Endogenous Oxytocin Concentrations Research Articles

Neurophysin I is an analytically robust surrogate biomarker for oxytocin

Oxytocin is a pleiotropic neuropeptide that plays roles in biological processes ranging from birth, lactation, and social bonding to immune function, cardiovascular repair, and regulation of appetite. Although measurements of endogenous oxytocin concentrations have been performed for more than 50 years, the ability to measure oxytocin accurately poses notable challenges. One potential solution for overcoming these challenges involves measurement of oxytocin’s carrier molecule – neurophysin I (NP-1) – as a surrogate biomarker. NP-1 is secreted in equimolar concentrations with oxytocin but has a longer half-life, circulates in higher concentrations, and can be measured using a sandwich immunoassay. We report experiments that 1) analytically validate a commercially available NP-1 sandwich immunoassay for use with human plasma and urine samples, 2) confirm the specificity of this assay, based on detection of NP-1 in plasma from wild-type but not oxytocin knockout mice, 3) demonstrate that NP-1 concentrations are markedly elevated in late pregnancy, consistent with studies showing substantial increases in plasma oxytocin throughout gestation, and 4) establish strong correlation between NP-1 and plasma oxytocin concentrations when oxytocin is measured in extracted (but not non-extracted) plasma. The NP-1 assay used in this study has strong analytical properties, does not require time-intensive extraction protocols, and the assay itself can be completed in < 2 h (compared to 16–24 h for a competitive oxytocin immunoassay). Our findings suggest that much like copeptin has become a useful surrogate biomarker in studies of vasopressin, measurements of NP-1 have similar potential to advance oxytocin research.

Endogenous oxytocin and human social interactions: A systematic review and meta-analysis.

While there has been an increase in studies investigating the relationship between endogenous oxytocin (OXT) concentrations and human social interactions over the past decades, these studies still seem far from converging, both in methodological terms and in terms of their results. This systematic review and meta-analysis were aimed at a comprehensive evaluation and synthesis of empirical evidence on the relationship between endogenous OXT concentrations and human social interactions by reviewing studies published between 1970 and July 2020 and addressing various related methodological and analytical limitations. Sixty-three studies were included in the qualitative synthesis, and results from 51 studies were pooled in a meta-analysis (n = 3,741 participants). The results indicated that social interaction did not lead to an expected hormonal response in causal designs, either in a pre-post design (g = 0.079) or when comparing experimental conditions with and without social interaction (g = 0.256). However, in correlational designs, the overall mean effect size (ES) of the correlations between indicators of social interaction and OXT concentrations was significantly different from zero (z = 0.137). In both designs, subgroup analyses revealed that studies involving either parent-child interactions, or the utilization of the enzyme-linked immunosorbent assay method for OXT analysis, or unrestricted eating, drinking, or exercise before biofluid collection showed significantly higher than zero mean ESs. This review exposes the observed inconsistencies and suggests that standardized, replicable, and reliable approaches to assessing social interaction and measuring OXT concentrations need to be developed to study neurochemical mechanisms of sociality in humans. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Specificity of plasma oxytocin immunoassays: A comparison of commercial assays and sample preparation techniques using oxytocin knockout and wildtype mice

Oxytocin has garnered much interest due to its role in affective states, social behaviors, and diverse physiological functions. However, approaches for measuring endogenous oxytocin concentrations have generated considerable controversy and debate. Common procedures for measuring oxytocin often produce uncorrelated results, and the detected concentrations frequently vary across two orders of magnitude. These findings have led some researchers to argue that immunoassays of plasma oxytocin may be unreliable and nonspecific, particularly when samples are not first processed using an extraction procedure. Here, we assess the specificity of oxytocin immunoassays using plasma samples from wildtype (WT) and oxytocin knockout (KO) mice. Plasma samples from both genotypes were measured using immunoassay and were measured with or without a solid-phase extraction. Using a commercially available kit from Arbor Assays, we demonstrate that both techniques generate a clear contrast between genotypes, with wildtype samples containing high concentrations of oxytocin (unextracted mean = 468 pg/ml; extracted mean = 381 pg/ml), while knockout samples measured below the lower limit of detection. Analytical validations demonstrated good parallelism and spike recovery for both methods. Furthermore, the same wildtype samples measured with both procedures were highly correlated (r = 0.95), although unextracted samples measured at significantly higher concentrations (p = 2.0 ×10−7, Cohen’s d = 2.65). To test the generalizability of these results across immunoassay kits, we performed additional assays with kits from Cayman Chemical and Enzo Life Sciences. The Cayman Chemical kit produced results similar to Arbor Assays with a clean signal differentiating WT and KO plasma, both with and without an extraction step. The Enzo kit also differentiated the genotypes, with correlation between extracted and unextracted samples, but was considerably more susceptible to interference without the extraction, as evidenced by false positive signal in KO plasma samples. The extent to which these results generalize to other species remains unknown and challenging to assess.

