Oxytocin Efficacy Research Articles

Interaction between time-of-day and oxytocin efficacy in mice and humans with and without gestational diabetes.

Management of labor in women with diabetes is challenging due to the high risk of peri- and postpartum complications. To avoid cesarean section and assist with labor progression, Pitocin, a synthetic oxytocin, is frequently used to induce and augment labor. However, the efficacy of Pitocin is often compromised in diabetic pregnancies, leading to increased cesarian delivery. As diabetes deregulates the body's circadian timekeeping system and the time-of-day of the first Pitocin administration contributes to labor duration, our objective was to determine how the time of day and the circadian clock gene, Bmal1 , gates oxytocin efficacy. Our studies in mice show that, compared to the rest phase of the day (lights on), the uterotonic efficacy of oxytocin is significantly increased during the active phase (lights off). Using in vitro studies, a myometrium-specific Bmal1 conditional knockout mouse model, and a mouse model of food-induced gestational diabetes, we find that Bmal1 is crucial for maintaining oxytocin receptor expression and response in the myometrium in mice. These findings also translate to humans, where oxytocin-induced human myometrial cell contraction is time-of-day dependent, and retrospective clinical data suggest that administration of Pitocin in the morning should be considered for pregnant women with gestational diabetes.

Comparison of Carbetocin and Oxytocin Efficacy in Preventing Postpartum Hemorrhage after C-Section

Introduction: Postpartum hemorrhage (PPH) is defined as a blood loss of more than 0.5 liters within 24 hours of birth, and a blood loss of more than 1 liter is considered a significant PPH. In low- and middle-income countries, PPH is a major factor causing maternal morbidity and mortality, whereas in high-income countries, the mortality is comparatively lower, but still PPH poses a major risk for postpregnancy complications. Uterine atony is the most frequent cause of the PPH, and it accounts for up to 80% of PPH cases. Aim: The aim of this study is to examine the prophylactic effects of oxytocin and carbetocin in preventing atonic PPH in individuals receiving recurrent elective CS under spinal anesthesia. Materials and Methods: A computerized, randomized, cross-sectional prospective comparative study was conducted on 100 pregnant women at Konaseema Institute of Medical Sciences and Research Foundation for the time period of an year, from October 2020 to October 2021. Inclusion Criteria: This study includes patients with singleton pregnancy, gestational age >38 weeks, spinal anesthesia and repeated C.S with cephalic, breech, or any malpresentations. Exclusion Criteria: Patients with placenta previa and placental abruption, uterine myomata, congenital uterine anomalies, gestational age before 38 weeks, women having emergency cesarean section for fetal or maternal distress, and patients with hepatic or pre-existing bleeding disorder were excluded from the study. The patients included based on the above criteria were split into two equal groups. Group I received carbetocin as a single dose of 100 microgram slow intravenous, and Group II received oxytocin as 5 IU intravenous drip followed by 20 IU of oxytocin infusion on 500 ml saline or lactated ringer with a rate of 150 ml per hour. Results: When compared to the oxytocin group, the blood loss was considerably reduced in the carbetocin group. The levels of Hb and hematocrit [HCT] were evaluated pre- and postoperative in both the groups. The levels of preoperative Hb and HCT showed nonsignificant difference between the two groups, while the levels of postoperative Hb and HCT were significantly higher in carbetocin group than oxytocin group concluding that carbetocin showed the better results in controlling the blood loss and maintaining the levels of Hb and HCT volume and the carbetocin group showed less need for administration of uterotonic agents (20%) in comparison with (32%) in oxytocin group but with no statistically significant difference. Only 8 (16%) patients showed PPH in carbetocin treatment, whereas 14 (28%) showed PPH in patients on oxytocin treatment.

Oxytocin in the Treatment of Psychiatric Disorders.

