injections</u>, as well as <u>sufficient control of fluctuations in testosterone and estrogen levels</u>, are necessary to <u>control the polycythemia</u>. These data suggest that <u>correctly timing the administration of TC injections and dosing of anastrozole</u>, if necessary, <u>decreases the overall fluctuation of both TT and E2 levels in the blood</u>. <u>Consistency of both TT and E2 levels</u> needed to be achieved before the patients were able to reach a point of <u>stabilization</u> with their treatment.</strong></em></strong></p><p></p><p><em><strong><em><strong>The most notable trend of the study was that <u>reaching</u>, and ultimately <u>maintaining, certain ranges of TT and E2 levels</u>, allowed patients to <u>minimize or even eliminate the polycythemia effect</u></strong>. <strong>Patients who were inconsistent with either their TC injections or anastrozole doses had <u>difficulty achieving and maintaining stability</u>. This suggests that <u>maintaining consistency of both TT and E2 levels allows for better hemoglobin control with TRT</u>.</strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong><u>Patients experienced fewer side effects when they remained consistent with the timing and dosage of TC and anastrozole</u>. <u>Patients frequently experienced acne, mood swings, and elevated hemoglobin levels when they were not consistent with both TC and anastrozole dosing</u>. This reinforced the theory that fluctuations in either testosterone or estradiol levels can cause unwanted side effects, including secondary polycythemia, commonly experienced with TRT.</strong></em></strong></em></p><p></p><p><strong><em><strong><u>Estrogen control was a vital component of hemoglobin stabilization in this study</u>. <u>Patients who started anastrozole generally saw an increase in their total testosterone level, allowing them to remain at lower TC doses overall</u>. <u>This was expected because TC conversion to E2 was inhibited</u>. <u>The average E2 level at stabilization was 17.50 pg/mL for patients previously on TRT and 18.21 pg/mL for patients never on TRT</u>. <u>The average anastrozole dosage at stabilization was 0.90 mg for patients previously on TRT and 0.75 mg for patients never on TRT</u>. However, when patients were started on anastrozole at the beginning of treatment they <u>frequently experienced side effects including hot flashes, and joint pain, as their E2 levels dropped too low</u>. <u>Therefore, it is suggested that anastrozole should only be started if patients begin experiencing symptoms of elevated estrogens, such as bloating, or their E2 level increases to >35pg/mL</u>.</strong></em></strong></p><p><strong><em><strong></strong></em></strong></p><p><strong><em><strong><em><strong><u>Additionally, the side effects started to outweigh the benefits of treatment when TT levels were >1051</u>. <u>The side effects observed at higher TT levels included acne, aggression, erectile dysfunction, difficulty losing weight, elevated E2 levels, hair loss, and increased body hair</u>. <u>Hair loss with TRT did not occur with appropriate dosing and management unless the patients had a family history of hair loss</u>. <u>In these cases, hair loss tended to accelerate, following their family history of male pattern baldness</u>. <u>Similarly, patients were more likely to experience acne if they had a personal history of acne or naturally oily skin</u>. <u>Regardless, maintaining relatively consistent and appropriate TT and E2 levels minimized all side effects and helped patients achieve the best results on treatment</u>. </strong></em></strong></em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Erythrocytosis Following Testosterone Therapy</strong></p><p><em>Samuel J. Ohlander, MD, Bibin Varghese, BS, and Alexander W. Pastuszak, MD, PhD</em></p><p></p><p></p><p><strong><em><strong>We review the literature examining T-induced erythrocytosis and summarize proposed mechanisms and risks of thromboembolic sequelae.