Plasma oxytocin levels in response to glucagon in patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls.

PURPOSE: We recently demonstrated an additional oxytocin (OT) deficiency in patients with arginine vasopressin (AVP) deficiency (central diabetes insipidus) by using 3,4-methylenedioxy-methamphetamine (MDMA) as a novel provocation test. However, the implication of the MDMA provocation test in clinical practice might be challenging. Glucagon effectively stimulates vasopressinergic neurons with a strong increase in plasma copeptin. We therefore hypothesized that this provocation test might also stimulate OT. METHODS: This is a predefined secondary analysis of a prospective double-blind, randomised, placebo-controlled cross-over trial involving ten patients with AVP deficiency and ten sex- and body-mass index-matched healthy participants at the University Hospital Basel, Switzerland. Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test (s.c. injection of 0.9% normal saline). Plasma OT levels were measured at baseline, 60, 120 and 180 min after injection. The primary objective was to determine whether glucagon stimulates OT and whether OT levels differ between patients with AVP deficiency and healthy participants. The primary outcome (maximum change in OT within 180 min) was compared between groups and conditions using a linear mixed effects model. RESULTS: In healthy participants, the median OT at baseline was 82.7 pg/ml [62.3-94.3] and slightly increased to a maximum of 93.3 pg/ml [87.2-121.1] after injection of glucagon, resulting in a change increase of 24.9 pg/ml [5.1-27.8]. Similarly, in patients with AVP deficiency, the median OT at baseline was 73.9 pg/ml [65.3-81.6] and slightly increased after glucagon injection to 114.9 pg/ml [70.9-140.9], resulting in a change increase of 36.8 pg/ml [-2.2 to 51.2]. The results from the mixed model showed no effect between glucagon compared to placebo on OT (difference: -0.5 pg/ml; 95%-CI [-25, 24]; p = 0.97) and no significant treatment-by-group interaction effect between patients compared to healthy participants (interaction: 28 pg/ml; 95%-CI [-7, 62]; p = 0.13). CONCLUSION: We found no effect of glucagon on plasma OT levels and no difference between patients with AVP deficiency and healthy participants.

Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency.

Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.

Oxytocin levels in response to pituitary provocation tests in healthy volunteers.

OBJECTIVE: Oxytocin, secreted into circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism; however, diagnostic testing for oxytocin deficiency has not been developed. The aim of this study was to investigate known pituitary provocation tests to stimulate plasma oxytocin. DESIGN: Sixty-five healthy volunteers underwent either the hypertonic saline or arginine infusion test, known to stimulate copeptin, or the oral macimorelin test, known to stimulate growth hormone. Plasma oxytocin was measured before and once plasma sodium level ≥ 150 mmol/L for the hypertonic saline, after 60 min for the arginine infusion, and after 45 min for the oral macimorelin test (expected peak of copeptin and growth hormone levels, respectively). Primary outcome was a change from basal to stimulated oxytocin levels using paired t-tests. RESULTS: As expected, copeptin increased in response to hypertonic saline and arginine infusion (P < 0.001), and growth hormone increased to oral macimorelin (P < 0.001). Oxytocin increased in response to hypertonic saline infusion from 0.4 (0.2) to 0.6 pg/mL (0.3) (P = 0.003) but with a high variance. There was no change to arginine infusion (P = 0.4), and a trend to lower stimulated levels to oral macimorelin (P = 0.05). CONCLUSION: Neither the arginine infusion nor the oral macimorelin test stimulates plasma oxytocin levels, whereas there was an increase with high variance upon hypertonic saline infusion. As a predictable rise in most participants is required for a reliable pituitary provocation test, none of the investigated pituitary provocation tests can be recommended diagnostically to identify patients with an oxytocin deficiency.

Oxytocin-MCH circuit regulates monosynaptic inputs to MCH neurons and modulates social recognition memory.

Oxytocin regulates social behaviors and has been linked to the etiology of autism and schizophrenia. Oxytocin and another hypothalamic neuropeptide, melanin concentrating hormone (MCH), share several physiological actions such as emotion, social behavior and recognition, maternal care, sexual behavior and stress, which suggests that these two systems may interact, however, how they would do it is not known. Here, we study the interactions between the oxytocin and MCH systems in behaviors related to autism and schizophrenia. Specifically, we examined the synaptic inputs of the oxytocin-to the MCH neurons. We selectively deleted oxytocin receptors (OXTR) from MCH neurons (OXTR-cKO mice) using a Cre/loxP recombinase-technology, and used rabies-mediated circuit mapping technique to reveal the changes in the direct monosynaptic inputs to MCH neurons. We examined the behavioral responses of OXTR-cKO mice. Deletion of OXTR from MCH neurons induced a significant decrease in the primary inputs received by MCH neurons from the paraventricular nucleus and the lateral hypothalamus, and from the nucleus accumbens and ventral tegmental area. While OXTR-cKO mice exhibited similar social interactions as control mice, they displayed significantly impaired social recognition memory and increased stereotypic behavior. Our study identifies a selective role for the oxytocin-MCH pathway in social recognition memory and stereotyped behavior that are relevant to psychiatric disorders such as schizophrenia and autism, and warrant further investigation of this circuit to uncover potential benefit of targeting the oxytocin-MCH circuit as a novel therapeutic target for treatment of social recognition deficits in these two disorders.

