How Does Testosterone Increase Red Blood Cells?

Testosterone raises red blood cell counts through at least three distinct biological pathways: it stimulates the kidneys to produce more erythropoietin (the hormone that tells bone marrow to make red blood cells), it suppresses a liver peptide called hepcidin so that more iron becomes available for new red blood cells, and it directly improves the survival of red blood cell precursors inside the bone marrow. The result is a roughly 7 to 10 percent rise in hemoglobin and hematocrit in people receiving testosterone therapy, with the biggest jump typically occurring in the first year. Understanding these mechanisms matters because the same process that corrects anemia can, if unchecked, push blood counts high enough to raise health concerns.

The Erythropoietin Signal

The most powerful route by which testosterone increases red blood cells runs through erythropoietin, commonly called EPO. EPO is produced mainly in the kidneys, and its job is to signal the bone marrow to ramp up production of new red blood cells. In one well-documented trial, EPO levels rose about 58 percent from baseline within the first month of testosterone treatment and remained elevated at three months.¹ Researchers have proposed that testosterone doesn’t just boost EPO temporarily; it actually recalibrates the body’s set point for how much EPO the kidneys release relative to the current hemoglobin level. In other words, the body starts treating a higher hemoglobin concentration as its new normal.²

Unlocking Iron Through Hepcidin Suppression

Making more red blood cells requires iron, and testosterone clears the way for that by suppressing hepcidin, a small peptide produced in the liver that acts as the body’s master regulator of iron availability. When hepcidin is high, iron stays locked inside cells and isn’t released into the bloodstream. When hepcidin drops, iron flows freely from the gut and from storage sites like the spleen, making it available to be packed into fresh hemoglobin molecules.

Testosterone drives hepcidin down fast. In a study of graded testosterone doses, high levels of the hormone markedly suppressed hepcidin within just one week, and the suppression was dose-dependent. Older men showed a more pronounced hepcidin drop than younger men, which corresponded to a greater rise in their hemoglobin.³ Hepcidin levels measured at four and eight weeks were predictive of how high hematocrit ultimately climbed, making it a useful early marker of what was coming.

Mouse studies have added a sharp mechanistic detail: testosterone directly reduces the gene expression of hepcidin in the liver, independent of its effects on EPO or on oxygen-sensing pathways. When researchers engineered mice whose livers constantly overproduced hepcidin, testosterone failed to raise hemoglobin at all, confirming that hepcidin suppression isn’t just a side effect of the process but a required step.⁴ In those same experiments, testosterone increased the amount of iron being shuttled out of the spleen into the bloodstream, and iron that was tagged with a tracer ended up incorporated into red blood cells at a significantly higher rate in testosterone-treated mice.

Direct Effects on Bone Marrow

EPO and iron availability explain the bulk of the effect, but testosterone also works inside the bone marrow itself. In lab experiments with human bone marrow cells, testosterone increased the formation of erythroid colonies, the clusters of young red blood cells growing from precursor cells. When testosterone and EPO were combined, the result was greater than adding their individual effects together, suggesting testosterone primes marrow cells to respond more strongly to EPO.⁵

Testosterone also improves the survival of early blood cell precursors in the marrow. In serum-free cultures where precursor cells would normally die off, testosterone extended their survival, keeping more of them alive long enough to mature into red blood cells.⁶ Follow-up work clarified that this survival-enhancing effect is mostly restricted to mature erythroid progenitors rather than all types of blood cell precursors, which helps explain why testosterone preferentially drives up red blood cells rather than, say, white blood cells or platelets.⁷

Longer-Living Red Blood Cells

Beyond making more red blood cells, testosterone appears to help each individual cell survive longer once it enters the bloodstream. In mouse experiments, both testosterone and its non-aromatizable derivative DHT were associated with longer erythrocyte half-lives. Because DHT cannot be converted to estrogen, this finding pointed squarely at androgen receptors as the mediators, not estrogen.⁸ If each red blood cell sticks around longer before being cleared by the spleen, fewer new cells need to be produced to maintain the same circulating count, and any increase in production leads to a proportionally higher hematocrit. This longer lifespan may partially explain why hematocrit continues to creep up gradually even years after the initial surge in production has slowed.

Why Estrogen Is Not the Go-Between

Testosterone can be converted to estradiol (a form of estrogen) by the enzyme aromatase, which raised an obvious question early in this research: is estrogen actually the molecule doing the red-blood-cell work? The evidence says no. Two men who genetically lacked aromatase were treated separately with testosterone and then with estradiol. Hemoglobin, hematocrit, and red cell count rose with testosterone but not with estradiol.⁹ The mouse lifespan data described above point the same direction: DHT, which cannot become estrogen, produced the same effects on red blood cell survival as testosterone itself.⁸ This distinction matters practically because some testosterone therapy protocols include aromatase inhibitors; those drugs will not blunt the rise in red blood cells.

