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

High SHBG with Normal Free Testosterone: Clinical Significance and Management

High sex hormone-binding globulin (SHBG) levels with normal free testosterone is generally not a clinical concern requiring intervention as long as symptoms are absent, since free testosterone is the biologically active form that determines hormonal effects in the body. 1

Understanding SHBG and Testosterone Relationship

SHBG is a glycoprotein that binds to sex hormones, particularly testosterone and estradiol, affecting their bioavailability. When interpreting hormone levels:

• Free testosterone represents the biologically active fraction available to tissues
• Total testosterone includes both free and bound (primarily to SHBG) testosterone
• SHBG levels influence the ratio between bound and free testosterone

Factors That Can Elevate SHBG

Several conditions and factors can cause elevated SHBG levels:

• Hyperthyroidism 2
• Liver disease, particularly hepatic cirrhosis 3, 2
• Estrogen therapy or high estrogen states
• Advanced age
• Low body mass index
• Certain medications

Clinical Assessment Algorithm

1. Evaluate for symptoms:

   • If free testosterone is normal and no symptoms of hypogonadism exist, no intervention is typically needed
   • If symptoms are present despite normal free testosterone, consider other causes

2. Rule out underlying conditions:

   • Check thyroid function (TSH, free T4) as hyperthyroidism commonly causes high SHBG 2
   • Evaluate liver function (ALT, AST, bilirubin, albumin) as liver disease affects SHBG production 3
   • Consider medication review for agents that may affect SHBG levels

3. Additional hormonal assessment if indicated:

   • Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to assess hypothalamic-pituitary axis function 1
   • Consider estradiol levels, especially if gynecomastia or other estrogen-related symptoms are present

Clinical Implications

High SHBG with normal free testosterone may have different implications:

• Cardiovascular risk: Some research suggests elevated SHBG may be associated with increased cardiovascular disease risk in men 4, though this relationship is complex and not fully established
• Metabolic health: SHBG levels correlate negatively with insulin resistance; high levels may reflect good insulin sensitivity 5
• Liver health: Elevated SHBG may be an early marker of liver dysfunction in some cases 3

Management Approach

If free testosterone is normal and no symptoms are present:

• Routine monitoring is sufficient
• Address any underlying conditions identified (thyroid disease, liver disease)

If symptoms of hypogonadism are present despite normal free testosterone:

• Consider other causes of sexual dysfunction 1
• Evaluate for psychological factors, cardiovascular disease, diabetes, or medication side effects
• Lifestyle modifications may be beneficial, including regular exercise, weight management, and Mediterranean diet 1

Important Caveats

• Free testosterone measurement methods vary in reliability; equilibrium dialysis is considered the gold standard but calculated free testosterone from total testosterone and SHBG is a reliable alternative in most clinical scenarios 6
• During pregnancy or with use of oral contraceptives, calculated free testosterone may be less reliable due to estradiol competing for SHBG binding sites 6
• SHBG levels can fluctuate based on numerous factors, so interpretation should consider the overall clinical picture

In summary, when free testosterone levels are normal, elevated SHBG alone is generally not a clinical concern requiring specific treatment, but may warrant investigation for underlying conditions that could be affecting SHBG production.