How do I evaluate and manage a patient with elevated growth hormone levels?

Evaluation and Management of Elevated Growth Hormone Levels

Begin evaluation with measurement of serum IGF-1 adjusted for age, sex, and Tanner stage, followed by an oral glucose tolerance test (OGTT) to assess GH suppression, then proceed with pituitary MRI and comprehensive hormonal assessment to identify the source and extent of GH excess. 1

Initial Clinical Assessment

Who to Test

• Test any patient with excess height (>2 SDS above normal), consistently elevated height velocity (>2 SDS), or acromegalic features including acral enlargement, coarsened facial features, prognathism, dental malocclusion, frontal bossing, or joint pain. 1
• Evaluate patients with delayed or arrested puberty combined with tall stature, as hypogonadism extends the growth window. 1
• Consider testing those with family history of pituitary adenomas or features suggesting syndromic disease. 1

Key Clinical Features to Document

• Serial height measurements and growth velocity plotted against age-adjusted, sex-adjusted, and ethnicity-adjusted norms 1
• Pubertal stage (Tanner staging) and bone age assessment 1
• Photographs over time to establish disease onset 1
• Symptoms of mass effect: headaches, visual field defects 1
• Metabolic complications: glucose intolerance, hypertension, sleep apnea, excessive sweating 1
• Signs of hormone co-secretion: galactorrhea (prolactin), features of hyperthyroidism (TSH) 1

Biochemical Diagnosis

Primary Screening Tests

• Measure serum IGF-1 using Tanner stage-matched, sex-matched, and age-matched reference ranges—this is the most reliable marker for GH excess. 1
• Perform OGTT with serial GH measurements: failure to suppress GH below 1 μg/L (or <0.4 μg/L with sensitive assays) supports GH excess in adults. 1

Critical Interpretation Caveats

• In adolescents, GH suppression is pubertal stage-specific: mid-puberty (Tanner 2-3) girls may have GH nadirs up to 1.57 μg/L, boys up to 0.48 μg/L—approximately 30% of tall children fail to suppress below 1 μg/L without pathology. 1
• IGF-1 may be falsely normal/low with severe hypothyroidism, malnutrition, or severe infection; falsely elevated with poorly controlled diabetes, hepatic/renal failure, or oral estrogen use. 1
• Elevated IGF-1 with apparently normal GH may represent early disease. 1
• Both GH and IGF-1 should be monitored at baseline and follow-up, as baseline GH levels predict surgical outcomes (higher levels = lower remission likelihood). 1

Comprehensive Hormonal Evaluation

Assess for Pituitary Dysfunction and Co-secretion

• Perform complete anterior pituitary hormone assessment including prolactin, TSH, free T4, cortisol, ACTH, LH, FSH, testosterone/estradiol—25-35% have hypopituitarism from tumor compression. 1
• Check prolactin specifically: 65% of pediatric acromegaly cases have hyperprolactinemia, and 34-36% of gigantism cases show prolactin co-secretion. 1
• TSH co-secretion occurs less frequently but must be evaluated. 1

Screen for Syndromic Causes

• Evaluate clinically for McCune-Albright syndrome (café-au-lait pigmentation, fibrous dysplasia, precocious puberty), Carney complex (skin pigmentation, myxomas, testicular/adrenal disease), MEN1 (pancreatic/parathyroid tumors), and X-linked acrogigantism (onset before age 5, disproportionate extremity enlargement). 1
• Offer biochemical screening for pituitary hormone excess to all patients with these syndromes. 1
• Consider GHRH-secreting pancreatic tumors in MEN1 patients. 1
• Measure plasma GHRH levels if ectopic secretion is suspected (normal/small pituitary with elevated GH/IGF-1). 2, 3

Imaging Studies

Pituitary Assessment

• Obtain contrast-enhanced pituitary MRI to identify adenoma, assess size/extension, and evaluate for mass effects on optic chiasm and surrounding structures. 4, 3
• Note that pituitary enlargement can occur with ectopic GHRH secretion (somatotroph hyperplasia), making adenoma diagnosis challenging. 2

