What are the risks of initiating testosterone replacement therapy (TRT) without assessing sex hormone-binding globulin (SHBG) levels?

Risks of Initiating Testosterone Replacement Therapy Without Measuring SHBG

While measuring SHBG is not an absolute requirement before starting testosterone replacement therapy (TRT), failing to assess it in men with borderline total testosterone levels or conditions that alter SHBG can lead to misdiagnosis of hypogonadism, inappropriate treatment initiation, and suboptimal dosing adjustments.

Why SHBG Measurement Matters

Diagnostic Accuracy

• Total testosterone alone may be misleading in men with conditions that alter SHBG levels, including obesity, diabetes, aging, liver disease, and thyroid disorders 1
• When total testosterone is near the lower limit of normal, free testosterone measurement (calculated using total testosterone, SHBG, and albumin) is essential to confirm true androgen deficiency 1, 2
• SHBG levels rise with aging, which can mask true hypogonadism by maintaining normal total testosterone while free (bioavailable) testosterone is actually low 3

Treatment Monitoring Implications

• SHBG levels change during testosterone therapy, particularly declining significantly with exogenous testosterone administration 4
• In Klinefelter's patients treated with testosterone enanthate, SHBG fell from 16.4 ± 2 to 4.3 ± 0.5 ng/mL, dramatically altering the free testosterone fraction 4
• Without baseline SHBG, clinicians cannot accurately interpret changes in total testosterone during treatment or calculate free testosterone levels for dose adjustments 5

Specific Risks of Omitting SHBG Assessment

Risk 1: Treating Men Who Don't Have True Hypogonadism

• Men with high SHBG may have normal total testosterone but low free testosterone, representing true hypogonadism requiring treatment 1
• Conversely, men with low SHBG (common in obesity) may have low-normal total testosterone but adequate free testosterone, making treatment unnecessary 3
• Inappropriate treatment exposes patients to unnecessary risks including polycythemia, cardiovascular events, and prostate complications 1

Risk 2: Inability to Optimize Dosing

• The AUA guideline recommends adjusting testosterone dosing to achieve total testosterone in the middle tertile of normal range 1
• Without knowing SHBG status, free testosterone levels cannot be accurately estimated, making it impossible to determine if symptoms persist due to inadequate free hormone availability despite "normal" total levels 2
• Older men show greater LH suppression during testosterone treatment, and this effect correlates with non-SHBG testosterone and estradiol levels, not total testosterone 5

Risk 3: Increased Adverse Event Risk

• Polycythemia risk varies with formulation and dosing, with injectable testosterone causing hematocrit >52% in 43.8% of patients versus 15.4% with transdermal patches 1
• Without SHBG data, clinicians may overdose patients with low SHBG (who have higher free testosterone at any given total testosterone level), increasing polycythemia, sleep apnea exacerbation, and cardiovascular risks 1
• Men with elevated hematocrit >50% at baseline should have testosterone therapy withheld until investigated, and hematocrit >54% on treatment warrants dose reduction or discontinuation 1

Risk 4: Missed Alternative Diagnoses

• Measuring SHBG alongside total testosterone helps identify conditions causing secondary changes in testosterone binding rather than true hypogonadism 3
• Elevated SHBG may indicate hyperthyroidism, liver disease, or HIV infection; low SHBG suggests obesity, hypothyroidism, or insulin resistance 1

Clinical Algorithm for SHBG Assessment

When SHBG Measurement is Essential:

1. Total testosterone between 8-12 nmol/L (230-350 ng/dL) - the borderline range where SHBG significantly impacts interpretation 2
2. Obesity (BMI >30 kg/m²) - typically associated with low SHBG 1, 3
3. Diabetes or metabolic syndrome - conditions that lower SHBG 1
4. Age >60 years - SHBG rises with aging 3
5. Liver disease, hyperthyroidism, or HIV - conditions that raise SHBG 1

When SHBG May Be Optional:

• Unequivocally low total testosterone (<8 nmol/L or <230 ng/dL) on two separate fasting morning measurements in symptomatic men 2
• No conditions known to alter SHBG and clear clinical hypogonadism 1

Monitoring Requirements When SHBG is Unknown

If TRT is initiated without baseline SHBG:

• Measure hemoglobin/hematocrit at baseline and monitor closely - check at 3-6 months initially, then annually 1
• Assess cardiovascular risk factors including lipids, blood pressure, and diabetes status before starting therapy 1
• PSA measurement in men >40 years before initiation 1
• Consider measuring SHBG at first follow-up (1-2 months) to guide dose adjustments if clinical response is suboptimal 1
• Monitor for signs of over-replacement including polycythemia, sleep apnea exacerbation, fluid retention, and gynecomastia 1

Key Pitfalls to Avoid

• Never rely on a single total testosterone measurement - the Endocrine Society requires two separate fasting morning measurements showing consistently low levels 2
• Don't assume normal total testosterone excludes hypogonadism in obese or diabetic men - these patients often have low SHBG and may have low free testosterone despite borderline total levels 1
• Avoid starting therapy in men with total testosterone >12 nmol/L (>350 ng/dL) without measuring free testosterone or SHBG 2
• Don't ignore the 20% of men who receive testosterone without any testosterone testing - this represents dangerous practice 1

The evidence consistently shows that while SHBG measurement is not universally required, omitting it in borderline cases or men with SHBG-altering conditions creates diagnostic uncertainty, dosing challenges, and potentially exposes patients to treatment risks without confirmed benefit 1, 5, 4, 3, 2.