What labs should be checked to evaluate testosterone levels in patients presenting with fatigue?

Laboratory Evaluation for Testosterone in Patients with Fatigue

Measure morning total testosterone (drawn between 8-10 AM) on two separate occasions, and if levels are below 300 ng/dL with consistent symptoms, proceed with additional hormonal testing including LH, FSH, and prolactin to determine the etiology of testosterone deficiency. 1

Initial Testosterone Assessment

• Obtain morning total testosterone levels between 8 AM and 10 AM on at least two separate days to confirm the diagnosis, as single measurements are insufficient due to day-to-day variations 1, 2
• The diagnosis of testosterone deficiency requires both low laboratory values (<300 ng/dL) AND clinical symptoms including reduced energy, fatigue, decreased libido, erectile dysfunction, reduced muscle mass, or poor concentration 1, 2, 3
• Total testosterone levels <300 ng/dL highly support hypogonadism, while levels >300 ng/dL are likely normal 1, 4

Free Testosterone Measurement

• Measure free testosterone by equilibrium dialysis (or calculate based on SHBG) when total testosterone is in the borderline range or when SHBG alterations are suspected (obesity, aging, liver disease) 1, 5
• Free testosterone assessment is particularly important in obese patients, as low total testosterone may be due solely to low SHBG with normal free testosterone 1
• Free testosterone <63 pg/mL confirms hypogonadism and correlates better with clinical symptoms than total testosterone alone 5

Essential Adjunctive Hormonal Testing

When testosterone deficiency is confirmed, the following tests determine etiology and guide treatment:

Luteinizing Hormone (LH)

• Measure serum LH in all patients with confirmed low testosterone to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 1
• Low or low-normal LH with low testosterone indicates secondary hypogonadism and requires further pituitary evaluation 1, 6

Prolactin

• Measure serum prolactin in patients with low testosterone AND low/normal LH levels to screen for hyperprolactinemia 1, 6
• If prolactin is elevated, repeat the measurement to confirm it is not spurious 1
• Persistently elevated prolactin warrants endocrinology referral and consideration of pituitary MRI 1

Follicle-Stimulating Hormone (FSH)

• Measure FSH in men interested in fertility preservation prior to testosterone therapy, as elevated FSH with low testosterone indicates impaired spermatogenesis 1
• Consider semen analysis if FSH is elevated (hypergonadotropic hypogonadism) 1

Additional Laboratory Considerations

Metabolic and Cardiovascular Screening

• Measure fasting glucose and/or HbA1c, as testosterone deficiency is highly prevalent in men with diabetes and metabolic syndrome 2, 4
• Obtain fasting lipid profile for cardiovascular risk assessment 2
• These metabolic parameters are both risk factors for hypogonadism and outcomes that may improve with treatment 2

Baseline Safety Monitoring

• Measure hemoglobin/hematocrit at baseline before considering testosterone therapy, as treatment increases red blood cell mass 1, 7
• Obtain PSA and perform digital rectal examination in men over 40 to screen for prostate abnormalities before treatment 1, 3
• Check liver function tests given hepatic metabolism of testosterone 8

Estradiol

• Measure serum estradiol only if breast symptoms or gynecomastia are present prior to testosterone therapy 1
• Elevated baseline estradiol warrants endocrinology referral 1

Critical Diagnostic Algorithm

For men with total testosterone <150 ng/dL combined with low/normal LH, obtain pituitary MRI regardless of prolactin levels, as non-secreting pituitary adenomas may be present 1

Common Pitfalls to Avoid

• Do not rely on screening questionnaires as substitutes for laboratory testosterone measurement—they have variable sensitivity/specificity and are not appropriate diagnostic tools 1
• Do not measure testosterone at random times of day—morning samples are essential for accurate diagnosis due to diurnal variation 1
• Do not diagnose hypogonadism based on symptoms alone—biochemical confirmation with low testosterone on two occasions is mandatory 1, 2, 3
• Do not skip LH/FSH/prolactin testing—these determine whether hypogonadism is primary or secondary and guide appropriate treatment selection 1, 6

Context-Specific Considerations

While fatigue evaluation guidelines mention screening for hypothyroidism and cardiac disease as potential causes 1, testosterone deficiency should be specifically evaluated when fatigue is accompanied by other hypogonadal symptoms (decreased libido, erectile dysfunction, reduced muscle mass) 1, 2. The workup differs from general fatigue evaluation in cancer survivors, where the focus is broader 1.