Testosterone treatment and risk of blood clots - what is new?
In discussions about side effects of testosterone treatment, prostate cancer and heart disease get most attention. However, as we have described in several study reports published here in the “Research News” section, the widespread fear of prostate cancer and heart disease is unfounded and not supported by medical research.
The expected potential side effect of testosterone treatment - which in fact is a therapeutic effect in men with anemia1-3 - is an increased level of red blood cells, known as erythrocytosis or polycythemia.4-7 In the context of testosterone treatment, erythrocytosis and polycythemia are used interchangeably to refer to an abnormal increase of hemoglobin or hematocrit, which may increase blood thickness.8,9
Elevated hematocrit is the most common side-effect of testosterone treatment.4-7 The consequences of a high hematocrit level is unclear, but it may theoretically be associated with an increased risk of blood clots.4 Here we summarize the results of an analysis of the effect of testosterone treatment on risk of blood clots, published in the Journal of Investigative Medicine.10
What is known
What is hemoglobin and hematocrit?
Hemoglobin is the protein contained in red blood cells that is responsible for delivery of oxygen to the tissues. To ensure adequate tissue oxygenation, a sufficient hemoglobin level must be maintained. The amount of hemoglobin in whole blood is expressed in grams per deciliter (g/dL). The normal Hemoglobin level is 14 to 18 g/dL for males and 12 to 16 g/dL for females.11 When the hemoglobin level is lower, the person has anemia. Erythrocytosis is a condition caused by too many red cells, which results in hemoglobin levels above normal, often accompanied by an elevated hematocrit.11
Hematocrit measures the volume of red blood cells compared to the total blood volume (red blood cells and the fluid part of blood); normal hematocrit levels for men is 40 to 54% and for women 36 to 48%.11 Both hemoglobin and hematocrit are based on whole blood and are therefore dependent on blood fluid volume. If a person is dehydrated, the hemoglobin and hematocrit will be higher.11
What does testosterone treatment do to hemoglobin and hematocrit levels?
Testosterone has a well-documented erythrogenic effect that increases red blood cell production.1,12-15 Testosterone treatment is associated with a dose-dependent increase in hemoglobin and hematocrit levels16-18; the increases in hemoglobin and hematocrit are greater in older men than in young men.18,19 The effect of testosterone therapy on erythropoiesis may become evident at three months and peaks after approximately twelve months.20
An increased hematocrit is associated with “blood thickening” (also known as increased blood viscosity), increased platelet activation/aggregation, decreased venous return and shortened bleeding time.8,9,21-25 Although stimulation of red blood cell production with an ensuing rise in hemoglobin and hematocrit is beneficial for patients with anemia, it is theoretically possible that elevations above the normal range may have unintended consequences.26,27
The potential risk of hematocrit elevations has been suggested by research in patients with polycythemia vera, which is a slow-growing blood cancer in which the bone marrow produces too many red blood cells. These excess red blood cells thicken the blood, slow down blood flow and cause complications, such as thrombosis, which can lead to a heart attack or stroke.28 In patients with polycythemia vera, a hematocrit target of less than 45% resulted in a significantly lower rate of blood clots and reduced cardiovascular death than a hematocrit target of 45 - 50%.29
However, several studies have demonstrated that in men without underlying blood diseases, high endogenous (i.e. produced by the body) testosterone levels are not associated with blood clots in the legs (also known as deep vein thrombosis or venous thromboembolism).30-32 In line with this, there is no undisputable evidence that hematocrit elevation following testosterone therapy increases incidence of blood clots, heart attack or stroke in the general population of men.10,33-37
What this analysis adds
Reported cases of venous thromboembolism after testosterone treatment were almost all confined to patients with a previously undiagnosed thrombophilia (a blood coagulation abnormality that increases the risk of blood clots).34,38 Men with thrombophilia are more likely to have the Factor V Leiden mutation, high Factor VIII and high Factor XI than men given testosterone therapy who did not have a venous thromboembolism.34,38 This is supported by a more recent study which showed that among adult men with low testosterone levels who were at low to moderate baseline risk of developing blood clots - which comprises the large majority of the general population of men - there is no significant association between testosterone treatment and risk of blood clots.37
