Can intramuscular testosterone administration cause elevated creatine kinase levels?

Can Intramuscular Testosterone Cause Elevated Creatine Kinase?

Yes, intramuscular testosterone injections can cause elevated creatine kinase (CK) levels, but this is due to the mechanical trauma of the injection itself rather than a direct pharmacological effect of testosterone. The elevation is typically transient, peaks at 12 hours post-injection, and should not be confused with cardiac or primary muscle pathology.

Mechanism of CK Elevation from IM Injections

• Any intramuscular injection causes local muscle damage that releases CK into the bloodstream, with the enzyme unable to enter via the transepithelial pathway due to its large molecular size (82 kDa) and instead requiring lymphatic clearance, which explains the delayed detectability in blood 1

• The mechanical stress of needle penetration damages muscle cell membranes, allowing CK to leak from the intracellular compartment into the interstitial fluid and subsequently into circulation 1

• Peak CK elevation occurs approximately 12 hours after intramuscular injection, with gradual return to baseline over 24-48 hours in most cases 2

Evidence Specific to IM Injections

• 58.3% of patients receiving intramuscular injections of various medications demonstrated significant CK elevation in a prospective study of 120 patients 2

• The magnitude of CK rise depends on the specific drug injected, with non-steroidal anti-inflammatory drugs producing the highest elevations (diclofenac caused a 10-fold increase), though testosterone was not specifically studied in this cohort 2

• Male sex and ethanol-based solvents increase the probability of CK elevation following IM injection, with men showing significantly higher rates (p=0.009) 2

Distinguishing Injection-Related CK from Pathological Elevation

Temporal Pattern

• Injection-related CK peaks at 12 hours and normalizes within 24-48 hours, whereas pathological muscle disease causes persistent or progressive elevation 2, 1

• Exercise-induced CK elevation is markedly elevated for 24 hours after the bout and gradually returns to basal levels with rest, showing a similar but more prolonged pattern than injection trauma 3

Magnitude and Isoenzyme Pattern

• The CK elevation from IM injection is predominantly the MM isoenzyme (skeletal muscle), with MB fraction (cardiac) remaining normal or only minimally elevated in the absence of cardiac pathology 4

• Only 7% of patients in one study showed significant CK elevation after IM injection, and among those with elevation, MB-CK was increased in only one patient, suggesting injection-related CK rise is less common and less pronounced than previously assumed 4

• Professional athletes after vigorous exercise can have elevated MB-CK without myocardial injury, with 4 of 7 athletes showing MB-CK elevation in the setting of very high total CK, demonstrating that MB-CK can originate from skeletal muscle under extreme stress 5

Clinical Algorithm for Interpreting CK in Testosterone Users

Step 1: Assess Timing

• If CK is measured within 48 hours of testosterone injection, attribute the elevation to injection trauma and repeat testing 72+ hours after the last injection 2

• If CK remains elevated >72 hours post-injection, proceed to Step 2 2, 1

Step 2: Evaluate Magnitude and Pattern

• Mild elevation (2-3× upper limit of normal) with recent injection history is likely benign and related to injection trauma 2

• Moderate to severe elevation (>5× ULN) or persistent elevation warrants investigation for underlying muscle pathology, particularly if accompanied by muscle weakness, pain, or dark urine 3, 6

Step 3: Consider Alternative Causes

• High CK at rest in athletes may reflect training status rather than pathology, as strength training and eccentric exercise cause physiological CK elevation that can persist chronically in high responders 3

• Persistently elevated CK (>1000 U/L) without clear cause requires full diagnostic workup including CK isoenzymes, aldolase, inflammatory markers, and consideration of genetic myopathies 6

• Testosterone therapy itself does not cause chronic CK elevation through a direct pharmacological mechanism; any persistent elevation requires investigation for concurrent muscle disease 1

Monitoring Recommendations for Testosterone Users

• Baseline CK is not routinely required before initiating testosterone therapy, as the primary hematologic concern is erythrocytosis (hematocrit >54%), not CK elevation 7, 8

• If CK monitoring is performed, draw levels at least 72 hours after the last injection to avoid confounding from injection-related trauma 2

• Routine CK monitoring is not recommended in asymptomatic testosterone users, as the focus should be on hematocrit, PSA, testosterone levels, and clinical response 7, 9

Critical Pitfalls to Avoid

• Do not attribute persistent CK elevation (>1 week) solely to testosterone injections without investigating for underlying myopathy, as injection-related CK normalizes within 48 hours 2, 6

• Do not assume elevated MB-CK always indicates cardiac pathology in athletes or patients receiving IM injections, as skeletal muscle can release MB-CK under conditions of extreme stress or damage 5

• Do not delay cardiac evaluation in patients with chest pain based on recent IM injection history, as the clinical notion that injections frequently cause significant CK elevation is not supported by evidence (only 7% in one study) 4

• Do not confuse physiological CK elevation from training (common in athletes, with high inter-individual variability) with pathological elevation requiring intervention 3