How do you interpret total testosterone levels in patients with symptoms of hypogonadism, considering age, sex, and medical history?

How to Interpret Total Testosterone Levels

Total testosterone should be measured on two separate mornings between 8-10 AM, with levels below 300 ng/dL supporting the diagnosis of hypogonadism—but diagnosis requires both biochemical confirmation AND specific symptoms such as diminished libido, erectile dysfunction, or reduced vitality. 1

Diagnostic Algorithm for Testosterone Interpretation

Step 1: Confirm Proper Testing Conditions

• Obtain two separate morning measurements (8-10 AM) using the same laboratory and methodology to account for assay variability and diurnal fluctuation 1
• Single measurements are insufficient due to day-to-day testosterone variability 1
• Afternoon or evening samples should be excluded from diagnostic consideration 2

Step 2: Apply Age-Appropriate Reference Ranges

The traditional 300 ng/dL cutoff was derived from older men and may not be appropriate for younger patients. 2 Consider these age-specific lower limits:

• Men in their 20s: 409-413 ng/dL 2
• Men in their 30s: 350-359 ng/dL 2
• Men in their 40s: 350 ng/dL 2, 3
• Men in their 50s: 216 ng/dL 3
• Men in their 60s: 196 ng/dL 3
• Men in their 70s: 156 ng/dL 3

The 2018 AUA guideline uses 300 ng/dL as a reasonable cutoff across all ages, but emerging evidence suggests younger men require higher thresholds 1, 2.

Step 3: Assess for Confounding Factors

Health status and lifestyle significantly impact testosterone levels and must be considered before diagnosing hypogonadism. 3

Factors that lower testosterone levels:

• Obesity (BMI >29 kg/m²) 3
• Chronic diseases (diabetes, heart disease, hypertension, cancer) 3
• Certain medications (opioids, corticosteroids) 1

Factors that raise testosterone levels:

• Smoking (paradoxically increases testosterone despite being unhealthy) 3

Apparently healthy men have significantly higher testosterone levels than unhealthy men at the same age, so reference ranges should account for these factors 3.

Step 4: Measure Free or Bioavailable Testosterone When Indicated

When total testosterone is borderline (250-350 ng/dL) or when alterations in binding proteins are suspected, measure free testosterone by equilibrium dialysis or calculate free androgen index. 1, 4

• Free testosterone = Total testosterone ÷ SHBG level 1
• This is particularly important in men with obesity, where SHBG may be low 4
• Avoid analog free testosterone assays available at most local laboratories—they have limited reliability 1

Step 5: Correlate with Clinical Symptoms

Biochemical hypogonadism alone does NOT warrant treatment—symptoms must be present. 1

Primary symptoms supporting treatment:

• Diminished libido 1, 4
• Erectile dysfunction 1, 4
• Reduced sense of vitality 4

Secondary symptoms (weaker evidence for treatment benefit):

• Fatigue 1
• Weight loss 1
• Depressive symptoms 1
• Reduced bone mineral density 1

Important caveat: Testosterone therapy produces only small improvements in sexual function (standardized mean difference 0.35) and little to no effect on physical functioning, energy, vitality, or cognition even in confirmed hypogonadism 1, 4.

Step 6: Distinguish Primary from Secondary Hypogonadism

Once low testosterone is confirmed, measure LH and FSH to determine the source of hypogonadism—this has critical treatment implications, especially for fertility preservation. 1, 4

• Elevated LH/FSH + low testosterone = Primary (testicular) hypogonadism 1, 4
• Low or low-normal LH/FSH + low testosterone = Secondary (hypothalamic-pituitary) hypogonadism 1, 4

Men with secondary hypogonadism who desire fertility MUST receive gonadotropin therapy (hCG + FSH), NOT testosterone, as testosterone causes azoospermia. 4

Step 7: Screen for Specific Populations Requiring Testing

Consider measuring testosterone even without symptoms in men with: 1

• Unexplained anemia
• Bone density loss
• Diabetes
• HIV/AIDS
• Chronic narcotic use
• History of chemotherapy or testicular radiation
• Male infertility
• Pituitary dysfunction
• Chronic corticosteroid use

Common Pitfalls to Avoid

Never diagnose hypogonadism based on symptoms alone without biochemical confirmation—symptom questionnaires lack specificity and are not recommended for diagnosis 1, 4.

Never start testosterone therapy in men actively seeking fertility—testosterone suppresses spermatogenesis and causes prolonged azoospermia 4.

Never use a single testosterone measurement—at least two morning samples are required due to assay variability 1.

Never ignore age-specific reference ranges in young men—using the 300 ng/dL cutoff may miss hypogonadism in men under 40 years old 2.

Never attempt to diagnose the type of hypogonadism while the patient is on testosterone therapy—exogenous testosterone suppresses LH/FSH, making results misleading 4.

Never assume normal total testosterone excludes hypogonadism in obese men—measure free testosterone or SHBG to calculate free androgen index 1, 4.

Monitoring After Diagnosis

If testosterone therapy is initiated, recheck levels at 2-3 months, then every 6-12 months once stable, targeting mid-normal range (500-600 ng/dL). 4

For injectable testosterone (cypionate/enanthate), measure levels midway between injections (days 5-7 after injection). 4

Monitor hematocrit periodically and withhold treatment if >54%. 4

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, as this prevents unnecessary long-term exposure without benefit 4.