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For patients who meet criteria for and desire TTh, a baseline Hb and Hct should be assessed. Transdermal, or subcutaneous formulations should be strongly considered in at risk populations in order to minimize significant alterations in Hb and Hct. The study showed a contrast in the rates of erythrocytosis between short acting IM formulations, such as T cypionate and T enanthate (up to 40%), and extended release IM T formulation, such as TU (up to 7%). Dobs et al.’s findings were the basis of the 2004 review by Rhoden et al. which addressed risks of TTh and recommendations for monitoring . Figure 1 illustrates the proposed direct and indirect effects of testosterone on erythropoiesis. Serum soluble transferrin receptor (sTR) concentration reflects erythroid activation and signifies plasma iron turnover and erythroid transferrin uptake.
This is likely caused by the transient supraphysiological peak testosterone concentrations that these depots more easily cause than other formulations (21). In this article, we will describe how TTh is thought to induce erythropoiesis, discuss the evidence of TTh-induced erythrocytosis as a cause of thrombosis, and conclude on the potential beneficial or detrimental impact of providing therapeutic phlebotomy as a ‘treatment’ for it. The persistent suppression of hematocrit follows after depletion of iron stores – as it puts the proverbial brakes on erythropoiesis by lack of substrate – and lowers tissue oxygen partial pressure (pO2), thereby triggering various biological pathways. A testosterone dosage reduction with one or two phlebotomies to accelerate the correction of hematocrit – with the dose reduction in order to persist this – is unlikely to cause harm. As such, the efficacy and safety of an intervention such as phlebotomy to decrease hematocrit should therefore be critically assessed per subtype of erythrocytosis. Testosterone therapy (TTh) guideline statements or recommendations from several endocrine organizations regarding phlebotomy or venesection for TTh-induced hematocrit elevations.
Some people naturally produce more red blood cells when testosterone rises. While TRT itself increases risk, several other factors make some people more likely to develop elevated hemoglobin. Many people see small changes in their blood counts within the first 3–6 months, but some do not show increases until a year or more later. While TRT helps raise testosterone to healthy levels, it also signals the body to make more red blood cells. In TRT, hematocrit usually rises because testosterone stimulates the body to make more red blood cells. Hematocrit rises when the number of red blood cells increases or when the plasma volume decreases (such as with dehydration). These checks usually include a complete blood count, or CBC, which measures hemoglobin, hematocrit, and red blood cell count.
While SubQ injections can still raise hemoglobin, they tend to do so less aggressively. They are usually given every 1 to 2 weeks, depending on the type of testosterone prescribed. Testosterone replacement therapy (TRT) affects each person differently. Phlebotomy is fast, effective, and often used when levels rise sharply or when other changes are not enough.
Thick blood can move more slowly to the hands and feet. Some people describe a heavy feeling in their chest or legs when they try to work out. When the blood is too thick, the heart must work harder to pump it.
Some people switch to gels if they develop high hemoglobin while using injections. They may still raise hemoglobin, but the risk is a bit lower. Right after an injection, the blood level of testosterone can be well above the normal range.
In contrast, in the T4DM trial, hematocrit increased to 54% or higher in 106 (22%) of participants randomized to TTh, with 25 participants (5%) discontinuing as a result (24). However, there are important differences between PV (and other causes of primary erythrocytosis) and secondary erythrocytosis, with good arguments against hematocrit being a driver of thrombotic risk (13). Indeed, several guidelines for the treatment of male hypogonadism also discuss phlebotomy as a means of reducing hematocrit in TTh-induced erythrocytosis (7, 8, 9, 10, 11) (Table 1), although some, such as the UK Society for Endocrinology (12), do not. Since measuring RCM is expensive, cumbersome, and virtually unavailable for the clinician, hematocrit or hemoglobin levels are used as a surrogate. Notably, whereas its stimulating effect on erythropoiesis can be beneficial for the correction of anemia in some patients, the same effect can lead to erythrocytosis in others – with a nearly fourfold greater risk for erythrocytosis compared with placebo (5). Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin ‘set point’, and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. What type of testosterone formulation poses the greatest risk for erythrocytosis?
Though not testosterone-induced, an increased thromboembolic risk from elevated Hct was demonstrated. Despite its positive effects, TTh has several common side effects, including increases in estrogen levels, gynecomastia, and erythrocytosis 10–15. High blood viscosity increases the risk for potential vascular complications involving the coronary, cerebrovascular, and peripheral vascular circulation, though there is limited evidence supporting a relationship between TTh and vascular complications. A rapid increase in awareness of androgen deficiency has led to substantial increases in prescribing of testosterone therapy (TTh), with the benefits of improvements in mood, libido, bone density, muscle mass, body composition, energy and cognition. Several guidelines by endocrine organizations for the treatment of male hypogonadism recommend against starting TTh in patients presenting with elevated hematocrit at baseline or stopping TTh when its levels cannot be controlled. Testosterone replacement therapy (TRT) can be an effective treatment for low testosterone in both males and females, addressing symptoms like fatigue, low libido, and loss of muscle mass.