</strong></em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>PATHOPHYSIOLOGY OF TESTOSTERONE INDUCED ERYTHROCYTOSIS</strong></p><p><strong></strong></p><p><strong><em><strong>Multiple explanations for the mechanism of T-induced erythrocytosis have been offered, with the proposed mechanisms outlined in a 2015 review by Jones et al.50 <u>Initial hypotheses posited increased production of erythropoietin (EPO) by the kidneys, and subsequent studies suggested direct stimulation of erythroid progenitor cells; however, more recent studies in humans have not supported this mechanism</u>.11,23,51-55 </strong></em></strong><em>In a study by Maggio et al,53 108 men older than 65 years withT levels lower than 475 ng/dL were randomized to 36 months ofT patch vs placebo in a double-blinded fashion. Of these, 67men (43 in treatment group, 24 in placebo group) ultimately had serum available for T, Hb, and EPO assays using samples from before and after treatment. Mean T and Hb levels increased significantly in the treatment group, but no significant changes in EPO were observed between the treatment and placebo groups (treatment-by-time interaction, b = 0.24, standarderror = 2.16, P = .9).</em></p><p></p><p><strong><em><strong>Bachman et al 56 <u>proposed a mechanism of T-induced erythrocytosis focused on the suppression of hepcidin, the master iron regulatory peptide, which subsequently results in increased iron absorption, increased systemic iron transport, and erythropoiesis</u>.</strong></em></strong><em>Graded doses of T were used to assess dose-dependent changes in hepcidin levels during 20 weeks of treatment, with findings that T potently suppressed hepcidin in a dose-dependent manner.<strong>This study was followed by further work by Bachman et al 57 that <u>hypothesized a multifactorial model suggesting that “testosterone stimulates EPO transiently, along with suppression of hepcidin,and these two mechanisms result in a new EPO ‘set point’ at a higher physiologic level of hemoglobin</u>.” </strong>In this study,166 subjects from the randomized, double-blinded, placebo controlled Testosterone in Older Men with Mobility Limitation Trial who had undergone at least 6 months of study intervention were examined. The subjects were older than 65 years and had limited mobility, total T levels of 100 to 350 ng/dL, and no contraindications to therapy. Subjects were randomized to placebo or T gel 10 g. Serum hepcidin and EPO were measuredi n conjunction with the study design and assessed at baseline and 1, 3, and 6 months after randomization. EPO levels increased 58% from baseline at 1 month of T treatment and remained significantly increased at 3 months. Then, EPO levels trended toward baseline at 6 months. No significant changes in EPO level were observed in the placebo cohort. They further noted that there was a shift in the EPO-Hb relation curve that suggested “testosterone administration had reset the ‘set point’ for EPO in relation to hemoglobin,” with these findings based on EPO levels remaining increased after an increase in Hb, thus suggesting a lack of negative feedback. Furthermore, T was associated with a 49% suppression of hepcidin, supporting the findings of the investigators’ prior study. Suppression persisted at 1 and 3 months but returned to baseline at 6 months. Serum soluble transferrin receptor concentration reflects erythroid activation and signifies plasma iron turnover and erythroid transferrin uptake. The investigators further noticed increased soluble transferrin receptor levels in the T treatment group but not in the placebo group. <strong>The observed hematologic changes suggest that T increases iron use for erythropoiesis, <u>hypothesizing a mechanism for T-induced increases in hematocrit</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>In contrast to the studies that focused on T, Calado et al 58 <u>focused on estradiol as a causative factor for erythrocytosis,basing their hypothesis on the known stimulation of hematopoietic cells by sex hormones</u>. Estradiol is produced by aromatization of T. </strong>Calado et al observed that in vitro exposure of peripheral blood lymphocytes and bone marrow to androgens increased the activity of telomerase, an enzyme involved in cell replication. Mutated cells with low telomerase activity exhibited normal telomerase levels at exposure to androgens, and estradiol treatment resulted in similar effects on restoration of telomerase activity. <strong>Downregulation of estrogen receptor-a, but not estrogen