How Low SHBG Contributes to Low Total Testosterone
Low SHBG directly reduces total testosterone measurements because less testosterone is bound in circulation, while free testosterone (the biologically active form) may remain within normal range. 1
Mechanism of SHBG's Effect on Total Testosterone
- Total testosterone in plasma is approximately 98% bound to sex hormone-binding globulin (SHBG), with only about 2% existing in the free, biologically active form 2
- When SHBG levels are low, less testosterone is bound, resulting in lower total testosterone measurements even when free testosterone remains normal 1
- The distribution of testosterone between free and bound forms is primarily determined by the amount of SHBG in plasma 2
Factors That Decrease SHBG Levels
- Obesity is a major contributor to low SHBG levels 3, 1
- Insulin resistance and metabolic syndrome are strongly associated with decreased SHBG production 3, 4
- Hypothyroidism reduces SHBG levels 3
- Medications including glucocorticoids, testosterone, and anabolic androgenic steroids can suppress SHBG production 3, 1
- Other conditions associated with low SHBG include Cushing's disease, acromegaly, nonalcoholic fatty liver disease, and nephrotic syndrome 3
Clinical Significance
- In obesity-related hypogonadism, low SHBG is a primary mechanism for decreased total testosterone, with many men having normal free testosterone levels despite low total testosterone 1
- Low SHBG is more strongly associated with metabolic syndrome than low total testosterone in older men 4
- Both total testosterone and SHBG independently predict development of metabolic syndrome, particularly in non-obese men 5
- The relationship between SHBG and insulin resistance is particularly strong, with SHBG potentially serving as an early marker for metabolic disorders 6
Diagnostic Implications
- When evaluating low total testosterone, measurement of SHBG and calculation of free testosterone is essential, especially in men with obesity or other conditions associated with low SHBG 1
- Men with low total testosterone due solely to low SHBG generally do not require testosterone replacement therapy if free testosterone levels are normal 1
- Morning measurements of total testosterone should be performed on two separate occasions for accurate diagnosis 1
- Calculating the free testosterone index (total testosterone/SHBG ratio) provides better assessment than total testosterone alone in cases of suspected abnormal SHBG levels 1
Clinical Management Approach
- Address underlying causes of low SHBG (such as obesity, insulin resistance) as the first approach 1
- Weight loss can increase both SHBG and total testosterone levels in men with obesity 1
- Consider testosterone replacement only when free testosterone is consistently low on multiple assessments, not solely based on low total testosterone in the setting of low SHBG 1
By understanding this relationship between SHBG and total testosterone, clinicians can avoid unnecessary testosterone replacement therapy in patients whose low total testosterone is primarily due to SHBG abnormalities rather than true hypogonadism 1, 4.