What Does SHBG Do?
Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that binds testosterone, dihydrotestosterone, and estradiol with high affinity, thereby regulating the concentration of free (biologically active) sex steroids available to tissues. 1
Primary Transport Function
- SHBG binds sex steroids in circulation with high affinity, reducing the fraction of hormone that is free and bioavailable for cellular uptake 2, 3
- Approximately 60-70% of circulating testosterone is bound to SHBG, with a smaller fraction bound to albumin and only 1-3% remaining as free testosterone 2
- Free testosterone represents the biologically active form that can enter cells and bind to intracellular androgen receptors 2
Regulation of Hormone Bioavailability
- When SHBG levels increase, a greater proportion of total testosterone becomes bound, which decreases the free and bioavailable testosterone fractions available for tissue effects 1
- The pituitary gland primarily senses free testosterone levels rather than total testosterone when regulating the hypothalamic-pituitary-gonadal axis 1
- Reduced free testosterone due to elevated SHBG can trigger compensatory increases in gonadotropin (FSH and LH) secretion to stimulate more testosterone production 1
Novel Membrane Receptor-Mediated Actions
Beyond simple transport, SHBG has direct signaling functions:
- SHBG binds to specific membrane receptors (R-SHBG) on target cells, where it can activate adenylyl cyclase and increase intracellular cAMP within minutes of steroid exposure 3, 4
- This membrane-mediated signaling represents an additional mode of steroid hormone action that does not require the steroid to enter the cell or interact with classic intracellular steroid receptors 3
- The steroid-binding and membrane-binding functions are intertwined in an allosteric relationship: occupation of SHBG's steroid-binding site inhibits its ability to bind membrane receptors 3
Tissue-Specific Accumulation
- SHBG accumulates in extravascular compartments of certain tissues and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action 5
- In humans, the SHBG gene is expressed primarily in the liver but also at low levels in other tissues including germ cells, where it produces an isoform that accumulates in the acrosome 5
Clinical Significance as a Biomarker
SHBG levels reflect multiple physiological states:
- SHBG is regulated by sex steroids, thyroid hormones, insulin, and other metabolic factors 6
- Obesity and insulin resistance powerfully suppress SHBG synthesis: insulin directly inhibits hepatic SHBG production, making low SHBG a component of metabolic syndrome 7, 8
- SHBG is positively correlated with HDL cholesterol and negatively correlated with triglycerides and insulin concentrations 8
- Conditions that increase SHBG include aging, hyperthyroidism, hepatic disease, certain medications (anticonvulsants, estrogens, thyroid hormone), and HIV/AIDS 1
- Conditions that decrease SHBG include obesity, insulin resistance, hypothyroidism, glucocorticoids, testosterone, and anabolic steroids 1, 7
Critical Clinical Pitfall
- Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG, where total testosterone appears normal but free testosterone is low 1
- Both total testosterone and either free testosterone (by equilibrium dialysis) or calculated free testosterone (using the Vermeulen equation from TT and SHBG) should be measured when evaluating androgen status, especially when SHBG abnormalities are suspected 2, 1
- A free androgen index (total testosterone ÷ SHBG) less than 0.3 indicates hypogonadism even when total testosterone is within normal limits 1