Causes of Elevated SHBG in Male Patients
Elevated sex hormone-binding globulin (SHBG) in male patients is primarily caused by medications (anticonvulsants, estrogens, thyroid hormone), hyperthyroidism, hepatic disease, aging, smoking, and HIV/AIDS. 1
Primary Etiologies
Medication-Induced Elevation
- Anticonvulsants are a major cause of elevated SHBG and should be reviewed in any patient with unexplained elevation 1
- Estrogen therapy or estrogen-containing compounds significantly increase SHBG levels 1
- Thyroid hormone replacement can raise SHBG, particularly when doses are supraphysiologic 1
Endocrine Disorders
- Hyperthyroidism is a critical cause to evaluate, as excess thyroid hormone directly stimulates hepatic SHBG production 1, 2
- Even subclinical hyperthyroidism can significantly affect SHBG levels and should not be overlooked 2
- Thyroid function tests (TSH, free T4) should be obtained in all patients with elevated SHBG 2
Hepatic Disease
- Liver disease impairs SHBG metabolism, leading to increased circulating levels 1, 2
- SHBG rises in early stages of liver disease but may paradoxically decline with progression to decompensated cirrhosis 2
- Liver function tests should be evaluated even in asymptomatic patients 2
- Hepatic cirrhosis in men is associated with high SHBG values 3
Age-Related Changes
- Aging is associated with naturally increasing SHBG levels in men 1, 2
- This physiological increase occurs independent of other pathology 1
Lifestyle and Infectious Factors
- Smoking is linked to higher SHBG concentrations 1, 2
- HIV/AIDS infection leads to elevated SHBG levels 1, 2
Clinical Significance and Pitfalls
Impact on Testosterone Assessment
- Elevated SHBG can lead to reduced free testosterone levels even when total testosterone appears normal 2, 4
- Focusing only on total testosterone is misleading; free or calculated free testosterone provides better insight into true androgen status 4, 5
- Elevated SHBG can contribute to symptoms of hypogonadism despite normal total testosterone 2, 4
Diagnostic Approach
- Measure morning total testosterone along with either free testosterone or calculate free testosterone index (total testosterone/SHBG ratio) 5
- A ratio of total testosterone/SHBG <0.3 indicates hypogonadism 5
- Review all medications, including over-the-counter drugs, as potential contributors 2
Regulatory Mechanisms
Metabolic Regulation
- SHBG levels are regulated by androgen/estrogen balance, thyroid hormones, insulin, and dietary factors 3
- SHBG is synthesized in the liver, with plasma concentrations affected by multiple metabolic factors 3
- Some evidence suggests SHBG regulation relates more to general metabolic factors, nutritional status, and growth than solely to estrogen/androgen balance 6
Common Clinical Pitfalls to Avoid
- Do not overlook subclinical thyroid disease, as it significantly affects SHBG levels 2
- Do not rely solely on total testosterone when SHBG is elevated, as this masks true androgen deficiency 2, 4
- Do not miss early liver disease, which may be asymptomatic but still elevate SHBG 2
- Review medication lists thoroughly, including supplements and over-the-counter preparations 2