Atila Cihan, Nikaj Andi, Leibnitz Svenja, Liechti Matthias E, Christ-Crain Mirjam
Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, 4031 Basel, Switzerland.
Department of Clinical Research, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
Eur J Endocrinol. 2025 Mar 27;192(4):502-510. doi: 10.1093/ejendo/lvaf078.
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, although 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 (±2), and menopause/hormonal contraceptives. Participants received a single oral dose of the strong OXT stimulator 3,4-methylenedioxymethamphetamine (MDMA, 100 mg) and placebo in random order, with a wash-out period of 2 weeks between both experimental sessions. NP-I and OXT levels were measured at 6 time points over 5 h after drug intake. Subjective drug effects were assessed using visual analog scales ranging from 0 = "not at all" to 100 = "extremely," or were bidirectionally ranging from -50 to +50 mm, with 0 being the neutral measure = "no effect." The primary endpoint-net incremental area under the curve (AUC) of NP-I from 0 to 300 min-was analyzed using a linear mixed-effects model.
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·5 h [1087-3696] and 97 pM·5 h [50-241] in healthy controls and patients, respectively, with a significant difference (2340 pM·5 h (95% CI, 1462-3218; P < .0001). NP-I increase correlated with OXT increase (R = 0.92) and increases in subjective effects, eg, "good effect," "liking effect," "feeling high," "trust," and "fear reduction" (all R > 0.5).
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.
催产素（OXT）缺乏是一种最近发现的新型心理神经内分泌实体，与焦虑和亲社会行为减少有关。然而，可靠测量OXT所面临的挑战阻碍了诊断和临床进展。神经垂体素I（NP-I）是OXT前体肽等摩尔共同释放的裂解产物，由于其稳定性，提供了一种有前景的替代生物标志物，尽管它需要验证。
材料/方法：对一项双盲、安慰剂对照、交叉研究进行分析，该研究包括15名下丘脑-垂体后叶功能障碍患者和15名根据年龄（±3岁）、性别、体重指数（±2）以及绝经/激素避孕药情况匹配的健康对照者。参与者随机接受单次口服强效OXT刺激剂3,4-亚甲基二氧基甲基苯丙胺（摇头丸，100毫克）和安慰剂，两次实验之间有2周的洗脱期。在服药后5小时内的6个时间点测量NP-I和OXT水平。使用视觉模拟量表评估主观药物效应，范围从0 = “完全没有”到100 = “极其强烈”，或双向范围从-50到+50毫米，0为中性测量 = “无效应”。使用线性混合效应模型分析NP-I从0到300分钟的主要终点净增量曲线下面积（AUC）。
在健康对照者中，摇头丸使OXT增加8倍（峰值：624皮摩尔[235 - 959]），使NP-I增加20倍（峰值：1508皮摩尔[911 - 2233]）。相比之下，在患者中，摇头丸未使OXT显著增加（峰值：92皮摩尔[79 - 110]），仅使NP-I轻度增加（峰值：263皮摩尔[140 - 300]）。摇头丸后NP-I的AUC在健康对照者和患者中分别为2279皮摩尔·5小时[1087 - 3696]和97皮摩尔·5小时[50 - 241]，差异显著（2340皮摩尔·5小时（95%置信区间，1462 - 3218；P <.0001）。NP-I的增加与OXT的增加相关（R = 0.92），也与主观效应的增加相关，例如“良好效应”、“喜欢效应”、“兴奋感”、“信任”和“恐惧减轻”（所有R > 0.5）。
这些结果验证了NP-I作为摇头丸刺激后内源性OXT分泌的生物标志物，解决了直接测量OXT方面长期存在的挑战。NP-I为研究OXT水平降低或信号传导中断相关的疾病，如自闭症谱系障碍、焦虑症和抑郁症，提供了新的机会。
