Sex Hormone-Binding Globulin (SHBG)
What Is SHBG?
Sex hormone-binding globulin (SHBG) is a liver-synthesized plasma glycoprotein that binds testosterone, dihydrotestosterone, and estradiol with high affinity, thereby regulating the concentration of free (biologically active) sex hormones in circulation. 1 SHBG acts as the primary carrier protein for these steroids, with approximately 44–65% of circulating testosterone bound to SHBG, 33–50% loosely bound to albumin, and only 1–3% existing as free testosterone available for tissue uptake 1.
How SHBG Regulates Free Testosterone and Estradiol
SHBG binds testosterone and estradiol with high affinity, reducing the fraction of hormone that is free and biologically active. When SHBG levels rise, a greater proportion of total testosterone becomes protein-bound, lowering free and bioavailable testosterone 2, 1.
The pituitary gland senses free testosterone rather than total testosterone when regulating the hypothalamic-pituitary-gonadal axis. Reduced free testosterone due to elevated SHBG triggers compensatory increases in LH and FSH secretion to stimulate more endogenous testosterone production 2.
SHBG also binds to specific membrane receptors (SHBG-R) on target cells, modulating sex-steroid signaling through an allosteric mechanism. When unliganded SHBG binds its receptor and a biologically active steroid is introduced, adenylate cyclase is activated and intracellular cAMP increases, representing an additional mode of steroid hormone action 3.
The testosterone-to-SHBG ratio (free androgen index) serves as a practical surrogate for free testosterone, helping to discriminate true androgen deficiency from normal physiology 1, 4. A free androgen index < 0.3 indicates hypogonadism even when total testosterone appears normal 2.
Factors That Increase SHBG Levels
Aging is associated with a gradual physiologic rise in SHBG concentrations 2.
Hyperthyroidism markedly elevates SHBG through increased hepatic synthesis 2, 1.
Chronic liver disease (especially cirrhosis) raises SHBG due to altered hepatic protein production 2, 1.
Medications that increase SHBG include anticonvulsants (phenytoin, carbamazepine), systemic estrogens (including oral contraceptives), and excessive thyroid hormone replacement 2, 1.
HIV/AIDS infection is associated with higher SHBG levels 2.
Current smoking raises SHBG concentrations 2.
Factors That Decrease SHBG Levels
Obesity and insulin resistance are the most common causes of low SHBG, with visceral adiposity particularly suppressing hepatic SHBG synthesis 5. Hyperinsulinemia directly inhibits SHBG production 5.
Hypothyroidism reduces SHBG levels 1.
Excess androgen states (including polycystic ovary syndrome, exogenous testosterone, and anabolic steroid use) suppress SHBG 1, 4.
Hyperprolactinemia lowers SHBG concentrations 1.
Medications that decrease SHBG include glucocorticoids, growth hormone, and androgens 2.
Acromegaly and Cushing's disease are associated with reduced SHBG 2.
Clinical Uses of SHBG Measurement
Diagnosis of Functional Hypogonadism
SHBG measurement is essential when total testosterone is borderline (231–346 ng/dL) or in obese men, because low SHBG can artificially lower total testosterone while free testosterone remains normal, whereas high SHBG can mask true androgen deficiency. 6, 2 In men with elevated SHBG (e.g., 74 nmol/L), total testosterone may appear normal or even elevated, concealing underlying functional hypogonadism 2.
Free testosterone should be measured by equilibrium dialysis (gold standard) or calculated using the free androgen index (total testosterone ÷ SHBG × 100). A free androgen index < 30 indicates true hypogonadism even when total testosterone is borderline-normal 6, 2.
Morning total testosterone (8–10 AM) plus SHBG should be obtained in all men with organic erectile dysfunction, especially those who have failed PDE5 inhibitor therapy, as approximately 36% of men seeking consultation for sexual dysfunction have hypogonadism 6, 2.
Assessment of Androgen Excess in Women
SHBG measurement helps identify women with hirsutism who are more likely to respond to estrogen therapy. Low SHBG in polycystic ovary syndrome contributes to increased free testosterone and worsening hyperandrogenic symptoms 2, 1.
The testosterone-to-SHBG ratio correlates well with both measured and calculated free testosterone values, discriminating subjects with excessive androgen activity from normal individuals 1.
Biomarker for Metabolic and Cardiovascular Disease
Low SHBG is a component of the metabolic syndrome, positively correlating with HDL cholesterol and insulin sensitivity, and negatively correlating with triglycerides and insulin concentrations 5, 4.
SHBG levels predict the risk for type 2 diabetes and cardiovascular disease, though whether SHBG is simply a biomarker or a causal participant remains under investigation 4.
Osteoporosis Risk Assessment
- High SHBG levels predict the occurrence of osteoporotic fractures of the vertebrae and proximal femur. An inverse correlation exists between serum SHBG and bone mineral density in both sexes 7. Serum SHBG determination may constitute a useful marker for predicting osteoporosis severity 7.
Common Clinical Pitfalls
Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG. Always measure free testosterone or calculate the free androgen index when SHBG abnormalities are suspected 6, 2.
Not considering the impact of medications and medical conditions on SHBG levels can lead to incorrect interpretation of testosterone test results. Screen for hyperthyroidism, liver disease, obesity, insulin resistance, and medication effects before diagnosing hypogonadism 6, 2.
In obese individuals, SHBG is typically reduced; therefore, an elevated SHBG in this context suggests an alternative underlying cause such as thyroid disease or medication effect 2.