Neurophysin-I dynamics upon different pituitary provocation tests in healthy participants

Background: Oxytocin (OXT) is known for its role in regulating social behaviour, such as emotion recognition and bonding. The evidence for clinically relevant OXT deficiency is constantly increasing, but measurement of OXT is challenging. In contrast, neurophysin-I (NP-I), the carrier protein of OXT, co-released equimolarly, is a stable surrogate biomarker for OXT. This study evaluated OXT and NP-I levels upon four different pituitary provocation tests. Design: Secondary analysis of four interventional diagnostic trials at the University Hospital Basel, Switzerland. Methods: Sixty-six participants underwent a pituitary provocation test, 11 the hypertonic saline test, 20 the arginine infusion test, 25 the oral macimorelin test, and 10 the glucagon injection test. Plasma NP-I and OXT were measured at baseline and once plasma sodium level reached ≥ 150 mmol/L for the hypertonic saline, after 60min for the arginine infusion, after 60min, 120min, and 180min for the glucagon injection, and after 45min for the oral macimorelin test. Primary outcome was change from baseline to maximally stimulated NP-I levels. Results: Median IQR NP-I levels increased minimally in response to hypertonic saline (baseline: 55 pM, stimulated: 59 pM, relative median change of -8% -16, +9) and significantly to glucagon injection (baseline: 82 pM, stimulated: 94 pM, relative median change of +18% +7, +28). Median OXT levels showed similar trends in response to hypertonic saline (baseline: 0.36, stimulated: 0.48, relative median change of +22% -15, +96) and to glucagon injection (baseline: 82.7 pg/ml 62.3, 94.3, stimulated: 93.4 pg/ml 87.2, 121, relative median change of +25% [+6, +59). There were no increases in NP-I plasma levels nor OXT levels upon arginine infusion and oral macimorelin. Conclusion: NP-I showed minimal responses to pituitary provocation tests, paralleling OXT dynamics. These findings highlight NP-I's potential as a reliable and technically robust surrogate biomarker for OXT activity, warranting further evaluation in clinical and experimental settings.