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The hook effect in macroprolactinomas: tumor size thresholds, prolactin patterns, and clinical consequences - a
Prashant Yadav1, Amir H Hamrahian1, Roberto Salvatori2
1Division of Endocrinology, Diabetes and Metabolism, and Pituitary Center Johns Hopkins, University School of Medicine, Baltimore, MD, 21287, USA.
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.
Insights
The hook effect in macroprolactinoma assays can cause falsely low prolactin (PRL) levels, leading to misdiagnosis. Serial dilution testing is crucial for pituitary macroadenoma to prevent unnecessary surgery and ensure timely treatment.
Area of Science:
- Endocrinology
- Clinical Chemistry
- Oncology
Background:
- The immunoassay hook effect can lead to spuriously low prolactin (PRL) measurements in patients with macroprolactinomas.
- This can result in misdiagnosis and inappropriate patient management.
Purpose of the Study:
- To determine the tumor size threshold for the hook effect in macroprolactinomas.
- To characterize pre-dilution PRL patterns and quantify PRL underestimation.
- To assess the clinical consequences of unrecognized hook effect.
Main Methods:
- Systematic review of PubMed, Embase, Scopus, Google Scholar, and Web of Science (Jan 2000-Aug 2025).
- Included studies reporting individual patient data with confirmed hook effect (pre- and post-dilution PRL, tumor size, serial dilution confirmation).
- Data synthesized using individual patient data (IPD) quantitative methods; registered on PROSPERO.
Main Results:
- 23 patients from 14 studies; median tumor diameter 48.0 mm (range 22-100 mm).
- Hook effect occurred in 39.1% of tumors below the 40 mm giant adenoma threshold.
- Median pre-dilution PRL 100.0 ng/mL, median post-dilution PRL 6,460.0 ng/mL (median 64.7× increase).
- Unrecognized hook effect led to unnecessary surgery in 55.6% of cases.
Conclusions:
- Pre-dilution PRL values can mimic stalk effect, necessitating further investigation.
- Serial dilution testing is recommended for pituitary macroadenoma with disproportionately low PRL relative to tumor size.
- This prevents misdiagnosis, unnecessary surgery, and delays in dopamine agonist therapy.
