Is it reasonable to trial testosterone supplementation in a man with symptoms of hypogonadism and low normal testosterone levels to bring levels to the mid-normal range?

Testosterone Supplementation for Low-Normal Testosterone with Hypogonadal Symptoms

A trial of testosterone supplementation is not recommended for men with low-normal testosterone levels, even in the presence of symptoms, as current FDA approval and major guidelines require documented low testosterone levels (below the normal range) on two separate morning measurements for treatment initiation. 1

Diagnostic Requirements Before Treatment

The diagnosis of hypogonadism requiring testosterone therapy must meet strict criteria:

• Two separate fasting morning total testosterone measurements must be obtained, both showing levels below the normal range (typically <300 ng/dL or 10.41 nmol/L) 2, 3
• Measurements should be performed using accurate and reliable assays 2
• Low-normal testosterone levels do not meet diagnostic criteria for testosterone replacement therapy 1

If total testosterone is near the lower limit of normal, free testosterone or bioavailable testosterone should be measured using equilibrium dialysis or calculated from total testosterone, sex hormone-binding globulin (SHBG), and albumin 2

Why Low-Normal Testosterone Does Not Qualify

The FDA labeling explicitly states that testosterone gel is indicated only for "conditions associated with a deficiency or absence of endogenous testosterone" in men with primary or hypogonadotropic hypogonadism 1. Critically, the FDA notes that "safety and efficacy of testosterone gel in men with 'age-related hypogonadism' have not been established" 1.

The evidence base supporting testosterone therapy specifically excluded or showed minimal benefit in men with baseline testosterone levels above 300 ng/dL 2. In the systematic review for the American College of Physicians guideline, only 20 of 38 trials had mean baseline testosterone ≤300 ng/dL, and five studies with baseline testosterone >400 ng/dL showed inconsistent results 2.

Clinical Approach for Symptomatic Men with Low-Normal Testosterone

For men with symptoms but low-normal testosterone levels, the appropriate approach is:

1. Address Reversible Causes First

• Weight loss and lifestyle modification should be the primary intervention, as obesity significantly lowers testosterone levels and these interventions can increase testosterone naturally 2
• Evaluate and treat sleep apnea, which is highly prevalent (up to 80% in obese men) and affects testosterone levels 2
• Review medications that may suppress testosterone production 4

2. Reassess After Lifestyle Interventions

• Repeat morning testosterone measurements after 3-6 months of lifestyle modifications 4
• If testosterone remains low-normal but symptoms persist, consider other causes of symptoms (depression, thyroid dysfunction, sleep disorders) 4

3. Consider Alternative Diagnoses

• Evaluate for other endocrine disorders that may present similarly (thyroid disease, hyperprolactinemia) 4
• Assess for depression, which shares many symptoms with hypogonadism 4

Target Testosterone Levels When Treatment Is Indicated

When testosterone therapy is appropriately prescribed (for documented hypogonadism with testosterone <300 ng/dL), the American Urological Association recommends adjusting dosing to achieve levels in the middle tertile of the normal reference range (450-600 ng/dL) 2. However, this target applies only to men who meet diagnostic criteria for hypogonadism.

The 2004 guideline notes that "if the patient reports an adequate clinical response to testosterone supplementation, there is no need for dosage adjustment, even if levels are in the low-normal range" 2. This statement, however, applies to men already on therapy for documented hypogonadism, not as justification to start therapy in men with low-normal baseline levels.

Safety Considerations That Preclude Empiric Trials

Testosterone therapy carries significant risks that argue against empiric trials:

• Increased coronary artery plaque volume in older men with hypogonadism 2
• Some studies show increased cardiovascular events, though evidence is inconsistent 2
• Polycythemia and erythrocytosis requiring monitoring 2
• Potential stimulation of occult prostate cancer, requiring PSA monitoring 2
• Suppression of spermatogenesis leading to infertility 2
• Venous thromboembolism risk 1

These risks make empiric therapeutic trials inappropriate when diagnostic criteria are not met 2, 1.

Alternative Treatments for Fertility Preservation

If fertility is a concern and true hypogonadism is documented, alternatives to testosterone include human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or aromatase inhibitors, which can increase testosterone while preserving fertility 5, 6. However, these are only appropriate when hypogonadism is confirmed, not for low-normal testosterone levels.

Common Pitfall to Avoid

The most critical pitfall is initiating testosterone therapy based on symptoms alone without meeting biochemical diagnostic criteria. Approximately 20% of men starting testosterone therapy in one study had testosterone levels >300 ng/dL, representing inappropriate prescribing 2. Symptoms attributed to hypogonadism are nonspecific (fatigue, decreased libido, mood changes) and overlap with many other conditions that should be evaluated first 2, 4.