What does it mean to have elevated Insulin-like Growth Factor-1 (IGF-1) levels?

What Does High IGF-1 Mean?

Elevated IGF-1 most commonly indicates acromegaly from a growth hormone (GH)-secreting pituitary adenoma, which increases mortality risk and requires immediate evaluation with pituitary imaging and confirmatory GH testing. 1

Primary Concern: Acromegaly

• Elevated GH and IGF-1 levels are high-quality predictors of mortality in acromegaly patients, making this the most critical diagnosis to rule out. 1
• Acromegaly typically results from a GH-secreting pituitary adenoma causing anatomical changes and metabolic dysfunction. 1
• Normalizing IGF-1 levels in acromegaly reduces mortality rates to those expected in the general population, underscoring the importance of diagnosis and treatment. 1

Diagnostic Approach

Confirm True Elevation

• Use age-matched, sex-matched, and pubertal stage-matched reference ranges specific to your laboratory's assay, as normal IGF-1 values vary significantly across the lifespan. 2
• IGF-1 assays require standardization and validation; familiarity with appropriate hormone standards, specificity, and sensitivity is essential. 1

Evaluate for Acromegaly

• Obtain pituitary MRI imaging to identify a GH-secreting adenoma. 1
• Measure random GH levels and perform oral glucose tolerance test (OGTT) with GH nadir measurement, though OGTT may show inconsistent results in medically treated patients. 1
• Current diagnostic criteria: GH nadir during OGTT <0.4 μg/L using sensitive assays (older cutoff of <1 μg/L is likely outdated). 1

Important Caveat: Biochemical Discordance

• The clinical significance of slightly elevated IGF-1 levels or biochemically discordant results (between GH and IGF-1) remains uncertain. 1
• Up to 24% of post-surgical acromegaly patients show discordant values (elevated IGF-1 with normal GH), particularly women with macroadenomas. 3
• Elevated IGF-1 with normal GH suppression on OGTT may not represent active acromegaly and requires individualized assessment. 3, 4

Alternative Causes of Elevated IGF-1

Clinically Silent GH-Secreting Tumors

• Routine IGF-1 evaluation is recommended in patients with suspected non-functioning pituitary adenomas (NFPAs) to rule out GH hypersecretion without clinical acromegaly features. 1
• Up to 8% of NFPAs may have slightly elevated IGF-1 despite lacking clinical suspicion for acromegaly. 1

Mixed Prolactin/GH-Secreting Tumors

• Prolactinomas may co-secrete GH, warranting IGF-1 evaluation in prolactinoma patients, especially when prolactin decreases without tumor size reduction. 5
• 69% of patients with discordant IGF-1/GH values had mammosomatotroph or mixed tumors. 3

Pre-analytical and Technical Pitfalls

• IGF-1 measurement is complicated by IGF binding proteins (IGFBPs) that bind approximately 98% of circulating IGF-1, requiring multiple pre-treatment steps that reduce reproducibility. 6
• Assay-specific variations can lead to false elevations. 1

Physiological and Pathological Conditions

• Oral estrogen therapy suppresses IGF-1 production (paradoxically, this causes low IGF-1, not high). 2
• Various physiological circumstances and pathological conditions can affect IGF-1 levels independent of acromegaly. 7

Clinical Implications and Management

If Acromegaly is Confirmed

• Treatment aims to reduce fasting morning GH and IGF-1 concentrations to as close to normal as possible. 1
• Medical treatment should prevent tumor growth and provide relief from compressive symptoms. 1
• Core clinical outcomes to monitor include mortality, tumor volume, comorbidities (hypertension, heart disease, diabetes, sleep apnea, bone/joint involvement), and symptoms (acral changes, headache, sweating). 1

If IGF-1 is Modestly Elevated Without Confirmatory Testing

• When IGF-1 is less than twice the upper limit of normal and OGTT shows normal GH suppression, acromegaly diagnosis cannot be established. 4
• Elevated IGF-1 alone is sufficient to diagnose acromegaly only when significantly elevated with compatible clinical features. 4

Critical Pitfalls to Avoid

• Never rely on IGF-1 or GH measurements alone for assessing disease control in surgically treated acromegaly patients—both markers are needed. 3
• Do not use OGTT results for follow-up of medically treated patients due to inconsistent results. 1
• Avoid misinterpreting modest IGF-1 elevation as definitive acromegaly without corroborative GH testing and clinical features. 7, 4
• Remember that GH concentrations rise when patients are treated with GH receptor antagonists (pegvisomant) as IGF-1 falls, reflecting diminished feedback inhibition. 8