Common Side Effects of Testosterone Replacement Therapy
The most common side effects of testosterone replacement therapy include erythrocytosis (elevated red blood cell count), skin reactions at application sites, testicular atrophy with infertility risk, and potential worsening of sleep apnea, with the frequency and severity varying significantly by formulation route. 1
Hematologic Effects (Most Common)
Erythrocytosis represents the most frequently encountered side effect, with incidence rates that vary dramatically by administration method 1:
- Transdermal formulations (gels/patches): 3-18% incidence
- Injectable testosterone: up to 44% incidence
This elevation in red blood cell count requires monitoring of hematocrit/hemoglobin at baseline and periodically during treatment 1, 2. The FDA label specifically mandates checking these levels to detect polycythemia 2.
Skin and Local Reactions
Skin reactions are extremely common but vary by formulation 1:
- Patches: up to 66% of patients experience reactions
- Gels: approximately 5% incidence
- Injections: rare occurrence
These reactions are typically the primary reason patients switch between formulations 3.
Reproductive System Effects
Testicular atrophy and infertility occur commonly, particularly in younger men, due to down-regulation of gonadotropins from the hypothalamic-pituitary axis 1. The FDA label also notes that oligospermia may develop after prolonged administration 2. These effects are generally reversible upon discontinuation but require counseling before initiating therapy 3.
Sleep-Related Effects
Sleep apnea may be exacerbated or newly develop during TRT, particularly in men with identifiable risk factors such as obesity or existing respiratory compromise 1. Assessment for sleep apnea history should be performed at baseline and monitored during follow-up 1, 4.
Prostate and Urinary Effects
While prostate cancer risk remains controversial with unknown absolute risk levels 1, benign prostatic hyperplasia may worsen, though clinical significance is generally low 1. The FDA label warns that patients with benign prostatic hypertrophy may develop acute urethral obstruction 2. Baseline PSA and digital rectal examination are recommended, with consideration of prostate biopsy for PSA increases ≥1.0 ng/mL in one year 1.
Cardiovascular Considerations
The cardiovascular effects remain an area of ongoing investigation. Evidence suggests testosterone therapy may have a neutral or possibly beneficial effect on cardiovascular risk, though long-term safety data is limited 1. However, some studies have shown increased risk for all-cause mortality, myocardial infarction, and stroke with a hazard ratio of 1.29 1. Fluid retention can occur but is rarely of clinical significance, except in men with congestive heart failure who require cautious use 1.
Less Common Effects
- Gynecomastia: rare and usually reversible 1, managed with aromatase inhibitors or tamoxifen when it occurs 3
- Priapism or excessive sexual stimulation: may develop and requires dose reduction 2
- Hepatotoxicity: primarily limited to oral testosterone preparations, which are infrequently used in the United States 1
Formulation-Specific Considerations
Oral testosterone preparations should be avoided due to hepatotoxicity risk 1. The FDA specifically contraindicated the oral formulation of testosterone undecanoate for age-related hypogonadism, citing demonstrated increases in blood pressure 5.
Critical Monitoring Parameters
Baseline assessment must include 1:
- PSA and digital rectal examination
- Hematocrit/hemoglobin levels
- Sleep apnea history
- Voiding symptoms evaluation
Common Pitfalls to Avoid
Inadequate monitoring of hematocrit can lead to hyperviscosity and increased thrombotic risk 4. Failing to counsel patients about fertility effects before initiating therapy, particularly in younger men, represents another critical oversight 1. Additionally, overlooking potential exacerbation of sleep apnea in at-risk patients can lead to significant morbidity 4.