What is the function and importance of Sex Hormone Binding Globulin (SHBG)?

Sex Hormone Binding Globulin (SHBG): Function and Clinical Importance

Sex hormone binding globulin (SHBG) is a critical glycoprotein produced primarily in the liver that regulates sex hormone bioavailability by binding to testosterone and estradiol, affecting their free concentrations and biological activity throughout the body. 1

Primary Functions of SHBG

SHBG serves several essential physiological functions:

• Transport of Sex Hormones: SHBG possesses high affinity binding for 17β-hydroxysteriod hormones, particularly testosterone and estradiol, serving as their primary transport protein in circulation 2

• Regulation of Free Hormone Levels: By binding approximately 44% of circulating testosterone and 20% of estradiol, SHBG controls the amount of biologically active (free) hormone available to target tissues 1

• Modulation of Hormone Action: Beyond simple transport, SHBG can bind to specific membrane receptors and participate in cellular signaling pathways, challenging the classic "free hormone hypothesis" 3

Regulation of SHBG Production

SHBG levels are influenced by multiple factors:

• Hormonal Regulation:

  • Estrogens increase SHBG synthesis
  • Androgens decrease SHBG levels
  • Thyroid hormones stimulate SHBG production
  • Insulin suppresses SHBG production 1, 2

• Metabolic Factors:

  • Obesity and insulin resistance decrease SHBG levels
  • Liver disease affects SHBG production 2

• Genetic Factors: Polymorphisms in the SHBG gene influence baseline levels and activity 4

Clinical Significance of SHBG

1. Diagnostic Value

SHBG measurements provide valuable clinical information in several conditions:

• Androgen Disorders: Essential for evaluating hirsutism, virilization, and hypogonadism 2

• Metabolic Conditions: Low SHBG serves as a marker for insulin resistance, metabolic syndrome, and type 2 diabetes risk 1

• Liver Disease: In chronic liver disease, SHBG levels initially rise but ultimately decline with progression to decompensated cirrhosis 2

• Polycystic Ovary Syndrome (PCOS): Typically shows decreased SHBG levels due to hyperandrogenism and insulin resistance 2

2. Interpretation of Hormone Levels

• Free vs. Total Hormone Assessment: When evaluating testosterone levels, particularly in men with symptoms of hypogonadism, measuring SHBG is crucial for accurate interpretation 2

• Free Testosterone Index: The ratio of total testosterone to SHBG provides a useful indicator of gonadal function, with a ratio ≥0.3 suggesting normal function and <0.3 indicating potential hypogonadism 1

• Misleading Total Hormone Levels: In conditions with elevated SHBG (like liver disease), total testosterone may appear normal or high while free testosterone is actually low 2

3. SHBG in Specific Conditions

Liver Disease

In advanced liver disease, SHBG synthesis is initially stimulated by elevated estrogen levels, contributing to the decline in free testosterone. However, as cirrhosis progresses from compensated to decompensated, SHBG levels ultimately fall 2

Metabolic Syndrome and Diabetes

Low SHBG levels are associated with insulin resistance and predict development of type 2 diabetes, making SHBG a potential biomarker for metabolic health 1

Hormone Replacement Therapy

SHBG levels are affected by different hormone formulations and administration routes. Oral estrogens significantly increase SHBG levels compared to transdermal routes, which has implications for thrombotic risk 2

Clinical Applications

• Hypogonadism Assessment: In men with symptoms of hypogonadism, measuring morning total testosterone and SHBG levels helps determine if low testosterone is due to true hypogonadism or secondary to other factors 2

• PCOS Evaluation: SHBG measurement aids in the diagnosis and management of PCOS, where low levels contribute to hyperandrogenism 2

• Metabolic Risk Assessment: SHBG can serve as a biomarker for metabolic syndrome, insulin resistance, and cardiovascular risk 1

• Monitoring Hormone Therapy: SHBG levels should be considered when monitoring hormone replacement therapy, as changes in SHBG affect interpretation of total hormone levels 1, 5

Common Pitfalls in SHBG Interpretation

• Relying solely on total testosterone: Without measuring SHBG, clinically significant hormone deficiencies may be missed when SHBG is elevated 1

• Ignoring SHBG in women with hirsutism: SHBG levels help identify women with hirsutism who are more likely to respond to estrogen therapy 6

• Failing to consider SHBG in liver disease: Sexual dysfunction in chronic liver disease is partly due to SHBG alterations affecting free hormone levels 2

SHBG remains an important but often underutilized marker in clinical medicine, serving both as a regulator of sex hormone action and as a valuable biomarker for various endocrine and metabolic disorders.