What are the management options for a patient with mildly elevated total testosterone and Sex Hormone-Binding Globulin (SHBG) but normal free testosterone?

Management of Mildly Elevated Total Testosterone and SHBG with Normal Free Testosterone

No testosterone therapy should be prescribed to this patient, as treatment is only indicated when both biochemical deficiency (total testosterone <300 ng/dL) and clinical symptoms are present—normal free testosterone indicates no functional androgen deficiency exists. 1

Understanding the Biochemical Picture

The clinical scenario of elevated total testosterone with elevated SHBG but normal free testosterone represents a physiologically normal state that requires no intervention:

• Free testosterone is the biologically active fraction and determines androgen status at the tissue level, not total testosterone 2, 3
• SHBG binds testosterone with high affinity, and when SHBG is elevated, total testosterone rises proportionally while free testosterone remains normal 3
• This pattern does not meet diagnostic criteria for testosterone deficiency, which requires total testosterone <300 ng/dL measured on two separate early morning occasions 4

Why Testosterone Therapy is Contraindicated

Testosterone therapy aims to normalize levels to 450-600 ng/dL—if free testosterone is already normal, therapy cannot improve upon normal physiology and the risk-benefit ratio becomes entirely unfavorable. 1

The AUA guideline explicitly states that treatment goals are "normalization of total testosterone levels combined with improvement in symptoms"—when free testosterone is normal, there is nothing to normalize 4

Concrete Risks Without Benefit

Since this patient has normal free testosterone, testosterone therapy would expose them to significant risks with zero therapeutic benefit:

• Complete suppression of spermatogenesis through negative feedback on the hypothalamic-pituitary-gonadal axis, causing severe oligospermia or azoospermia 4
• Cardiovascular risks that cannot be definitively ruled out, with current literature unable to prove safety regarding major adverse cardiovascular events 4
• Polycythemia risk requiring hematocrit monitoring, with therapy withheld if hematocrit exceeds 50% and intervention required if >54% 4
• Prostate monitoring burden for men over 40, with PSA increases >1.0 ng/mL in the first year or >0.4 ng/mL per year thereafter mandating urologic evaluation 4

Diagnostic Workup to Identify Underlying Cause

The elevated SHBG itself warrants investigation, as multiple conditions can increase SHBG levels:

• Hyperthyroidism is a common cause of elevated SHBG and should be evaluated with TSH and free T4 3
• Hepatic cirrhosis in men causes elevated SHBG 3
• Medications including estrogens, thyroid hormones, and anticonvulsants raise SHBG 3
• HIV infection is associated with elevated SHBG in up to one-third of patients 5

Management Algorithm

Step 1: Confirm the laboratory findings

• Repeat morning total testosterone, SHBG, and calculated or directly measured free testosterone to verify the pattern 4

Step 2: Evaluate for secondary causes of elevated SHBG

• Measure TSH and free T4 to screen for hyperthyroidism 3
• Review medication list for drugs that increase SHBG (estrogens, thyroid hormones, anticonvulsants) 3
• Assess for liver disease with hepatic function panel if clinically indicated 3

Step 3: Address any symptoms through alternative approaches

• Lifestyle modifications including weight loss and increased physical activity should be the primary recommendation if the patient has symptoms they attribute to low testosterone 4
• High body mass index warrants weight loss counseling for cardiovascular risk reduction, not testosterone therapy 4

Step 4: Reassure the patient

• Explain that normal free testosterone indicates normal androgen activity at the tissue level 2, 3
• Clarify that elevated total testosterone with elevated SHBG is a compensatory mechanism maintaining normal free testosterone 2

Common Pitfall to Avoid

Do not prescribe testosterone therapy based on total testosterone alone when SHBG is elevated. The evidence supports treating deficiency to normal, not pushing normal to supraphysiologic—starting with normal free testosterone levels guarantees that testosterone therapy will not provide symptomatic relief and only exposes the patient to harm 1. The AUA guideline is clear that if patients "do not experience symptomatic relief after reaching the specified target testosterone levels or remain testosterone deficient in the setting of symptom/sign improvement, testosterone therapy should be stopped" 4—this patient already has normal free testosterone, making therapy futile from the outset.