The risk of reaching hematocrit >54% is determined by the duration of supraphysiologic testosterone levels, which in turn is determined by testosterone formulation (and hence pharmacokinetics) and dose.18,26,55-57 Short-acting intramuscular testosterone formulations (testosterone cypionate and testosterone enanthate) are associated with the most rapid and marked increases in testosterone levels – and hence hematocrit elevation - with supraphysiologic testosterone levels achieved within days of an injection and a return to baseline after 10 to 14 days, followed by a decrease to sub-physiologic levels within 3 weeks if not re-injected.26,58 In contrast, other testosterone formulations that result in a slower and more stable increase in testosterone levels, such as long-acting testosterone undecanoate injections, transdermal gels and pellets, result in a low incidence of erythrocytosis that is dependent on dose and achieved testosterone level, and independent of duration of testosterone therapy.18,55,56 Long-acting testosterone undecanoate maintains stable testosterone levels within the normal range for approximately 12 weeks.59 Hemoglobin and hematocrit increase initially over the first 3-6 months of treatment but then stabilize and remain within the normal range over the entire treatment period.60,61
A prospective observational study specifically examined adverse effects, including hematocrit elevations, of long-acting testosterone undecanoate; 347 hypogonadal men received a total of 3,022 testosterone undecanoate injections over 3.5 years.54 Only 14 patients (4%) developed a hematocrit level higher than 52% and 25 patients (7%) developing a hematocrit level higher than 54%.54 In stark contrast, among men receiving short-acting testosterone enanthate injections formulations, up to 67% experience hematocrit elevations higher than 50%.53 A previous pharmacokinetic study comparing long-acting testosterone undecanoate (1,000 mg every 6 weeks, followed by 1,000 mg every 9 weeks) and short-acting testosterone enanthate (250 mg every 3 weeks) also showed higher, stable trough testosterone levels for testosterone undecanoate at the time of injections (14.9 to 16.5 nmol/L) compared with testosterone enanthate (<10 nmol/L).59
Almost all previously reported cases of testosterone treatment related venous thromboembolism were seen in patients with a previously undiagnosed thrombophilia.34,38 Considering the low annual incidence of venous thromboembolism in the general population - 48 to 120 per 100 000 people 62-64 - fear of venous thromboembolism should not preclude the large majority of suffering hypogonadal men from receiving testosterone therapy and its well documented health benefits. The prevalence of hereditary thrombophilia has been reported to be 9% in a healthy population.65 While screening for thrombophilia before starting testosterone therapy is warranted for men with a history or family history of thrombosis, data do not justify universal screening because the absolute risk remains low.66
The risk of elevated hematocrit seen in patients with polycythemia vera cannot be extrapolated to hematocrit elevations seen during testosterone therapy in men without blood cancer or genetic mutations. Data suggest that testosterone therapy has effects that may counteract the potentially increased risk of venous thromboembolism. For example, testosterone therapy is one of the few treatments that reduces lipoprotein(a) [Lp(a)] levels, in the impressive range of 20-59%.67-69 In line with this, suppression of endogenous testosterone in young healthy men significantly increases Lp(a) levels, up to 40-60% above baseline.70 It has been suggested that Lp(a) may be a risk factor for venous thromboembolism.71-73 Mendelian randomization studies did not confirm an association between Lp(a) with the risk of venous thrombosis in the general population studies.74,75 However, a meta-analysis of eight studies in pediatric populations showed that elevated Lp(a) levels are associated with a 4.5-fold (odds ratio 4.50) increased risk of first onset venous thromboembolism.76 Lp(a) may not necessarily be prothrombotic, but may tilt the balance towards thrombosis due to the potential loss of fibrinolytic activity.77 Interestingly, the Mendelian randomization studies which did not find an association between Lp(a) with the risk of venous thrombosis did show an association between Lp(a) and factor V Leiden (which increases risk of blood clotting).74,75 Although further study is needed, this suggests that elevated Lp(a) may need a second underlying factor to generate a thrombus and that reductions in Lp(a) levels may reduce the overall thrombotic propensity.77
A second reason that elevations in hematocrit with testosterone treatment may not be inherently dangerous is that low testosterone levels are associated with higher levels of prothrombotic factors in men, regardless of age, obesity, body fat distribution, and related metabolic parameters.78
Finally, an experimental study suggests that there are adaptive physiological mechanisms that restore whole-blood viscosity to normal during prolonged testosterone administration.79 This study comprehensively assessed the effects of testosterone on whole-blood viscosity, plasma viscosity, and erythrocyte deformability, and compared sex differences after short-term as well as longer-term testosterone treatments.79 Results showed that long-term testosterone treatment did not adversely affect whole-blood viscosity or plasma viscosity in adult mice, even when supraphysiologic testosterone levels were reached. Interestingly, erythrocyte deformability was increased after long-term high-dose testosterone treatment. In contrast, short-term treatment with high-dose testosterone transiently raised whole-blood viscosity in association with increased hematocrits in female and castrated male mice.79 The increased erythrocyte deformability may offset whole-blood viscosity to a much lower level than that predicted from exceptionally high hematocrits.79,80 Notably, testosterone treatment in hypogonadal men has been shown to improve erythrocyte membrane composition and fluidity 81, which likely improves blood rheology and contributes to a reduced thrombosis risk.82 Testosterone also has vasodilator and anti-atherosclerotic effects that in addition may explain the lack of increase in cardiovascular events with elevated hematocrit during testosterone therapy.83-85
Support for the better tolerance to hematocrit elevations during testosterone treatment with testosterone undecanoate comes from a study where one patient showed constantly elevated hematocrit values when treated with testosterone enanthate.86 This patient showed no elevated hematocrit levels in the 27 month follow-up study when receiving testosterone undecanoate treatment.86 This suggests that men who experience marked hematocrit elevations with short-acting injectable testosterone formulations may be better able to tolerate treatment with testosterone undecanoate.
A notable study retrospectively reviewed the charts of 217 hypogonadal men older than 65 years who were treated with testosterone therapy, to determine the prevalence of thrombotic events and all-cause mortality.36 There was increased all-cause mortality in hypogonadal men not treated with testosterone compared to men who received testosterone treatment.36 There was no difference in incidence of myocardial infarction, transient ischemic attack, stroke or deep vein thrombosis/pulmonary embolism between patients treated with testosterone and hypogonadal men not treated with testosterone.36 In the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trial, of 155 men who were treated with testosterone for 3 years, 13 men (8%) experienced hematocrit greater than 54%. Hence, the incidence of large hematocrit elevations during long-term testosterone therapy is small. Considering the significant reduction in mortality seen in several studies in testosterone treated men compared to non-treated men 36,87-90, the small number of men experiencing hematocrit elevations reaching 54% - the consequences of which are still unproven 32-36 - should not deter physicians from prescribing testosterone treatment to suffering hypogonadal men.