receptor-b, inhibited telomerase function, <u>thus isolating the target for estradiol-mediated telomerase expression, which could lead to increased hematopoietic cell proliferation</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Other studies have <u>correlated dihydrotestosterone with increased Hct, independent of T and free T levels</u>, implicating dihydrotestosterone in T-induced erythrocytosis.59-61</strong> Several randomized control trials have attempted to further elucidate a relation between dihydrotestosterone and T-induced erythrocytosis by examining whether patients on 5a-reductase inhibitors and TTh were less likely to develop erythrocytosis.62 Although one study showed a 4.7% increase in Hct, another showed no difference in post-treatment Hct.63-65 <strong><u>However, all these studies suggested indirect effects of T levels on bone marrow hyperplasia without describing a clear mechanism</u>.Figure 1 illustrates the <u>proposed direct and indirect effects of T on erythropoiesis</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>A <u>proposed genetic correlation between TTh and increases in Hb and Hct</u> was investigated by Zitzmann and Nieschlag66 who showed that the <u>erythropoietic response to T is inversely related to androgen receptor CAG repeats</u>, which have been associated with androgen receptor activity. <u>They observed that men with fewer than 20 CAG repeats had the highest incidence of blood hyperviscosity</u></strong></em></p><p></p><p></p><p></p><p></p><p><strong>EFFECTS OF T FORMULATION</strong></p><p></p><p><em><strong><u>Of the available T formulations, short-acting IM injections (TC and TE) have the highest incidence of erythrocytosis (approaching 40%)</u>.14 <u>Recent studies support a unified hypothesis in which T formulation, dose, and pharmacokinetics collectively determine the risk of erythrocytosis by establishing the duration of supraphysiologic T levels</u>.52 T formulations that result in <u>stable serum concentrations</u> (pellets, transdermal gels and patches, and extended-release IM TU) <u>result in a low incidence of erythrocytosis that is dependent on dose and serum leveland independent of duration of therapy</u>.11,52,67 The relation of individual T formulations and associated effects on average T levels and incidence of erythrocytosis are presented in Table 1.</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong>Figure 1. Impact of testosterone on erythropoiesis. EPO = erythropoietin; ERa = estrogen receptor-a. Figure 1 is available in color at <a href="http://www.smr.jsexmed.org" target="_blank">www.smr.jsexmed.org</a>.</strong></em></p><p><em><strong>[ATTACH=full]42287[/ATTACH]</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 277373, member: 13851"] [I][B]*The mechanism behind secondary erythrocytosis from TT is multifactorial[/B][/I] [B][I]*Estradiol, a breakdown product of testosterone via aromatase, may also play a role in polycythemia *Therefore the increase in estradiol via increased aromatization in men on TT may increase telomerase activity, resulting in increased hematopoietic stem cell proliferation and survival[/I][/B] [URL unfurl="true"]https://www.excelmale.com/threads/trt-and-erythrocytosis.24753/[/URL] [I][B][U]The mechanism behind secondary erythrocytosis from TT is multifactorial[/U]. [/B]See Fig. 1 for a schematic representation of the current understanding of the pathophysiology. [B]Hepcidin is a hepatic protein that acts as a regulator of iron metabolism; increasing levels of hepcidin decrease gut absorption of iron increases intracellular iron storage and thus decreases hemoglobin production.[/B] The role of hepcidin was first proposed by Bachman et al. as a key player in the relationship between testosterone and erythropoiesis [20]. This study followed 109 men for 20 weeks during TT and found that increased testosterone levels inhibited hepcidin by more than 50% in all age groups and in a dose-dependent manner. This suppression was persistent throughout the duration of TT. [B][U]The marked decrease in hepcidin is hypothesized to increase iron metabolism, systemic absorption of iron, and erythropoiesis[/U].[/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.