What is Bioavailable Testosterone
Bioavailable testosterone represents the fraction of circulating testosterone that is not bound to sex hormone-binding globulin (SHBG) and includes both free (unbound) testosterone and albumin-bound testosterone, reflecting the portion readily available for cellular uptake and biological activity. 1
Biochemical Composition
Bioavailable testosterone consists of two components:
- Free testosterone: The unbound fraction (0.5-3% of total testosterone) that is metabolically active and can freely penetrate cells 2, 3
- Albumin-bound testosterone: Testosterone weakly bound to albumin, which is readily dissociable and thus considered bioavailable for tissue uptake 2, 3
- Excludes SHBG-bound testosterone: The tightly bound fraction (representing the majority of circulating testosterone) is not bioavailable because SHBG binding prevents cellular entry 4, 2
Measurement Methods
Direct Assay Method
- Ammonium sulfate precipitation: The reference method involves adding radiolabeled testosterone to serum, precipitating the SHBG-bound fraction with 50% saturated ammonium sulfate, then measuring the remaining bioavailable fraction 5, 6
- This assayed bioavailable testosterone (aBT) is considered more accurate than calculated values when using standard association constants 6
Calculated Method
- Calculation from total testosterone, SHBG, and albumin: Uses mathematical formulas based on the law of mass action with association constants for testosterone binding to SHBG (Ks) and albumin (Ka) 1
- Standard theoretical constants (Ks = 1 × 10⁹ L/mol, Ka = 3.6 × 10⁴ L/mol) often overestimate bioavailable testosterone by 50-85% compared to direct assay 5, 6
- Optimized constants (Ks = 1.9 × 10⁹ L/mol, Ka = 2.45 × 10⁴ L/mol) provide calculated values closer to assayed bioavailable testosterone 5
Clinical Utility
Diagnostic Applications
- Hyperandrogenism in PCOS: Calculated bioavailable testosterone shows moderate diagnostic accuracy with sensitivity of 0.64-0.76 and specificity of 0.83 at thresholds around 0.78 nmol/L 1
- Male hypogonadism: Particularly useful when total testosterone falls in the "grey zone" (8-12 nmol/L), where SHBG alterations may mask true androgen status 1, 7
- SHBG-related conditions: Essential when SHBG levels are abnormal due to obesity, aging, liver disease, hyperthyroidism, or medications, as these conditions alter total testosterone without changing bioavailable testosterone 4, 2
Advantages Over Total Testosterone
- More accurate reflection of androgen activity: Total testosterone can be misleading when SHBG concentrations are altered, as most testosterone is SHBG-bound and biologically inactive 4, 2
- Better correlation with clinical symptoms: Men with cardiovascular disease have lower free and bioavailable testosterone despite variable total testosterone levels 1
Important Clinical Caveats
Measurement Limitations
- Lack of standardization: Different laboratories use different association constants, leading to significant variability in calculated values 5, 6
- Population-specific constants needed: Optimal association constants vary by population studied, and using theoretical constants can produce values differing by >30% from assayed bioavailable testosterone in 78-86% of samples 6
- Androstenediol interference: Including 5-androstenediol as a competitive SHBG inhibitor in calculations slightly improves accuracy 5
When to Measure
- Total testosterone in grey zone: When initial total testosterone is 8-12 nmol/L in men being evaluated for hypogonadism 7
- Suspected SHBG abnormalities: When conditions known to alter SHBG are present (obesity, diabetes, liver disease, thyroid disorders) 1, 4
- Discordance between symptoms and total testosterone: When clinical presentation doesn't match total testosterone levels 2, 7