Oxytocin is a peptide hormone that is most known for its role in reproduction. However, many effects other than reproduction have been defined. The lifetime prevalence of mental disorders is approximately 20%, and they have a significant ratio among the diseases that lead to disability. Treatment resistance may cause the mental disorder to become chronic and increase disability. With the examination of the oxytocinergic system, both the elucidation of the etiology of the diseases and their evaluation as a new treatment option have come to the fore. In various studies, it has been desired to create a more effective treatment model by measuring the level of oxytocin in psychiatric disorders, examining its receptor, and applying exogenous oxytocin in the treatment. In this review, an overview of oxytocin's efficacy in treatment is presented by considering the relationship between psychiatric disorders and the oxytocinergic system.

RETRACTED ARTICLE: Oxytocin versus a combination of tranexamic acid and ethamsylate in reducing intraoperative bleeding during abdominal myomectomy: a randomized clinical trial

ObjectiveMyomectomy is the preferred surgical approach to manage uterine fibroids. However, uterine fibroids are highly vascular tumors and, consequently, extremely susceptible to problems from myomectomy-related hemorrhage. Hence, we aim to compare oxytocin efficacy and safety profile versus tranexamic acid (TA) with ethamsylate for reducing bleeding during myomectomy.MethodsThis randomized, double-blinded multicenter study was performed between 20th August 2020 and 20th October 2020 at El-Galaa Teaching Hospital, El Hussein University Hospital, Al-Azhar University Hospitals of Assiut, and Al-Azhar University Hospitals of Damietta. One hundred and eighty patients were enrolled and divided into three groups: group (1) received an injection of 30 IU of oxytocin in 500 ml of normal saline; group (2) received injections of 1 g of TA, 250 mg of Ethamsylate, and 110 ml of normal saline IV; and group (3) received an injection of 110 ml of normal saline IV just before surgical incision.ResultsIn 180 premenopausal women, oxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy (666.25 ± 183.03, 630.72 ± 145.83, and 646.67 ± 168.92, respectively (P = 0.506)). Non-significant trends were observed for a reduction in operation time (P = 0.760), intra/postoperative blood transfusion (P = 0.624), hospital stay (P = 0.986), postoperative fever (P = 0.659), and wound infection (P = 1).ConclusionOxytocin and TA with ethamsylate had no significant value in lowering intraoperative blood loss compared with the placebo for abdominal myomectomy which opens a new question about the role of the use of the hemostatic drug during myomectomy especially in centers with limited resources and had higher rates.Trial registrationThe study was registered on Pan African Clinical Trials Registry with the following number: PACTR202008739887429 and was approved on 24/08/2020.

A randomized, double-blind, placebo-controlled clinical trial of 8-week intranasal oxytocin administration in adults with obesity: Rationale, study design, and methods

BackgroundObesity affects more than one-third of adults in the U.S., and effective treatment options are urgently needed. Oxytocin administration induces weight loss in animal models of obesity via effects on caloric intake, energy expenditure, and fat metabolism. We study intranasal oxytocin, an investigational drug shown to reduce caloric intake in humans, as a potential novel treatment for obesity. MethodsWe report the rationale, design, methods, and biostatistical analysis plan of a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin for weight loss (primary endpoint) in adults with obesity. Participants (aged 18–45 years) were randomly allocated (1:1) to oxytocin (four times daily over eight weeks) versus placebo. Randomization was stratified by biological sex and BMI (30 to <35, 35 to <40, ≥40 kg/m2). We investigate the efficacy, safety, and mechanisms of oxytocin administration in reducing body weight. Secondary endpoints include changes in resting energy expenditure, body composition, caloric intake, metabolic profile, and brain activation via functional magnetic resonance imaging in response to food images and during an impulse control task. Safety and tolerability (e.g., review of adverse events, vital signs, electrocardiogram, comprehensive metabolic panel) are assessed throughout the study and six weeks after treatment completion. ResultsSixty-one male and female participants aged 18–45 years were randomized (mean age 34 years, mean BMI 37 kg/m2). The study sample is diverse with 38% identifying as non-White and 20% Hispanic. ConclusionInvestigating intranasal oxytocin's efficacy, safety, and mechanisms as an anti-obesity medication will advance the search for optimal treatment strategies for obesity and its associated severe sequelae.

Impact of Magnesium on Oxytocin Receptor Function.

