Erythrocytosis in transgender men using testosterone; isn’t it ironic?
Authors:   , Madsen Milou Cecilia 
Published: September 2023

Testosterone therapy
In Chapter 2, published literature on the three most commonly used testosterone preparations is compared. In both hypogonadal men and transgender men all three administration types are effective. With all three administration types an increase in red blood cells is seen. However, in the very few comparative studies, injections gave the most chance of erythrocytosis. All administration types showed an increase in BMI, however this was mainly contributable to an increase in Lean Body Mass.

Transgender men with erythrocytosis
In Chapter 3A a large retrospective cohort study describes the time relation between initiation of testosterone therapy and erythrocytosis in transgender men. The biggest increase in hematocrit levels was seen in the first year, but also in the years after this erythrocytosis still occurred for the first time. In this study, determinants for erythrocytosis during testosterone therapy were also described. Patient related factors were: tobacco use, a positive medical history for lung disease (chronic obstructive pulmonary disease, asthma, obstructive sleep apnea), higher age at initiation of testosterone therapy and BMI >25 kg/m2. Testosterone-related determinants were the use of injections compared to gel and testosterone levels. Lastly, this study looked at the prevalence of testosteron induced erythrocytosis in transgender men. This was 11%, 3.7% or 0.5% depending on the used cut-off values for hematocrit. Which cut-off value to use in an ongoing topic of debate in transgender care. In Chapter 3B, a response to a letter to the editor describes the consideration around this topic in the context of hematocrit levels. In Chapter 4 we present a practical approach for the management of testosterone induced erythrocytosis. In this chapter it is advised to perform a phlebotomy if hematocrit levels exceed 0.55 l/l. If levels are between 0.52-0.55 l/l measures should be taken to prevent a further increase. These entail referral to a smoking cessation program, weight loss if BMI >25, switching from injections to gel and a dose reduction. Besides, OSAS diagnostics should be considered. The possibility of a newly diagnosed Polycythemia Vera or pulmonary disease should always be taken into consideration, especially when measures to reduce hematocrit levels are not effective.

The effect of testosterone on erythropoiesis
Chapter 5 investigates the mechanisms behind testosterone’s effect on erythropoiesis. In this chapter we zoom in on different aspects of erythropoiesis and iron parameters in a small group of transgender men. The main conclusion of this study is that the effect of testosterone is most likely directly on the erythroblasts in the bone marrow. Consequently, iron parameters adapt to the new situation. An increase in iron absorption and transportation throughout the body was seen. In the first weeks after initiation of testosterone therapy iron storage went down, which was supplemented again after one year.

Iron and the vascular endothelium
In Chapter 6, the effect of iron on the endothelium was described. We discovered that Fe3+ induces a reduction in barrier integrity of human umbilical cord venous endothelial cells (HUVECs) which could be prevented by the addition of ROS scavengers and ROCK inhibitors. This implies that the disruption of endothelial barrier due to Fe3+ in HUVECs is, at least partially, regulated through these two mechanisms. Moreover, iron had a synergistic effect when combined with TNF, an inflammatory cytokine, indicating that iron could have additional effects against the background of a low grade pro-inflammatory state (e.g. atherosclerosis). Because we already observed this increase after 48 hours, it could be hypothesized that, although we did not find an increase in iron status over the first year after TT in Chapter 5, “short-term” increased iron trafficking could already have a damaging effect on the vascular endothelium