TRT, Haemoglobin & Haematocrit: What Actually Matters

One of the most common lab changes in men on testosterone replacement therapy (TRT) is a rise in haemoglobin (Hb) and haematocrit (Hct). This worries patients and sometimes clinicians because of the long-standing belief that "thicker blood equals clots." While that concern has merit at extreme supraphysiological levels seen in bodybuilders, the reality for men on therapeutic TRT is far more nuanced.

This article breaks down what the evidence actually says: how much rise is normal, when to investigate further, whether TRT-related haematocrit elevation truly increases clot risk, and why phlebotomy should be a last resort rather than a first-line response.

How Testosterone Raises Haemoglobin and Haematocrit

Testosterone stimulates erythropoiesis (red blood cell production) through a dual mechanism. It increases erythropoietin (EPO) production and simultaneously suppresses hepcidin, the hormone that regulates iron availability. Together, these shifts establish a new, higher EPO/haemoglobin set point in men on TRT (Bachman et al., 2014).

This is a dose-dependent effect. A landmark study by Coviello et al. (2008) showed that graded doses of testosterone enanthate (25 to 600 mg/week) produced linear, dose-dependent increases in both Hb and Hct. Older men were more sensitive than younger men at every dose level.

How Much Rise Is Normal?

In TRT populations, it is typical to see:

• Haemoglobin rise by approximately 5 to 15 g/L
• Haematocrit increase by approximately 2 to 5 percentage points

Data from the Testosterone Trials (TTrials) in 788 older men showed that testosterone corrected unexplained anaemia in 58% of participants versus 22% on placebo, with Hb increasing by 1.0+ g/dL in over half the treatment group (Roy et al., 2017).

Some men are more sensitive and will exceed typical reference ranges. Incidence of erythrocytosis can reach up to 40% with intramuscular formulations (Ohlander et al., 2018). Importantly, lab "normal ranges" are based on general populations, not hormonally optimised TRT cohorts. A mild elevation alone does not automatically indicate a problem.

When Should You Look Deeper?

Not all elevated Hb/Hct is caused by TRT. Other contributors should be evaluated, especially if levels are rising rapidly or disproportionately:

• Sleep apnoea: intermittent hypoxia drives RBC production. A study of 474 hypogonadal men on TRT found that obstructive sleep apnoea (OSA) doubled the odds of developing polycythaemia (OR 2.09), even after adjusting for age, BMI, and peak testosterone (Lundy et al., 2020). A systematic review confirmed that Hct elevation in OSA correlates with the severity of hypoxaemia rather than the apnoea-hypopnoea index itself (Nguyen & Holty, 2017).
• Smoking or vaping: chronic oxygen stress stimulates compensatory erythropoiesis
• Dehydration: reduces plasma volume, causing falsely elevated Hct readings
• Chronic lung or cardiac disease: any condition causing chronic hypoxia
• High altitude exposure: lower ambient oxygen drives EPO production
• Polycythaemia vera or other myeloproliferative disorders: rare but important to exclude
• Excess androgen dosing: supraphysiological peaks from large, infrequent injections

Does Higher Haematocrit From TRT Actually Cause Clots?

This is where the discussion becomes controversial. Much of the fear around elevated haematocrit comes from studies in polycythaemia vera (PV), a JAK2-driven clonal myeloproliferative neoplasm with inherent thrombotic, fibrotic, and leukaemic transformation risk. TRT-induced erythrocytosis is physiologically different: it is EPO-driven, non-clonal, and does not carry the same pathological clotting biology (McMullin et al., 2019).

What the TRT Literature Shows

A systematic review and meta-analysis by Houghton et al. (2018) concluded that "current evidence is of low certainty but does not support an association between testosterone use and VTE [venous thromboembolism] in men."

A 2022 review in the International Journal of Impotence Research reinforced this finding, noting that "the evidence for secondary polycythaemia causing harm during testosterone therapy is scarce" and that guideline haematocrit thresholds (such as the 54% cutoff) appear arbitrary, with no randomised or prospective studies documenting a direct relationship between TRT-related erythrocytosis and thromboembolic events (White et al., 2022).

Key problems with the existing research:

• Most studies are observational and underpowered
• Confounding factors (age, obesity, sleep apnoea, smoking) are rarely controlled adequately
• The populations studied often include men with comorbidities that independently increase clot risk
• Evidence is extrapolated from polycythaemia vera, which has a fundamentally different pathophysiology

In short: the evidence linking TRT-related Hct elevation alone to meaningful clot risk is weak and inconsistent. That does not mean risk is zero, but the relationship is far less clear than often portrayed.

Mitigation Strategies

If Hb/Hct rises beyond your comfort zone or a clinical threshold, several strategies can help before resorting to phlebotomy.

1. Subcutaneous Injections

Subcutaneous (SC) administration of testosterone cypionate or testosterone enanthate often produces smoother hormone kinetics and lower peak androgen levels compared to intramuscular (IM) injection. A systematic review found that SC testosterone achieves comparable mean serum levels to IM with a lower peak-to-trough ratio, which may reduce erythropoietic stimulation (Figueiredo et al., 2022).

2. Smaller, More Frequent Injections

A network meta-analysis of 29 randomised controlled trials (3,393 men) demonstrated that IM testosterone cypionate/enanthate caused significantly higher mean Hct increases than transdermal formulations (Nackeeran et al., 2022). The supraphysiological peaks from large, infrequent IM doses are the primary driver. Splitting the weekly dose into two or three smaller injections blunts these peaks and reduces erythropoietic stimulation.

3. Dose Optimisation

Many erythrocytosis cases are simply dose-related. More testosterone is not always better. If Hct is rising excessively, reducing the dose to the minimum effective amount often resolves the issue while preserving symptom relief.