Oxytocin and social anxiety: Interactions with sex hormones

Oxytocin has been associated with anxiolytic and stress reducing effects in a number of studies. Less is known about the associations of endogenous oxytocin concentrations and their interaction with other hormones such as sex hormones in relation to self-reported anxiety levels. In this study, endogenous oxytocin and sex hormone levels were analyzed in 99 high (51 women) and 100 low (50 women) socially anxious individuals. Regression analyses showed that women with high oxytocin and estradiol levels reported a lower total Liebowitz Social Anxiety Score (LSAS) as well as a lower score on the subscale LSAS Fear. This association of hormonal interaction with social anxiety scores was significant in the subsample of high socially anxious women. In men there were no significant associations for endogenous hormones with LSAS scores. These findings suggest that in women the link between oxytocin and anxiety might be dependent on basal anxiety levels as well as on individual sex hormone levels.

The Effects of Intranasal Oxytocin on Neural and Behavioral Responses to Social Touch in the Form of Massage.

Manually-administered massage can potently increase endogenous oxytocin concentrations and neural activity in social cognition and reward regions and intranasal oxytocin can increase the pleasantness of social touch. In the present study, we investigated whether intranasal oxytocin modulates behavioral and neural responses to foot massage applied manually or by machine using a randomized placebo-controlled within-subject pharmaco-fMRI design. 46 male participants underwent blocks of massage of each type where they both received and imagined receiving the massage. Intranasal oxytocin significantly increased subjective pleasantness ratings of the manual but not the machine massage and neural responses in key regions involved in reward (orbitofrontal cortex, dorsal striatum and ventral tegmental area), social cognition (superior temporal sulcus and inferior parietal lobule), emotion and salience (amygdala and anterior cingulate and insula) and default mode networks (medial prefrontal cortex, parahippocampal gyrus, posterior cingulate, and precuneus) as well as a number of sensory and motor processing regions. Both neural and behavioral effects of oxytocin occurred independent of whether subjects thought the massage was applied by a male or female masseur. These findings support the importance of oxytocin for enhancing positive behavioral and neural responses to social touch in the form of manually administered massage and that a combination of intranasal oxytocin and massage may have therapeutic potential in autism.Clinical Trials RegistrationThe Effects of Oxytocin on Social Touch; registration ID: NCT03278860; URL: https://clinicaltrials.gov/ct2/show/NCT03278860.

Demographic, sampling- and assay-related confounders of endogenous oxytocin concentrations: A systematic review and meta-analysis.

Studies on endogenous oxytocin concentrations are often criticized for the debatable comparability between specimens and the variation in reported values. We performed meta-regressions on k = 229 studies (n = 12 741 participants), testing whether specimen, extraction, sex, age, time of day, or fasting instructions influenced oxytocin measurements. Predicted oxytocin concentrations differed depending on specimen and extraction: Measurements were extremely high in unextracted blood, compared to extracted blood and other specimens. Measurements were higher in samples with more female participants and higher age. Instructions not to smoke before sampling were correlated with higher oxytocin in unextracted samples. There was no impact of instructions to refrain from eating, drinking, consume caffeine, alcohol or exercising. Oxytocin concentrations increased from morning to afternoon. Our results showed that oxytocin is differentially reflected in blood, saliva, urine and cerebrospinal fluid. Extraction impacts oxytocin measurements, particularly in blood. Considering relevant confounders might increase comparability between studies.

Menstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis.

Oxytocin affects physiological and psychological functions that are often expressed sex-specifically, suggesting interactions between oxytocin and sex hormones. As female sex hormone concentrations change during the menstrual cycle, oxytocin might fluctuate, too. This systematic review and meta-analysis investigated endogenous oxytocin concentrations across menstrual cycle phases in healthy women. Data from 13 studies (120 women) showed a significant increase of oxytocin concentrations from the early follicular phase to ovulation (g = 0.39 [0.25; 0.53], p < .001) and a significant decrease from ovulation to the mid-luteal phase (g = -0.50 [-0.81; -0.18], p < .001). There were no significant differences between the early follicular and mid-luteal phase (g = -0.19 [-0.70; -0.32], p = .471). These findings contribute to a deeper understanding of differences in normal and abnormal psychobiological processes in women. They highlight the necessity to consider the menstrual cycle phase in studies on oxytocin in women.

Foot massage evokes oxytocin release and activation of orbitofrontal cortex and superior temporal sulcus