Extrapituitary Imaging

• Perform chest/abdominal CT or octreotide scan if plasma GHRH is elevated, pituitary is normal-sized, or clinical features suggest carcinoid, pancreatic neuroendocrine tumor, or other ectopic source. 2, 3

Assessment of Complications

Metabolic and Cardiovascular

• Screen for glucose intolerance with fasting glucose, HbA1c, and OGTT. 1
• Measure blood pressure and perform echocardiography to assess for left ventricular hypertrophy and diastolic dysfunction. 3, 5
• Evaluate for sleep apnea with polysomnography if symptoms present. 3

Skeletal and Joint

• Assess for arthropathy, carpal tunnel syndrome, and joint hypermobility. 1
• Obtain bone age radiographs to determine remaining growth potential. 1

Management Algorithm

First-Line Treatment

• Transsphenoidal surgery by an experienced pituitary neurosurgeon is first-line therapy for GH-secreting adenomas, achieving approximately 50% remission in experienced centers. 6, 3, 5
• Surgery should be offered even when complete cure appears unlikely, as debulking improves medical therapy response. 6
• For ectopic GHRH-secreting tumors, surgical resection of the peripheral tumor reverses GH hypersecretion—pituitary surgery is unnecessary. 2

Medical Therapy for Residual Disease

• Offer somatostatin receptor ligands (octreotide, lanreotide) as monotherapy or combination therapy for post-operative residual disease or when surgery is not feasible. 6, 7
• Lanreotide dosing for acromegaly: start 90 mg subcutaneously every 4 weeks for 3 months, then adjust based on GH/IGF-1 levels (60-120 mg every 4 weeks, or 120 mg every 6-8 weeks for controlled patients). 7
• Use GH receptor antagonist (pegvisomant) for patients resistant to somatostatin analogs—it normalizes IGF-1 in adequate doses. 6, 3, 5
• Consider dopamine agonists as adjunctive therapy, particularly with prolactin co-secretion. 6, 5

Radiotherapy

• Offer pituitary radiotherapy for uncontrolled tumor growth despite surgical and medical therapy, except in McCune-Albright syndrome with skull base fibrous dysplasia. 6
• Recognize that radiotherapy requires up to 10 years for full GH suppression effect. 6

Special Consideration: Metabolic Acidosis

• If metabolic acidosis is present, administer alkali therapy (sodium bicarbonate or citrate) targeting plasma bicarbonate >22 mmol/L, as acidosis creates GH resistance impairing treatment response. 6

Monitoring Strategy

Biochemical Monitoring

• Monitor both GH and IGF-1 levels at baseline and during follow-up—IGF-1 correlates linearly with GH only up to 4 μg/L, then plateaus around 10 μg/L. 1
• Reassess GH/IGF-1 levels 6 weeks after any dosing regimen change. 7

Surveillance for Complications

• Monitor periodically for cholelithiasis with ultrasound, as somatostatin analogs reduce gallbladder motility—discontinue if cholecystitis, cholangitis, or pancreatitis develops. 7
• Continue surveillance for glucose intolerance, hypertension, and cardiovascular complications. 1
• Lifelong follow-up is required as relapse can occur years after apparent remission. 1

Common Pitfalls to Avoid

• Do not rely solely on OGTT GH suppression in adolescents—interpret with IGF-1, clinical phenotype, height velocity, and pubertal stage. 1
• Do not miss ectopic GHRH secretion by assuming all GH excess is pituitary—measure plasma GHRH when clinical suspicion exists. 2
• Do not overlook hormone co-secretion or hypopituitarism—comprehensive pituitary assessment is mandatory. 1
• Do not ignore syndromic features—nearly 50% of pediatric gigantism has identifiable genetic basis. 1
• Do not use adult IGF-1 reference ranges in children—must be Tanner stage-matched and assay-specific. 1