What is the best course of action for a patient with low free testosterone levels, specifically hypogonadism, but normal overall testosterone levels, and potential symptoms such as low libido, fatigue, or osteoporosis?

Management of Low Free Testosterone with Normal Total Testosterone

If your free testosterone is truly low at 5 (ng/dL) despite normal total testosterone, you need testosterone replacement therapy after confirming the diagnosis with a second morning measurement and completing the hypogonadal workup. 1

Confirm the Diagnosis First

The scenario of low free testosterone with normal total testosterone is uncommon and requires verification before treatment:

• Repeat the free testosterone measurement using equilibrium dialysis (the gold standard method) on a second morning between 8-10 AM to confirm the low value, as testosterone shows significant diurnal variation 2, 1
• Verify your total testosterone is actually normal by obtaining a second early morning measurement (should be ≥300 ng/dL to be considered normal) 2, 1
• This pattern most commonly occurs in obesity, where increased aromatization of testosterone to estradiol in adipose tissue can lower free testosterone while total testosterone remains in the normal range 2

Essential Workup Before Treatment

Once low free testosterone is confirmed on two separate occasions, complete the following evaluation:

• Measure serum luteinizing hormone (LH) to distinguish primary hypogonadism (elevated LH) from secondary hypogonadism (low or low-normal LH) 2, 3
• Measure serum prolactin if LH is low or low-normal, as hyperprolactinemia can cause secondary hypogonadism 2, 3
• Measure hemoglobin before starting testosterone therapy to establish baseline 3
• Assess cardiovascular risk factors including dyslipidemia, hypertension, diabetes, and smoking status 3
• Document symptoms such as reduced energy, reduced endurance, fatigue, depression, reduced motivation, poor concentration, impaired memory, reduced sex drive, erectile dysfunction, or infertility 2, 1
• Perform targeted physical examination for body habitus, virilization status (body hair patterns), BMI/waist circumference, gynecomastia, testicular size and consistency, and prostate examination 2, 1

When to Treat

Testosterone replacement therapy is indicated when:

• Free testosterone is frankly low on at least two separate morning assessments by equilibrium dialysis 2
• AND you have symptoms consistent with testosterone deficiency 2, 1
• AND the hypogonadal workup is complete to rule out secondary causes unrelated to obesity 2

Do not treat if:

• Free testosterone normalizes on repeat testing despite initial low value 1
• You are asymptomatic, as treatment requires both low levels AND symptoms 2, 1

Treatment Options

For confirmed symptomatic hypogonadism with low free testosterone:

• Transdermal testosterone gel (1.62%) is the preferred first-line option for most men because it produces stable serum testosterone concentrations and is most convenient 2, 4

  • Starting dose: 40.5 mg daily (two pump actuations) applied to upper arms and shoulders 4
  • Apply to clean, dry skin in the morning after showering 4
  • Cover application site with clothing after gel dries to prevent transfer to others 4
  • Avoid swimming/showering for minimum 2 hours after application 4

• Intramuscular testosterone injections are an alternative that avoids daily administration and costs less, beneficial for patients with reduced adherence or resources 2

• Testosterone patches minimize variable absorption seen with gels but may cause skin irritation 2

• Implantable testosterone pellets provide long-term delivery but require a procedure 2

Monitoring After Treatment Initiation

• Measure testosterone levels at 2-3 months after starting therapy or after any dose change to ensure normal serum concentrations are achieved 2, 3
• For gel preparations, measure levels at any time after application once steady state is reached 2
• For injections, measure midway between injections 2
• Target mid-normal testosterone range during treatment 5
• Once stable on a given dose, monitor every 6-12 months 2
• Monitor hematocrit and PSA annually in men 40 years or older 6

Critical Pitfalls to Avoid

• Do not skip the LH measurement - this is the single most important test to guide further workup and determine if you have primary versus secondary hypogonadism 3
• Do not rely on screening questionnaires instead of laboratory testing, as they have variable specificity and sensitivity and should not be used to diagnose testosterone deficiency 2, 3
• Do not start treatment without confirming low free testosterone on two separate occasions, as single measurements can be misleading 2, 1
• Do not treat asymptomatic patients - clinical diagnosis requires both low levels AND symptoms 2, 1
• Do not apply testosterone gel to genitals, chest, abdomen, or axillae - only upper arms and shoulders to minimize transfer risk 4
• Ensure strict precautions to prevent secondary exposure to women and children, as virilization has been reported in postmarketing surveillance 4

Contraindications to Treatment

Do not initiate testosterone therapy if you have:

• Breast cancer or prostate cancer 4, 5
• Hematocrit >50% 5
• Severe untreated obstructive sleep apnea 5
• Uncontrolled or poorly controlled heart failure 5
• Severe lower urinary tract symptoms (International Prostate Symptom Score >19) 5