Sex Hormone-Binding Globulin and Testosterone Regulation

Introduction to SHBG

• Sex hormone-binding globulin (SHBG) is a glycoprotein that binds to sex hormones, regulating their bioavailability in circulation and serving as an important biomarker in various clinical disorders, according to the American Association for the Study of Liver Diseases 1
• SHBG levels can be influenced by various factors, including thyroid function, liver disease, and certain medications, as stated by the European Association of Urology and the American Association for the Study of Liver Diseases 2, 1

Regulation of SHBG

• The liver is the primary site of SHBG synthesis, and levels increase in chronic liver disease, according to the American Association for the Study of Liver Diseases 1
• Hormonal imbalances, such as those associated with liver disease, can affect SHBG levels, and evaluation of liver function is necessary in patients with suspected liver disease, as recommended by the European Society for Medical Oncology and the American Association for the Study of Liver Diseases 3, 1
• Oral estrogens, including oral contraceptives, increase SHBG levels, as noted by the American Academy of Family Physicians 4
• Certain medications, such as estrogens, anticonvulsants, and thyroid hormone replacement, can increase SHBG levels, as stated by the European Association of Urology 2

Clinical Significance of SHBG

• Measuring SHBG is crucial in assessing biochemical hyperandrogenism in individuals with polycystic ovary syndrome (PCOS), as recommended by the Endocrine Society 5
• SHBG measurement also helps in interpreting testosterone measurements in men with advanced liver disease, as noted by the American Association for the Study of Liver Diseases 1
• SHBG levels are an essential component of assessing and managing PCOS, according to the Obesity Society 6

Diagnosis of Testosterone Deficiency

• Baseline luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels should be assessed to differentiate between primary ovarian failure and hypothalamic dysfunction, with elevated FSH/LH levels indicating ovarian failure in patients with premature ovarian failure (POF), as recommended by 7
• The American Urological Association recommends measuring morning total testosterone levels on at least two separate occasions, where both levels are <300 ng/dL, to indicate testosterone deficiency, with essential laboratory tests including:

8, 9, 10

• Measuring sex hormone-binding globulin (SHBG) levels is essential, as high SHBG is the most common cause of normal total testosterone with low free testosterone, according to the American Diabetes Association 11

Treatment of Testosterone Deficiency

• Testosterone replacement therapy should be considered in men with morning serum total testosterone levels less than 300 ng/dL on at least two separate measurements, symptoms of hypogonadism, and no contraindications, with target testosterone levels in the mid-normal range of 350-600 ng/dL, as recommended by the National Comprehensive Cancer Network and the American Urological Association 12, 13, 14
• Known or suspected prostate or breast cancer is a contraindication for testosterone replacement therapy, as is desire for fertility, as testosterone suppresses spermatogenesis, according to the European Association of Urology 2
• Primary hypogonadism is typically treated with testosterone therapy only, which compromises fertility, whereas secondary hypogonadism has the potential for both fertility and normal testosterone with appropriate treatment, such as gonadotropin therapy 2

Lifestyle Modifications

• Lifestyle modifications such as increased physical activity, smoking cessation, weight loss if obese, and reduction of alcohol consumption are recommended to improve libido, as suggested by the National Comprehensive Cancer Network 15
• Regular physical exercise and a Mediterranean diet may improve sexual function and cardiovascular health, according to the American Heart Association and the European Society of Cardiology 14, 13
• Weight optimization through weight loss can improve testosterone bioavailability in obese patients, as recommended by the American Gastroenterological Association 16
• A logical therapeutic approach should include optimization of lifestyle factors (weight loss, regular physical activity), treatment of identified comorbidities (diabetes, hypertension, dyslipidemia), correction of hormonal imbalances, and specific treatment of erectile dysfunction, as recommended by The Journal of Urology 17
• Erectile dysfunction is a significant risk marker for underlying cardiovascular disease, and cardiac risk stratification using established algorithms should be considered, as recommended by the American Urological Association 8, 10