Adverse Effects of Injectable Testosterone at 850 ng/dL in a 59-Year-Old Male for Performance Enhancement
Using testosterone for performance enhancement in a 59-year-old male—even at a target level of 850 ng/dL—carries significant cardiovascular, hematologic, and other risks that are not justified by the evidence, particularly since testosterone therapy is not indicated for athletic performance and produces minimal benefits beyond sexual function in men with confirmed hypogonadism.
Critical Context: Testosterone for Performance Enhancement Is Not Evidence-Based
Testosterone therapy is FDA-approved only for men with confirmed biochemical hypogonadism (two morning testosterone measurements <300 ng/dL) plus specific symptoms such as diminished libido or erectile dysfunction—not for performance enhancement, muscle building, or athletic performance in men with normal testosterone levels. 1
The FDA explicitly warns that testosterone "has not been shown to be safe and effective for the enhancement of athletic performance" and states that "because of the potential risk of serious adverse health effects, this drug should not be used for such purpose." 1
Major guideline societies explicitly recommend against testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength. 2
In men with confirmed hypogonadism, testosterone produces little to no clinically meaningful effect on physical functioning, energy, vitality, or muscle strength—the standardized mean difference for energy/fatigue is only 0.17, well below clinical significance. 2
Cardiovascular Risks
Evidence of Increased Cardiovascular Events
The TOM trial (Testosterone in Older Men with Mobility Limitation) was halted prematurely in 2009 after 23 cardiovascular-related adverse events occurred in the testosterone group versus only 5 in the placebo group, even after adjustment for baseline cardiovascular risk factors. 2, 3
On multivariate analysis, the post-treatment increase in serum free testosterone was directly associated with adverse cardiovascular events (10.6 ng/dL increase in men with CV events vs. 5.2 ng/dL in men without events; P=0.05). 2
The TOM trial enrolled men aged ≥65 years with mobility limitations and a high prevalence of hypertension (85% in testosterone arm), hyperlipidemia (63%), and diabetes—a profile that may overlap with a 59-year-old using testosterone for performance, particularly if cardiovascular risk factors are present. 2, 3
Conflicting Evidence and Uncertainty
A 2020 systematic review by the American College of Physicians found that pooled cardiovascular risk did not differ significantly between testosterone and placebo groups (Peto OR 1.22, CI 0.66–2.23), though the certainty of evidence was rated as low. 2
The 2015 Mayo Clinic systematic analysis concluded that "TRT was not clearly associated with adverse CV events based on the systematic analysis," noting that the TOM trial outcomes "have not been borne out by the other high-quality studies." 2
However, most trials excluded men with advanced heart failure or recent myocardial infarction/stroke, and none were adequately powered to assess cardiovascular risk—meaning the true cardiovascular safety profile remains uncertain, particularly in older men or those with subclinical cardiovascular disease. 2
Clinical Implications for a 59-Year-Old Male
At age 59, cardiovascular risk is already elevated compared to younger men, and adding testosterone—particularly at supraphysiologic or high-normal levels (850 ng/dL)—may increase the risk of myocardial infarction, stroke, or other cardiovascular events, especially if hypertension, hyperlipidemia, diabetes, or obesity are present. 2, 3
Injectable testosterone produces supraphysiologic peak levels 2–5 days after injection, which are associated with higher cardiovascular risk compared to transdermal preparations that provide more stable day-to-day levels. 4
Hematologic Risks: Erythrocytosis
Incidence and Severity
Erythrocytosis (elevated hematocrit) is the most common and clinically significant adverse effect of testosterone therapy, occurring in approximately 43.8% of men receiving injectable testosterone compared to 15.4% with transdermal preparations. 4, 5
A 2022 study comparing 100 mg weekly vs. 200 mg biweekly intramuscular testosterone found that men receiving 200 mg biweekly were significantly more likely to develop hematocrit >54% (8% vs. 1%, P=0.023), indicating that higher average serum testosterone over the dosing interval increases erythrocytosis risk. 6
A 2010 meta-analysis confirmed that testosterone treatment significantly increases hemoglobin (weighted mean difference 0.80 g/dL) and hematocrit (weighted mean difference 3.18%), with the clinical significance of these changes remaining uncertain. 5
Cardiovascular Consequences of Elevated Hematocrit
Elevated hematocrit increases blood viscosity, which can exacerbate coronary, cerebrovascular, and peripheral vascular disease—particularly dangerous in older adults or those with pre-existing cardiovascular disease. 4
Hematocrit >54% is considered an absolute intervention threshold; testosterone therapy must be withheld at this level, and therapeutic phlebotomy should be considered in high-risk cases. 4
Even modest hematocrit elevations (50–52%) in elderly or cardiovascular-high-risk patients raise blood viscosity and thrombotic risk and should not be ignored. 4
Monitoring Requirements
Hematocrit must be measured at baseline (before initiating therapy), at 1–2 months, every 3–6 months during the first year, and annually thereafter. 4
If hematocrit rises above 54%, testosterone must be immediately discontinued, and therapeutic phlebotomy (removing 500 mL blood every 1–2 weeks until hematocrit <52%) should be considered. 4
Prostate-Related Risks
Prostate Cancer and PSA Monitoring
Testosterone therapy is absolutely contraindicated in men with active or treated prostate cancer or male breast cancer. 1
PSA must be measured at baseline in all men ≥40 years; a PSA >4.0 ng/mL requires urologic evaluation and a documented negative prostate biopsy before initiating therapy. 4, 7
During treatment, PSA should be monitored every 3–6 months during the first year, then annually; urologic referral is required if PSA increases >1.0 ng/mL within the first 6 months or >0.4 ng/mL per year thereafter. 4, 7
