madman
Super Moderator
Abstract
Context: Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events.
Objectives: To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone.
Design: A twenty-year follow-up study in adult trans men who started testosterone therapy, and had monitoring of hematocrit at our center (n=1073).
Results: Erythrocytosis occurred in 11% (hematocrit>0.50 l/l), 3.7% (hematocrit>0.52 l/l) and 0.5% (hematocrit>0.54 l/l) of trans men. Tobacco use (OR 2.2, 95%CI 1.6-3.3), long-acting undecanoate injections (OR 2.9, 95%CI 1.7-5.0), age at initiation of hormone therapy (OR 5.9, 95%CI 2.8- 12.3), BMI (OR 3.7, 95%CI 2.2-6.2) and pulmonary conditions associated with erythrocytosis and polycythemia vera (OR 2.5, 95%CI 1.4-4.4) were associated with hematocrit >0.50 l/l. In the first year of testosterone therapy hematocrit increased most: 0.39 l/l at baseline to 0.45 l/l after 1 year. Although there was only a slight continuation of this increase in the following 20 years, the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 10 years).
Conclusion: Erythrocytosis occurs in trans men using testosterone. The largest increase in hematocrit was seen in the first year, but also after the first years, there is a substantial number of people that present with hematocrit >0.50 l/l. A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking and to switch to a transdermal administration route and if BMI is high, to lose weight.
Introduction
People diagnosed with gender dysphoria (trans people) experience distress due to an incongruence between a subject's gender identity and the sex assigned at birth.1 To reduce this distress, gender affirmative hormone therapy can be given to induce physical and mental changes towards the experienced sex.2 In trans men, who are assigned as female at birth, testosterone therapy induces virilization.3,4 This includes deepening of the voice, an increase in facial and body hair, a more masculine body composition, and psychological and sexual changes.5-7 Also, hematological and biochemical changes occur due to the treatment, and therefore regular laboratory monitoring is recommended.3
It is known from studies in hypogonadal cis men (birth-assigned male, male gender identity) that testosterone has a dose-dependent stimulating effect on erythropoiesis.8 Hence, one of the changes due to testosterone therapy is the rise in hematocrit levels. This results in secondary erythrocytosis, a potentially serious adverse effect of testosterone therapy as it is associated with an increased risk of thromboembolic events by an increase in blood viscosity.9,10 Hematocrit is one of the major determinants of blood viscosity with an increased risk of coronary heart disease (relative risk of 1.16)11 and unprovoked venous thromboembolism (2.4-fold increased risk in the 20th highest percentile compared to lowest 40th percentile in men).12,13
Erythrocytosis is previously described in both cis men and trans men on testosterone therapy.14 Prevalence of erythrocytosis (hematocrit >0.50) in testosterone-treated hypogonadal cis men is described between 5% and 66%. The largest increase was seen in the first year after the initiation of testosterone therapy.14-17 Prevalence of erythrocytosis (hematocrit >0.50) in testosterone-treated trans men is 11.5% in previous literature.18 Studies in testosterone-treated hypogonadal cis men described the highest risk of erythrocytosis with injectable testosterone therapy (both short-acting esters and long-acting undecanoate) when compared to transdermal administration. Studies in testosterone-treated trans men also described the highest risk of erythrocytosis (hematocrit >0.50) with injectable testosterone (both short-acting esters and long-acting undecanoate) compared to gel and the biggest increase in the first three months to one year (follow-up 1-5 years in these studies).19-21
Current guidelines on the management of secondary erythrocytosis in trans men on testosterone therapy refer to the guideline for testosterone treated hypogonadal cis men and consider hematocrit levels >0.50 l/l as potentially dangerous as it has a very high risk of adverse outcome.3,22 This guideline advises a cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy when hematocrit levels exceed 0.54 l/l to reduce the risk of adverse events. For levels between 0.50-0.54 l/l no clear advice is given in these guidelines. The question remains whether these guidelines are applicable to trans men as the duration of testosterone therapy is much longer in trans men and hormone treatment can often not be discontinued.
