In an adult, is a sex hormone‑binding globulin (SHBG) level of 65.4 nmol/L considered elevated, and what are the possible causes?

SHBG of 65.4 nmol/L: Interpretation and Clinical Approach

An SHBG level of 65.4 nmol/L is elevated and warrants investigation for underlying causes, particularly hyperthyroidism, chronic liver disease, medication effects, or age-related physiological increase. 1, 2

Is This Level Elevated?

• Yes, 65.4 nmol/L exceeds the typical reference range observed in clinical populations of men presenting to men's health centers, where mean SHBG is approximately 32 nmol/L (range 6–109 nmol/L). 3
• In younger men (≤54 years), mean SHBG is 27.7 nmol/L, while in older men (≥55 years) it rises to 36.6 nmol/L, with only 9% of older men exceeding 60 nmol/L. 3
• This level falls in the upper 5–10% of the distribution, indicating a clinically significant elevation that requires evaluation. 3

Critical Diagnostic Implication

When SHBG is elevated to 65.4 nmol/L, total testosterone measurements become unreliable for assessing androgen status because increased SHBG binds more testosterone, reducing free (bioavailable) testosterone despite normal or even elevated total testosterone. 1, 2

• You must measure both total testosterone (drawn 8:00–10:00 AM) AND free testosterone by equilibrium dialysis to accurately diagnose functional hypogonadism. 1
• Calculate the free androgen index (total testosterone ÷ SHBG); a ratio <0.3 confirms hypogonadism even when total testosterone appears normal. 1, 2
• The pituitary gland senses free testosterone rather than total testosterone, so reduced free testosterone triggers compensatory increases in LH and FSH. 1

Primary Causes to Investigate

Endocrine Disorders

• Hyperthyroidism is the most important reversible cause: Thyroid hormones upregulate hepatic nuclear factor-4α, directly increasing hepatic SHBG synthesis. 2, 4
  • Order TSH and free T4 immediately; SHBG normalizes after treating thyroid overactivity. 1, 2
  • SHBG remains normal in thyroid hormone resistance syndromes, helping differentiate these conditions from true thyrotoxicosis. 4

Hepatic Disease

• Chronic liver disease (cirrhosis, chronic hepatitis) elevates SHBG through impaired hepatic synthetic function and can simultaneously disrupt the hypothalamic-pituitary axis, altering FSH and LH secretion. 2
• Check liver function tests (AST, ALT, alkaline phosphatase, bilirubin, albumin) to screen for hepatic pathology. 1

Medication-Induced Elevation

• Oral estrogen therapy (including oral contraceptives in transgender patients) markedly raises SHBG while simultaneously reducing hepatic IGF-1 production. 2
• Thyroid hormone replacement at supraphysiologic doses increases SHBG. 2
• Anticonvulsants (phenytoin, carbamazepine) are recognized SHBG elevators. 1, 2
• Perform a comprehensive medication review to identify and discontinue or substitute offending agents when clinically feasible. 1

Physiological and Lifestyle Factors

• Advancing age is associated with progressive SHBG elevation; mean SHBG rises from 27.7 nmol/L in men ≤54 years to 36.6 nmol/L in men ≥55 years. 3
• Current cigarette smoking modestly increases SHBG concentrations. 2
• HIV/AIDS infection is linked to elevated SHBG; consider HIV testing in appropriate clinical contexts. 1, 2

Clinical Consequences of Elevated SHBG

Symptoms of Functional Hypogonadism

• Reduced libido, erectile dysfunction, decreased muscle mass, and fatigue can occur despite normal total testosterone when free testosterone is low. 1
• In men with erectile dysfunction unresponsive to phosphodiesterase-5 inhibitors, simultaneous testosterone and SHBG measurement is essential for accurate androgen assessment. 2

Cardiovascular and Metabolic Associations

• In contrast to low SHBG (which correlates with insulin resistance and cardiovascular risk), high SHBG in men is positively correlated with HDL cholesterol. 4
• Low SHBG—not high SHBG—is associated with increased risk for type 2 diabetes and overall mortality in postmenopausal women. 4

Gonadotropin Response

• In functional hypothalamic amenorrhea without polycystic ovarian morphology, higher SHBG levels correlate with higher FSH concentrations, reflecting the pituitary's response to reduced free estradiol. 1, 2

Management Algorithm

Step 1: Identify and Treat the Underlying Cause

• If hyperthyroidism is confirmed, initiate antithyroid drugs, radioactive iodine, or surgery before considering testosterone replacement. 1
• For hepatic disease, manage according to etiology (antiviral therapy for viral hepatitis, lifestyle modification for fatty liver). 1
• Discontinue or substitute SHBG-elevating medications when medically appropriate. 1
• In HIV-related cases, optimize antiretroviral therapy to control viral load. 1

Step 2: Assess Androgen Status

• Measure morning total testosterone (8:00–10:00 AM) using a validated assay. 1
• Quantify free testosterone by equilibrium dialysis (gold standard) or calculate the free androgen index. 1
• Measure LH and FSH to differentiate primary from secondary hypogonadism if free testosterone is low. 1

Step 3: Consider Testosterone Replacement Therapy

Indications for TRT:

• Documented low free testosterone (or free androgen index <0.3) plus persistent symptoms (reduced libido, erectile dysfunction, decreased muscle mass, fatigue). 1
• Failure to correct the underlying SHBG-elevating condition after appropriate targeted therapy. 1

Expected benefits:

• Improved sexual function and libido. 1
• Enhanced overall well-being and mood. 1
• Increased muscle mass and strength. 1
• Positive effect on bone mineral density. 1

Monitoring requirements:

• Baseline digital rectal exam and PSA before initiating therapy. 1
• PSA every 3–6 months during the first year, then annually. 1
• Periodic hematocrit/hemoglobin checks to monitor for polycythemia. 1
• Evaluate for urinary symptoms, sleep apnea exacerbation, and gynecomastia at each visit. 1
• Consider prostate biopsy if PSA rises >1.0 ng/mL within any calendar year. 1

Fertility warning:

• TRT suppresses the hypothalamic-pituitary-gonadal axis and impairs spermatogenesis; counsel patients of reproductive age before initiating therapy. 1

Common Pitfalls to Avoid

• Never rely solely on total testosterone when SHBG is elevated; you will miss functional hypogonadism caused by low free testosterone. 1, 2
• Always perform thyroid function testing in patients with unexplained SHBG elevation, as hyperthyroidism is a reversible cause. 2
• Do not overlook medication effects; oral estrogens, thyroid hormone, and anticonvulsants are common culprits. 1, 2
• In obese individuals, SHBG is typically reduced; an elevated SHBG in this context strongly suggests an alternative cause such as thyroid disease or medication effect. 1