The New Frontier in Oxytocin Physiology: The Oxytonic Contraction.

Oxytocin (Oxt) is a nine amino acid peptide important in energy regulation and is essential to stress-related disorders. Specifically, low Oxt levels are associated with obesity in human subjects and diet-induced or genetically modified animal models. The striking evidence that Oxt is linked to energy regulation is that Oxt- and oxytocin receptor (Oxtr)-deficient mice show a phenotype characterized by late onset obesity. Oxt-/- or Oxtr-/- develop weight gain without increasing food intake, suggesting that a lack of Oxt reduce metabolic rate. Oxt is differentially expressed in skeletal muscle exerting a protective effect toward the slow-twitch muscle after cold stress challenge in mice. We hypothesized that Oxt potentiates the slow-twitch muscle as it does with the uterus, triggering "the oxytonic contractions". Physiologically, this is important to augment muscle strength in fight/flight response and is consistent with the augmented energetic need at time of labor and for the protection of the offspring when Oxt secretion spikes. The normophagic obesity of Oxt-/- or Oxtr-/- mice could have been caused by decreased skeletal muscle tonicity which drove the metabolic phenotype. In this review, we summarized our findings together with the recent literature on this fascinating subjects in a "new oxytonic perspective" over the physicology of Oxt.

Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder.

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

Relay of peripheral oxytocin to central oxytocin neurons via vagal afferents for regulating feeding.

Oxytocin (Oxt), a neurohormone synthesized in the neurons of hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus induces milk-ejection and uterine contraction and regulates social behavior, stress responses, memory and food intake. Peripheral (intraperitoneal and subcutaneous) infusion of Oxt decreases food intake and body weight in obese animals via mechanisms involving vagal afferent nerves and in obese subjects when administered nasally. Peripherally injected and intracerebroventricularly injected Oxt inhibit food intake to similar extent and with similar time course. Thus, peripheral Oxt mimics the effects of central Oxt, however, underlying mechanisms are unclear. In the present study we explored whether intraperitoneal Oxt activates Oxt neurons in PVN via vagal afferents and whether this pathway is linked to inhibition of feeding. We here show that intraperitoneal Oxt injection induces c-Fos expression in PVN largely in Oxt neurons and inhibits food intake, and these effects are blunted by subdiaphragmatic vagotomy. The intraperitoneal Oxt-induced inhibition of food intake was blunted in Oxt KO mice, by intracerebroventricular injection of Oxt receptor antagonist, and by vagotomy. These results demonstrate that intraperitoneal Oxt injection activates PVN Oxt neurons via vagal afferent nerves, thereby inhibiting food intake. This vagal afferents-mediated Oxt's peripheral-to-central coupling may serve to promote satiety and possibly a series of neural functions of Oxt and to treat their disorders.

Low Plasma Oxytocin Levels and Increased Psychopathology in Hypopituitary Men With Diabetes Insipidus.

CONTEXT: Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established. OBJECTIVES: We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology. DESIGN: Cross-sectional. SETTING: Clinical research center. PARTICIPANTS: Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years. INTERVENTIONS: Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology. MAIN OUTCOMES: Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life. RESULTS: The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009). CONCLUSIONS: We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency.

Oxytocin is indispensable for conspecific-odor preference and controls the initiation of female, but not male, sexual behavior in mice.

