Testosterone Raised Red Blood Cell Levels in Trans Men: 38% Crossed the Male Erythrocytosis Threshold Within 10 Years

Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years

Cohort & registry studies Cross-sex hormones

Authors: Milou Cecilia Madsen, Dennis van Dijk, Chantal M. Wiepjes, Elfi B. Conemans, Abel Thijs, Martin den Heijer
Journal: The Journal of Clinical Endocrinology & Metabolism
Year: 2021
Source: https://doi.org/10.1210/clinem/dgab089

Summary

Testosterone makes the body produce more red blood cells. Blood that becomes too thick raises the risk of clots, heart attack and stroke. Amsterdam doctors reviewed blood tests from 1,073 trans men on testosterone over up to 20 years. About one in nine had repeatedly high levels by male standards. The chance of ever crossing the limit kept rising for years, reaching 38% after a decade, so someone stable for years can still develop it. Long-acting injections, smoking, higher weight, older age and lung disease raised the risk. The authors advise checking blood for as long as testosterone is used. More than half of the clinic's trans men were left out for missing data. Using the normal limits for women would label far more people as affected (26%, the authors said in a reply to a letter), so the true scale may be higher.

Key findings

Of 1,073 trans men on testosterone, 11% had too-thick blood (more than half the blood volume made of red cells) on two tests by male standards; 3.7% and 0.5% passed higher limits.
24% had at least one blood test above the male limit.
On average, the share of blood made of red cells rose from 39% before treatment to 45% after one year, then rose only slightly over 20 years.
Among the 776 men with starting data, the chance of ever going above the male limit reached 38% after 10 years and 50% after 14 years.
Long-acting testosterone injections were linked to about 3 times the odds of too-thick blood compared with gel; smoking (about twice the odds), higher weight, older starting age and lung conditions also raised risk.
Using the normal limit for women instead, 26% would have qualified on two tests, the authors said in a reply to a published letter.
The study measured only blood tests, not actual health events such as blood clots or heart attacks.

Abstract

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.

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. The authors add that regular hematocrit control seems warranted for as long as testosterone is used.

Methodological limitations

More than half left out: Of 2,398 trans men in the clinic database, 1,325 (55%) were excluded because hormone start dates or lab results were missing. This could make the true rate higher or lower than reported.
People who stopped were dropped: Anyone who stopped testosterone during the study was excluded. That removes people who may have stopped because of side effects like thick blood, and detransitioners.
Male limits used: Thick blood was defined using limits for men. A letter by Laidlaw and colleagues (2021) argued the limits for women should be used. The authors' reply revealed that 26% passed the lower female limit twice, a figure not in the paper.
Missing treatment details: The way testosterone was taken was unknown for about 38% of blood tests, which weakens the comparison between injections and gel.
Irregular testing: How often people had blood tests varied a lot. So the study could not tell how long high levels lasted, and the rate found depends on how often people were tested.
Blood tests only: No blood clots or heart problems were counted, so the real health effects of these blood levels are unknown.
Based on old records: Smoking, weight and lung conditions came from clinic notes, which had gaps. Other factors, such as undiagnosed sleep apnoea (breathing pauses during sleep), may have played a part.
Few people followed long-term: Lab data only started in 2004, so the 10- to 20-year estimates rely on a shrinking group (776 men in that analysis).
One clinic's dosing: The Amsterdam clinic aimed for testosterone levels that the authors note may be higher than in typical men, so results may not apply to clinics that dose differently.

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Summary

Key findings

Abstract

Conclusion