Sex hormone-binding globulin (SHBG) is a glycoprotein produced primarily in the liver that plays a critical role in the transport and regulation of sex hormones in the bloodstream. It binds to androgens, such as testosterone, and estrogens, including estradiol, controlling their bioavailability and activity at target tissues. Understanding the normal levels of SHBG is essential for evaluating hormonal balance, diagnosing endocrine disorders, and guiding treatment strategies. Deviations from normal SHBG concentrations can indicate underlying conditions such as polycystic ovary syndrome (PCOS), thyroid dysfunction, liver disease, or metabolic syndrome. Knowledge of normal SHBG values also aids clinicians in interpreting total versus free hormone levels, which is vital for accurate assessment of reproductive health and systemic hormonal regulation.
Structure and Function of SHBG
Sex hormone-binding globulin is a homodimeric protein that circulates in plasma and binds tightly to sex steroids. By binding to these hormones, SHBG regulates their access to tissues, protecting them from metabolism and modulating their physiological effects. Approximately 30-45% of circulating testosterone in men and 90-95% of circulating estradiol in women are bound to SHBG. The bound fraction is biologically inactive, while the unbound or free hormone fraction exerts effects on target tissues. Consequently, SHBG levels directly influence hormone activity, and abnormal levels can lead to clinical manifestations related to androgen or estrogen excess or deficiency.
Normal Reference Ranges of SHBG
SHBG concentrations vary by age, sex, and physiological conditions. Typical reference ranges for adults are as follows
- Adult men10-57 nmol/L
- Adult women18-144 nmol/L
These ranges can differ slightly depending on the laboratory, assay method, and population studied. Factors such as pregnancy, oral contraceptive use, and hormonal replacement therapy can increase SHBG levels, while obesity, insulin resistance, and androgen excess can decrease them. Accurate interpretation requires consideration of these variables to avoid misdiagnosis and inappropriate interventions.
Age and Sex Variations
- In prepubertal children, SHBG levels are generally higher relative to total sex hormones due to low steroid production.
- During puberty, SHBG concentrations decrease in boys as testosterone levels rise, whereas girls may maintain higher levels due to estrogen effects.
- In older adults, SHBG levels often increase, contributing to changes in free hormone availability and potential clinical implications such as reduced libido or altered bone metabolism.
Factors Influencing SHBG Levels
SHBG concentrations are influenced by multiple physiological, pathological, and lifestyle factors, making it an important marker for overall endocrine health.
Physiological Influences
- Sex hormonesEstrogen increases SHBG production, while androgens decrease it.
- PregnancyElevated estrogen levels during pregnancy lead to increased SHBG.
- AgeAging may result in higher SHBG, affecting free testosterone in men.
Pathological Conditions
- Liver diseaseAs SHBG is produced in the liver, hepatic dysfunction can alter levels.
- Thyroid disordersHyperthyroidism increases SHBG, whereas hypothyroidism reduces it.
- Insulin resistance and metabolic syndromeLower SHBG levels are associated with these conditions and are often linked to obesity and type 2 diabetes.
Medications and Lifestyle Factors
- Oral contraceptives and estrogen therapy elevate SHBG.
- Androgenic steroids and high testosterone therapy decrease SHBG.
- Weight loss and exercise may modestly increase SHBG by improving insulin sensitivity.
Clinical Significance of Normal SHBG
Maintaining SHBG within normal ranges is essential for hormonal balance, reproductive health, and metabolic regulation. Clinicians use SHBG measurements alongside total hormone levels to calculate free hormone concentrations, which provide a more accurate picture of hormone bioactivity. For example, in men with symptoms of hypogonadism, normal total testosterone with low SHBG can indicate elevated free testosterone, whereas low SHBG may mask androgen deficiency.
Use in Reproductive Health Assessment
- In women, SHBG helps assess conditions like PCOS, where decreased SHBG contributes to hyperandrogenism and menstrual irregularities.
- High SHBG may be seen in women on estrogen therapy or during pregnancy, requiring adjustment when evaluating free estradiol.
Role in Metabolic and Cardiovascular Health
- Low SHBG levels are linked to insulin resistance, type 2 diabetes, and metabolic syndrome.
- SHBG may serve as an early marker for cardiovascular risk, as low levels correlate with obesity and adverse lipid profiles.
Laboratory Measurement of SHBG
SHBG can be measured using immunoassays, including radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). Blood samples are typically collected in the fasting state to minimize variability, and results are reported in nmol/L. Interpretation requires comparison with age- and sex-specific reference ranges and consideration of factors that may alter SHBG levels. Clinicians may also calculate free androgen index (FAI) or free estradiol using SHBG values and total hormone levels to assess bioavailable hormone fractions.
Implications of Abnormal SHBG Levels
Low SHBG
- Associated with obesity, insulin resistance, PCOS, and type 2 diabetes.
- Leads to increased free testosterone, which may cause hirsutism, acne, and menstrual irregularities in women.
- May contribute to cardiovascular risk and metabolic disturbances.
High SHBG
- Occurs in hyperthyroidism, liver disease, and estrogen therapy.
- Leads to reduced free androgen levels, potentially causing fatigue, decreased libido, and bone density changes.
- May mask androgen deficiency in men, necessitating careful interpretation of total versus free hormone levels.
Normal sex hormone-binding globulin levels play a crucial role in maintaining hormonal balance, regulating sex hormone bioavailability, and influencing reproductive and metabolic health. Typical ranges differ by sex and age, with men generally having lower levels than women. Understanding the physiological, pathological, and lifestyle factors that affect SHBG is essential for accurate interpretation of hormone tests, diagnosis of endocrine disorders, and monitoring of therapeutic interventions. By maintaining SHBG within normal limits, clinicians can better assess free hormone fractions, evaluate conditions such as hypogonadism, PCOS, and metabolic syndrome, and provide targeted treatments to optimize patient health. Awareness of SHBG’s impact on hormone dynamics allows for comprehensive evaluation of endocrine function, ensuring precise clinical decisions and improved long-term outcomes in both men and women.