4. Address Contributing Factors

Treat sleep apnoea, improve hydration status, and stop smoking or vaping. These interventions can lower Hct independently of any TRT adjustment.

Therapeutic Phlebotomy: Last Resort, Not First Line

Removing blood lowers haematocrit quickly, but it is not physiologically neutral. A critical 2024 review argued that evidence supporting phlebotomy efficacy or safety for TRT-induced erythrocytosis is lacking (Bond et al., 2024).

Potential Downsides of Regular Phlebotomy

• Iron deficiency: each 500 mL phlebotomy removes approximately 200 to 250 mg of iron. Repeated sessions cause ferritin depletion, leading to fatigue and impaired performance, which defeats the purpose of being on TRT in the first place
• Reduced oxygen delivery capacity: iron-deficient red blood cells carry less oxygen, even if haematocrit looks "better" on paper
• Compensatory rebound erythropoiesis: iron depletion triggers the HIF (hypoxia-inducible factor) pathway, paradoxically stimulating even more red blood cell production in the weeks following the procedure
• Frequent venesection burden: regular clinic visits, needle fatigue, and the cumulative physiological toll

For some patients with genuinely dangerous haematocrit levels, phlebotomy is appropriate. But it should not replace fixing the underlying driver: adjusting the TRT protocol, treating sleep apnoea, or optimising hydration.

Practical Monitoring Recommendations

For men on TRT, a sensible monitoring approach includes:

1. Baseline bloods before starting TRT: Hb, Hct, RBC, ferritin, and a full blood count
2. Repeat at 3, 6, and 12 months, then annually if stable
3. Track trends, not single values: a slow, steady Hct of 51% is very different from a rapid climb to 52% in three months
4. Screen for sleep apnoea if Hct rises disproportionately, especially with snoring, daytime fatigue, or elevated BMI
5. Check ferritin if you have had phlebotomy, to ensure you are not developing iron deficiency

Key Takeaways

• Testosterone raises haemoglobin and haematocrit through increased EPO and suppressed hepcidin. This is a normal, dose-dependent physiological response
• In TRT populations, expect Hb to rise by 5 to 15 g/L and Hct by 2 to 5 percentage points
• TRT-induced erythrocytosis is physiologically different from polycythaemia vera. The thrombotic risk data is weak and inconsistent
• Sleep apnoea, dehydration, smoking, and excessive dosing are common contributors that should be evaluated before blaming TRT alone
• Subcutaneous injections and more frequent dosing reduce supraphysiological peaks and lower erythrocytosis rates
• Phlebotomy depletes iron, causes rebound erythropoiesis, and should be a last resort after protocol optimisation
• Monitor trends over time rather than reacting to single snapshots. Context matters more than arbitrary reference ranges

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References

1. Coviello, A. D., Kaplan, B., Lakshman, K. M., Chen, T., Singh, A. B., & Bhasin, S. (2008). Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. Journal of Clinical Endocrinology & Metabolism, 93(3), 914-919. PubMed

2. Bachman, E., Travison, T. G., Basaria, S., Davda, M. N., Guo, W., Li, M., Connor Westfall, J., Bae, H., Gordeuk, V., & Bhasin, S. (2014). Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. Journal of Gerontology Series A: Biological Sciences and Medical Sciences, 69(6), 725-735. PubMed

3. Roy, C. N., Snyder, P. J., Stephens-Shields, A. J., et al. (2017). Association of testosterone levels with anemia in older men: a controlled clinical trial. JAMA Internal Medicine, 177(4), 480-490. PubMed

4. Nguyen, C. D., & Holty, J. C. (2017). Does untreated obstructive sleep apnea cause secondary erythrocytosis? Respiratory Medicine, 130, 27-34. PubMed

5. Lundy, S. D., Parekh, N. V., & Shoskes, D. A. (2020). Obstructive sleep apnea is associated with polycythemia in hypogonadal men on testosterone replacement therapy. Journal of Sexual Medicine, 17(7), 1297-1303. PubMed

6. McMullin, M. F. F., Mead, A. J., Ali, S., et al. (2019). A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis. British Journal of Haematology, 184(2), 161-175. PubMed

7. Houghton, D. E., Alsawas, M., Barrioneuvo, P., et al. (2018). Testosterone therapy and venous thromboembolism: a systematic review and meta-analysis. Thrombosis Research, 172, 94-103. PubMed

8. White, J., Petrella, F., & Ory, J. (2022). Testosterone therapy and secondary erythrocytosis. International Journal of Impotence Research, 34(7), 693-697. PubMed

9. Figueiredo, M. G., Gagliano-Juca, T., & Basaria, S. (2022). Testosterone therapy with subcutaneous injections: a safe, practical, and reasonable option. Journal of Clinical Endocrinology & Metabolism, 107(3), 614-626. PubMed

10. Nackeeran, S., Kohn, T., Gonzalez, D., White, J., Ory, J., & Ramasamy, R. (2022). The effect of route of testosterone on changes in hematocrit: a systematic review and Bayesian network meta-analysis of randomized trials. Journal of Urology, 207(1), 44-51. PubMed

11. Bond, P., Verdegaal, T., & Smit, D. L. (2024). Testosterone therapy-induced erythrocytosis: can phlebotomy be justified? Endocrine Connections, 13(10), e240283. PubMed

12. Ohlander, S. J., Varghese, B., & Pastuszak, A. W. (2018). Erythrocytosis following testosterone therapy. Sexual Medicine Reviews, 6(1), 77-85. PubMed

13. Bhasin, S., Brito, J. P., Cunningham, G. R., et al. (2018). Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism, 103(5), 1715-1744. PubMed