madman
Super Moderator
A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate
Abstract
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 the 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.
Discussion
To the best of our knowledge, this is the only study comparing the prevalence of secondary polycythemia in testosterone deficient patients treated with either intranasal testosterone (Natesto) or IM TC therapy. There was a lower prevalence of secondary polycythemia (Hct ≥54%) in the cohort treated with Natesto (0%) compared to that on TC therapy (10%). In addition, using various cutoffs for Hct, significant differences were seen between treatment groups. In men treated with TC, 33.3% (10/30) had a Hct ≥50% and 20% (6/30) had a Hct ≥52% on follow-up, compared to men treated with Natesto, which had no one develop a Hct ≥50% during treatment. The prevalence of secondary polycythemia due to TC is comparable to previous studies that have evaluated this phenomenon.19
A study performed by Bachman et al. showed that supraphysiologic T levels suppressed hepcidin in a dose- and t age-dependent manner by > 50% and resulted in an increased hematocrit along with stable erythropoietin levels. His study also supported the hypothesis that older men respond to testosterone with a relatively greater level of hepcidin suppression than younger men. This mechanism may be responsible for the difference in the prevalence of polycythemia and change in Hct seen in TC patients, as the average age was 17.4 years older in our cohort. Since men interested in fertility preservation were treated with Natesto, this group was younger than the TC group, who were not interested in fertility preservation. Additionally, post-treatment levels of testosterone were significantly higher than Natesto (983.1 ± 394.1 ng/dL vs 640.3 ± 302.4 ng/dL), and this could have contributed to the observed difference. However, in an attempt to further analyze the effect of different independent variables on follow-up Hct, we performed a multivariable analysis that was adjusted by variables including age, BMI, smoking history, and testosterone on follow-up. Our findings indicate that the most influential factor contributing to an increase in Hct on follow-up was the use of TC.
Previous studies have demonstrated that different T formulations may have varying effects on erythropoiesis, and some have proposed that the troughs in serum T between doses are most predictive of developing polycythemia20,21 Importantly, the pharmacokinetic profile and TID dosing of Natesto allows T levels to return to baseline multiple times daily, whereas TC leads to steady-state levels over days. This property of Natesto was highlighted in our published clinical trial, in which the majority of men on Natesto maintained semen parameters during treatment. This was likely attributed to the maintenance of pulsatile secretion of GnRH that allowed the daily release of gonadotropins.22 Regardless of the proposed mechanisms for the erythrogenic effect of T,10-12 Natesto’s short half-life and frequent troughs in T during treatment would have less of an influence on these mechanisms. Of note, although Natesto can provide symptom relief similar to that of TC, the TID administration that Natesto requires can be cumbersome for patients when compared to a single injection that lasts for weeks.22
Our study had several limitations, including its retrospective nature, variability in dosages of TC taken and although adequately powered, a relatively small sample size and a non-age matched cohort. Strengths of the study are the novelty in the literature, adequate power, directly comparing the biochemical effects of TC and short-acting Natesto, multivariable regression analysis demonstrating the mode of therapy as an independent predictor of polycythemia. Further prospective randomized trials are needed, in which men are matched by age, serum testosterone, and hematocrit levels on baseline to confirm our findings.
Conclusions
The prevalence of polycythemia in men treated with Natesto were markedly lower compared to the men who received testosterone cypionate injections. Given that the most frequent adverse effect of TRT is the resulting polycythemia, Natesto could be a potential option if this is a concern, although larger prospective studies with age-matched cohorts are needed to validate the finding in our cross-sectional study.
Abstract
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 the 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.
Discussion
To the best of our knowledge, this is the only study comparing the prevalence of secondary polycythemia in testosterone deficient patients treated with either intranasal testosterone (Natesto) or IM TC therapy. There was a lower prevalence of secondary polycythemia (Hct ≥54%) in the cohort treated with Natesto (0%) compared to that on TC therapy (10%). In addition, using various cutoffs for Hct, significant differences were seen between treatment groups. In men treated with TC, 33.3% (10/30) had a Hct ≥50% and 20% (6/30) had a Hct ≥52% on follow-up, compared to men treated with Natesto, which had no one develop a Hct ≥50% during treatment. The prevalence of secondary polycythemia due to TC is comparable to previous studies that have evaluated this phenomenon.19
A study performed by Bachman et al. showed that supraphysiologic T levels suppressed hepcidin in a dose- and t age-dependent manner by > 50% and resulted in an increased hematocrit along with stable erythropoietin levels. His study also supported the hypothesis that older men respond to testosterone with a relatively greater level of hepcidin suppression than younger men. This mechanism may be responsible for the difference in the prevalence of polycythemia and change in Hct seen in TC patients, as the average age was 17.4 years older in our cohort. Since men interested in fertility preservation were treated with Natesto, this group was younger than the TC group, who were not interested in fertility preservation. Additionally, post-treatment levels of testosterone were significantly higher than Natesto (983.1 ± 394.1 ng/dL vs 640.3 ± 302.4 ng/dL), and this could have contributed to the observed difference. However, in an attempt to further analyze the effect of different independent variables on follow-up Hct, we performed a multivariable analysis that was adjusted by variables including age, BMI, smoking history, and testosterone on follow-up. Our findings indicate that the most influential factor contributing to an increase in Hct on follow-up was the use of TC.
Previous studies have demonstrated that different T formulations may have varying effects on erythropoiesis, and some have proposed that the troughs in serum T between doses are most predictive of developing polycythemia20,21 Importantly, the pharmacokinetic profile and TID dosing of Natesto allows T levels to return to baseline multiple times daily, whereas TC leads to steady-state levels over days. This property of Natesto was highlighted in our published clinical trial, in which the majority of men on Natesto maintained semen parameters during treatment. This was likely attributed to the maintenance of pulsatile secretion of GnRH that allowed the daily release of gonadotropins.22 Regardless of the proposed mechanisms for the erythrogenic effect of T,10-12 Natesto’s short half-life and frequent troughs in T during treatment would have less of an influence on these mechanisms. Of note, although Natesto can provide symptom relief similar to that of TC, the TID administration that Natesto requires can be cumbersome for patients when compared to a single injection that lasts for weeks.22
Our study had several limitations, including its retrospective nature, variability in dosages of TC taken and although adequately powered, a relatively small sample size and a non-age matched cohort. Strengths of the study are the novelty in the literature, adequate power, directly comparing the biochemical effects of TC and short-acting Natesto, multivariable regression analysis demonstrating the mode of therapy as an independent predictor of polycythemia. Further prospective randomized trials are needed, in which men are matched by age, serum testosterone, and hematocrit levels on baseline to confirm our findings.
Conclusions
The prevalence of polycythemia in men treated with Natesto were markedly lower compared to the men who received testosterone cypionate injections. Given that the most frequent adverse effect of TRT is the resulting polycythemia, Natesto could be a potential option if this is a concern, although larger prospective studies with age-matched cohorts are needed to validate the finding in our cross-sectional study.
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