Simple SummaryWhat is already known: Mg2+ levels modulate the affinity of oxytocin receptors for oxytocin in vitro, low serum Mg2+ is correlated with migraine headache onset. What this study adds: Electrophysiologic and behavioral assays demonstrate that Mg2+ increases the efficacy of oxytocin; oxytocin efficacy is limited by Mg2+ availability. Clinical significance: Modulating Mg2+ levels may enhance oxytocin efficacy for pain, other uses, and endogenous processes.Background and Purpose: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to the activation of the OTR, and a low serum Mg2+ concentration is predictive of a migraine headache. We, therefore, examined the functional impact of Mg2+ concentration on OT-OTR binding efficacy using two complimentary bioassays. Experimental Approach: Current clamp recordings of rat trigeminal ganglia (TG) neurons measured the impact of Mg2+ on an OT-induced reduction in excitability. In addition, we assessed the impact of Mg2+ on intranasal OT-induced craniofacial analgesia in rats. Key Results: While OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, the addition of 1.75 mM Mg2+ significantly enhanced this effect. Similarly, while the intranasal application of OT produced dose-dependent craniofacial analgesia, Mg2+ significantly enhanced these effects. Conclusions and Implications: OT efficacy may be limited by low ambient Mg2+ levels. The addition of Mg2+ to OT formulations may improve its efficacy in reducing headache pain as well as for other OT-dependent processes.

Oxytocin Receptor Activation Rescues Opioid-Induced Respiratory Depression by Systemic Fentanyl in the Rat.

Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v.) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest (P = 0.0057) and restoring baseline burst frequency (P = 0.0016) and amplitude (P = 0.0025) at low but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (arrest: P = 0.0066, frequency: P = 0.0207, amplitude: P = 0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD (P = 0.0170 to P < 0.0001), resulting in classic sigmoidal dose-response curves, and prevented (P = 0.0135) transient hypertension from V1aR cross-activation (P = 0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest (P = 0.6184). The nonpeptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD (P < 0.0001), with rapid recovery of PNA frequency (P = 0.0011) and amplitude (P = 0.0044) without adverse hemodynamic consequences (P = 0.9991). Findings indicate that peptide and nonpeptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia. SIGNIFICANCE STATEMENT: Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the US Food and Drug Administration-approved agonist oxytocin and the nonpeptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms

BackgroundOxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown.MethodsThe current study explored metabolites representing the molecular mechanisms of oxytocin’s efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial.ResultsAmong the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = − 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37).LimitationsThe metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes.ConclusionOur findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin’s efficacy.Trial registration: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703) (UMIN000015264).

Oxytocin, Tolerance, and the Dark Side of Addiction.

Substance use disorders blight the lives of millions of people and inflict a heavy financial burden on society. There is a compelling need for new pharmacological treatments as current drugs have limited efficacy and other major drawbacks. A substantial number of animal and recent clinical studies indicate that the neuropeptide, oxytocin, is a particularly promising therapeutic agent for human addictions, especially alcohol use disorders. In preliminary trials, we found that oxytocin administered by the intranasal route, which produces some neuropeptide penetration into the CNS, potently blocked withdrawal and reduced alcohol consumption in heavy drinkers. A considerable body of earlier animal studies demonstrated that oxytocin inhibits tolerance to alcohol, opioids, and stimulants as well as withdrawal from alcohol and opioids. Based on these preclinical findings and our clinical results, we hypothesize that oxytocin may exert therapeutic effects in substance dependence by the novel mechanism of diminishing established tolerance. A newer wave of studies has almost unanimously found that oxytocin decreases self-administration of a number of addictive substances in several animal models of addiction. Reduction of established tolerance should be included among the potential explanations of oxytocin effects in these studies and changes in tolerance should be examined in future studies in relationship to oxytocin influences on acquisition and reinstatement of self-administration as well as extinction of drug seeking. Oxytocin efficacy in reducing anxiety and stress responses as well as established tolerance suggests it may be uniquely effective in reducing negative reinforcement (Koob's "dark side" of addiction) that maintains chronic substance use.

Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism.