Massage may be an important method for increasing endogenous oxytocin concentrations and of potential therapeutic benefit in disorders with social dysfunction such as autism where basal oxytocin levels are typically reduced. Here we investigated oxytocin release and associated neural responses using functional near infrared spectroscopy (fNIRS) during hand- or machine-administered massage. 40 adult male subjects received 10 min of light foot massage either by hand or machine in a counterbalanced order and then rated pleasure, intensity, arousal and how much they would pay for the massage. Blood samples were taken before and after each massage condition to determine plasma oxytocin concentrations. Neural responses from medial and lateral orbitofrontal cortex, superior temporal sulcus and somatosensory cortex were measured (fNIRS oxy-Hb) together with skin conductance responses (SCR), ratings of the massage experience, autistic traits and sensitivity to social touch. Results showed subjects gave higher ratings of pleasure, but not intensity or arousal, after hand- compared with machine-administered massage and there were no differential effects on SCR. Subjects were also willing to pay more for the hand massage. Plasma oxytocin increased after both massage by hand or machine, but more potently after massage by hand. Both basal oxytocin concentrations and increases evoked by hand-, but not machine-administered massage, were negatively associated with trait autism and attitudes towards social touch, but massage by hand-evoked changes were significant in higher as well as lower trait individuals. Increased neural responses to hand vs. machine-administered massage were found in posterior superior temporal sulcus and medial/lateral orbitofrontal cortex but not somatosensory cortex. Orbitofrontal cortex and superior temporal cortex activation during hand massage was associated with the amount of money subjects were willing to pay and between orbitofrontal cortex activation and autism scores. Thus, hand-administered massage can potently increase oxytocin release and activity in brain regions involved in social cognition and reward but not sensory aspects of affective touch. Massage by hand induced changes in both oxytocin concentrations and neural circuits involved in processing social affective trust may have therapeutic potential in the context of autism.

Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life

The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits.

Positive social behaviours are induced and retained after oxytocin manipulations mimicking endogenous concentrations in a wild mammal.

The neuropeptide hormone oxytocin modulates numerous social and parental behaviours across a wide range of species, including humans. We conducted manipulation experiments on wild grey seals (Halichoerus grypus) to determine whether oxytocin increases proximity-seeking behaviour, which has previously been correlated with endogenous oxytocin concentrations in wild seal populations. Pairs of seals that had never met previously were given intravenous injections of 0.41 µg kg−1 oxytocin or saline and were observed for 1 h post-manipulation. The dose was designed to mimic endogenous oxytocin concentrations during the observation period, and is one of the lowest doses used to manipulate behaviour to date. Seals given oxytocin spent significantly more time in close proximity to each other, confirming that oxytocin causes conspecifics to seek others out and remain close to one another. Aggressive and investigative behaviours also significantly fell after oxytocin manipulations. Despite using a minimal oxytocin dose, pro-social behavioural changes unexpectedly persisted for 2 days despite rapid dose clearance from circulation post-injection. This study verifies that oxytocin promotes individuals staying together, demonstrating how the hormone can form positive feedback loops of oxytocin release following conspecific stimuli, increased motivation to remain in close proximity and additional oxytocin release from stimuli received while in close proximity.

Maternal Oxytocin Is Linked to Close Mother-Infant Proximity in Grey Seals (Halichoerus grypus).

Maternal behaviour is a crucial component of reproduction in all mammals; however the quality of care that mothers give to infants can vary greatly. It is vital to document variation in maternal behaviour caused by the physiological processes controlling its expression. This underlying physiology should be conserved throughout reproductive events and should be replicated across all individuals of a species; therefore, any correlates to maternal care quality may be present across many individuals or contexts. Oxytocin modulates the initiation and expression of maternal behaviour in mammals; therefore we tested whether maternal plasma oxytocin concentrations correlated to key maternal behaviours in wild grey seals (Halichoerus grypus). Plasma oxytocin concentrations in non-breeding individuals (4.3 ±0.5 pg/ml) were significantly lower than those in mothers with dependent pups in both early (8.2 ±0.8 pg/ml) and late (6.9 ±0.7 pg/ml) lactation. Maternal plasma oxytocin concentrations were not correlated to the amount of nursing prior to sampling, or a mother’s nursing intensity throughout the dependant period. Mothers with high plasma oxytocin concentrations stayed closer to their pups, reducing the likelihood of mother-pup separation during lactation which is credited with causing starvation, the largest cause of pup mortality in grey seals. This is the first study to link endogenous oxytocin concentrations in wild mammalian mothers with any type of maternal behaviour. Oxytocin’s structure and function is widely conserved across mammalian mothers, including humans. Defining the impact the oxytocin system has on maternal behaviour highlights relationships that may occur across many individuals or species, and such behaviours heavily influence infant development and an individual’s lifetime reproductive success.

A human tendency to anthropomorphize is enhanced by oxytocin

In the course of human evolution, the brain has evolved into a highly sensitive detector of social signals. As a consequence of this socially driven adaptation, humans display a tendency to anthropomorphize, that is they attribute social meaning to non-social agents. The evolutionarily highly conserved hypothalamic peptide oxytocin (OXT) has been identified as a key factor attaching salience to socially relevant cues, but whether it contributes to spontaneous anthropomorphism is still elusive. In the present study involving 60 healthy female participants, we measured salivary OXT concentrations and explored the effect of a single intranasal dose of synthetic OXT (24 IU) or placebo (PLC) on anthropomorphic tendencies during participants׳ verbal descriptions of short video clips depicting socially and non-socially moving geometric shapes. Our results show that endogenous OXT concentrations at baseline positively correlated with the attribution of animacy to social stimuli. While intranasal OXT had no modulatory effect on arousal ratings and did not make the participants more talkative, the treatment boosted anthropomorphic descriptions specifically for social stimuli. In conclusion, we here provide first evidence indicating that spontaneous anthropomorphism in women is facilitated by oxytocin, thereby enabling a context-specific upregulation of the propensity to anthropomorphize environmental cues.