Endocrine Abstracts

JOINT768

Background: Oxytocin (OXT) deficiency is a recently identified new neuroendocrine entity associated with anxiety and reduced prosocial behavior. However, diagnosis and clinical progress have been hindered by challenges in reliably measuring OXT due to its instability and short half-life. Neurophysin I (NP-I), an equimolarly co-released cleavage product of the OXT precursor peptide, offers a promising alternative biomarker due to its stability and longer half-life, though it requires validation.

Methods: Analysis of a double-blind, placebo-controlled, cross-over study including 15 patients with hypothalamic-posterior-pituitary dysfunction and 15 matched healthy controls (according to age (+/-3), sex, body mass index [BMI] (+/-2), and menopause/hormonal contraceptives). Participants received a single oral of the strong OXT stimulator 3,4-methylenedioxymethamphetamine (MDMA, 100mg) and placebo, separated by two weeks. NP-I and OXT levels were measured at six time points over five hours. Subjective drug effects were assessed using visual analog scales. The area under the curve (AUC) in plasma NP-I from 0 to 300 minutes between both groups was analyzed using linear mixed-effects regression model. The AUC in receiver-operating characteristics curve (ROC) was assessed for MDMA-stimulated NP-I and OXT in differentiating patients from healthy controls.

Results: The median age was 34 years [IQR 25-46] in patients and 35 years [IQR 26-48] in controls, with both groups consisting of 53% (n = 8) females. In healthy controls, MDMA induced an 8-fold increase in OXT (peak: 624 pM [235-959]) and a 20-fold increase in NP-I (peak: 1508 pM [911-2233]). In contrast, in patients, no notable increase in OXT (peak: 92 pM [79-110]) and only a mild increase in NP-I (peak: 263 pM [140-300]). The AUC of NP-I after MDMA was 2279 pM•5h [1087-3696] in healthy controls and 97 pM•5h [50-241] in patients, with a significant difference of 2340 pM•5h (95%-CI [1462-3218]; P < 0.0001). NP-I strongly correlated with OXT (r = 0.92) and increases in subjective effects, e.g., ‘liking effect,’ ‘feeling high,’ ‘trust,’ and ‘fear reduction’ (all R>0.5). MDMA-stimulated NP-1 demonstrated strong diagnostic performance in differentiating patients with OXT deficiency from healthy controls with a ROC-AUC of 100%.

Conclusion: These results validate NP-I as a biomarker for endogenous OXT secretion, addressing long-standing challenges in direct OXT measurement. NP-I offers novel opportunities for research in conditions where reduced OXT levels or disruptions in signaling are implicated, such as autism spectrum disorder, anxiety, and depression.