Oxytocin appears beneficial for autism spectrum disorder (ASD), and more than 20 single-nucleotide polymorphisms (SNPs) in oxytocin receptor (OXTR) are relevant to ASD. However, neither biological functions of OXTR SNPs in ASD nor critical OXTR SNPs that determine oxytocin’s effects on ASD remains known. Here, using a machine-learning algorithm that was designed to evaluate collective effects of multiple SNPs and automatically identify most informative SNPs, we examined relationships between 27 representative OXTR SNPs and six types of behavioral/neural response to oxytocin in ASD individuals. The oxytocin effects were extracted from our previous placebo-controlled within-participant clinical trial administering single-dose intranasal oxytocin to 38 high-functioning adult Japanese ASD males. Consequently, we identified six different SNP sets that could accurately predict the six different oxytocin efficacies, and confirmed the robustness of these SNP selections against variations of the datasets and analysis parameters. Moreover, major alleles of several prominent OXTR SNPs—including rs53576 and rs2254298—were found to have dissociable effects on the oxytocin efficacies. These findings suggest biological functions of the OXTR SNP variants on autistic oxytocin responses, and implied that clinical oxytocin efficacy may be genetically predicted before its actual administration, which would contribute to establishment of future precision medicines for ASD.

Peripheral oxytocin administration reduces ethanol consumption in rats

The neuropeptide oxytocin interacts with mesolimbic dopamine neurons to mediate reward associated with filial behaviors, but also other rewarding behaviors such as eating or taking drugs of abuse. Based on its efficacy to decrease intake of other abused substances, oxytocin administration is implicated as a possible treatment for excessive alcohol consumption. We tested this hypothesis by measuring ethanol intake in male Sprague–Dawley rats injected with oxytocin or saline using two different ethanol self-administration paradigms. First, a dose–response curve was constructed for oxytocin inhibition of fluid intake using a modified drinking-in-the-dark model with three bottles containing .05% saccharine, 10% ethanol in saccharine, and 15% ethanol in saccharine. Doses of oxytocin tested were 0.05, 0.1, 0.3, and 0.5mg/kg (I.P.). Next, rats received 0.3mg/kg oxytocin preceding operant sessions in which they were trained to lever-press for either plain gelatin or ethanol gelatin in order to compare oxytocin inhibition of ethanol intake versus caloric intake. For the three-bottle choice study, rats consumed significantly less ethanol when treated with the three higher doses of oxytocin on the injection day. In the operant study, 0.3mg/kg oxytocin significantly decreased ethanol gel consumption to a greater extent than plain gel consumption, both in terms of the amount of gel eaten and calories consumed. These data affirm oxytocin's efficacy for decreasing ethanol intake in rats, and confirm clinical studies suggesting oxytocin as a potential treatment for alcoholism.

Longitudinal assessment of oxytocin efficacy on bone and bone marrow fat masses in a rabbit osteoporosis model through 3.0-T magnetic resonance spectroscopy and micro-CT.

This study aims to longitudinally assess the effect of oxytocin on bone and bone fat masses using micro-CT, in vivo magnetic resonance spectroscopy (MRS), and histopathological adipocyte quantification. Early in vivo oxytocin (OT) treatment to the osteoporosis (OP) rabbit model may reliably inhibit bone degeneration and reduce bone marrow fat accumulation by decreasing marrow adipocyte size and density. This study aims to longitudinally assess the effect of early OT treatment on bone and bone fat masses in a rabbit OP model by comparing the results of MRS and micro-CT with histopathological findings. Sixty 20-week-old female rabbits were randomly assigned into three groups. The control and OP groups were subjected to either sham surgery or bilateral ovariectomy (OVX). The OT group was subcutaneously injected with OT daily from the second week after OVX for 8 weeks. The left proximal femurs of the rabbits were evaluated through MRS, micro-CT, and histopathological examination at 0, 4, 8, 10, and 12 weeks after operation. Differences in fat fraction (FF) values, micro-CT parameters, and calculated pathological marrow adipocytes among three groups were analyzed. The FF values of the OP group significantly increased (p = 0.019), but the tissue mineral density (TMD) decreased (p = 0.037) from eighth week compared with those of the control group. The FF values of the OT group significantly decreased (p = 0.044), but the TMD values increased (p = 0.042) from eighth week compared with those of the OP group. The adypocyte diameter of the OT group significantly decreased (p = 0.041) from eighth week and then adypocyte density did so too from tenth week, compared with those of the OP group at the same time point. No difference in adypocyte calculation was found between the OT and control groups until the 12th week after operation. Early in vivo OT treatment slowed down bone deterioration and reduced bone marrow adiposity accumulation in a rabbit OP model, which is consistent with pathologic findings. OT treatment is a promising preventive OP therapy.

