Very High SHBG: Genetic Factors and Management
Can Very High SHBG Be Genetic?
While SHBG levels are influenced by genetic factors, very high SHBG is typically caused by acquired conditions rather than primary genetic disorders. The most common causes of elevated SHBG include hyperthyroidism, hepatic disease, aging, certain medications (anticonvulsants, estrogens, thyroid hormone), smoking, and HIV/AIDS 1. SHBG is primarily synthesized in the liver, and its production is regulated by hormonal and metabolic signals rather than being a primary genetic condition 2, 3.
How to Lower High SHBG
Identify and Address Underlying Causes
The most effective approach to lowering SHBG is identifying and treating the underlying condition causing the elevation 1. Work through this systematic evaluation:
Check for Thyroid Dysfunction
- Measure thyroid-stimulating hormone (TSH) and free T4 to rule out hyperthyroidism, which is a major cause of elevated SHBG 1
- Hyperthyroidism stimulates SHBG secretion by increasing its mRNA concentrations in the liver 4
- Treating hyperthyroidism will normalize SHBG levels 3
Review Medications
- Discontinue or substitute medications that increase SHBG if medically appropriate 1:
- Anticonvulsants
- Estrogens (including oral contraceptives)
- Thyroid hormone supplementation (if excessive)
- These medications directly stimulate hepatic SHBG production 4
Evaluate for Liver Disease
- Assess liver function tests as hepatic disease can elevate SHBG 1
- Hepatic cirrhosis in men is associated with high SHBG concentrations 3
Screen for HIV/AIDS
- Consider HIV testing in appropriate clinical contexts, as HIV/AIDS is associated with elevated SHBG 1
Lifestyle Modifications to Lower SHBG
Weight gain and dietary changes can effectively reduce SHBG levels through their effects on insulin:
Optimize Body Weight and Insulin Sensitivity
- SHBG levels correlate negatively with body mass index and fasting insulin levels 4
- Insulin and insulin-like growth factor-1 have inhibitory effects on SHBG secretion by liver cells 5, 4
- In obese men, a low-fat diet (<10% calories) plus daily exercise decreased insulin from 222 to 126 pmol/L and increased SHBG from 18 to 25 nmol/L over three weeks 6
However, for patients with very high SHBG, the opposite approach may be needed:
- Increasing caloric intake and reducing excessive exercise can lower SHBG by increasing insulin levels 5
- This is particularly relevant in conditions like functional hypothalamic amenorrhea where high SHBG is associated with low body weight 7
Dietary Factors
- Higher fat intake and adequate caloric consumption can increase insulin levels, which inhibits SHBG production 5, 4
- Dietary factors are known regulators of plasma SHBG concentrations 3
Pharmacological Approaches
Medications that decrease SHBG include 1:
- Growth hormone
- Glucocorticoids
- Testosterone or anabolic androgenic steroids
Important caveat: These medications should only be used when clinically indicated for other conditions, not solely to lower SHBG, as they carry significant side effects and risks.
Clinical Monitoring
Measure both total and free testosterone when evaluating the clinical significance of high SHBG 7:
- High SHBG binds more testosterone, reducing free and bioavailable fractions 7
- The pituitary primarily senses free testosterone levels, not total testosterone 7
- A free testosterone index (total testosterone/SHBG ratio) <0.3 indicates hypogonadism 7
Key Clinical Pitfalls to Avoid
- Do not rely solely on total testosterone measurements when SHBG is elevated, as this can miss functional hypogonadism 7
- Always consider medication effects on SHBG levels before attributing elevation to disease 1, 7
- Recognize that SHBG serves as a marker of metabolic and endocrine health rather than being a primary target of therapy 2, 4