What additional labs should be ordered for a 46-year-old male complaining of fatigue with a history of low testosterone (hypogonadism)?

Laboratory Workup for Fatigue and Low Testosterone in a 46-Year-Old Male

Order serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to determine whether the hypogonadism is primary (testicular) or secondary (hypothalamic-pituitary), and measure serum prolactin if LH is low or normal to screen for hyperprolactinemia. 1, 2

Essential Hormonal Testing

Confirm the testosterone deficiency first:

• Repeat morning total testosterone measurement (if only one prior value exists) to confirm levels below 300 ng/dL on two separate occasions using the same laboratory 1, 2
• If total testosterone is close to the lower limit (300 ng/dL range), measure free testosterone via equilibrium dialysis or calculate using total testosterone, sex hormone-binding globulin (SHBG), and albumin 1

Determine the etiology of hypogonadism:

• Serum LH and FSH levels are mandatory to differentiate primary from secondary hypogonadism 1, 2
• Serum prolactin if LH is low or normal, as hyperprolactinemia can suppress gonadotropins and cause hypogonadism 2
• Consider pituitary MRI if total testosterone is <150 ng/dL with low/normal LH, regardless of prolactin levels 2

Additional pituitary function assessment (if secondary hypogonadism suspected):

• Morning cortisol and ACTH (drawn around 8 AM) to evaluate for adrenal insufficiency, which commonly accompanies pituitary dysfunction 1
• TSH and free T4 to assess thyroid function, as central hypothyroidism frequently coexists with hypogonadotropic hypogonadism 1

Metabolic and Comorbidity Screening

Given the patient's age and fatigue, screen for common conditions associated with low testosterone:

• Hemoglobin A1c (HbA1c) or fasting glucose to screen for diabetes, which is strongly associated with low testosterone 1
• Complete blood count (CBC) to evaluate for unexplained anemia, which warrants testosterone measurement 1
• Lipid panel as part of cardiovascular risk assessment 2
• Liver function tests (ALT, AST) and platelet count to calculate FIB-4 score if the patient has metabolic risk factors, as nonalcoholic fatty liver disease is highly prevalent in men with metabolic syndrome 1

Pre-Treatment Baseline Assessment

If testosterone replacement is being considered, obtain these baseline values:

• Hemoglobin and hematocrit to monitor for polycythemia development during treatment 2
• Prostate-specific antigen (PSA) before initiating therapy 2
• Serum estradiol if the patient has gynecomastia or breast symptoms 2

Clinical Context and Pitfalls

The distinction between pathologic hypogonadism requiring treatment and obesity-related pseudo-hypogonadism is critical. Obesity causes reductions in SHBG and total testosterone with normal LH/FSH, representing a eugonadal state that improves with weight loss rather than testosterone therapy 3. Measuring LH and FSH is essential to avoid inappropriate testosterone treatment in men whose low testosterone is secondary to obesity and metabolic dysfunction rather than true HPT axis pathology. 3

For secondary hypogonadism (low testosterone with low/normal LH), comprehensive pituitary evaluation is necessary because approximately 50% of patients with hypophysitis present with panhypopituitarism (adrenal insufficiency, hypothyroidism, and hypogonadism), and missing adrenal insufficiency can be life-threatening 1. Always start corticosteroid replacement before thyroid hormone if both deficiencies are present to avoid precipitating adrenal crisis. 1

The American Urological Association emphasizes that testosterone deficiency requires both low laboratory values AND clinical symptoms—laboratory values alone do not justify treatment 1. However, certain high-risk conditions warrant testosterone measurement even without typical symptoms, including diabetes, unexplained anemia, bone density loss, chronic narcotic use, and history of chemotherapy or testicular radiation 1.