The oxytocin paradox

In 2005, Kosfeld et al. published their now seminal paper showing that intranasal oxytocin (OXT) administration increased interpersonal trust (Kosfeld et al., 2005). This finding spawned broad interest into the effects of OXT on social and emotional behavior in humans (Bos et al., 2012), and its implications for translational medicine (Meyer-Lindenberg et al., 2011; Striepens et al., 2011). Over the years OXT has gained the reputation of facilitating empathy and affiliation, based on early findings reporting beneficial effects of OXT on trust (Kosfeld et al., 2005), social support (Heinrichs et al., 2003), and processing social information (Hollander et al., 2007; Savaskan et al., 2008; Unkelbach et al., 2008; Hurlemann et al., 2010). This view is supported by studies showing that OXT improves cognitive empathic abilities such as mindreading (Domes et al., 2007; Bartz et al., 2010; Guastella et al., 2010) and recognizing positive emotional expressions (Marsh et al., 2010). As a result of these positive effects on social behavior, there has been considerable speculation about OXT's therapeutic potential in people with social and emotional disabilities. This prosocial view of OXT has been challenged by findings showing that the effects of OXT are strongly context-dependent (Bartz et al., 2011; Bos et al., 2012). For example, OXT has also been shown to increase envy and gloating (Shamay-Tsoory et al., 2009), defensiveness toward out-group members (De Dreu et al., 2010, 2011) and increased in-group conformity (Stallen et al., 2012). Although this ethnocentrism might be considered prosocial within one's own group, defensiveness toward an out-group is not, and extreme ethnocentrism often leads to nationalism or even racism. This paradox gives rise to two questions. First, how can the beneficial effects of OXT on empathy, trust and affiliation be compatible with its seemingly contradictory anti-social effects? Second, what implication does this have for the therapeutic potential of OXT in social and emotional neurodevelopmental conditions? With regard to the first question, we provide a brief overview of the literature aiming to understand the mechanism(s) underlying OXT's efficacy. There are two main perspectives on how OXT affects social behavior (via anxiety reduction or increasing social salience), which try to reconcile its pro- and anti-social roles, but there have been no attempts to date to integrate these into a single viewpoint. A potential third factor, reward sensitivity might aid this integration. We propose a model that unites these perspectives, providing new avenues of research into OXT's efficacy in social and emotional neurodevelopmental conditions.

Oxytocin Dosage in Turtles

Oxytocin dosage was determined experimentally for the red-eared slider (Trachemys scripta elegans). Five dosages including 20, 10, 5, 4, and 2 units/kg were experimentally compared in 253 female turtles in a series of experiments conducted in 1999 and 2000. The 3 highest doses were equally effective overall following a maximum of 2 injections. The 2 lower doses were equally effective overall following a maximum of 2 injections. Success rate (i.e., turtles laid all eggs or retained 2 or fewer eggs following a maximum of 2 injections) ranged from 100% (20 and 10 unit/kg doses) to an average of 88.9% for the lowest doses (4 and 2 units/kg). When reduction in oxytocin exposure is desired, the lower dosages are recommended; when turtles are being treated for egg retention, the higher dosages may be more desirable. No difference in oxytocin efficacy was found among 3 species of chelonians (red-eared slider; stinkpot, Sternotherus odoratus; and painted turtle, Chrysemys picta) when oxytocin was given at 4 units/kg. No difference in efficacy was found among 2669 red-eared sliders from 2 collecting areas in west-central Illinois induced with 4 units/kg between 2000 and 2005.