Plasma Oxytocin as a Superior Preoperative Biomarker for Predicting Transient Postoperative Arginine Vasopressin Deficiency Following Transsphenoidal Pituitary Surgery

Highlight

• Oxytocin (OXT) plasma levels measured preoperatively predict transient arginine vasopressin deficiency (AVP-D) after transsphenoidal pituitary surgery (TPS) with high sensitivity.
• Preoperative OXT shows better predictive accuracy than copeptin, traditionally used to evaluate AVP status.
• Patients developing AVP-D exhibit significantly lower OXT levels before surgery, immediately after, and persistently at 3 months postoperatively, suggesting diminished posterior pituitary reserve.
• These findings highlight the potential use of plasma OXT as a biomarker to guide perioperative risk assessment and management in pituitary surgery.

Study Background

Arginine vasopressin deficiency (AVP-D), a complication frequently encountered after transsphenoidal pituitary surgery (TPS), presents clinical challenges due to its unpredictable onset and the lack of reliable early biomarkers. AVP-D can lead to transient or permanent diabetes insipidus, resulting in dysregulated water homeostasis and hypernatremia, which complicates postoperative management and patient outcomes. Although copeptin, the C-terminal segment of the vasopressin precursor peptide, has been evaluated as a surrogate biomarker for AVP secretion, its utility in predicting postoperative AVP-D remains limited and inconsistent.

Oxytocin (OXT), a neuropeptide synthesized in the hypothalamus and secreted by the posterior pituitary alongside AVP, has recently emerged as a candidate biomarker due to its co-release and shared neurosecretory pathways with AVP. Prior to this study, the comparative predictive value of plasma oxytocin versus copeptin for postoperative AVP-D after pituitary surgery had not been directly assessed.

Study Design

This prospective observational study included 74 consecutive patients undergoing transsphenoidal pituitary surgery at a university hospital neurosurgical department. The cohort was divided according to postoperative development of AVP deficiency versus normonatremic status. Blood samples were obtained preoperatively, one day postoperatively, and three months after surgery for measurement of plasma oxytocin and copeptin concentrations.

The primary endpoint was to compare plasma levels of OXT and copeptin between patients who developed AVP-D and those who did not. Secondary objectives included establishing cutoff values for these markers to predict AVP-D and assessing their postoperative temporal dynamics.

Key Findings

Patients who developed transient postoperative AVP deficiency demonstrated significantly lower plasma oxytocin levels at all measured time points: before surgery, day 1 postoperatively, and even three months after surgery. In contrast, copeptin levels were significantly reduced only immediately after surgery, with no significant preoperative difference.

The study identified a preoperative oxytocin cutoff value of 69 pg/ml, which predicted postoperative AVP-D with a sensitivity of 90% and specificity of 66%, corresponding to an area under the receiver operating characteristic curve (AUC) of 0.76 (p = 0.0089). No preoperative copeptin cutoff with statistically significant predictive value was established.

Persistent lower oxytocin levels at three months post-TPS in AVP-D patients suggests ongoing reduced posterior pituitary function, whereas copeptin levels normalized, indicating potential recovery of vasopressin secretion.

This first comparative evaluation establishes plasma oxytocin as a superior biomarker relative to copeptin for preoperative risk stratification of patients undergoing pituitary surgery who are at risk for developing AVP deficiency.

Expert Commentary

This investigation represents a noteworthy advance in the neuroendocrine management of pituitary surgery patients. The demonstration that preoperative plasma oxytocin provides reliable prognostic information about posterior pituitary functional reserve offers a new tool to anticipate AVP-D complications.

The persistence of lower oxytocin levels months after surgery highlights the neurosecretory neuron injury or loss that may occur during TPS, impacting not only AVP but also oxytocin pathways. As oxytocin is more easily measurable than vasopressin itself, its use could facilitate earlier and more accurate identification of at-risk patients, optimizing fluid management and potentially guiding tailored therapeutic interventions to mitigate hypernatremia and associated morbidity.

Study limitations include the single-center design and the relatively small sample size. Future multicenter validation and investigation into the mechanistic underpinnings of the differential peptide secretion are warranted. Additionally, integration of oxytocin measurement into routine clinical workflows requires assay standardization and cost-effectiveness evaluation.

Conclusion

This study establishes plasma oxytocin as a promising and superior preoperative biomarker compared to copeptin for predicting transient postoperative arginine vasopressin deficiency following transsphenoidal pituitary surgery. Measurement of plasma oxytocin can serve as an indicator of posterior pituitary reserve, enabling improved perioperative risk stratification and guiding clinical management to prevent AVP-D related complications.

Implementation of plasma OXT measurement may transform postoperative care pathways, reduce morbidity, and inform patient counseling in pituitary surgery. Further research should seek to validate these findings in larger cohorts and explore targeted interventions for patients with low preoperative oxytocin.

Funding and Clinical Trial Registration

The study was conducted at the neurosurgical department of a university hospital with no disclosed external funding sources. No clinical trial registration was reported.

References

1. Nicolson J, Verbalis JG. “Arginine Vasopressin in the Pathophysiology of Diabetes Insipidus.” Endocr Rev. 2018;39(5): 506-525.
2. Morgenthaler NG, Struck J, Alonso C, Bergmann A. “Assay for the Measurement of Copeptin, a Stable Peptide Derived from the Vasopressin Precursor.” Clin Chem. 2006;52(1):112-119.
3. Constanthin PE, Isidor N, De Seigneux S, et al. “Plasma oxytocin, early predictor of transient postoperative arginine vasopressin deficiency.” J Clin Endocrinol Metab. 2026 Jul 8; PMID: 42417428.
4. Verbalis JG. “Disorders of Water Balance.” Best Pract Res Clin Endocrinol Metab. 2016;30(2):195-205.