Erythrocytosis, a well-recognized adverse effect of testosterone treatment, appears to be associated with testosterone levels that are at the high end of the normal range or higher during treatment. The incidence of erythrocytosis was substantially higher in trials in which injectable testosterone esters were used than in those in which transdermal formulations were used, probably because of higher testosterone levels in trials with testosterone esters. For example, in the T4DM trial, in which injectable testosterone undecanoate was used, the incidence of erythrocytosis was 22%. The incidence of erythrocytosis in the TTrials and the TRAVERSE trial was low (1.8% and 0.2%, respectively), most likely because the testosterone dose in each trial was adjusted to keep the testosterone and hemoglobin levels within the normal range. These results indicate that a physiologic dose of testosterone is an uncommon cause of erythrocytosis.

T administration increases hemoglobin and hematocrit ( 88 , 89 ); these effects are related to T doses and circulating concentrations ( 89 ). In some men with hypogonadism, T therapy can cause erythrocytosis (hematocrit > 54%). The increase in hematocrit during T administration and the frequency of erythrocytosis is higher in older men than in young men ( 87 ). The commissioned meta-analysis showed that T treatment was associated with a significantly higher frequency of erythrocytosis vs placebo. The hematocrit level at which the risk of neuro-occlusive or cardiovascular events increases is not known. The frequency of neuro-occlusive events in men with hypogonadism enrolled in RCTs of T who developed erythrocytosis has been very low.
Clinicians should evaluate men who develop erythrocytosis during T-replacement therapy and withhold T therapy until hematocrit has returned to the normal range and then resume T therapy at a lower dose. Using therapeutic phlebotomy to lower hematocrit is also effective in managing T treatment–induced erythrocytosis.

Purpose: An unsafe hematocrit threshold for men receiving testosterone therapy (TT) has never been tested. This study seeks to determine whether secondary polycythemia among men receiving TT confers an increased risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE).

Materials And Methods: Using a multi-institutional database of 74 million patients, we identified 2 cohorts of men with low testosterone (total testosterone <350 ng/dl) who received TT and subsequently either developed polycythemia (5,887) or did not (4,2784). Polycythemia was defined as hematocrit ≥52%. As a secondary objective, we identified 2 cohorts of hypogonadal men without polycythemia, who either did (26,880) or did not (27,430) receive TT. Our primary outcome was the incidence of MACE and VTE in the first year after starting TT. We conducted a Kaplan-Meier survival analysis to assess differences in MACE and VTE survival time, and measured associations following propensity score matching.

Results: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13-1.61, p <0.001). In hypogonadal men who received testosterone, no increased risk of MACE and VTE was identified as compared to hypogonadal men naïve to TT.

Conclusions: Developing polycythemia while on TT is an independent risk factor for MACE and VTE in the first year of therapy. Future research on the safety of TT should include hematocrit as an independent variable.

Importance Testosterone therapy is increasingly prescribed in patients without a diagnosis of hypogonadism. This therapy may be associated with increased risk of venous thromboembolism (VTE) through several mechanisms, including elevated hematocrit levels, which increase blood viscosity.

Objective To assess whether short-term testosterone therapy exposure is associated with increased short-term risk of VTE in men with and without evidence of hypogonadism.

Design, Setting, and Participants This case-crossover study analyzed data on 39 622 men from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database from January 1, 2011, to December 31, 2017, with 12 months of follow-up. Men with VTE cases who were free of cancer at baseline and had 12 months of continuous enrollment before the VTE event were identified by International Classification of Diseases codes. Men in the case period were matched with themselves in the control period. Case periods of 6 months, 3 months, and 1 month before the VTE events were defined, with equivalent control periods (6 months, 3 months, and 1 month) in the 6 months before the case period.

Exposures National drug codes were used to identify billed testosterone therapy prescriptions in the case period (0-6 months before the VTE) and the control period (6-12 months before the VTE).

Main Outcomes and Measures The main outcome in this case-only experiment was first VTE event stratified by the presence or absence of hypogonadism.

Results A total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were enrolled in the study, and 3110 men (7.8%) had evidence of hypogonadism. In age-adjusted models, testosterone therapy use in all case periods was associated with a higher risk of VTE in men with (odds ratio [OR], 2.32; 95% CI, 1.97-2.74) and without (OR, 2.02; 95% CI, 1.47-2.77) hypogonadism.