In light of these considerations the aim of this study is twofold:
1. To study the prevalence and determinants in the development of erythrocytosis in trans men on testosterone therapy.
2. To study the time relation between duration of testosterone therapy and hematocrit levels over the course of 20 years. Based on the results of this study we discuss how these findings affect current practices regarding erythrocytosis in trans men.
Time relation:
The time relation between the initiation of testosterone therapy and hematocrit is depicted in Figure 1. The largest increase in hematocrit level was seen in the first year after initiation of testosterone therapy. A slight increase was seen until twenty years after the initiation of testosterone therapy. Figure 2 shows the probability of developing hematocrit levels >0.50 and >0.52. In this subgroup analysis 776 trans men were included. After 1 year the cumulative risk of developing hematocrit levels >0.50 was 8%, after 10 years 38% and at the end of follow up, after 14 years, the cumulative incidence was 50%. For hematocrit levels of >0.52, the cumulative risk after 1 year was 4% and 16% after 10 years.
The results of this study show the largest increase in hematocrit in the first year after initiation of testosterone therapy, with a slight continuation of this increase up to 20 years. This is in line with previous literature and reflected in current guidelines.18,21,24,36 Our study confirmed that this is also the case in trans men. The probability of developing the first-time erythrocytosis increases over the course of 14 years. It implicates that a person who is stable on testosterone therapy for years still can develop the first-time erythrocytosis. Therefore, regular control of hematocrit seems warranted as long as people use testosterone.
Recommendations for clinical practice
From this study, a few recommendations for clinical practice can be formulated. Firstly, regular control of hematocrit seems warranted as long as people use testosterone. If hematocrit levels are between 0.50-0.54 l/l, reasonable first steps to prevent further increase would be:
Consider switching injectable testosterone therapy to transdermal administration. We cannot exclude that dose-reduction has the same effect.
If BMI levels are >25 the people should be advised to lose weight to reach a BMI in the healthy range (18.5-25)
People should strongly be advised to stop smoking.
Treatment optimization for chronic lung disease or sleep apnea should be pursued
Context: Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events.
Objectives: To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone.
Design: A twenty-year follow-up study in adult trans men who started testosterone therapy, and had monitoring of hematocrit at our center (n=1073).
Results: Erythrocytosis occurred in 11% (hematocrit>0.50 l/l), 3.7% (hematocrit>0.52 l/l) and 0.5% (hematocrit>0.54 l/l) of trans men. Tobacco use (OR 2.2, 95%CI 1.6-3.3), long-acting undecanoate injections (OR 2.9, 95%CI 1.7-5.0), age at initiation of hormone therapy (OR 5.9, 95%CI 2.8- 12.3), BMI (OR 3.7, 95%CI 2.2-6.2) and pulmonary conditions associated with erythrocytosis and polycythemia vera (OR 2.5, 95%CI 1.4-4.4) were associated with hematocrit >0.50 l/l. In the first year of testosterone therapy hematocrit increased most: 0.39 l/l at baseline to 0.45 l/l after 1 year. Although there was only a slight continuation of this increase in the following 20 years, the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 10 years).
Conclusion: Erythrocytosis occurs in trans men using testosterone. The largest increase in hematocrit was seen in the first year, but also after the first years, there is a substantial number of people that present with hematocrit >0.50 l/l. A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking and to switch to a transdermal administration route and if BMI is high, to lose weight.
