What does an elevated growth hormone level indicate, and how should it be evaluated and managed?

Increased Growth Hormone: Clinical Significance and Management

An elevated growth hormone level most commonly indicates a GH-secreting pituitary adenoma (somatotrophinoma), which manifests as gigantism in children before epiphyseal closure or acromegaly in adults, and requires immediate biochemical confirmation with IGF-1 measurement and oral glucose suppression testing. 1

Primary Diagnostic Considerations

Pathologic GH Excess

• GH-secreting pituitary adenomas are the predominant cause of pathologic GH hypersecretion, accounting for the majority of cases in both children and adults 2
• Approximately 50% of pediatric gigantism cases have an identifiable genetic basis, making genetic testing essential in young patients 2
• Rare causes include somatotroph hyperplasia associated with McCune-Albright syndrome, Carney complex, X-linked acrogigantism, or GHRH-secreting tumors (particularly in MEN-1) 1

Functional (Non-Pathologic) GH Elevation

While the guidelines focus on pathologic causes, functional GH hypersecretion can occur in:

• Normal puberty (especially mid-puberty, Tanner stages 2-3) 1
• Malnutrition, anorexia nervosa, or malabsorption states 3
• Poorly controlled Type 1 diabetes mellitus 3
• Liver cirrhosis or renal failure 3
• Hyperthyroidism 3

Critical Pitfall: Random GH measurements alone are unreliable for diagnosis because GH is secreted in a pulsatile manner with high variability 4. Always correlate with IGF-1 levels and clinical features.

Biochemical Evaluation Algorithm

Step 1: Measure Age-Adjusted IGF-1

An elevated serum IGF-1 level (adjusted for age, sex, and Tanner stage) is the most reliable initial screening marker for GH excess 1, 2

Important caveats for IGF-1 interpretation:

• Falsely low in severe hypothyroidism, malnutrition, severe infection 1
• Falsely elevated in poorly controlled diabetes, hepatic failure, renal failure 1
• Oral estrogens reduce hepatic IGF-1 production, potentially masking GH excess 1, 2
• Marginal elevation during adolescent growth spurts requires cautious interpretation 1

Step 2: Oral Glucose Tolerance Test (OGTT)

Failure to suppress GH below 1 μg/L after oral glucose load confirms GH excess in adults 1, 2

Pediatric-specific considerations:

• Complete GH suppression is difficult to achieve in normal adolescence 1
• Approximately 30% of tall children fail to suppress GH below 1 μg/L despite not having GH excess 1
• GH nadir varies by sex and pubertal stage: highest in mid-puberty (Tanner 2-3), especially in girls (mean ± 2 SD: 0.22 ± 0.03-1.57 μg/L in girls vs. 0.21 ± 0.09-0.48 μg/L in boys) 1

The relationship between GH and IGF-1 is linear only up to GH levels of ~4 μg/L, after which IGF-1 plateaus around 10 μg/L 1

Step 3: Comprehensive Pituitary Assessment

Evaluate for other pituitary hormone abnormalities (both hypofunction and hyperfunction) 1

Key findings:

• Hyperprolactinemia occurs in 65% of pediatric acromegaly and 34-36% of gigantism cases, often causing pubertal delay 1, 2
• Hypofunction of other pituitary hormones occurs in 25-35% due to tumor mass compression 1
• TSH co-secretion is less common than prolactin but should be assessed 1
• Hypogonadism and delayed bone age are particularly relevant as they extend the window for longitudinal growth 1

Clinical Phenotype Assessment

In Children and Adolescents (Gigantism)

Height >2 SDS above age/sex-adjusted norms OR >2 SDS above mid-parental height, combined with persistently elevated growth velocity (>2 SDS), is the hallmark 1, 2

Additional features include:

• Acral enlargement (disproportionately enlarged hands and feet) 1
• Delayed bone age despite excessive height 1, 2
• Pubertal delay or arrest 1, 2
• Coarsened facial features, prognathism, dental malocclusion, frontal bossing 1
• Headache, visual field defects, joint pain 1

In Adults (Acromegaly)

Features develop after epiphyseal closure and include progressive soft tissue overgrowth, acral enlargement, and metabolic complications 5

Syndrome-Specific Presentations Requiring Evaluation

X-linked acrogigantism: Tall stature onset before age 5 (usually before age 2), teeth separation, acanthosis nigricans, markedly increased BMI and appetite 1, 2

McCune-Albright syndrome: Early-onset GH excess (from age 3 onwards), café-au-lait pigmentation, fibrous dysplasia, precocious puberty 1, 2

Carney complex: Skin pigmentation, myxomas, testicular and adrenal disease 1

Offer biochemical screening for pituitary hormone excess to all patients with Carney complex, McCune-Albright syndrome, and MEN1 or MEN1-like disease 1

Imaging and Genetic Workup

• Contrast-enhanced pituitary MRI is the imaging modality of choice for detecting somatotroph adenomas 2
• Genetic testing is strongly recommended in all children and adolescents with GH excess, given the 50% prevalence of identifiable genetic causes 2
• Systematic clinical evaluation for syndromic causes should be performed in all patients 1, 2

Assessment of Complications

Patients require evaluation and treatment of GH excess complications:

• Glucose intolerance and diabetes mellitus 1
• Hypertension 1
• Left ventricular hypertrophy and diastolic dysfunction 2
• Sleep apnea 2
• Carpal tunnel syndrome 2

Management Principles

Medical Therapy

Somatostatin analogs (octreotide, lanreotide) normalize IGF-1 in approximately 66% of patients and can achieve significant tumor shrinkage 6

FDA-approved octreotide dosing for acromegaly:

• Initial dose: 50 μg three times daily subcutaneously 7
• Titrate based on IGF-1 levels every 2 weeks 7
• Goal: GH levels <5 ng/mL or IGF-1 <1.9 U/mL (males) or <2.2 U/mL (females) 7
• Most effective dose: 100 μg three times daily, with some patients requiring up to 500 μg three times daily 7
• Doses >300 μg/day seldom provide additional benefit 7

Dopamine agonists (cabergoline) normalize IGF-1 in approximately 37% of patients 6

GH receptor antagonists (pegvisomant) normalize IGF-1 in virtually all treated patients 6

Offer monotherapy or combination medical therapy for post-operative residual disease 1

Monitoring Strategy

• Monitor both GH and IGF-1 at baseline and during follow-up, as baseline GH levels predict surgical outcomes and adenoma activity 1, 2
• Assess efficacy by both auxological measurements (height velocity, bone age) and biochemical parameters 1
• Re-evaluate IGF-1 or GH levels at 6-month intervals 7

Critical Management Considerations

In gigantism, rapid and aggressive treatment is essential to prevent irreversible excessive linear growth before epiphyseal closure 2

Delayed puberty worsens final height outcome by extending the period of longitudinal growth, making treatment of hyperprolactinemia and hypogonadism particularly important 2

Common Pitfalls to Avoid

• Never rely solely on random GH measurements for diagnosis due to pulsatile secretion patterns 3, 4
• Do not dismiss tall stature in adolescents without evaluating for acromegalic features and growth velocity trends 2
• Approximately 30% of tall children fail GH suppression testing despite not having GH excess, so interpret OGTT results within clinical context 1, 2
• Do not overlook genetic testing in pediatric cases, as nearly 50% have identifiable mutations 2
• Always evaluate for hyperprolactinemia, given its 65% prevalence in pediatric acromegaly and role in pubertal delay 1, 2
• Serial height measurements and photographic documentation are essential for accurately determining disease onset and progression 2