What does a free testosterone of 32.8 pg/mL and total testosterone of 1,047 ng/dL in an adult male signify, and what are the appropriate diagnostic and management steps?

Interpretation of Testosterone Levels: Total 1,047 ng/dL and Free 32.8 pg/mL

Your testosterone levels are markedly elevated—total testosterone of 1,047 ng/dL is well above the normal adult male range (264–916 ng/dL), and free testosterone of 32.8 pg/mL is far below the expected range (66–309 pg/mL for all men, 120–368 pg/mL for men 19–39 years), creating a biochemical discordance that strongly suggests either laboratory error, exogenous testosterone use, or a rare condition affecting sex hormone-binding globulin (SHBG). 1, 2

Immediate Diagnostic Steps

1. Verify Laboratory Accuracy and Timing

• Repeat both total and free testosterone measurements using a CDC-certified liquid chromatography tandem mass spectrometry (LC-MS/MS) assay between 8:00–10:00 AM in a fasting state, as testosterone levels exhibit significant diurnal variation and assay-dependent variability. 1, 3
• Ensure free testosterone is measured by equilibrium dialysis (the gold standard), not direct immunoassay, because immunoassays are notoriously inaccurate when SHBG is abnormal. 3, 4, 2, 5
• The discordance between very high total testosterone and very low free testosterone is physiologically implausible unless SHBG is profoundly elevated or the free testosterone assay is erroneous. 6, 5

2. Measure Sex Hormone-Binding Globulin (SHBG)

• Obtain SHBG immediately to calculate the free androgen index (FAI = [total testosterone ÷ SHBG] × 100). 1
• If SHBG is markedly elevated (e.g., >80 nmol/L), it would explain low free testosterone despite high total testosterone, indicating functional hypogonadism. 1
• Screen for causes of elevated SHBG: hyperthyroidism (TSH), liver disease (liver function tests, hepatitis serologies), HIV/AIDS (if risk factors present), and review medications (anticonvulsants, estrogens, thyroid hormone). 1

3. Rule Out Exogenous Testosterone Use

• Directly ask about testosterone supplementation (injections, gels, creams, pellets) or anabolic steroid use, as exogenous testosterone raises total testosterone while suppressing endogenous production. 1
• If the patient is on testosterone therapy, measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—both will be suppressed (<1.5 IU/L) with exogenous use. 1
• If the patient denies exogenous use but LH/FSH are suppressed, consider surreptitious anabolic steroid use or a rare androgen-secreting tumor.

4. Assess for Androgen-Secreting Tumors (Rare)

• If exogenous testosterone is ruled out and SHBG does not explain the findings, consider testicular or adrenal tumors secreting testosterone. 1
• Obtain dehydroepiandrosterone sulfate (DHEA-S) to assess adrenal androgen production; markedly elevated levels suggest an adrenal source. 1
• Perform scrotal ultrasound if testicular examination reveals nodules or asymmetry. 1
• Obtain abdominal/pelvic CT or MRI if DHEA-S is elevated or clinical suspicion for adrenal pathology exists.

Most Likely Explanations

Scenario A: Laboratory Error (Most Common)

• Free testosterone of 32.8 pg/mL is far below the 2.5th percentile (66 pg/mL) for healthy men, while total testosterone of 1,047 ng/dL is at the 97.5th percentile (916 ng/dL). 1, 2
• This discordance is physiologically impossible unless SHBG is astronomically high (>200 nmol/L), which is exceedingly rare. 1, 5
• Action: Repeat both tests using LC-MS/MS for total testosterone and equilibrium dialysis for free testosterone at a certified laboratory. 3, 4, 2

Scenario B: Exogenous Testosterone Use

• If the patient is using testosterone therapy (injections, gels, creams), total testosterone can be supraphysiologic (>1,000 ng/dL) while free testosterone may appear low if measured incorrectly or if SHBG is suppressed. 1
• Action: Measure LH and FSH—both will be suppressed (<1.5 IU/L) if exogenous testosterone is present. 1
• If confirmed, discontinue testosterone therapy and allow a 2–4 week washout before retesting to assess endogenous production. 1

Scenario C: Markedly Elevated SHBG

• Conditions such as hyperthyroidism, cirrhosis, or HIV can raise SHBG to levels that bind nearly all circulating testosterone, leaving very little free testosterone despite high total levels. 1
• Action: Measure SHBG, TSH, liver function tests, and consider HIV testing if risk factors are present. 1
• If SHBG is >80 nmol/L, calculate FAI; an FAI <30 confirms functional hypogonadism despite high total testosterone. 1

Management Algorithm

Step 1: Confirm Laboratory Accuracy

• Repeat total testosterone (LC-MS/MS) and free testosterone (equilibrium dialysis) between 8:00–10:00 AM, fasting. 3, 4, 2

Step 2: Measure SHBG and Calculate FAI

• If SHBG is markedly elevated, treat the underlying cause (hyperthyroidism, liver disease, etc.). 1
• If FAI <30, consider testosterone therapy only if the patient has diminished libido or erectile dysfunction. 1

Step 3: Assess for Exogenous Testosterone

• Measure LH and FSH; if both are suppressed, confirm exogenous use and discontinue therapy. 1

Step 4: Rule Out Rare Causes

• If exogenous use is excluded and SHBG is normal, measure DHEA-S and consider imaging (scrotal ultrasound, abdominal CT/MRI) to exclude androgen-secreting tumors. 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism or hypergonadism based on a single measurement; repeat testing is mandatory due to assay variability and diurnal fluctuation. 1, 3, 6
• Do not rely on direct immunoassays for free testosterone; use equilibrium dialysis or calculate FAI when SHBG is abnormal. 3, 4, 2, 5
• Do not assume the patient is not using exogenous testosterone; directly ask and measure LH/FSH to confirm. 1
• Do not ignore markedly elevated SHBG; it can cause functional hypogonadism despite high total testosterone. 1