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Testosterone therapy and secondary erythrocytosis

International Journal of Impotence Research volume 34, pages 693–697 (2022)Cite this article

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Abstract

Secondary erythrocytosis is one of the most common adverse events associated with testosterone therapy (TT). Upon encountering this, clinicians will often either adjust TT dosing, stop therapy, order a phlebotomy, or recommend a combination of these. Despite this, the evidence for secondary polycythemia causing harm during TT is scarce, and the hematocrit-based cutoffs present in multiple guidelines appear to be arbritrarily chosen. In this review, we present the pathophysiology behind TT and secondary erythrocytosis, the evidence connecting TT, secondary erythrocytosis and major adverse cardiovascular events (MACE), and the data supporting varying interventions upon diagnosis of secondary erythrocytosis.

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Fig. 1: Current understanding of testosterone replacement therapy on increased erythrocyte production.

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References

  1. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab. 2018;103(May):1715–44. 1

    Article  PubMed  Google Scholar 

  2. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in hypogonadal men with Type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34(Apr):828–37. 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. 2000;85:15.

  4. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol. 2005;63(Sep):280–93.

    Article  CAS  Google Scholar 

  5. Elliott J, Kelly SE, Millar AC, Peterson J, Chen L, Johnston A, et al. Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis. BMJ Open. 2017;e015284:10.

    Google Scholar 

  6. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173(Aug):1465. 12

    Article  PubMed  PubMed Central  Google Scholar 

  7. Baillargeon J, Kuo Y-F, Westra JR, Urban RJ, Goodwin JS. Testosterone prescribing in the United States, 2002–2016. JAMA 2018;320(Jul):200. 10

    Article  PubMed  PubMed Central  Google Scholar 

  8. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE. 2014;9.

  9. Vigen R. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310(Nov):1829. 6

    Article  CAS  PubMed  Google Scholar 

  10. Ory J, White JT, Moore J, Grantmyre J. Canadian trends in testosterone therapy. Can Urol Assoc J. 2020;15:210–12.

  11. Ohlander SJ, Varghese B, Pastuszak AW.Erythrocytosis following testosterone therapy.Sex Med Rev. 2018;6(Jan):77–85.

    Article  PubMed  Google Scholar 

  12. Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95(Jun):2560–75.

    Article  PubMed  Google Scholar 

  13. Keohane C, McMullin MF, Harrison C. The diagnosis and management of erythrocytosis. BMJ 2013;347(Nov):f6667–f6667. 18nov18 1

    Article  PubMed  Google Scholar 

  14. Mulhall JP, Trost LW, Brannigan RE, Kurtz EG, Redmon JB, Chiles KA, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(Aug):423–32.

    Article  PubMed  Google Scholar 

  15. Grober ED, Krakowsky Y, Khera M, Holmes DT, Lee JC, Grantmyre JE, et al. Canadian urological association clinical practice guideline on testosterone deficiency in men: evidence-based Q&A. Can Urol Assoc J 2021;15(Feb):E234–43. 23

    PubMed  PubMed Central  Google Scholar 

  16. Walker RF, Zakai NA, MacLehose RF, Cowan LT, Adam TJ, Alonso A, et al. Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism. JAMA Intern Med. 2020;180(Feb):190. 1

    Article  CAS  PubMed  Google Scholar 

  17. Saad F, Haider A, Haider K, Doros G, Traish A. SUN-055 reduction of Mortality and Major Adverse Cardiovascular Events (MACE) in men with hypogonadism treated with long-term Testosterone Therapy (TTh) with Testosterone Undecanoate Injections (TU): 10-year data from a registry study in a urological setting. J Endocr Soc 2019;3(Apr):SUN–055. 30Suppl 1

    PubMed Central  Google Scholar 

  18. Golde DW, Hocking WG, Koeffler HP, Adamson JW. Polycythemia: mechanisms and management. Ann Intern Med. 1981;95:71–87.

    Article  CAS  PubMed  Google Scholar 

  19. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997;82:3793–6.

    Article  CAS  PubMed  Google Scholar 

  20. Bachman E, Feng R, Travison T, Li M, Olbina G, Ostland V, et al. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis. J Clin Endocrinol Metab. 2010;95:4743–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, et al. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci. 2014;69(Jun):725–35. 1

    Article  CAS  PubMed  Google Scholar 

  22. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood 2009;114:2236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jones SD, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJG.Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male.Sex Med Rev. 2015;3(Apr):101–12.

    Article  PubMed  Google Scholar 

  24. Lundy SD, Parekh NV, Shoskes DA. Obstructive sleep apnea is associated with polycythemia in hypogonadal men on testosterone replacement therapy. J Sex Med. 2020;17:1297–303.

    Article  CAS  PubMed  Google Scholar 

  25. Hoffstein V, Herridge M, Mateika S, Redline S, Strohl KP. Hematocrit levels in sleep apnea. Chest 1994;106:787–91.

    Article  CAS  PubMed  Google Scholar 

  26. Farber NJ, Vij SC, Shoskes DA. Failure of testosterone replacement therapy to improve symptoms correlates with burden of systemic conditions. Transl Androl Urol. 2020;9:1108.

