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.
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