About the Condition

Description/definition:

Men with biochemical evidence of low testosterone and symptoms of hypogonadism may benefit from testosterone therapy. Proposed benefits of testosterone therapy include: improved sexual function, bone mineral density as well as increased strength improved lipid profiles.

The most common dose-limiting effect of testosterone therapy is erythrocytosis or polycythemia:

  • Formally defined as an erythrocyte mass exceeding 125% predicted based on sex and body mass.
  • Practically defined by an elevated hematocrit of 48% up to 55% (depending on practice guideline).

Objective increases in hematocrit are typically noted after one-three months of therapy. The percentage increase in hematocrit continues to increase in a linear dose-dependent fashion. Men receiving testosterone therapy have a 315% greater risk for developing erythrocytosis when compared to controls.

Erythrocytosis confers an increased blood viscosity and concerns rise from the potential increased risk of thromboembolic events including myocardial infarction and cerebrovascular accidents.

Risk of erythrocytosis in individuals taking testosterone therapy is increased in those with:

  • Obstructive sleep apnea
  • Advanced age
  • Obesity
  • Type II diabetes mellitus
  • Elevated baseline hematocrit (>50%)
  • High altitude residence

Of the various formulations, intramuscular injections have an estimated rate of erythrocytosis of 40% followed by subcutaneous pellets at 35%. Short-acting TT through transdermal and androgel have been associated with lower rates of polycythemia; 15% and 3% respectively. The safest formulations include intranasal testosterone (0–2%) and oral testosterone (0.03%).

Pathophysiology:

Several mechanisms have been implicated in testosterone-induced erythrocytosis:

  • Estradiol, a breakdown product of testosterone via aromatase, is responsible for an increase in hematopoietic stem cell proliferation and survival.
  • Testosterone increases erythropoiesis by increasing iron availability via reduced hepcidin levels, a hormone responsible for iron sequestration:
    • Increased testosterone levels inhibit hepcidin by more than 50% in all age groups and in a dose dependent manner.
    • The marked decrease in hepcidin is hypothesized to increase iron metabolism, systemic absorption of iron and erythropoiesis.
    • This suppression is persistent throughout the duration of treatment.
  • Testosterone therapy causes a transient spike in erythropoietin. This results in a new set point for erythropoietin expression, where its release is triggered by a smaller drop in hematocrit.

While an increased red blood cell mass can lead to increased oxygen carrying capacity, it may also have negative outcomes at a supraphysiological level owing to increases in blood viscosity.

Clinical presentation:

Hematocrit increase after testosterone therapy is usually seen within the first few months of treatment (may become evident at one-three months and peaks at twelve months) and returns to baseline within one year of treatment cessation.

Typically asymptomatic. However, may present with symptoms of hyperviscosity including:

  • Parasthesias
  • Blurred vision
  • Fatigue
  • Headaches

Diagnosis:

Diagnosis based on evaluation of the complete blood count.

Treatment:

Who not to treat with testosterone

OrganizationRecommendationsComments
American Urological AssociationBefore starting T, if patient has elevated
Hct above 50%, T should be withheld until the etiology is formally investigated.
Prior to offering T therapy, clinicians should measure hemoglobin and Hct and inform patients regarding the increased risk of polycythemia.
Endocrine SocietyShould not give T to patients with elevated
Hct, defined as above
the upper limit of normal for the individual lab (typically > 48%, or > 50% for men living at high altitude).
European Association of UrologyBaseline Hct >54% is an absolute contraindication for T treatment; baseline Hct 48–50% is a relative contraindication.Perform hematological, assessment before the start of treatment.
European Academy of AndrologyWe suggest against T treatment in men with documented polycythemia and/or elevated Hct
(>48%-50%) depending on cardiovascular risk and associated morbidities without further evaluation.
Hct, hematocrit; T, testosterone

What to do with patient taking testosterone who develops erythrocytosis

OrganizationRecommendationsComments
American Urological AssociationWhile on T therapy, a Hct 54% warrants intervention, such as dose reduction or temporary discontinuation.Evaluate Hct at 3, 6 and 12 months, and then annually thereafter.

If Hct increases above 54% but serum T is not in therapeutic range, the AUA guidelines recommend checking a sex hormone binding globin and free T to assess biochemical levels.
Endocrine SocietyIf Hct is >54%, stop therapy until Hct decreases to a safe level; evaluate the
patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose. Using therapeutic phlebotomy to lower Hct is also effective in managing T treatment–induced erythrocytosis.
Monitoring includes measuring T and Hct at 3 to 6 months (depending upon the formulation) and measuring T and Hct at 12 months and annually after initiating
T therapy; check Hct at baseline, 3–6 months after starting treatment,
and then annually.
European Association of UrologyHct should not exceed 0.54%. if the hematocrit is greater than 0.54%, stop T and reintroduce at a lower dose once Hct has normalized. Alternatively, consider venesection (500 mL) and repeat if necessary. Monitor T, Hct at three, six and twelve months and thereafter annually.
European Academy of AndrologyIf Hct is >54%, T should be discontinued until Hct decreases to a safe level; evaluate the patient for
hypoxia and sleep apnea; consider reinitiating testosterone treatment with
a reduced dose.
We recommend measuring the
Hct 3-6 months after initiation of T treatment and then annually.
Hct, hematocrit; T, testosterone

Prognosis:

The clinical significance of a high hematocrit level is unclear, but it may be associated with hyperviscosity and thrombosis. The hematocrit value of > 54% is based on the slightly increased risk of cardiovascular mortality from the Framingham Heart Study. However, the study was not stratified according to use of testosterone. While primary erythrocytosis has been well established as a risk factor for thromboembolic events, the risk of secondary erythrocytosis related to testosterone therapy is less clear.