Oxytocin (OT) has been demonstrated to be involved in various social behaviors in mammals. However, OT gene knockout (OTKO) mice can conceive and deliver successfully, though females cannot rear their pups because of lack of lactation. Here, we investigated the sociosexual behavior of both sexes in two experimental setups: olfactory preference for sexual partner's odor and direct social interaction in an enriched condition. In the preference test, mice were given a choice of two airborne odors derived from intact male and receptive female mice, or from intact or castrated male mice. Wild-type (WT) mice significantly preferred opposite-sex odors, whereas OTKO mice showed vigorous but equivalent exploration to all stimuli. In social interactions in the enriched condition, no difference in sexual behavior was found between WT and OTKO males. In contrast, WT female initiated sexual behavior at the second week test, while OTKO females required 4 weeks to receive successful mounts. Neuronal activation by odor stimulation was compared between WT and OTKO mice. The numbers of cFos-immunoreactive cells increased in the medial amygdala and the preoptic area after exposure to opposite-sex odors in WT mice, whereas the increase was suppressed in OTKO mice. We conclude that OT plays an important role in the regulation of olfactory-related social behavior in both male and female mice. The influence of OT was greater in female mice, especially during social interactions involving the acquisition of sexual experience.

Oxytocin therapy in hypopituitarism: Challenges and opportunities.

Patients with hypopituitarism display impaired quality of life and excess morbidity and mortality, despite apparently optimal pituitary hormone replacement. Oxytocin is a neuropeptide synthesized in the anterior hypothalamus which plays an important role in controlling social and emotional behaviour, body weight and metabolism. Recent studies have suggested that a deficiency of oxytocin may be evident in patients with hypopituitarism and craniopharyngioma, and that this may be associated with deficits in cognitive empathy. Preliminary data hint at potential benefits of oxytocin therapy in improving these deficits and the accompanying metabolic disturbances that are common in these conditions. However, several challenges remain, including an incomplete understanding of the regulation and mechanisms of action of oxytocin, difficulties in accurately measuring oxytocin levels and in establishing a diagnosis of oxytocin deficiency, and a need to determine both the optimal mode of administration for oxytocin therapy and an acceptable safety profile with long-term use. This review considers the data linking oxytocin to the neuropsychological and metabolic disturbances evident in patients with craniopharyngioma and hypopituitarism, and describes the challenges that need to be overcome before replacement therapy can be considered as a therapeutic option in clinical practice.

Alterações na epigenética do sistema ocitocinérgico em resposta ao cuidado materno negligente / Epigenetics changes into the oxytocinergic system in response to negligent maternal care

O cuidado materno negligente, a falta de afeto e a dificuldade de interagir socialmente estão relacionadas com o desequilíbrio neurofisiológico da ocitocina, neurormônio com papel importante de modulação dos comportamentos sociais. Em seres humanos existem ligações conhecidas entre o estresse pré-natal e perinatal e transtornos psiquiátricos e de desenvolvimento. O objetivo deste estudo foi revisar o conceito de epigenética com foco no efeito a longo prazo do cuidado materno negligente e sua relação com alterações do sistema ocitocinérgico baseado em estudos com animais e humanos. Uma revisão narrativa da literatura foi realizada entre junho de 2017 e janeiro de 2019 através da busca de estudos na base PUBMED, com foco nos resultados qualitativos das relações epigenéticas com a negligência infantil, doenças psiquiátricas e sistema ocitocinérgico. Os estudos referidos demonstram que o cuidado materno negligente é um fator de risco para o desenvolvimento de transtornos mentais, principalmente os que incluem sintomas de desordem social. A ocitocina, por agir como uma potente mediadora das interações sociais, confiança e controle da ansiedade, parece ter papel fundamental neste contexto. A notória transgeracionalidade dos transtornos encontrados em proles de mães negligentes parece estar envolvida com mecanismos epigenéticos que inativam genes específicos do sistema ocitocinérgico no sistema nervoso central. (AU)

Negligent maternal care, lack of affection and difficulty in social interaction are related to a neurophysiological imbalance in oxytocin levels, an important modulator of social behaviors. In humans there are known links between prenatal and perinatal stress and psychiatric and developmental disorders. This study aimed to review the concept of epigenetics with a focus on the long-term effect of negligent maternal care and its relationship to changes in the oxytocinergic system, based on animal and human studies. A narrative review of the literature was conducted using studies from June 2017 to January 2019 available in the PUBMED database, focusing on qualitative results of epigenetic relationships with child neglect, psychiatric diseases and oxytocinergic system. These studies demonstrate that negligent maternal care is a risk factor for the development of mental disorders, especially those that include symptoms of social disorder. Oxytocin, as a neurohormone that acts as a potent mediator of social interactions, confidence and anxiety control, seems to play a fundamental role in this context. The notorious transgenerationality of the disorders found in the offspring of negligent mothers seems to be due to epigenetic mechanisms that inactivate specific genes of the oxytocinergic system in the central nervous system.

Oxytocin and the warm outer glow: Thermoregulatory deficits cause huddling abnormalities in oxytocin-deficient mouse pups.