Introduction
People diagnosed with gender dysphoria (trans people) experience distress due to an incongruence between a subject's gender identity and the sex assigned at birth.1 To reduce this distress, gender affirmative hormone therapy can be given to induce physical and mental changes towards the experienced sex.2 In trans men, who are assigned as female at birth, testosterone therapy induces virilization.3,4 This includes deepening of the voice, an increase in facial and body hair, a more masculine body composition, and psychological and sexual changes.5-7 Also, hematological and biochemical changes occur due to the treatment, and therefore regular laboratory monitoring is recommended.3
It is known from studies in hypogonadal cis men (birth-assigned male, male gender identity) that testosterone has a dose-dependent stimulating effect on erythropoiesis.8 Hence, one of the changes due to testosterone therapy is the rise in hematocrit levels. This results in secondary erythrocytosis, a potentially serious adverse effect of testosterone therapy as it is associated with an increased risk of thromboembolic events by an increase in blood viscosity.9,10 Hematocrit is one of the major determinants of blood viscosity with an increased risk of coronary heart disease (relative risk of 1.16)11 and unprovoked venous thromboembolism (2.4-fold increased risk in the 20th highest percentile compared to lowest 40th percentile in men).12,13
Erythrocytosis is previously described in both cis men and trans men on testosterone therapy.14 Prevalence of erythrocytosis (hematocrit >0.50) in testosterone-treated hypogonadal cis men is described between 5% and 66%. The largest increase was seen in the first year after the initiation of testosterone therapy.14-17 Prevalence of erythrocytosis (hematocrit >0.50) in testosterone-treated trans men is 11.5% in previous literature.18 Studies in testosterone-treated hypogonadal cis men described the highest risk of erythrocytosis with injectable testosterone therapy (both short-acting esters and long-acting undecanoate) when compared to transdermal administration. Studies in testosterone-treated trans men also described the highest risk of erythrocytosis (hematocrit >0.50) with injectable testosterone (both short-acting esters and long-acting undecanoate) compared to gel and the biggest increase in the first three months to one year (follow-up 1-5 years in these studies).19-21
Current guidelines on the management of secondary erythrocytosis in trans men on testosterone therapy refer to the guideline for testosterone treated hypogonadal cis men and consider hematocrit levels >0.50 l/l as potentially dangerous as it has a very high risk of adverse outcome.3,22 This guideline advises a cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy when hematocrit levels exceed 0.54 l/l to reduce the risk of adverse events. For levels between 0.50-0.54 l/l no clear advice is given in these guidelines. The question remains whether these guidelines are applicable to trans men as the duration of testosterone therapy is much longer in trans men and hormone treatment can often not be discontinued.
In light of these considerations the aim of this study is twofold:
1. To study the prevalence and determinants in the development of erythrocytosis in trans men on testosterone therapy.
2. To study the time relation between duration of testosterone therapy and hematocrit levels over the course of 20 years. Based on the results of this study we discuss how these findings affect current practices regarding erythrocytosis in trans men.
Time relation:
The time relation between the initiation of testosterone therapy and hematocrit is depicted in Figure 1. The largest increase in hematocrit level was seen in the first year after initiation of testosterone therapy. A slight increase was seen until twenty years after the initiation of testosterone therapy. Figure 2 shows the probability of developing hematocrit levels >0.50 and >0.52. In this subgroup analysis 776 trans men were included. After 1 year the cumulative risk of developing hematocrit levels >0.50 was 8%, after 10 years 38% and at the end of follow up, after 14 years, the cumulative incidence was 50%. For hematocrit levels of >0.52, the cumulative risk after 1 year was 4% and 16% after 10 years.
The results of this study show the largest increase in hematocrit in the first year after initiation of testosterone therapy, with a slight continuation of this increase up to 20 years. This is in line with previous literature and reflected in current guidelines.18,21,24,36 Our study confirmed that this is also the case in trans men. The probability of developing the first-time erythrocytosis increases over the course of 14 years. It implicates that a person who is stable on testosterone therapy for years still can develop the first-time erythrocytosis. Therefore, regular control of hematocrit seems warranted as long as people use testosterone.
Recommendations for clinical practice
From this study, a few recommendations for clinical practice can be formulated. Firstly, regular control of hematocrit seems warranted as long as people use testosterone. If hematocrit levels are between 0.50-0.54 l/l, reasonable first steps to prevent further increase would be:
Consider switching injectable testosterone therapy to transdermal administration. We cannot exclude that dose-reduction has the same effect.
If BMI levels are >25 the people should be advised to lose weight to reach a BMI in the healthy range (18.5-25)
People should strongly be advised to stop smoking.
Treatment optimization for chronic lung disease or sleep apnea should be pursued