Two large population studies have compared the rate of venous thromboembolism in men receiving testosterone treatment versus a control group comprised of men not receiving testosterone treatment).39,40 The first study – which we have written about previously “Risk of Venous Thromboembolism in Men Receiving Testosterone Therapy” - showed that testosterone treatment is not associated with an increased risk of blood clots.39 The second study concluded that starting testosterone treatment is associated with an increased risk of blood clots during the first 6 months of testosterone treatment, and declines thereafter.40
The study in the Journal of Investigative Medicine conducted a meta-analysis of these two studies.10 A meta-analysis is a statistical approach to combine the results from multiple studies in an effort to increase statistical power (over individual studies), improve estimates of the effect size and/or to resolve uncertainty when studies disagree.41,42 This meta-analysis showed that testosterone treatment is not associated with an increased risk of blood clots, even when the analysis was confined to the first 6 months of testosterone therapy.10 Risk of blood clots seems to be more strongly associated with estrogen and estrogen treatment.43-47 The contribution of estrogen as a causal factor in venous thromboembolism is supported by the World Professional Association for Transgender Health (WPATH), which report that the greatest risk factor of male-to-female estrogen hormone treatment is blood clotting.45 This is not the case in female-to-male transsexuals, who are treated with testosterone.45,47
Even though it has not been directly proven that testosterone-induced elevations in hematocrit may increase risk of venous thromboembolism, since it is mechanistically plausible, regular monitoring of hematocrit during testosterone therapy is important.4-6,48 In clinical practice, erythrocytosis commonly translates to a hemoglobin level higher than 18.5g/dL or a hematocrit level higher than 52% in men, although the exact cut-off varies between guidelines. The Endocrine Society uses a hematocrit level higher than 50% as a relative contraindication to the initiation of testosterone therapy and a hematocrit level higher than 54% as a reason to stop testosterone therapy until hematocrit returns to a lower level.48 The European Association of Urology (EAU) also recommends 54% as the upper safe hematocrit threshold.4 Other professional societies use hematocrit levels ranging from 52% to 55% as thresholds to modify or discontinue testosterone therapy.49 All major guidelines strongly recommend measuring hematocrit at baseline, at 3 and 6 months after start of testosterone therapy, and then annually.4-6,48 It should be noted that isolated hematocrit elevations can be the result of insufficient fluid intake on a hot day or dehydration following vigorous exercise. Only repeated measures of hematocrit above 54% should be followed by concomitant administration of aspirin, therapeutic phlebotomy and/or discontinuation of testosterone treatment until hematocrit declines below 54%. After normalization of hematocrit level testosterone treatment may be continued with a reduced dosage.4-6,48,50-52
Almost all previously reported cases of testosterone treatment related blood clots 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 people53-55 - fear of blood clots should not preclude the large majority of suffering hypogonadal men from receiving testosterone therapy and its well documented health benefits. If you have a family history of blood clotting, it may be wise to do some extra blood tests to see if you have any blood clotting abnormalities before starting testosterone treatment. But data do not support universal screening of all men with testosterone deficiency before start of testosterone treatment.56
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 levels of lipoprotein(a) [Lp(a)] by the impressive range of 20-59%.57-59 Lp(a) may be an indirect risk factor for blood clots.60-66
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.67
Finally, an experimental study suggests that there are adaptive physiological mechanisms that restore whole-blood viscosity to normal during prolonged testosterone administration.68 Results from this study showed that long-term testosterone treatment did not adversely affect blood thickness in adult mice, even when extremely high 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 hematocrit and blood thickness in association.68 The increased erythrocyte deformability may offset blood thickness to a much lower level than that predicted from exceptionally high hematocrits.68,69 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.70-72
Another study reviewed the charts of 217 testosterone deficient men older than 65 years who were treated with testosterone therapy, to determine the prevalence of blood clots and all-cause mortality.36 There was increased all-cause mortality in testosterone deficient men not treated with testosterone compared to men who received testosterone treatment.36 There was no difference in incidence of blood clots, heart attack or stroke between testosterone treated men compared to untreated men.36 In the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) study, 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 men36,73-76, the small number of men experiencing hematocrit elevations reaching 54% - the consequences of which are still unproven10,33-36 - should not deter doctors from prescribing testosterone treatment to suffering hypogonadal men.