[/B] Bachman et al. were also able to demonstrate that TT causes a transient spike in EPO. This results in a new set point for EPO expression, where cytokine release is triggered by a smaller drop in hematocrit [21].[B] [U]EPO levels failed to decline after subsequent hemoglobin rises, demonstrating the possibility for uninhibited stimulation[/U].[/B][/I] [B][I]Estradiol, a breakdown product of testosterone via aromatase, may also play a role in polycythemia. [/I][/B][I]Calado et al. found that estradiol increased hematopoietic telomerase, an enzyme that prevents the shortening of telomeres during cell division [22].[/I][B][I] [U]Therefore the increase in estradiol via increased aromatization in men on TT may increase telomerase activity, resulting in increased hematopoietic stem cell proliferation and survival [/U][23].[/I][/B] Take home points from post #1 this thread: [B][I][B][I]*The data also suggest that the timing of injections, as well as sufficient control of fluctuations in testosterone and estrogen levels, are necessary to control the polycythemia *Patients frequently experienced acne, mood swings, and elevated hemoglobin levels when they were not consistent with both TC and anastrozole dosing. This reinforced the theory that fluctuations in either testosterone or estradiol levels can cause unwanted side effects, including secondary polycythemia, commonly experienced with TRT. *[B]Estrogen control was a vital component of hemoglobin stabilization in this study. Patients who started anastrozole generally saw an increase in their total testosterone level, allowing them to remain at lower TC doses overall. This was expected because TC conversion to E2 was inhibited.[/B] *The side effects observed at higher TT levels included acne, aggression, erectile dysfunction, difficulty losing weight, elevated E2 levels, hair loss, and increased body hair. *Regardless, maintaining relatively consistent and appropriate TT and E2 levels minimized all side effects and helped patients achieve the best results on treatment[/I][/B][/I][/B] post #1 (this thread) [B][I][B]However, the data provided in this study suggest that most of the patients experiencing the polycythemia effect were either being overdosed or incorrectly dosed during treatment. The data also suggest that the [U]timing of injections[/U], as well as [U]sufficient control of fluctuations in testosterone and estrogen levels[/U], are necessary to [U]control the polycythemia[/U]. These data suggest that [U]correctly timing the administration of TC injections and dosing of anastrozole[/U], if necessary, [U]decreases the overall fluctuation of both TT and E2 levels in the blood[/U]. [U]Consistency of both TT and E2 levels[/U] needed to be achieved before the patients were able to reach a point of [U]stabilization[/U] with their treatment.[/B][/I][/B] [I][B][I][B]The most notable trend of the study was that [U]reaching[/U], and ultimately [U]maintaining, certain ranges of TT and E2 levels[/U], allowed patients to [U]minimize or even eliminate the polycythemia effect[/U][/B]. [B]Patients who were inconsistent with either their TC injections or anastrozole doses had [U]difficulty achieving and maintaining stability[/U]. This suggests that [U]maintaining consistency of both TT and E2 levels allows for better hemoglobin control with TRT[/U]. [U]Patients experienced fewer side effects when they remained consistent with the timing and dosage of TC and anastrozole[/U]. [U]Patients frequently experienced acne, mood swings, and elevated hemoglobin levels when they were not consistent with both TC and anastrozole dosing[/U]. This reinforced the theory that fluctuations in either testosterone or estradiol levels can cause unwanted side effects, including secondary polycythemia, commonly experienced with TRT.