Low SHBG and Low Testosterone: Metabolic Risks for Health

Sex hormone-binding globulin (SHBG) and testosterone play crucial roles in metabolic health. When both are low, it can signal underlying issues beyond reproductive function, affecting energy levels, body composition, and disease risk.

Role Of SHBG In Hormone Balance

Sex hormone-binding globulin (SHBG), a glycoprotein produced by the liver, regulates the bioavailability of sex hormones, particularly testosterone and estradiol. By binding to these hormones in circulation, SHBG controls the proportion of free, biologically active testosterone that interacts with androgen receptors in tissues. Only unbound testosterone, or free testosterone, exerts direct physiological effects on metabolism, muscle maintenance, and fat distribution. Fluctuations in SHBG levels influence the balance between bound and free testosterone, affecting hormonal activity and overall health.

SHBG has a higher affinity for testosterone than estradiol, meaning small changes in SHBG concentration can significantly impact androgen availability. In men, lower SHBG levels often translate to increased free testosterone, but this does not always mean improved hormonal function. Low SHBG is frequently linked to metabolic disturbances such as insulin resistance, obesity, and type 2 diabetes, indicating its active role in endocrine regulation.

Beyond hormone transport, SHBG interacts with cellular receptors, including the SHBG receptor found in various tissues. Research suggests SHBG may have direct signaling functions, influencing androgen receptor sensitivity. Even with adequate testosterone levels, low SHBG may reduce the hormone’s effectiveness, highlighting the complexity of hormone balance where both absolute levels and binding dynamics determine physiological outcomes.

Metabolic Correlation With Low SHBG And Low Testosterone

Low SHBG and testosterone levels are linked to metabolic dysfunction, often serving as indicators of disturbances in glucose regulation, lipid metabolism, and body composition. Research shows that reduced SHBG is associated with insulin resistance, where cells fail to respond effectively to insulin, leading to compensatory hyperinsulinemia. Elevated insulin levels suppress hepatic SHBG production, reducing its concentration and increasing free testosterone. However, low SHBG is often accompanied by a decline in total testosterone, exacerbating metabolic dysregulation.

Testosterone plays a role in maintaining insulin sensitivity and muscle-to-fat ratio, both critical for metabolic health. A study in Diabetes Care found that men with lower testosterone levels had a significantly higher risk of developing type 2 diabetes, independent of other risk factors. This relationship is partly mediated by testosterone’s effects on skeletal muscle, where it promotes glucose uptake and mitochondrial function. When testosterone levels drop, muscle mass declines, reducing insulin sensitivity and increasing visceral fat accumulation—a hallmark of metabolic syndrome associated with hypertension, dyslipidemia, and hyperglycemia.

The interplay between SHBG and testosterone also affects lipid homeostasis. Low SHBG is linked to unfavorable lipid profiles, including elevated triglycerides and reduced high-density lipoprotein (HDL) cholesterol. A study in The Journal of Clinical Endocrinology & Metabolism found that men with low SHBG and testosterone had a higher prevalence of atherogenic dyslipidemia, contributing to arterial plaque formation and increased risk of coronary artery disease. One proposed mechanism involves androgens’ regulatory influence on hepatic lipid metabolism. Testosterone modulates key enzymes involved in lipid synthesis and breakdown, and when levels decline, fat storage increases while lipid clearance diminishes.

Factors That Influence SHBG Concentration

SHBG levels are shaped by genetic, hormonal, and environmental factors that influence its production and clearance. The liver synthesizes SHBG, regulated by endocrine signals, particularly insulin, thyroid hormones, and estrogens. Insulin suppresses SHBG production at the transcriptional level, explaining why individuals with insulin resistance or type 2 diabetes often have lower SHBG. In contrast, estrogens stimulate SHBG synthesis, which is why women generally have higher levels than men.

Genetic variation also affects baseline SHBG levels. Genome-wide association studies (GWAS) have identified polymorphisms in the SHBG gene that influence circulating concentrations by altering liver expression. While genetics set an individual’s baseline, external factors modulate SHBG dynamically. Thyroid function plays a significant role—hyperthyroidism elevates SHBG, while hypothyroidism suppresses it, mediated by thyroid hormones’ effects on hepatic SHBG gene expression.

Diet and body composition also impact SHBG levels. Diets high in refined carbohydrates and saturated fats are associated with lower SHBG, likely due to their effects on insulin sensitivity and liver metabolism. In contrast, higher fiber intake and diets rich in unsaturated fats, such as the Mediterranean diet, are linked to increased SHBG. Visceral adiposity is inversely correlated with SHBG levels, as adipose tissue releases inflammatory cytokines that contribute to insulin resistance, further suppressing SHBG.

Laboratory Analysis

Assessing low SHBG and testosterone levels requires precise laboratory testing to evaluate hormone availability and metabolic implications. Blood tests measuring total testosterone, free testosterone, and SHBG are primary diagnostic tools, sometimes supplemented by albumin levels to calculate bioavailable testosterone. Since SHBG binds a significant portion of circulating testosterone, its concentration influences total testosterone results. A low SHBG level can artificially elevate free testosterone readings, potentially masking androgen deficiency if only free testosterone is considered. Evaluating both SHBG and total testosterone provides a clearer picture of hormonal status.

Testosterone follows a diurnal rhythm, peaking in the early morning, which is why samples are typically collected between 7:00 and 10:00 AM. SHBG levels are more stable but can fluctuate due to nutritional status, liver function, and metabolic conditions. Laboratories use different assay techniques, such as radioimmunoassay or liquid chromatography–mass spectrometry (LC-MS), with LC-MS considered the gold standard for testosterone measurement due to its high specificity and sensitivity. Clinicians must account for individual variability, as reference ranges differ based on age, sex, and health status.

Combined Effects On Overall Health

Low SHBG and testosterone together create a hormonal environment that impacts multiple physiological systems, increasing the risk of cardiovascular disease, musculoskeletal decline, and cognitive impairment. Their combined deficiency is not just correlative but mechanistic, as both interact with pathways governing inflammation, endothelial function, and neuromuscular maintenance. These effects contribute to a gradual decline in overall health, particularly in aging populations where SHBG and testosterone naturally decrease over time.

Cardiovascular implications are particularly significant. Low SHBG and testosterone have been linked to increased atherosclerosis and arterial stiffness. Epidemiological studies, including data from the European Male Aging Study, show that men with lower testosterone and SHBG levels face a higher risk of myocardial infarction and stroke. Testosterone plays a role in modulating nitric oxide production, essential for vascular dilation and endothelial function. SHBG is inversely correlated with markers of systemic inflammation, such as C-reactive protein (CRP), suggesting its deficiency may contribute to a pro-inflammatory state. Over time, these effects create conditions conducive to cardiovascular disease progression.