How Quickly Red Blood Cells Rise

The timeline is front-loaded. EPO climbs within weeks, hepcidin drops within a week, and the downstream effect on hematocrit becomes measurable in the first few months. In a large, long-term cohort of trans men receiving testosterone, the steepest jump in hematocrit happened during the first year of therapy. After that, there was a slow, continued drift upward extending out to about twenty years of follow-up.¹⁰ The cumulative risk of hematocrit crossing above 50 percent was about 8 percent after one year, roughly 38 percent after ten years, and about half of the cohort by fourteen years, showing that erythrocytosis is not just a first-year phenomenon but an ongoing, accumulating risk.¹⁰

A separate cohort looking at the first twenty months of injectable testosterone cypionate found a lower early incidence: about 13 percent crossed the 50.4 percent hematocrit mark, and severe erythrocytosis (above 54 percent) was rare at under 1 percent.¹¹ The discrepancy between the two studies likely reflects differences in follow-up length, dosing, and population characteristics, but the pattern is consistent: most of the action is early, with a long slow tail.

Why Delivery Method Matters

Not all testosterone formulations drive red blood cells up equally. Injectable testosterone produces higher peak blood levels than gels or pellets, and those peaks seem to matter. In a direct comparison, roughly two-thirds of people on injectable testosterone developed hematocrit above 50 percent, compared to about a third on pellets and only about one in eight on gels.¹² Erythrocytosis also appeared sooner with injections, averaging about ten and a half months compared to roughly fourteen months for gels and sixteen for pellets.

Long-acting undecanoate injections carried the highest risk among injectable types. Compared to testosterone gel, long-acting undecanoate had almost three times the odds of pushing hematocrit above 50 percent. Short-acting ester injections had similar odds to gel.¹⁰ Intranasal testosterone gel sits at the other extreme: in one matched-cohort analysis, hematocrit actually decreased slightly with the intranasal route, likely because its systemic exposure is lower and more transient than any other formulation.¹³

Who Is Most Susceptible

The same dose of testosterone can produce very different hematocrit responses in different people, and several identifiable factors shift the odds.

Age: Older men show a larger increase in hemoglobin and hematocrit at the same dose. This is dose-dependent and has been confirmed in controlled comparisons of young versus older men receiving graded doses of testosterone.¹⁴ The more pronounced hepcidin suppression in older men may be a key reason.³
Body mass index: Higher BMI is independently associated with developing elevated hematocrit on testosterone therapy.¹⁵
Baseline hematocrit: People who start with higher hematocrit before therapy are more likely to cross into erythrocytosis territory. A baseline measurement is predictive of who will end up above a clinically relevant threshold.¹⁵
Sleep apnea: Obstructive sleep apnea doubles the odds of developing polycythemia in hypogonadal men on testosterone, even after adjusting for age, BMI, and peak testosterone levels.
Tobacco use: Smoking independently raises the odds of hematocrit crossing above 50 percent, likely because carbon monoxide from smoking already reduces the oxygen-carrying efficiency of red blood cells, prompting compensatory production.¹⁰

Because these risk factors are additive, a person with several of them, say an older smoker with a high BMI and borderline-high baseline hematocrit, faces a substantially different risk profile from a young, lean non-smoker starting at a low baseline. Monitoring schedules and formulation choices often reflect this.

The Cardiovascular Question

The worry behind monitoring hematocrit is straightforward: thicker blood flows less easily. When hematocrit climbs, blood viscosity rises, and the heart has to work harder to push it through the circulatory system. The consequences of that change depend on the vascular bed involved and vary from person to person.¹⁶ A rise in hematocrit after starting testosterone therapy has been linked to an increased risk of major adverse cardiovascular events in a large retrospective analysis of claims data.¹⁷

When it comes to blood clots specifically, the picture is murkier. In a cohort of transgender individuals on testosterone, about one in five developed hematocrit above 50 percent, but actual blood clot events were uncommon, occurring in under 1 percent of participants.¹⁸ A systematic review and meta-analysis of vein clot risk found no significantly elevated risk in randomized trials of testosterone therapy, and observational data actually suggested a slightly reduced risk, though the analysis had substantial variability between studies.¹⁹ So the fear that high hematocrit from testosterone automatically means clots doesn’t hold up cleanly in the available data, but the broader cardiovascular signal is enough to warrant keeping an eye on blood counts.