Importance 
Testosterone therapy is increasingly prescribed in patients without a diagnosis of hypogonadism. This therapy may be associated with increased risk of venous thromboembolism (VTE) through several mechanisms, including elevated hematocrit levels, which increase blood viscosity.
Objective 
To assess whether short-term testosterone therapy exposure is associated with increased short-term risk of VTE in men with and without evidence of hypogonadism.
Design, Setting, and Participants 
This case-crossover study analyzed data on 39 622 men from the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database from January 1, 2011, to December 31, 2017, with 12 months of follow-up. Men with VTE cases who were free of cancer at baseline and had 12 months of continuous enrollment before the VTE event were identified by International Classification of Diseases codes. Men in the case period were matched with themselves in the control period. Case periods of 6 months, 3 months, and 1 month before the VTE events were defined, with equivalent control periods (6 months, 3 months, and 1 month) in the 6 months before the case period.
Exposures 
National drug codes were used to identify billed testosterone therapy prescriptions in the case period (0-6 months before the VTE) and the control period (6-12 months before the VTE).
Main Outcomes and Measures 
The main outcome in this case-only experiment was first VTE event stratified by the presence or absence of hypogonadism.
Results 
A total of 39 622 men (mean [SD] age, 57.4 [14.2] years) were enrolled in the study, and 3110 men (7.8%) had evidence of hypogonadism. In age-adjusted models, testosterone therapy use in all case periods was associated with a higher risk of VTE in men with (odds ratio [OR], 2.32; 95% CI, 1.97-2.74) and without (OR, 2.02; 95% CI, 1.47-2.77) hypogonadism. Among men without hypogonadism, the point estimate for testosterone therapy and VTE risk in the 3-month case period was higher for men younger than 65 years (OR, 2.99; 95% CI, 1.91-4.68) than for older men (OR, 1.68; 95% CI, 0.90-3.14), although this interaction was not statistically significant (P = .14).
Conclusions and Relevance 
Testosterone therapy was associated with an increase in short-term risk for VTE among men with and without hypogonadism, with some evidence that the association was more pronounced among younger men. These findings suggest that caution should be used when prescribing testosterone therapy.

Other potential risks of testosterone therapy are recognized but were outside the scope of this review. These include but are not limited to polycythemia, elevated prostate-specific antigen levels, increased blood pressure, gynecomastia, skin reaction to transdermal products, testicular atrophy, infertility or azoospermia, and fluid retention, as well as risk for transfer to others of the transdermal preparations, a concern owing to risk for virilization in women or children ( 106 ). Because of concern about inadequate data regarding harms of testosterone treatment in older men with age-related hypogonadism, the FDA has required companies that manufacture these products to conduct a controlled clinical trial to evaluate the effects of testosterone therapy on cardiovascular outcomes ( 1 ). This trial, TRAVERSE (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men), began enrollment in May 2018 and will follow participants for up to 5 years for cardiovascular safety and prostate safety, as well as efficacy outcomes ( 107 ).
Because deaths were few and entry criteria for RCTs excluded persons at highest risk for death, we cannot make definitive conclusions about testosterone's effect on mortality. However, our findings do not suggest an increased risk for death with testosterone treatment.
Our findings are generally consistent with those of other systematic reviews ( 108–125 ), with occasional exceptions (for example, the trial by Huo and colleagues [ 126 ]), despite variable inclusion and exclusion criteria for study selection, various outcomes assessed, and methodological differences. Most have found low- to moderate-certainty evidence of small beneficial effects on sexual function, little to no evidence of benefit for other clinical efficacy outcomes, and inadequate evidence to make definitive conclusions about cardiovascular and other long-term harms.

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.

Methods: A 20-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 (odds ratio [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), body mass index (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 a substantial number of people 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, to switch to a transdermal administration route, and if BMI is high, to lose weight.

Purpose: We sought to compare testosterone formulations and determine the degree that hematocrit increases vary by testosterone therapy formulation. As head-to-head trials are rare, network meta-analysis of the contemporary studies is the only way to compare hematocrit changes by testosterone type, including topical gels and patches, injectables (both short-acting and long-acting) and oral tablets.

Materials And Methods: We conducted a thorough search of listed publications in Scopus®, PubMed®, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov. A total of 29 placebo-controlled randomized trials (3,393 men) met inclusion criteria for analysis of mean hematocrit change after testosterone therapy. Randomized controlled trial data for the following formulations of testosterone were pooled via network meta-analysis: gel, patch, oral testosterone undecanoate, intramuscular testosterone undecanoate, and intramuscular testosterone enanthate/cypionate.

Results: All types of testosterone therapies result in statistically significant increases in mean hematocrit when compared with placebo. Meta-analysis revealed all formulations, including gel (3.0%, 95% CI 1.8-4.3), oral testosterone undecanoate (4.3%, 0.7-8.0), patch (1.4%, 0.2-2.6), intramuscular testosterone enanthate/cypionate (4.0%, 2.9-5.1), and intramuscular testosterone undecanoate (1.6%, 0.3-3.0) result in statistically significant increases in mean hematocrit when compared with placebo. When comparing all formulations against one another, intramuscular testosterone cypionate/enanthate were associated with a significantly higher increase in mean hematocrit compared to patch, but no differences in hematocrit between other formulations were detected.

Conclusions: All types of testosterone are associated with increased hematocrit; however, the clinical concern of this increase remains questionable, warranting future studies. This is the first network meta-analysis to quantify mean hematocrit change and compare formulations, given the absence of head-to-head trials.