How High SHBG Causes Fertility Issues in Men
High levels of Sex Hormone-Binding Globulin (SHBG) cause male fertility issues primarily by reducing the bioavailability of testosterone, leading to functional hypogonadism despite potentially normal total testosterone levels.
Mechanism of SHBG-Related Fertility Problems
Impact on Testosterone Bioavailability
- SHBG has a high-affinity binding for testosterone, which renders the bound testosterone biologically unavailable to target tissues 1
- When SHBG levels are elevated, a greater proportion of total testosterone becomes bound, reducing the free (bioavailable) testosterone fraction 2
- Free testosterone is the biologically active form that supports spermatogenesis and male reproductive function
Hormonal Imbalance
- Elevated SHBG disrupts the androgen-estrogen balance crucial for normal reproductive function 1
- This imbalance can negatively affect the hypothalamic-pituitary-gonadal axis, further compromising fertility 2
- Sperm DNA fragmentation has been shown to negatively correlate with testosterone levels, suggesting that reduced bioavailable testosterone due to high SHBG may contribute to DNA damage in sperm 3
Clinical Manifestations of High SHBG in Male Fertility
Impact on Semen Parameters
- Strong positive correlations exist between SHBG levels and sperm count, motility, and morphology when SHBG is within normal range 4
- However, when SHBG is excessively elevated, the resulting decrease in free testosterone can lead to:
- Decreased sperm production (oligozoospermia)
- Reduced sperm motility (asthenozoospermia)
- Abnormal sperm morphology (teratozoospermia) 2
Genetic Factors
- Polymorphisms in the SHBG gene can influence SHBG levels and male fertility
- The (TAAAA)n repeat polymorphism with longer repeats (>8) has been associated with higher risk of infertility 4
- The Asp327Asn polymorphism in the SHBG gene has been linked to variations in SHBG levels and fertility outcomes 4
Conditions Associated with High SHBG
Liver Disease
- In chronic liver disease, SHBG synthesis is stimulated by elevated estrogen levels 2
- SHBG levels rise in compensated cirrhosis but may ultimately decline with progression to decompensated cirrhosis 2
- The combination of increased SHBG and elevated estrogen levels in liver disease contributes to hypogonadism and fertility issues 2
Other Medical Conditions
- Hyperthyroidism can increase SHBG production 1
- Certain medications, particularly estrogen-containing compounds, can elevate SHBG 1
- Advanced age is associated with higher SHBG levels, with significantly higher mean SHBG in men ≥55 years (36.6 nmol/L) compared to younger men (27.7 nmol/L) 5
Clinical Implications and Management
Diagnostic Considerations
- SHBG measurement should be included when evaluating male infertility, especially when total testosterone appears normal but clinical symptoms suggest hypogonadism 5
- A remarkably wide distribution of SHBG concentrations exists in clinical populations, with values ranging from 6-109 nmol/L 5
- Calculating free testosterone is essential when SHBG is abnormal 1
Treatment Approaches
- For idiopathic infertility with high SHBG, selective estrogen receptor modulators (SERMs) may be considered to increase endogenous testosterone production, though benefits are modest 2
- Addressing underlying conditions that elevate SHBG (thyroid disorders, liver disease) is essential 1
- For men with hypogonadotropic hypogonadism and elevated SHBG, human chorionic gonadotropin (hCG) therapy may increase testosterone production without further elevating SHBG 6
Conclusion
High SHBG levels contribute to male infertility through multiple mechanisms, primarily by reducing bioavailable testosterone. Proper diagnosis requires measuring both total testosterone and SHBG levels to accurately assess the hormonal environment. Treatment should focus on addressing underlying causes of elevated SHBG and optimizing the hormonal milieu to support spermatogenesis.