Clinical Thresholds and the Phlebotomy Debate

Most clinical guidelines flag a hematocrit of 54 percent as the point where something needs to change: either reducing the testosterone dose, switching to a lower-peak formulation, or removing blood through phlebotomy (therapeutic blood donation). One study found that an increase in hematocrit up to about 52 percent during testosterone therapy was independently associated with reduced mortality, suggesting that moderate increases may be beneficial rather than harmful and supporting a management-change threshold of 54 percent.²⁰

Phlebotomy is frequently used in practice to bring hematocrit back down, but the evidence behind it is surprisingly thin. A recent review concluded that evidence supporting the efficacy or safety of therapeutic phlebotomy for testosterone-induced erythrocytosis is lacking.²¹ The concern is that repeated blood draws deplete iron stores, and once iron becomes the bottleneck, the body simply revs up the same EPO and hepcidin mechanisms even harder, creating a cycle of escalating production signals. Some clinicians have started to move toward dose reduction or formulation switching as first-line management instead, reserving phlebotomy for acute situations.

The Natural Sex Gap in Hemoglobin

All of these mechanisms explain a phenomenon people take for granted: men have higher hemoglobin than women. The gap averages about 12 percent and is found across many species of mammals, birds, and reptiles, suggesting it serves some deep physiological purpose rather than being an accident of human biology.²² Before puberty, boys and girls have similar hemoglobin levels. The divergence begins when testosterone surges during male puberty, activating the same EPO, hepcidin, and marrow pathways described above. This sex gap has practical consequences for clinical reference ranges: what counts as “anemia” or “erythrocytosis” depends on whether you’re comparing to male or female norms, and transgender individuals on testosterone therapy can find themselves evaluated against ranges that don’t quite fit either category.

A Note on Athletic Performance

Given that EPO doping has been a long-standing issue in endurance sports, you might expect testosterone’s ability to raise red blood cell counts to be a major factor in its performance-enhancing effects. The reality is more complicated. In a controlled trial of moderately increased testosterone in young healthy women over ten weeks, hemoglobin mass, blood volume, and red cell volume were all unchanged despite a significant rise in lean muscle mass and a small increase in hematocrit within the testosterone group.²³ VO₂ max did go up, but this tracked with the increase in lean mass rather than with changes in oxygen-carrying capacity. At moderate dose levels and short time frames, testosterone’s effects on muscle may outweigh its effects on red blood cells. Over longer periods or at higher doses, the hematologic changes become more pronounced, and the distinction between muscle-mediated and blood-mediated performance gains blurs.

1
PubMed Central. Erythrocytosis Following Testosterone Therapy
2
PubMed Central. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point
3
PubMed Central. Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis
4
PubMed Central. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells
5
Blood. Effects of Testosterone and Erythropoietin on Erythroid Colony Formation in Human Bone Marrow Cultures
6
PubMed. Testosterone and synthetic and androgens improve the in vitro survival of human marrow progenitor cells in serum-free suspension cultures
7
PubMed Central. Direct and indirect effects of androgens on survival of hematopoietic progenitor cells in vitro
8
The Journal of Clinical Endocrinology & Metabolism. Testosterone and Erythrocyte Lifespan
9
PubMed. Testosterone action on erythropoiesis does not require its aromatization to estrogen: Insights from the testosterone and estrogen treatment of two aromatase-deficient men
10
PubMed Central. Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years
11
PubMed Central. Erythrocytosis in Gender-Affirming Care With Testosterone
12
Sexual Medicine. Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate‐Specific Antigen
13
PubMed Central. Prevalence of secondary erythrocytosis in men receiving testosterone therapy A matched-cohort analysis of intranasal gel, injections, and pellets
14
The Journal of Clinical Endocrinology & Metabolism. Effects of Graded Doses of Testosterone on Erythropoiesis in Healthy Young and Older Men
15
PubMed Central. Prevalence and predictive factors of testosterone-induced erythrocytosis: a retrospective single center study
16
PubMed. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics
17
PubMed. Rises in Hematocrit Are Associated With an Increased Risk of Major Adverse Cardiovascular Events in Men Starting Testosterone Therapy: A Retrospective Cohort Claims Database Analysis
18
Thrombosis Research. Erythrocytosis and thromboembolic events in transgender individuals receiving gender-affirming testosterone
19
PubMed Central. Testosterone replacement therapy and vascular thromboembolic events: a systematic review and meta-analysis
20
Androgens: Clinical Research and Therapeutics. Testosterone Therapy: Increase in Hematocrit is Associated with Decreased Mortality
21
PubMed Central. Testosterone therapy-induced erythrocytosis: can phlebotomy be justified?
22
PubMed. The sex difference in haemoglobin levels in adults – mechanisms, causes, and consequences
23
Frontiers in Physiology. Enhanced Skeletal Muscle Oxidative Capacity and Capillary-to-Fiber Ratio Following Moderately Increased Testosterone Exposure in Young Healthy Women