    Article  PubMed  PubMed Central  Google Scholar 

  27. McMullin MF, Bareford D, Campbell P, Green A, Harrison C, Hunt B, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol. 2005;130:174–95.

    Article  PubMed  Google Scholar 

  28. Wells RE, Merrill EW. Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Investig. 1962;41:1591–8.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hellem AJ, Borchgrevink CF, Ames SB. The role of red cells in haemostasis: the relation between haematocrit, bleeding time and platelet adhesiveness. Br J Haematol. 1961;7:42–50.

    Article  CAS  PubMed  Google Scholar 

  30. Guyton AC, Richardson TQ. Effect of hematocrit on venous return. Circ Res. 1961;9:157–64.

    Article  CAS  PubMed  Google Scholar 

  31. Griesshammer M, Kiladjian J-J, Besses C. Thromboembolic events in polycythemia vera. Ann Hematol. 2019;98:1071–82.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Drinka PJ, Jochen AL, Cuisinier M, Bloom R, Rudman I, Rudman D. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels. J Am Geriatr Soc. 1995;43:899–901.

    Article  CAS  PubMed  Google Scholar 

  33. Schubert M, Minnemann T, Hübler D, Rouskova D, Christoph A, Oettel M, et al. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89(Nov):5429–34.

    Article  CAS  PubMed  Google Scholar 

  34. Borst SE, Mulligan T. Testosterone replacement therapy for older men. Clin Interv Aging. 2007;2:561–66.

  35. Rogol A, Tkachenko N, Bryson N. NatestoTM, a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men. Andrology. 2016;4:46–54.

    Article  CAS  PubMed  Google Scholar 

  36. 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. Can Urol Assoc J 2021;15:E118.

    PubMed  Google Scholar 

  37. Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male. 2003;6(Jan):207–11.

    Article  CAS  PubMed  Google Scholar 

  38. Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. 2008;93(Mar):914–9. 1

    Article  CAS  PubMed  Google Scholar 

  39. Cervi A, Balitsky AK. Testosterone use causing erythrocytosis. Can Med Assoc J. 2017;189(Oct):E1286–8. 16

    Article  Google Scholar 

  40. Salonia A, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. European Association of Urology Guidelines on Sexual and Reproductive Health-2021 Update: Male Sexual Dysfunction. Eur Urol. 2021;80:333–57.

  41. Gagnon DR, Zhang T-J, Brand FN, Kannel WB. Hematocrit and the risk of cardiovascular disease—the Framingham study: a 34-year follow-up. Am Heart J. 1994;127(Mar):674–82.

    Article  CAS  PubMed  Google Scholar 

  42. Toss F, Nordström A, Nordström P. Association between hematocrit in late adolescence and subsequent myocardial infarction in Swedish men. Int J Cardiol. 2013;168(Oct):3588–93.

    Article  PubMed  Google Scholar 

  43. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with testosterone administration. N. Engl J Med. 2010;363(Jul):109–22. 8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. The U.S. Food and Drug Administration. FDA drug safety communication: FDA evaluating risk of stroke, heart attack, and death with FDA-approved testosterone products. 2015.

  45. Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(Oct):1327–51.

    Article  CAS  PubMed  Google Scholar 

  46. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, et al. Long-term Testosterone Gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(May):2085–98.

    Article  CAS  PubMed  Google Scholar 

  47. Siddique H, Smith JC, Corrall RJM. Reversal of polycythaemia induced by intramuscular androgen replacement using transdermal testosterone therapy. Clin Endocrinol. 2004;60(Jan):143–5.

    Article  CAS  Google Scholar 

  48. Bou Assi T, Baz E Current applications of therapeutic phlebotomy. Blood Transfus [Internet]. 2014 [cited 2021 May 9]; Available from: https://doi.org/10.2450/2013.0299-12

  49. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N. Engl J Med. 2013;368(Jan):22–33. 3

    Article  CAS  PubMed  Google Scholar 

  50. Hazegh K, Bravo MD, Kamel H, Dumont L, Kanias T. The prevalence and demographic determinants of blood donors receiving testosterone replacement therapy at a large USA blood service organization. Transfus. 2020;60(May):947–54.

    Article  CAS  Google Scholar 

  51. Chin-Yee B, Lazo-Langner A, Butler-Foster T, Hsia C, Chin-Yee I. Blood donation and testosterone replacement therapy: blood donation and TRT. Transfus. 2017;57(Mar):578–81.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Dalhousie University Department of Urology, Halifax, NS, Canada

    Joshua White & Jesse Ory

  2. McGill University Department of Urology, Montreal, QC, Canada

    Francis Petrella

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JW was the primary author of the manuscript. The secondary author FP completed sections of the manuscript as well as the table and figure. JO was the senior author both creating an outline and integral to the review process.

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Correspondence to Joshua White.

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White, J., Petrella, F. & Ory, J. Testosterone therapy and secondary erythrocytosis. Int J Impot Res 34, 693–697 (2022). https://doi.org/10.1038/s41443-021-00509-5

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