[/B][/I][/B][/I] [B][I][B][U]Estrogen control was a vital component of hemoglobin stabilization in this study[/U]. [U]Patients who started anastrozole generally saw an increase in their total testosterone level, allowing them to remain at lower TC doses overall[/U]. [U]This was expected because TC conversion to E2 was inhibited[/U]. [U]The average E2 level at stabilization was 17.50 pg/mL for patients previously on TRT and 18.21 pg/mL for patients never on TRT[/U]. [U]The average anastrozole dosage at stabilization was 0.90 mg for patients previously on TRT and 0.75 mg for patients never on TRT[/U]. However, when patients were started on anastrozole at the beginning of treatment they [U]frequently experienced side effects including hot flashes, and joint pain, as their E2 levels dropped too low[/U]. [U]Therefore, it is suggested that anastrozole should only be started if patients begin experiencing symptoms of elevated estrogens, such as bloating, or their E2 level increases to >35pg/mL[/U]. [I][B][U]Additionally, the side effects started to outweigh the benefits of treatment when TT levels were >1051[/U]. [U]The side effects observed at higher TT levels included acne, aggression, erectile dysfunction, difficulty losing weight, elevated E2 levels, hair loss, and increased body hair[/U]. [U]Hair loss with TRT did not occur with appropriate dosing and management unless the patients had a family history of hair loss[/U]. [U]In these cases, hair loss tended to accelerate, following their family history of male pattern baldness[/U]. [U]Similarly, patients were more likely to experience acne if they had a personal history of acne or naturally oily skin[/U]. [U]Regardless, maintaining relatively consistent and appropriate TT and E2 levels minimized all side effects and helped patients achieve the best results on treatment[/U]. [/B][/I][/B][/I] Erythrocytosis Following Testosterone Therapy[/B] [I]Samuel J. Ohlander, MD, Bibin Varghese, BS, and Alexander W. Pastuszak, MD, PhD[/I] [B][I][B]We review the literature examining T-induced erythrocytosis and summarize proposed mechanisms and risks of thromboembolic sequelae.[/B][/I] PATHOPHYSIOLOGY OF TESTOSTERONE INDUCED ERYTHROCYTOSIS [I][B]Multiple explanations for the mechanism of T-induced erythrocytosis have been offered, with the proposed mechanisms outlined in a 2015 review by Jones et al.50 [U]Initial hypotheses posited increased production of erythropoietin (EPO) by the kidneys, and subsequent studies suggested direct stimulation of erythroid progenitor cells; however, more recent studies in humans have not supported this mechanism[/U].11,23,51-55 [/B][/I][/B][I]In a study by Maggio et al,53 108 men older than 65 years withT levels lower than 475 ng/dL were randomized to 36 months ofT patch vs placebo in a double-blinded fashion. Of these, 67men (43 in treatment group, 24 in placebo group) ultimately had serum available for T, Hb, and EPO assays using samples from before and after treatment. Mean T and Hb levels increased significantly in the treatment group, but no significant changes in EPO were observed between the treatment and placebo groups (treatment-by-time interaction, b = 0.24, standarderror = 2.16, P = .9).[/I] [B][I][B]Bachman et al 56 [U]proposed a mechanism of T-induced erythrocytosis focused on the suppression of hepcidin, the master iron regulatory peptide, which subsequently results in increased iron absorption, increased systemic iron transport, and erythropoiesis[/U].[/B][/I][/B][I]Graded doses of T were used to assess dose-dependent changes in hepcidin levels during 20 weeks of treatment, with findings that T potently suppressed hepcidin in a dose-dependent manner.[B]This study was followed by further work by Bachman et al 57 that [U]hypothesized a multifactorial model suggesting that “testosterone stimulates EPO transiently, along with suppression of hepcidin,and these two mechanisms result in a new EPO ‘set point’ at a higher physiologic level of hemoglobin[/U].” [/B]In this study,166 subjects from the randomized, double-blinded, placebo controlled Testosterone in Older Men with Mobility Limitation Trial who had undergone at least 6 months of study intervention were examined. The subjects were older than 65 years and had limited mobility, total T levels of 100 to 350 ng/dL, and no contraindications to therapy. Subjects were randomized to placebo or T gel 10 g. Serum hepcidin and EPO were measuredi n conjunction with the study design and assessed at baseline and 1, 3, and 6 months after randomization. EPO levels increased 58% from baseline at 1 month of T treatment and remained significantly increased at 3 months. Then, EPO levels trended toward baseline at 6 months. No significant changes in EPO level were observed in the placebo