Is a high Sex Hormone-Binding Globulin (SHBG) level with normal bioavailable testosterone a concern?

High SHBG with Normal Bioavailable Testosterone Is Generally Not a Clinical Concern

High Sex Hormone-Binding Globulin (SHBG) levels with normal bioavailable testosterone typically do not require intervention as long as the patient is asymptomatic.

Understanding SHBG and Testosterone Fractions

SHBG is a glycoprotein that binds to sex hormones, particularly testosterone, affecting the amount of free (biologically active) testosterone available in the bloodstream 1. When evaluating testosterone status, it's important to understand the different fractions:

• Total testosterone: Includes both bound and unbound testosterone
• Free testosterone: The biologically active form that mediates androgen effects at target tissues
• Bioavailable testosterone: Includes free testosterone plus albumin-bound testosterone (which is weakly bound and biologically available)
• SHBG-bound testosterone: Tightly bound and not biologically available

Clinical Significance of High SHBG with Normal Bioavailable Testosterone

When SHBG is elevated (99 nmol/L in this case) but bioavailable testosterone remains normal, this indicates that:

1. The body is maintaining adequate levels of the biologically active hormone
2. The elevated SHBG is not causing clinical hypogonadism
3. No testosterone replacement therapy is indicated 2

Causes of Elevated SHBG

Several conditions can cause elevated SHBG levels:

• Liver disease/cirrhosis (SHBG is produced in the liver) 2
• Low body mass index/malnutrition 2
• Hyperthyroidism 1
• Advanced age
• Certain medications (estrogens, anticonvulsants, thyroid hormones) 1

Evaluation Algorithm for High SHBG

1. Assess for symptoms of hypogonadism:

   • Decreased sexual desire
   • Erectile dysfunction
   • Decreased energy and well-being
   • Reduced muscle mass and strength
   • Hot flashes
   • Gynecomastia 2

2. If asymptomatic with normal bioavailable testosterone:

   • No immediate intervention needed
   • Consider evaluating for underlying causes of high SHBG

3. If symptomatic despite normal bioavailable testosterone:

   • Confirm with repeat morning testing of total and free/bioavailable testosterone
   • Consider additional testing (LH, FSH, prolactin) to determine etiology 2

4. Consider liver function testing:

   • Elevated SHBG is associated with liver dysfunction
   • Basic liver function tests can rule out hepatic causes 2

Monitoring Recommendations

For patients with high SHBG but normal bioavailable testosterone:

• Annual monitoring of hormone levels is reasonable if asymptomatic 2
• No testosterone replacement therapy is indicated unless bioavailable testosterone decreases and symptoms develop

Potential Pitfalls

1. Relying solely on total testosterone: Total testosterone may appear low in the setting of high SHBG, despite normal free/bioavailable testosterone levels. This could lead to inappropriate diagnosis of hypogonadism 3.

2. Using inappropriate testing methods: Free testosterone should be measured by equilibrium dialysis or calculated using accurate formulas that include total testosterone, SHBG, and albumin 2, 3.

3. Misinterpreting the free androgen index (FAI): The ratio of total testosterone to SHBG can be misleading when SHBG levels are very high or very low 3.

Key Takeaway

In the absence of symptoms and with normal bioavailable testosterone levels, elevated SHBG alone does not warrant treatment but may indicate the need to evaluate for underlying conditions that affect SHBG production.