In a 52‑year‑old man with total testosterone of 124 ng/dL and free testosterone of 11.8 pg/mL, should testosterone replacement therapy be initiated?

Does This Testosterone Level Require Treatment?

No, a total testosterone of 124 ng/dL with free testosterone of 11.8 pg/mL in a 52-year-old man does require treatment—but only if he has specific qualifying symptoms (diminished libido or erectile dysfunction) and the diagnosis is confirmed with a second morning measurement. The current single value falls well below the diagnostic threshold of 300 ng/dL, but diagnosis mandates two separate fasting morning measurements plus symptom assessment before initiating therapy. 1

Diagnostic Confirmation Required Before Treatment

Repeat Morning Testosterone Measurement

• Obtain a second fasting morning total testosterone (8–10 AM) on a separate day to confirm persistent hypogonadism, as single measurements are insufficient due to diurnal variation and assay variability. 1, 2
• Both measurements must be below 300 ng/dL to establish biochemical hypogonadism. 1
• The current value of 124 ng/dL is well below this threshold, making true hypogonadism highly likely if confirmed on repeat testing. 2

Measure Free Testosterone by Equilibrium Dialysis

• The reported free testosterone of 11.8 pg/mL appears low, but free testosterone should be measured by equilibrium dialysis (gold standard) rather than direct immunoassay, which is unreliable. 1, 3
• Free testosterone assessment is essential when total testosterone is borderline or in men with obesity/diabetes where SHBG alterations may affect interpretation. 1

Obtain LH and FSH Levels

• Measure serum LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism. 1
• This distinction is critical because secondary hypogonadism may respond to gonadotropin therapy if fertility preservation is desired, whereas testosterone therapy causes azoospermia. 1

Symptom Assessment: The Key Determinant

Symptoms That Justify Treatment

• Diminished libido and erectile dysfunction are the primary symptoms with proven testosterone responsiveness and constitute the main indication for therapy. 1, 4
• Decreased spontaneous or morning erections reliably improve with testosterone replacement. 1
• Testosterone therapy produces a small but significant improvement in sexual function (standardized mean difference 0.35). 1

Symptoms That Do NOT Justify Treatment

• Fatigue, low energy, depressed mood, poor concentration, and reduced physical strength show little to no correlation with testosterone levels and exhibit minimal or no improvement after therapy. 1, 4
• Testosterone therapy produces little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition—even with confirmed hypogonadism. 1
• Do not initiate testosterone for these nonspecific complaints alone, as they lack proven benefit and overlap with many other conditions. 1

Pre-Treatment Laboratory Evaluation

Mandatory Baseline Tests

• PSA and digital rectal examination in men over 40 years; PSA >4.0 ng/mL requires urologic evaluation and negative prostate biopsy before starting therapy. 1
• Baseline hematocrit/hemoglobin to monitor for erythrocytosis during treatment; hematocrit >54% is an absolute contraindication. 1, 5
• Fasting glucose and HbA1c to exclude diabetes. 1
• Prolactin if LH/FSH are low or loss of libido is present; prolactin >1.5× upper limit of normal mandates pituitary MRI. 1

Pituitary Imaging Indications

• Order pituitary MRI immediately if total testosterone <150 ng/dL with LH <1.5 IU/L and FSH <1.5 IU/L, even without elevated prolactin. 1
• Also obtain MRI if visual field defects, anosmia, or prolactin >1.5× upper limit of normal are present. 1

Treatment Decision Algorithm

Step 1: Confirm Diagnosis

1. Repeat morning total testosterone (8–10 AM) on a second occasion. 1
2. If both values <300 ng/dL, measure free testosterone by equilibrium dialysis and obtain LH/FSH. 1
3. Complete baseline safety labs (PSA, hematocrit, glucose, prolactin). 1

Step 2: Assess Symptoms

• If diminished libido or erectile dysfunction are present: proceed to treatment after confirming the patient does not desire fertility. 1
• If only fatigue, low energy, or mood complaints: counsel that testosterone provides minimal to no benefit for these symptoms and consider alternative diagnoses. 1

Step 3: Initiate Therapy (If Indicated)

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line due to stable serum levels and lower erythrocytosis risk (15% vs. 44% with injectables). 1, 5
• Intramuscular testosterone cypionate/enanthate 100–200 mg every 2 weeks is a cost-effective alternative ($156/year vs. $2,135/year for transdermal). 1
• Target mid-normal testosterone levels of 450–600 ng/dL. 1, 6

Monitoring Protocol

Initial Follow-Up (2–3 Months)

• Measure total testosterone (midway between injections for injectables), hematocrit, and PSA. 1
• Assess clinical response, particularly sexual function and libido. 1
• Adjust dose if symptoms persist with suboptimal levels. 7

Ongoing Monitoring (Every 3–6 Months First Year, Then Annually)

• Repeat testosterone, hematocrit, PSA, and digital rectal examination. 7, 1
• Withhold treatment if hematocrit >54% and consider phlebotomy in high-risk cases. 1
• Refer to urology if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 7, 1

Discontinuation Criteria

• Stop therapy at 12 months if no improvement in sexual function, as this is the primary proven benefit. 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single measurement; two morning values are mandatory. 1
• Do not rely on symptoms alone without biochemical confirmation; symptoms are nonspecific. 1
• Never initiate testosterone without confirming the patient does not desire fertility, as therapy causes prolonged azoospermia. 1
• Do not prescribe testosterone for fatigue, energy, or mood complaints alone, as these show minimal to no benefit. 1
• Do not omit LH/FSH testing after confirming low testosterone; this distinction directs therapy and fertility counseling. 1
• Approximately 25–30% of men receiving testosterone therapy do not meet diagnostic criteria, highlighting the need for strict adherence to testing protocols. 1
• Nearly 50% of men on testosterone never have their levels rechecked, representing a significant safety gap. 1

Special Considerations for This Patient

Obesity-Related Secondary Hypogonadism

• If LH/FSH are low or inappropriately normal, consider obesity-associated secondary hypogonadism, where excess adipose tissue increases aromatization of testosterone to estradiol, suppressing LH secretion. 1
• Attempt weight loss through hypocaloric diet (500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2–3 times/week) before initiating testosterone, as 5–10% weight loss can significantly increase endogenous testosterone. 1

Reversible Causes to Exclude

• Screen for chronic systemic diseases (type 2 diabetes, HIV, chronic organ failure, inflammatory conditions) that can transiently suppress the hypothalamic-pituitary axis. 1
• Review medications (opiates, corticosteroids) known to cause hypogonadism. 2