The hook effect in macroprolactinomas: tumor size thresholds, prolactin patterns, and clinical consequences - a systematic review.

Clinical Snapshot

Key Findings

• P Value: Not applicable for descriptive systematic review

• Effect Size: Median 64.7-fold increase in prolactin after serial dilution

• Primary Outcome: Hook effect documented in tumors as small as 22mm diameter

• Nnt Or Sensitivity: 39.1% of hook effect cases occurred in tumors <40mm (below giant adenoma threshold)

• Confidence Interval: 95% CI: 62.9-93.0% of cases had pre-dilution PRL 26-200 ng/mL

Clinical Application

Serial dilution testing readily available in most Australian laboratories Relevant to Australian endocrinology practice; serial dilution should be routine for suspected cases to prevent unnecessary neurosurgery and optimize dopamine agonist therapy timing Patients with pituitary macroadenomas and disproportionately low prolactin relative to tumor size

Abstract

PURPOSE: The immunoassay "hook effect" may cause spuriously low prolactin (PRL) measurements in patients with macroprolactinomas, leading to misdiagnosis and inappropriate management. This systematic review aimed to determine the tumor size threshold and distribution at which the hook effect has been documented, characterize the pre-dilution PRL pattern, quantify the magnitude of PRL underestimation, and assess the clinical consequences of unrecognized hook effect. METHODS: PubMed, Embase, Scopus, Google Scholar, and Web of Science were searched for articles published between January 2000 and August 2025. Studies reporting individual patient data with confirmed hook effect (pre- and post-dilution PRL, tumor size, and confirmation by serial dilution) were included. Quality was assessed using the JBI Critical Appraisal Checklist for Case Reports. Data were synthesized using individual patient data (IPD) quantitative methods. The review was registered on PROSPERO (CRD420261375863) and reported per PRISMA 2020 guidelines. RESULTS: Twenty-three patients from 14 studies across 9 countries were included, with a median maximum tumor diameter of 48.0 mm (IQR 35.5-55.0; range 22-100 mm); the smallest confirmed hook-effect tumor diameter measured 22 mm, reported in two independent cases, and 9 of 23 cases (39.1%) occurred in tumors below the conventional giant adenoma threshold (≥ 40 mm). Median pre-dilution PRL was 100.0 ng/mL (IQR 62.0-164.5), while median post-dilution PRL was 6,460.0 ng/mL (IQR 3,608.5-16,657.5), yielding a median fold increase of 64.7× (IQR 46.8-141.5). Pre-dilution PRL ranged from 26 to 200 ng/mL in 82.6% of cases (95% CI: 62.9-93.0%), values often misattributed to stalk effect. Unrecognized hook effect led to unnecessary surgery in 55.6% of cases with documented clinical outcomes. The hook effect was documented across multiple immunoassay platforms. CONCLUSIONS: Pre-dilution PRL values often overlap with the range attributed to stalk effect, and serial dilution testing should be considered for pituitary macroadenoma with PRL disproportionately low relative to tumor size, regardless of whether the tumor meets the giant adenoma threshold to prevent misdiagnosis, unnecessary surgical intervention and delayed initiation of dopamine agonist therapy.

References

1. 1.Yadav, P., Hamrahian, A. H., & Salvatori, R. (2026). The hook effect in macroprolactinomas: tumor size thresholds, prolactin patterns, and clinical consequences - a systematic review. Pituitary. https://doi.org/10.1001/jama.2023.5444