What is the likely diagnosis for a 36-year-old male with low free testosterone, low bioavailable testosterone, and high sex hormone binding globulin?

Likely Diagnosis: Elevated SHBG with Compensated Testosterone Production

This patient has elevated sex hormone-binding globulin (SHBG) causing reduced free and bioavailable testosterone despite normal total testosterone (450 ng/dL), representing a state where increased protein binding reduces testosterone bioavailability but the hypothalamic-pituitary-gonadal axis is likely compensating appropriately. 1

Understanding the Laboratory Pattern

The key finding is the discordance between normal total testosterone and low free/bioavailable testosterone:

• Total testosterone of 450 ng/dL is within the normal adult male range (300-800 ng/dL), indicating adequate testicular production 2
• Elevated SHBG (67, high) binds more circulating testosterone, reducing the free fraction available for tissue uptake 3
• Low free testosterone (31.9) and bioavailable testosterone (65.5) reflect increased protein binding rather than inadequate production 4
• The body typically compensates through negative feedback mechanisms - when SHBG rises and free testosterone drops, the pituitary increases LH secretion to stimulate more testicular testosterone production, maintaining adequate bioavailable levels 1

Essential Next Diagnostic Step

Measure serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to determine if true hypogonadism exists or if the pituitary is appropriately compensating for the elevated SHBG. 2

• If LH is normal or elevated (typically >4-7 IU/L), this indicates the pituitary is responding appropriately to maintain adequate free testosterone, and the patient does not have true hypogonadism despite the low free testosterone values 1
• If LH is low or low-normal with persistently low free testosterone, this would indicate secondary (central) hypogonadism requiring further evaluation 2
• Measure serum prolactin if LH is low or low-normal to screen for hyperprolactinemia and potential pituitary pathology 2

Clinical Symptom Assessment Required

The diagnosis of testosterone deficiency requires BOTH low testosterone measurements AND the presence of specific symptoms/signs - laboratory values alone are insufficient. 2

Specifically assess for:

• Reduced libido, erectile dysfunction, decreased energy, reduced endurance, diminished work/physical performance, fatigue 2
• Depression, reduced motivation, poor concentration, impaired memory, irritability 2
• Physical examination findings: reduced body hair in androgen-dependent areas, gynecomastia, reduced testicular size/consistency, increased body mass index or waist circumference 2

Higher SHBG levels, independently of total testosterone, are associated with more severe hypogonadal symptoms (measured by ANDROTEST score) and objective markers of reduced testosterone bioactivity including lower PSA and hematocrit. 4

Causes of Elevated SHBG to Investigate

• Hyperthyroidism - though TSH is normal (1.40) in this patient, making this unlikely 3
• Hepatic cirrhosis or chronic liver disease - check liver function tests 3
• Medications: estrogens, thyroid hormones, anticonvulsants - obtain medication history 3
• Aging - SHBG naturally increases with age 3
• Low body weight or low insulin states - obesity and insulin resistance typically lower SHBG 2

Treatment Considerations

Testosterone replacement therapy should ONLY be considered if:

1. Morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments 2
2. The patient has documented symptoms/signs of hypogonadism 2
3. LH/FSH evaluation confirms the etiology 2
4. Contraindications are ruled out 5

In patients with elevated SHBG and normal total testosterone who have low or low-normal LH levels, selective estrogen receptor modulators (SERMs) may be considered as an alternative to testosterone replacement, particularly in those wishing to preserve fertility. 2

Critical Pitfall to Avoid

Do not initiate testosterone replacement based solely on low free testosterone values when total testosterone is normal without first measuring LH/FSH and confirming true hypogonadism. 2, 1 Many men with elevated SHBG maintain adequate testosterone bioactivity through compensatory increases in total testosterone production, and treating them with exogenous testosterone would suppress their endogenous production unnecessarily. 1

Incidental Finding

The mild leukopenia (WBC 3.6) with normal differential requires monitoring but is likely unrelated to the testosterone/SHBG findings. Consider repeat CBC and evaluation for causes of leukopenia if persistent or worsening.