AndroGel (Testosterone Topical) and Erythrocytosis: The Biology of Why It Happens

What Erythrocytosis Means on a Testosterone Gel

Testosterone therapy causes erythrocytosis, and that risk is well established [2]. The prescribing information for testosterone gel 1% describes the change as increases in hematocrit, reflective of increases in red blood cell mass, and notes that an increase in red blood cell mass may increase the risk of thromboembolic events [4]. Erythrocytosis is the name for that rise. One review of testosterone therapy defines it as a hematocrit above 0.52 [5]; a retrospective comparison of formulations used a cutoff above 50% [6].

The label details quoted on this page come from the prescribing information for testosterone gel 1%, a different marketed gel from the 1.62% product tested in TRAVERSE [4][7].

The Biology: One Tested Step, Several Proposed Ones

A review of testosterone-induced erythrocytosis describes candidate mechanisms rather than a single settled pathway: hepcidin, iron sequestration and turnover, erythropoietin production, bone marrow stimulation and genetic factors [2]. One of these has been tested directly in men.

Hepcidin suppression

Hepcidin is an iron-regulatory peptide [1]. In a 20-week study, 53 healthy younger men (19 to 35) and 56 older men (59 to 75) received weekly testosterone enanthate at doses of 25, 50, 125, 300 or 600 mg while a monthly GnRH agonist shut down their own testosterone production. High levels of testosterone markedly suppressed serum hepcidin within one week. Suppression was dose-dependent in the older men and more pronounced than in the younger men, and it corresponded to a greater rise in hemoglobin in the older group. Hepcidin levels at weeks 4 and 8 predicted the change in hematocrit from baseline to peak [1]. The authors concluded that greater increases in hematocrit in older men are related to greater suppression of hepcidin [1].

Erythropoietin and bone marrow stimulation

The review also lists increased erythropoietin production and direct stimulation of the bone marrow among the candidate mechanisms, alongside hepcidin rather than as steps in a fixed order [2].

What Else Adds to the Rise

Genetic factors appear on the review's list of proposed contributors [2]. Outside testosterone itself, one real-world factor has been measured: among US veterans with type 2 diabetes, adding an SGLT-2 inhibitor to testosterone therapy was associated with higher odds of a hematocrit above 54% than testosterone alone, with an adjusted odds ratio of 2.49 [8].

How a Gel Compares With an Injection

The clearest route comparison comes from a network meta-analysis of 29 placebo-controlled randomized trials covering 3,393 men. Every formulation raised mean hematocrit compared with placebo: gel by 3.0% (95% CI 1.8 to 4.3), intramuscular testosterone enanthate or cypionate by 4.0% (2.9 to 5.1), oral testosterone undecanoate by 4.3%, the patch by 1.4% and intramuscular undecanoate by 1.6% [3]. Intramuscular enanthate or cypionate raised hematocrit significantly more than the patch; the other head-to-head comparisons, including gel versus injection, were not statistically significant [3].

A retrospective single-center review of 178 hypogonadal men followed for three years found hematocrit above 50% in 66.7% of men on injectable testosterone, 12.8% on gels and 35.1% on pellets. The injection group was younger (mean 42.5 versus 54.1 years) with a higher baseline hematocrit, and the study was not randomized [6]. A 2018 review likewise reports that short-acting injectable formulations carry the highest incidence of erythrocytosis [2].

In a 24-week randomized comparison of 66 men, injections of enanthate 200 mg every two weeks produced supraphysiologic testosterone levels for several days after each dose, while a transdermal patch kept levels within the normal range; abnormal hematocrit elevations occurred in 43.8% of the injection group and 15.4% of the patch group [9]. That study used a patch, not a gel, and did not test whether the peaks caused the difference.

How Often It Happens, and How Soon

A 2024 retrospective study of 247 men on testosterone replacement (194 on testosterone undecanoate, 18 on enanthate and 35 on gel) is useful for timing. The 92 patients included in the hematocrit-change analysis had an average increase of 0.04 from baseline. Fifty-seven percent of patients reached a hematocrit above 0.46, 23% above 0.5 and 5% above 0.54. Of the patients who reached a hematocrit above 0.46, 46% had their highest value within the first year of treatment. A higher starting hematocrit and a higher body mass index were both associated with higher hematocrit on therapy [10].

In the testosterone gel 1% clinical trial program, the adverse-event category called lab test abnormal, which included elevated hemoglobin or hematocrit among other laboratory changes, was reported in 6% of men on 50 mg, 5% on 75 mg and 3% on 100 mg during a 180-day controlled trial, and in 9.3% of 162 men during a 3-year extension [4]. A review of the wider literature reported that men on testosterone replacement had a 315% greater risk of erythrocytosis, defined as a hematocrit above 0.52, than controls [5].

What the Labels Say to Watch

The AndroGel 1.62% label says to check hematocrit before starting treatment, re-evaluate it 3 to 6 months after starting, and then check it annually; if hematocrit becomes elevated, therapy should be stopped until it decreases to an acceptable concentration, and an increase in red blood cell mass may increase the risk of thromboembolic events [14]. The generic testosterone gel 1% label has the same wording and adds that increases in hematocrit may require lowering or discontinuing testosterone [4]. Neither names a numeric cutoff.

The 2018 Endocrine Society guideline recommends against starting testosterone therapy in men with an elevated hematocrit and recommends monitoring hematocrit during the first year of treatment [11]. A 2025 narrative review of testosterone adverse-effect management states that therapeutic phlebotomy is indicated when hematocrit exceeds 52% [12].

Does a Higher Hematocrit Mean More Clots?

The link is not established. One review notes that high blood viscosity increases the risk of vascular complications in the coronary, cerebrovascular and peripheral circulations, while pointing to limited evidence for a direct relationship with testosterone-induced erythrocytosis [2]. Another concludes that the connection between testosterone-related erythrocytosis and venous thromboembolism remains inconclusive [5].

What the trial data show is a small numerical difference in events. The testosterone gel 1% label reports TRAVERSE venous thromboembolism rates of 1.7% on testosterone gel versus 1.2% on placebo, including deep vein thrombosis in 0.6% versus 0.5% and pulmonary embolism in 0.9% versus 0.5% [4]. TRAVERSE tested a 1.62% gel, and major adverse cardiovascular events were similar between groups, 7.0% versus 7.3% [13]. The trial compared gel with placebo; it did not test whether hematocrit was the mechanism behind the clot difference.