Erythrocytosis

[Michael Scally MD]

Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis Following Testosterone Therapy. Sex Med Rev. http://www.sciencedirect.com/science/article/pii/S2050052117300410

INTRODUCTION: A rapid increase in awareness of androgen deficiency has led to substantial increases in prescribing of testosterone therapy (TTh), with benefits of improvements in mood, libido, bone density, muscle mass, body composition, energy, and cognition. However, TTh can be limited by its side effects, particularly erythrocytosis. This review examines the literature on testosterone-induced erythrocytosis and polycythemia.

AIM: To review the available literature on testosterone-induced erythrocytosis, discuss possible mechanisms for pathophysiology, determine the significance of formulation, and elucidate potential thromboembolic risk.

METHODS: A literature review was performed using PubMed for articles addressing TTh, erythrocytosis, and polycythemia.

MAIN OUTCOME MEASURES: Mechanism, pharmacologic contribution, and risk of testosterone-induced erythrocytosis.

RESULTS: For men undergoing TTh, the risk of developing erythrocytosis compared with controls is well established, with short-acting injectable formulations having the highest associated incidence. Potential mechanisms explaining the relation between TTh and erythrocytosis include the role of hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation, and genetic factors. High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulations, although there is limited evidence supporting a relation between TTh and vascular complications.

CONCLUSION: Short-acting injectable testosterone is associated with greater risk of erythrocytosis compared with other formulations. The mechanism of the pathophysiology and its role on thromboembolic events remain unclear, although some data support an increased risk of cardiovascular events resulting from testosterone-induced erythrocytosis.

 

[Michael Scally MD]

[OA] Testosterone replacement therapy (TRT) and its effect on bone marrow. How serious is it and is there a true polyglobulia?

INTRODUCTION: TRT in men with testosterone deficiency syndrome (TDS) had multiple positive effects and restore a quality of life of affected men. Polyglobulia is the most common dose-limiting adverse effect of TRT, but the mechanisms of TRT-mediated erythropoesis remain unclear. In this study, we evaluated long term haematological side effects of TRT: polyglobulia, elevated hemoglobin (Hb) and haematocrit (Ht).

METHODS: In a cross-sectional descriptive study, the authors treated 69 men with TDS and the average age 59 years and the follow-up period 81.32 months. The men were treated with three-month i.m. injections of 1000 mg testosterone undecanoate. The elevated values were: Hb above 176 g/l, Ht above 0.52 and erythrocytes (Ery) above 6.0 mil/mcl.

RESULTS: 21 out of 69 patients (30.43 %) had an increased Hb, Ht or Ery during treatment. The interesting fact was that only five men (7.24 %) had increased the number of Ery (true polyglobulia). No men with elevated level of Hb, Ht or Ery had other side effects (like thrombosis).

CONCLUSION: It is still not clear, why in some men on TRT the feedback does not work and bone marrow production of red blood cells continues even if the upper limit is reached. Authors expect that only 7% of men had true polyglobulia, other men had elevated Hb or Ht. Based on our own experience we recommend a regular check of men on TRT on order to avoid possible serious side-effects.

Levcikova M, Breza J, Jr., Luha J, Dubravicky J, Kovacova E, Fillo J. Testosterone replacement therapy (TRT) and its effect on bone marrow. How serious is it and is there a true polyglobulia? Bratislavske lekarske listy 2017;118:654-7. Bratislava Medical Journal Vol.118, No.11, p.654-657, 2017

 

[Michael Scally MD]

Testosterone Administration During Energy Deficit Suppresses Hepcidin and Increases Iron Availability for Erythropoiesis

Context: Severe energy deprivation markedly inhibits erythropoiesis by restricting iron availability for hemoglobin synthesis.

Objective: The objective of this study was to determine whether testosterone supplementation during energy deficit increased indicators of iron turnover and attenuated the decline in erythropoiesis compared to placebo.

Design: This was a 3-phase, randomized, double-blind, placebo-controlled trial.

Setting: The study was conducted at the Pennington Biomedical Research Center.

Patients or other participants: Fifty healthy young males.

Intervention(s): Phase 1 was a 14-d free-living, eucaloric controlled-feeding phase; phase 2 was a 28-d inpatient phase were participants were randomized to 200 mg testosterone enanthate/week or an isovolumetric placebo/week during an energy deficit of 55% of total daily energy expenditure; phase 3 was a 14-d free-living, ad libitum recovery period.

