Do most people with high Sex Hormone-Binding Globulin (SHBG) and high serum testosterone have symptoms?

Symptoms Associated with High SHBG and High Serum Testosterone

Most people with high Sex Hormone-Binding Globulin (SHBG) and high serum testosterone do not typically experience symptoms, as the bioavailable testosterone (free testosterone) often remains within normal range despite these elevations.

Understanding SHBG and Testosterone Relationship

SHBG is a glycoprotein that binds to sex hormones, particularly testosterone, affecting their bioavailability. The relationship between SHBG, total testosterone, and symptoms is complex:

• SHBG binds tightly to testosterone, potentially rendering the bound fraction biologically unavailable 1
• Despite high total testosterone, if SHBG is also elevated, free testosterone (the biologically active form) may remain normal 2
• In vivo studies show that higher SHBG levels are actually associated with higher total testosterone but have minimal impact on non-SHBG-bound testosterone 2

Clinical Considerations in High SHBG/High Testosterone States

Common Causes of Elevated SHBG

• Aging (SHBG naturally increases with age) 3
• Medications: anticonvulsants, estrogens, thyroid hormone 3
• Hyperthyroidism 3, 4
• Hepatic disease 3
• Smoking 3
• HIV/AIDS 3

Clinical Assessment

When evaluating patients with high SHBG and high testosterone:

1. Calculate free testosterone index (total testosterone/SHBG ratio)

   • A ratio <0.3 indicates hypogonadism despite high total testosterone 3, 5
   • This calculation is essential as high SHBG is the most common cause of normal/high total testosterone with low free testosterone 5

2. Evaluate for specific symptoms related to testosterone status:

   • Sexual symptoms: reduced libido, erectile dysfunction, decreased morning erections 3
   • Physical symptoms: decreased energy, physical strength, and activity 3
   • Psychological symptoms: low mood, decreased motivation, fatigue 3

Special Clinical Scenarios

Liver Disease

In chronic liver disease, SHBG synthesis is stimulated by elevated estrogens, leading to:

• Increased SHBG levels
• Elevated total testosterone
• However, with progression from compensated to decompensated cirrhosis, SHBG levels ultimately decline 3

Hyperthyroidism

In thyrotoxicosis, there is a pathogenetic sequence:

• Thyroid hormone excess leads to increased SHBG production
• This is accompanied by an increase in total testosterone
• Despite these increases, there is typically a fall in non-SHBG-bound testosterone
• Free testosterone concentration often remains unchanged in men but may decrease in women 4

Clinical Implications

The wide variability in SHBG concentrations (up to 20-fold difference between individuals) significantly impacts the interpretation of testosterone results 1. This explains why many patients with elevated SHBG and total testosterone remain asymptomatic - their free testosterone levels often stay within normal range.

When symptoms do occur despite high total testosterone, they typically resemble those of testosterone deficiency due to the reduced bioavailable fraction. In these cases, calculating the free testosterone index is crucial for proper diagnosis 5.

Key Takeaways

• High SHBG with high total testosterone often results in normal free testosterone levels, explaining the lack of symptoms in most patients
• When evaluating testosterone status, both SHBG and total testosterone should be measured
• The free testosterone index (total testosterone/SHBG ratio) is more clinically relevant than either value alone
• Routine SHBG testing should be considered for all patients with suspected testosterone abnormalities 1