Sex Hormone-Binding Globulin (SHBG) Levels Change Significantly with Age
SHBG levels increase with age in both men and women, with significant variation between individuals that impacts hormone bioavailability and associated health risks.
Age-Related Changes in SHBG
Men
- SHBG levels are significantly higher in older men compared to younger men 1
- In a clinical cohort study, mean SHBG was 27.7 nmol/L in men ≤54 years versus 36.6 nmol/L in men ≥55 years (p<0.001) 1
- There is remarkable interindividual variability, with nearly 20-fold difference from lowest to highest values (range 6-109 nmol/L) 1
- 9% of men ≥55 years had SHBG >60 nmol/L compared to only 2.2% of younger men 1
Women
- Postmenopausal women show significant variations in SHBG levels that correlate with health outcomes 2
- Lower SHBG levels in postmenopausal women are associated with increased risk of ischemic stroke 2
- Women in the lowest SHBG quintile had 61% higher risk of ischemic stroke compared to those in the highest quintile (HR 1.61,95% CI 1.19-2.19) 2
Factors Affecting SHBG Levels
Increasing SHBG
- Advanced age 3, 1
- Estrogen exposure 3, 4
- Hyperthyroidism/thyrotoxicosis 3, 4
- Hepatic disease 3
- Smoking 3
- HIV/AIDS 3
Decreasing SHBG
- Obesity 3, 4
- Insulin resistance 3, 4
- Hypothyroidism 3
- Metabolic syndrome 3
- Type 2 diabetes 3
- Growth hormone deficiency 5
Clinical Significance of Age-Related SHBG Changes
Hormone Bioavailability
- Higher SHBG in older adults reduces bioavailable testosterone and estradiol 4
- SHBG tightly binds testosterone, rendering the bound fraction biologically unavailable 1
- In growth hormone-deficient boys, higher SHBG results in lower bioavailable testosterone despite normal total testosterone levels 5
Cardiovascular Risk
- Elevated SHBG in men is independently associated with incident cardiovascular disease (OR 1.54,95% CI 1.15-2.06 per SD increase) 6
- In women, low SHBG is associated with increased ischemic stroke risk 2
- SHBG levels correlate positively with HDL cholesterol in men 4
Metabolic Health
- SHBG can serve as a marker of insulin resistance and hyperinsulinism 4
- Decreased SHBG levels in postmenopausal women are associated with increased risk for non-insulin-dependent diabetes 4
Clinical Applications
Diagnostic Considerations
- SHBG measurement is essential when evaluating sex hormone status, particularly in older adults 3
- Reference ranges for testosterone should consider age-related changes in SHBG 3
- Free or bioavailable testosterone measurements are preferred in conditions affecting SHBG 3
- Routine SHBG testing should be considered for men suspected of testosterone deficiency 1
Interpretation Pitfalls
- Failure to account for age-related SHBG changes may lead to misinterpretation of total testosterone levels 1
- Normal total testosterone with low free testosterone may be due to high SHBG 3
- Laboratory reference ranges for IGF1 should be age-adjusted, sex-adjusted, and Tanner stage-matched 7
- SHBG levels should be interpreted in context of concurrent conditions affecting its production 3
Monitoring Considerations
- When evaluating hypogonadism, measure SHBG along with total testosterone on at least two separate occasions 3
- Consider calculating free testosterone index (total testosterone/SHBG ratio) where a ratio <0.3 confirms hypogonadism 3
- In transgender individuals on gender-affirming hormone therapy, SHBG levels may change significantly 7
- For patients with suspected growth hormone excess, IGF1 values should be interpreted with caution in adolescence during peak growth spurt 7