Main outcome measure(s): Indices of erythropoiesis, iron status, and hepcidin and erythroferrone were determined.

Results: Hepcidin declined by 41%, indicators of iron turnover increased, and functional iron stores were reduced with testosterone administration during energy deficit compared to placebo.

Testosterone administration during energy deficit increased circulating concentrations of erythropoietin and maintained erythropoiesis, as indicated by an attenuation in the decline in hemoglobin and hematocrit with placebo.

Erythroferrone did no differ between groups, suggesting that the reduction in hepcidin with testosterone occurs through an erythroferrone-independent mechanism.

Conclusions: These findings indicate that testosterone suppresses hepcidin, through either direct or indirect mechanisms, to increase iron turnover and maintain erythropoiesis during severe energy deficit.

Hennigar SR, Berryman CE, Harris MN, et al. Testosterone administration during energy deficit suppresses hepcidin and increases iron availability for erythropoiesis [published online ahead of print, 2020 Jan 2]. J Clin Endocrinol Metab. 2020;dgz316. Testosterone administration during energy deficit suppresses hepcidin and increases iron availability for erythropoiesis

 

[Michael Scally MD]

[OA] A Cross-Sectional Comparison of Secondary Polycythemia in Testosterone-Deficient Men Treated with Nasal Testosterone Gel Vs. Intramuscular Testosterone Cypionate

Introduction: Secondary polycythemia is a known adverse effect of testosterone replacement therapy (TRT). Different testosterone formulations are available, with significantly different half-lives, which have varying influences on the development of secondary polycythemia. Herein, we compared the prevalence of secondary polycythemia in testosterone-deficient men treated with intranasal testosterone gel (Natesto) vs. intramuscular testosterone cypionate (TC) therapy.

Methods: We performed a cross-sectional analysis of secondary polycythemia (hematocrit [Hct] ≥54%) in men who received TRT. We included a total of 60 men: 30 men who received Natesto (4.5% testosterone gel [tid, 5.5 mg/nostril, 11 mg/dose, 33 mg/day]), and 30 who received TC (between 0.5 and 1.0 mL or 100-200 mg intramuscularly weekly). A univariable and multiple regression analysis was performed considering last Hct measurement as the main outcome. The analyzed variables included were age, body mass index (BMI), smoking history, treatment group, and testosterone levels on followup.

Results: We identified polycythemia (Hct ≥54%) in 10% (3/30) of men who received TC. Additionally, in men treated with TC, 33.3% (10/30) had a Hct ≥50% during therapy. None of the men who received Natesto had a Hct ≥50% during therapy. On multivariable linear regression analysis, we demonstrated that the use of TC increased Hct by 3.24% (95% confidence interval [CI] 0.74-5.73%; p=0.012) compared to Natesto.

Conclusions: The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received TC therapy.

Best JC, Gonzalez D, Masterson TA, Blachman-Braun R, Pai R, Ramasamy R. A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate [published online ahead of print, 2020 Jul 27]. Can Urol Assoc J. 2020;10.5489/cuaj.6651. doi:10.5489/cuaj.6651 A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate | Canadian Urological Association Journal

 

[Michael Scally MD]

[OA] Investigation and Management of Erythrocytosis

KEY POINTS

· Primary erythrocytosis — or autonomous production of excess erythrocytes — most commonly occurs due to polycythemia vera (PV), a myeloproliferative neoplastic process that may be asymptomatic or may present with thrombosis, constitutional or vasomotor symptoms, or splenomegaly.

· Secondary erythrocytosis, which is more common than PV, has a broad differential diagnosis that includes hypoxic lung disease, cyanotic congenital heart disease, medications (e.g., testosterone) and erythropoietin-producing malignant disorders.

· Differentiating between PV and secondary erythrocytosis requires clinical evaluation and specialized investigations including measurement of the serum erythropoietin level and Janus kinase 2 mutation testing.

· To reduce the risk of thrombosis, most patients with PV are treated with low-dose acetylsalicylic acid and phlebotomy to achieve a target hematocrit value of less than 0.45, whereas patients at high risk for thrombosis may receive cytoreductive therapy.

· Treatment of secondary erythrocytosis should be directed at the underlying cause, and phlebotomy is not routinely recommended.

Mithoowani S, Laureano M, Crowther MA, Hillis CM. Investigation and management of erythrocytosis. Canadian Medical Association Journal 2020;192:E913. Investigation and management of erythrocytosis