In a child or adolescent with short stature and low sex‑hormone‑binding globulin (SHBG), what endocrine work‑up and management steps are recommended?

Low SHBG and Short Stature: Endocrine Work-Up and Management

In a child or adolescent with short stature and low SHBG, prioritize evaluation for insulin resistance, metabolic syndrome, and growth hormone deficiency, as low SHBG is a marker of hyperinsulinemia that can impair growth and is inversely associated with insulin levels. 1, 2

Initial Clinical Assessment

Document precise growth parameters:

• Measure current height and calculate height standard deviation score (SDS) to determine if height is below the 3rd percentile (SDS < -1.88) 3
• Calculate height velocity over the past 6-12 months to assess if it falls below the 25th percentile for age and sex 3, 4
• Determine mid-parental target height using parental heights to contextualize genetic potential 4, 5
• Assess pubertal development using Tanner staging, as this critically affects SHBG interpretation 4, 5, 6

Evaluate body composition and metabolic risk:

• Calculate BMI and assess for obesity, as body fat percentage correlates negatively with SHBG levels (R² = 0.18 in boys, R² = 0.23 in girls) 6
• Look for acanthosis nigricans, which suggests insulin resistance 3
• Document any features of metabolic syndrome 1, 2

Biochemical Work-Up

Core endocrine evaluation:

• Measure serum IGF-1 and compare to local Tanner stage-matched, sex-matched, and age-matched reference ranges 3, 4, 5
• Obtain TSH and free T4 to exclude hypothyroidism, which can falsely lower IGF-1 and impair growth 3, 4, 5
• Measure fasting insulin and glucose to assess for insulin resistance, as insulin is a potent inhibitor of SHBG production in the liver 1, 7, 2
• Calculate hemoglobin A1c to screen for diabetes mellitus type 2, as low SHBG is a useful marker for identifying presymptomatic individuals 2

Additional metabolic screening:

• Assess serum creatinine, electrolytes, bicarbonate, calcium, phosphorus, alkaline phosphatase, and albumin to exclude chronic kidney disease and metabolic bone disease 5
• If chronic kidney disease is suspected, measure parathyroid hormone and 25-OH vitamin D 5

Radiographic assessment:

• Obtain left wrist radiograph to determine bone age and assess remaining growth potential 3, 4, 5
• Delayed bone age (>2 years behind chronological age) suggests growth hormone deficiency, while normal bone age suggests familial short stature 8, 9

Interpretation of Low SHBG in Context

Understanding SHBG physiology in growth disorders:

• Low SHBG in the setting of short stature suggests insulin resistance or hyperinsulinemia, which can impair growth 1, 2
• Conversely, growth hormone deficiency is associated with high SHBG levels (mean 123 nmol/L in hypopituitary boys vs. 76 nmol/L in normal boys, P<0.001), and GH treatment normalizes SHBG by decreasing it 9
• This creates a diagnostic paradox: if SHBG is low with short stature, consider insulin resistance as the primary driver rather than isolated GH deficiency 7, 9

Critical distinction:

• If IGF-1 is severely low (e.g., <20 ng/mL when normal range is 67-405 ng/mL) with delayed bone age and proportionate short stature, growth hormone deficiency is likely despite low SHBG 8
• If IGF-1 is normal or mildly low with low SHBG and elevated insulin, insulin resistance is the primary problem 1, 2

Management Algorithm

When growth hormone deficiency is confirmed (severely low IGF-1, delayed bone age, proportionate short stature):

• Initiate recombinant human GH therapy at 0.045-0.05 mg/kg/day by daily subcutaneous injection 8
• Monitor for adequate response: height velocity should increase by >2 cm/year over baseline during the first year 3
• Expect SHBG to decrease during GH treatment (from mean 154 nmol/L to 106 nmol/L after 12 months), which is a normal response 9
• Continue treatment until height velocity drops below 2 cm/year or epiphyseal growth plates close on radiography 3

When insulin resistance is the primary driver (low SHBG, elevated insulin, normal/mildly low IGF-1):

• Address metabolic factors first: optimize nutrition, increase physical activity, and manage obesity 3
• Consider metformin if frank insulin resistance or prediabetes is present 1, 2
• Re-evaluate growth parameters after 3-6 months of metabolic optimization 3

Contraindications to GH therapy:

• Active malignancy, uncontrolled diabetes mellitus, closed epiphyses, or papilledema on fundoscopic examination 3
• Hypersensitivity to GH or its components 3

Common Pitfalls and Caveats

Avoid misinterpreting SHBG in isolation:

• Low SHBG does not indicate GH deficiency; in fact, GH deficiency typically causes high SHBG 9
• Always interpret SHBG in context with insulin levels, IGF-1, and clinical phenotype 7, 2, 9

Recognize that insulin is the dominant regulator of SHBG:

• Studies show insulin has a consistently inverse relationship with SHBG levels, while IGF-1 does not directly correlate with SHBG 7
• Low SHBG with elevated insulin suggests the metabolic syndrome phenotype, which requires different management than isolated GH deficiency 1, 2

Monitor for non-response to GH therapy:

• If height velocity does not increase by >2 cm/year over baseline after 6 months, assess adherence, measure serum IGF-1 levels, verify weight-adjusted dosing, and re-evaluate nutritional and metabolic factors 3
• Consider discontinuing GH if no adequate response occurs after 6 months of optimized therapy 3