cohort. They further noted that there was a shift in the EPO-Hb relation curve that suggested “testosterone administration had reset the ‘set point’ for EPO in relation to hemoglobin,” with these findings based on EPO levels remaining increased after an increase in Hb, thus suggesting a lack of negative feedback. Furthermore, T was associated with a 49% suppression of hepcidin, supporting the findings of the investigators’ prior study. Suppression persisted at 1 and 3 months but returned to baseline at 6 months. Serum soluble transferrin receptor concentration reflects erythroid activation and signifies plasma iron turnover and erythroid transferrin uptake. The investigators further noticed increased soluble transferrin receptor levels in the T treatment group but not in the placebo group. [B]The observed hematologic changes suggest that T increases iron use for erythropoiesis, [U]hypothesizing a mechanism for T-induced increases in hematocrit[/U]. In contrast to the studies that focused on T, Calado et al 58 [U]focused on estradiol as a causative factor for erythrocytosis,basing their hypothesis on the known stimulation of hematopoietic cells by sex hormones[/U]. Estradiol is produced by aromatization of T. [/B]Calado et al observed that in vitro exposure of peripheral blood lymphocytes and bone marrow to androgens increased the activity of telomerase, an enzyme involved in cell replication. Mutated cells with low telomerase activity exhibited normal telomerase levels at exposure to androgens, and estradiol treatment resulted in similar effects on restoration of telomerase activity. [B]Downregulation of estrogen receptor-a, but not estrogen receptor-b, inhibited telomerase function, [U]thus isolating the target for estradiol-mediated telomerase expression, which could lead to increased hematopoietic cell proliferation[/U]. Other studies have [U]correlated dihydrotestosterone with increased Hct, independent of T and free T levels[/U], implicating dihydrotestosterone in T-induced erythrocytosis.59-61[/B] Several randomized control trials have attempted to further elucidate a relation between dihydrotestosterone and T-induced erythrocytosis by examining whether patients on 5a-reductase inhibitors and TTh were less likely to develop erythrocytosis.62 Although one study showed a 4.7% increase in Hct, another showed no difference in post-treatment Hct.63-65 [B][U]However, all these studies suggested indirect effects of T levels on bone marrow hyperplasia without describing a clear mechanism[/U].Figure 1 illustrates the [U]proposed direct and indirect effects of T on erythropoiesis[/U]. A [U]proposed genetic correlation between TTh and increases in Hb and Hct[/U] was investigated by Zitzmann and Nieschlag66 who showed that the [U]erythropoietic response to T is inversely related to androgen receptor CAG repeats[/U], which have been associated with androgen receptor activity. [U]They observed that men with fewer than 20 CAG repeats had the highest incidence of blood hyperviscosity[/U][/B][/I] [B]EFFECTS OF T FORMULATION[/B] [I][B][U]Of the available T formulations, short-acting IM injections (TC and TE) have the highest incidence of erythrocytosis (approaching 40%)[/U].14 [U]Recent studies support a unified hypothesis in which T formulation, dose, and pharmacokinetics collectively determine the risk of erythrocytosis by establishing the duration of supraphysiologic T levels[/U].52 T formulations that result in [U]stable serum concentrations[/U] (pellets, transdermal gels and patches, and extended-release IM TU) [U]result in a low incidence of erythrocytosis that is dependent on dose and serum leveland independent of duration of therapy[/U].11,52,67 The relation of individual T formulations and associated effects on average T levels and incidence of erythrocytosis are presented in Table 1. Figure 1. Impact of testosterone on erythropoiesis. EPO = erythropoietin; ERa = estrogen receptor-a. Figure 1 is available in color at [URL='http://www.smr.jsexmed.org']www.smr.jsexmed.org[/URL]. [ATTACH type="full" alt="1710262638388.png"]42287[/ATTACH][/B][/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Controlling the polycythemia effect associated with TRT
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