SHBG produced by the liver reduces free testosterone and estradiol by binding them.

Sex hormone-binding globulin (SHBG) is a specialized glycoprotein that serves as a primary regulator of sex steroid bioavailability. Its production and binding capacity are central to maintaining hormonal balance, particularly in the postmenopausal period.

Hepatic production and regulation

SHBG is primarily synthesized and secreted by hepatocytes in the liver. This process is highly sensitive to metabolic and hormonal signals.

• Transcriptional Control: The master regulator of SHBG synthesis is Hepatocyte Nuclear Factor 4α (HNF4α). Research indicates that metabolic disturbances, such as hyperglycemia and hepatic steatosis (fatty liver), suppress HNF4α, leading to a significant reduction in SHBG production.
• Metabolic Inhibitors: Insulin and high-fat diets act as negative regulators. In patients with hyperinsulinemia or metabolic syndrome, hepatic SHBG synthesis is often suppressed, serving as a clinical marker for insulin resistance.
• Hormonal Stimulators: Conversely, thyroid hormones (T4) and oral estrogens stimulate hepatic synthesis, increasing circulating SHBG levels.

Impact on hormonal bioavailability

SHBG modulates the biological activity of testosterone and estradiol by sequestering them within the bloodstream.

• High-Affinity Binding: SHBG contains a single binding site with a high affinity for C19 androgens (like testosterone) and a lower affinity for estrogens (estradiol). While most circulating hormones are bound to SHBG or albumin, only the "free" fraction is typically considered bioavailable to enter cells and trigger receptors.
• The "Free Hormone" Hypothesis: Higher SHBG levels reduce the fraction of free (bioactive) testosterone and estradiol. In postmenopausal women, higher SHBG concentrations are consistently associated with lower calculated free androgen and estrogen indices.
• Physiological Consequences: Because SHBG reduces the amount of estradiol available to tissues, elevated levels in older women are clinically linked to an increased risk of hip fractures and lower bone mineral density (BMD). For example, studies have shown that women in the highest quartile of SHBG concentration have a significantly higher risk of vertebral and hip fractures compared to those in the lowest quartile.

Clinical implications for postmenopausal health

In a 73-year-old female, SHBG levels provide a critical window into both metabolic and skeletal health.

• Metabolic Signaling: Low SHBG in this demographic is often an early indicator of non-alcoholic fatty liver disease (NAFLD) and cardiovascular risk, reflecting the protein's role as a hepatic integrator of metabolic health.
• Skeletal Health: Conversely, high SHBG levels—while metabolically "favorable"—may necessitate closer monitoring of bone density, as the resulting lower bioavailable estradiol can accelerate bone loss.

Bottom line

The claim is strongly supported: SHBG is produced by the liver, and higher levels directly reduce the bioavailable (free) fractions of testosterone and estradiol by sequestering them in circulation. This mechanism is a key driver of hormonal activity and has significant implications for bone and metabolic health in postmenopausal women.