Eur J Endocrinol. 2025 Apr 10:lvaf078. doi: 10.1093/ejendo/lvaf078. Online ahead of print.
ABSTRACT
INTRODUCTION: Oxytocin (OXT) deficiency is a recently identified novel psycho-neuroendocrine entity associated with anxiety and reduced prosocial behavior. However, diagnosis and clinical progress have been hindered by challenges in reliably measuring OXT. Neurophysin I (NP-I), an equimolarly co-released cleavage product of the OXT precursor peptide, offers a promising alternative biomarker due to its stability, though it requires validation.
MATERIALS/METHODS: Analysis of a double-blind, placebo-controlled, cross-over study including 15 patients with hypothalamic-posterior-pituitary dysfunction and 15 healthy controls matched according to age (+/-3), sex, body mass index [BMI] (+/-2), and menopause/hormonal contraceptives. Participants received a single oral dose of the strong OXT stimulator 3,4-methylenedioxymethamphetamine (MDMA, 100mg) and placebo in random order, with a wash-out period of two weeks between sessions. NP-I and OXT levels were measured at 6-time points over 5 hours after drug intake. Subjective drug effects were assessed using visual analog scales. The primary endpoint-net incremental area under the curve (AUC) of NP-I from 0 to 300 minutes-was analysed using a linear mixed-effects model.
RESULTS: 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, MDMA induced 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] and 97 pM·5h [50-241] in healthy controls and patients, respectively, with a significant difference (2340 pM·5h (95%-CI [1462 to 3218]; p<0.0001). NP-I increase correlated with OXT increase (R=0.92) and increases in subjective effects, e.g., ‘good effect,’ ‘liking effect,’ ‘feeling high,’ ‘trust,’ and ‘fear reduction’ (all R>0.5).
CONCLUSION: These results validate NP-I as a biomarker for endogenous OXT secretion after stimulation with MDMA, 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.
PMID:40209095 | DOI:10.1093/ejendo/lvaf078
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