Benign Prostatic Hyperplasia (BPH)
Geriatric patients treated with androgens may be at increased risk of developing prostatic hypertrophy, though conclusive evidence is lacking. 1
Digital rectal examination should be performed at baseline and at each follow-up visit to assess for prostate abnormalities. 4, 7
Other Adverse Effects
Hepatic Risks
Prolonged use of high doses of androgens has been associated with hepatic adenomas, hepatocellular carcinoma, and peliosis hepatis—all potentially life-threatening complications. 1
A 2022 study found that men with elevated endogenous testosterone (>800 ng/dL) had significantly higher AST (βi 8.48, P=0.04) and ALT (βi 12.23, P=0.04) compared to men with normal testosterone, though the clinical significance of these elevations is unclear. 8
Fluid Retention and Edema
- Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. 1
Gynecomastia
- Gynecomastia may develop and occasionally persists in patients being treated for hypogonadism. 1
Suppression of Endogenous Testosterone Production
Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, leading to testicular atrophy and potentially prolonged or irreversible azoospermia (absence of sperm production). 4, 7
This is particularly relevant for a 59-year-old male who may still desire fertility preservation or who may wish to discontinue therapy in the future—recovery of endogenous testosterone production after cessation can take months to years, and may not fully recover. 4, 7
Lack of Proven Benefits for Performance Enhancement
Minimal Effect on Physical Function and Muscle Strength
In men with confirmed hypogonadism, testosterone therapy produces little to no clinically meaningful effect on physical functioning, energy, vitality, or muscle strength. 2
The 2015 Mayo Clinic systematic analysis found inconsistent findings concerning the effects of testosterone on physical function and lower-extremity strength, with most studies showing no significant improvement. 2
The TOM trial demonstrated significant improvements in leg press strength, chest press strength, and climbing power with load, but no changes in climbing without a carried load or gait speed—indicating that functional benefits are limited. 2
No Benefit for Energy, Mood, or Cognition
Testosterone therapy produces minimal or no improvement in energy, vitality, depressive symptoms, or cognition, even in men with confirmed hypogonadism. 2
The standardized mean difference for energy/fatigue is only 0.17 (CI 0.01–0.32), well below the threshold for clinical significance. 2
Specific Risks of Targeting 850 ng/dL
Supraphysiologic Levels and Increased Risk
A target testosterone level of 850 ng/dL is at the upper end of the normal range (264–916 ng/dL) and may result in supraphysiologic peak levels with injectable testosterone, particularly if dosing is not carefully titrated. 4, 7
The TOM trial found that higher post-treatment free testosterone levels were directly associated with cardiovascular events, suggesting that targeting higher testosterone levels may increase risk. 2
A 2022 study found that men with naturally elevated endogenous testosterone (>800 ng/dL) had higher hematocrit (βi 1.30, P<0.01) compared to men with normal testosterone (300–800 ng/dL), though this was not associated with clinically significant adverse events in men with naturally elevated levels. 8
Injectable Testosterone and Peak-Trough Variability
Injectable testosterone produces supraphysiologic peak levels 2–5 days after injection, often transiently exceeding the upper limit of normal, followed by a return to baseline by days 10–14. 4, 7
This "roller-coaster" pattern of testosterone levels is associated with a higher risk of erythrocytosis and potentially cardiovascular events compared to transdermal preparations that provide more stable day-to-day levels. 4
A 2022 study found that men receiving 200 mg biweekly injections (which produce higher average testosterone over the dosing interval) were significantly more likely to develop hematocrit >54% compared to men receiving 100 mg weekly injections. 6
Monitoring Requirements and Practical Considerations
Baseline Assessments
- Before initiating testosterone therapy, the following baseline assessments are mandatory:
- Two fasting morning total testosterone measurements (8–10 AM) to confirm hypogonadism (both <300 ng/dL). 4, 7
- Hematocrit/hemoglobin (absolute contraindication if >54%). 4, 7
- PSA and digital rectal examination (for men ≥40 years; PSA >4.0 ng/mL requires urologic evaluation). 4, 7
- Fasting glucose and HbA1c (to screen for diabetes). 4, 7
- Lipid profile. 4, 7
- LH and FSH (to differentiate primary from secondary hypogonadism). 4, 7
Follow-Up Monitoring
First follow-up at 1–2 months: measure testosterone (midway between injections, targeting 500–600 ng/dL), hematocrit, and PSA; assess clinical response. 4, 7
Every 3–6 months during the first year: repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination. 4, 7
Annually thereafter: continue the same monitoring panel if stable. 4, 7
Discontinuation Criteria
Discontinue testosterone therapy at 12 months if there is no documented improvement in sexual function (the only proven benefit of testosterone therapy). 4, 7
Immediately discontinue testosterone if hematocrit rises >54%, PSA increases >1.0 ng/mL within the first 6 months or >0.4 ng/mL per year thereafter, or if cardiovascular events occur. 4, 7
Common Pitfalls and Caveats
Do not assume that testosterone therapy will improve physical performance, muscle mass, energy, or mood—the evidence does not support these benefits, even in men with confirmed hypogonadism. 2
Do not ignore mild erythrocytosis (hematocrit 50–52%) in older men or those with cardiovascular risk factors—even modest elevations increase blood viscosity and thrombotic risk. 4
Do not continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy. 4
Do not rely on peak testosterone levels measured 2–5 days after an injection—these supraphysiologic peaks do not reflect average exposure and may lead to inappropriate dose adjustments. 4, 7
Do not prescribe testosterone for performance enhancement, weight loss, or general energy improvement—these are not evidence-based indications and expose the patient to unnecessary risks. 2, 1