Oxytocin is a social and reproductive hormone that also plays critical roles in a range of homeostatic processes, including thermoregulation. Here, we examine the role of oxytocin (OT) as a mediator of brown adipose tissue (BAT) thermogenesis, cold-induced huddling, and thermotaxis in eight-day-old (PD8) OT 'knock out' (OTKO) mouse pups. We tested OTKO and wildtype (WT) pups in single- and mixed-genotype groups of six, exposing these to a period of ambient warmth (~35°C) followed by a period of cold (~21.5°C). Whether huddling exclusively with other OTKO or alongside WT pups, OTKO pups showed reduced BAT thermogenesis and were significantly cooler when cold-challenged. Huddles of OTKO pups were also significantly less cohesive than WT huddles during cooling, suggesting that thermoregulatory deficits contribute to contact abnormalities in OTKO pups. To further explore this issue, we examined thermotaxis in individuals and groups of four OTKO or WT pups placed on the cool end of a thermocline and permitted to freely locomote for 2h. When tested individually, male OTKO pups displayed abnormal thermotaxis, taking significantly longer to move up the thermocline and settling upon significantly lower temperatures than WT pups during the 2h test. OTKO mouse pups thus appear to have deficits in both thermogenesis and thermotaxis-the latter deficit being specific to males. Our results add to a growing body of work indicating that OT plays critical roles in thermoregulation and also highlight the entanglement of social and thermoregulatory processes in small mammals such as mice.

[Oxytocin in the treatment of the social deficits associated to autism spectrum disorders]. / La oxitocina en el tratamiento de los déficits sociales asociados a los trastornos del espectro autista.

INTRODUCTION: The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD). AIMS: To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field. DEVELOPMENT: Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin. CONCLUSION: The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime.

TITLE: La oxitocina en el tratamiento de los deficits sociales asociados a los trastornos del espectro autista.Introduccion. La implicacion de la oxitocina en la conducta social de animales y humanos ha llevado a estudiar los efectos de su administracion en el comportamiento y cognicion social de pacientes con trastornos del espectro autista (TEA). Objetivos. Revisar la investigacion sobre el potencial terapeutico de la oxitocina en el tratamiento de los deficits sociales de la poblacion con TEA y discutir las probables direcciones futuras de los estudios en este campo. Desarrollo. Diversos trabajos han relacionado la oxitocina con la fisiopatologia de los TEA. La mayoria de los estudios que han administrado oxitocina, generalmente por via intranasal (24 UI), ha observado mejoras significativas en el rendimiento social, sin detectar efectos secundarios destacables. No obstante, existen datos contradictorios debido a la heterogeneidad de las variables analizadas por los diferentes estudios, al uso de muestras heterogeneas y pequeñas o a la diferente duracion de los tratamientos. Las limitaciones relacionadas con la falta de comprension de los mecanismos de accion de la oxitocina y la diversidad sintomatologica de los TEA dificultan el establecimiento de este peptido como tratamiento de los pacientes autistas. Estudios recientes destacan la conveniencia de explorar el efecto de la combinacion del tratamiento de oxitocina con programas conductuales de intervencion en habilidades sociales, asi como la potenciacion de la secrecion endogena de oxitocina. Conclusiones. Los efectos de la administracion de oxitocina resultan prometedores en relacion con el tratamiento de los deficits sociales en individuos con TEA. Estudios futuros deberian facilitar la comprension de las vias de accion de la oxitocina y el establecimiento de pautas optimas de tratamiento.

Oxytocin and bone.

One of the most meaningful results recently achieved in bone research has been to reveal that the pituitary hormones have profound effect on bone, so that the pituitary-bone axis has become one of the major topics in skeletal physiology. Here, we discuss the relevant evidence about the posterior pituitary hormone oxytocin (OT), previously thought to exclusively regulate parturition and breastfeeding, which has recently been established to directly regulate bone mass. Both osteoblasts and osteoclasts express OT receptors (OTR), whose stimulation enhances bone mass. Consistent with this, mice deficient in OT or OTR display profoundly impaired bone formation. In contrast, bone resorption remains unaffected in OT deficiency because, even while OT stimulates the genesis of osteoclasts, it inhibits their resorptive function. Furthermore, in addition to its origin from the pituitary, OT is also produced by bone marrow osteoblasts acting as paracrine-autocrine regulator of bone formation modulated by estrogens. In turn, the power of estrogen to increase bone mass is OTR-dependent. Therefore, OTR(-/-) mice injected with 17ß-estradiol do not show any effects on bone formation parameters, while the same treatment increases bone mass in wild-type mice. These findings together provide evidence for an anabolic action of OT in regulating bone mass and suggest that bone marrow OT may enhance the bone-forming action of estrogen through an autocrine circuit. This established new physiological role for OT in the maintenance of skeletal integrity further suggests the potential use of this hormone for the treatment of osteoporosis.

Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin.

Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.

Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters.

OBJECTIVE: Preclinical data indicate that oxytocin, a hormone produced in the hypothalamus and secreted into the peripheral circulation, is anabolic to bone. Oxytocin knockout mice have severe osteoporosis, and administration of oxytocin improves bone microarchitecture in these mice. Data suggest that exercise may modify oxytocin secretion, but this has not been studied in athletes in relation to bone. We therefore investigated oxytocin secretion and its association with bone microarchitecture and strength in young female athletes. DESIGN: Cross-sectional study of 45 females, 14-21 years (15 amenorrheic athletes (AA), 15 eumenorrheic athletes (EA), and 15 nonathletes (NA)), of comparable bone age and BMI. METHODS: We used high-resolution peripheral quantitative CT to assess bone microarchitecture and finite element analysis to estimate bone strength at the weight-bearing distal tibia and non-weight-bearing ultradistal radius. Serum samples were obtained every 60  min, 2300-0700  h, and pooled for an integrated measure of nocturnal oxytocin secretion. Midnight and 0700  h samples were used to assess diurnal variation of oxytocin. RESULTS: Nocturnal oxytocin levels were lower in AA and EA than in NA. After controlling for estradiol, the difference in nocturnal oxytocin between AA and NA remained significant. Midnight and 0700  h oxytocin levels did not differ between groups. At the tibia and radius, AA had impaired microarchitecture compared with NA. In AA, nocturnal oxytocin correlated strongly with trabecular and cortical microarchitecture, particularly at the non-weight-bearing radius. In regression models that include known predictors of microarchitecture in AA, oxytocin accounted for a substantial portion of the variability in microarchitectural and strength parameters. CONCLUSIONS: Nocturnal oxytocin secretion is low in AA compared with NA and associated with site-dependent microarchitectural parameters. Oxytocin may contribute to hypoestrogenemic bone loss in AA.

Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass.

OBJECTIVE: Anorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data show that oxytocin has an anabolic effect on bone and stimulates osteoblast function. There is limited information about oxytocin levels or their relationship to decreased bone mineral density in anorexia nervosa. Our objective was to investigate the relationship between oxytocin levels, bone mineral density, and body composition in women with anorexia nervosa. METHOD: We studied 36 women, mean ± SEM age 27.6 ± 1.3 years: 17 with DSM-IV anorexia nervosa and 19 healthy controls in a cross-sectional study. Oxytocin levels were determined from pooled serum samples obtained every 20 minutes from 8 pm to 8 am during an inpatient overnight visit. Fasting leptin levels were measured. Bone mineral density at the anterior-posterior and lateral spine and hip and body composition were assessed by dual energy x-ray absorptiometry. The study was conducted from September 2004 to June 2008. RESULTS: Subjects with anorexia nervosa versus healthy controls had lower mean ± SEM oxytocin levels (14.3 ± 1.5 vs 31.8 ± 5.1 pg/mL, P = .003), leptin levels (2.7 ± 0.5 vs 11.4 ± 1.1 ng/mL, P < .0001), bone mineral density (anterior-posterior spine: 0.83 ± 0.02 vs 1.04 ± 0.03; lateral spine: 0.63 ± 0.02 vs 0.81 ± 0.02; total hip: 0.79 ± 0.03 vs 0.97 ± 0.03 g/cm², P < .0001), and fat mass (8.8 ± 0.6 vs 19.7 ± 0.9 kg, P < .0001). Oxytocin levels were associated with bone mineral density at the anterior-posterior (r = 0.40, P = .02) and lateral (r = 0.36, P = .04) spine, fat mass (r = 0.42, P = .01), and leptin levels (r = 0.55, P = .001). CONCLUSIONS: Overnight secretion of oxytocin in women with anorexia nervosa is decreased compared with healthy women. Low oxytocin levels are associated with decreased bone mineral density and body fat and may contribute to anorexia nervosa-induced bone loss.

Plasma oxytocin concentration during pregnancy is associated with development of postpartum depression.

Postpartum depression (PPD) affects up to 19% of all women after parturition. The non-apeptide oxytocin (OXT) is involved in adjustment to pregnancy, maternal behavior, and bonding. Our aim was to examine the possible association between plasma OXT during pregnancy and the development of PPD symptoms. A total of 74 healthy, pregnant women were included in this prospective study. During the third trimester of pregnancy and within 2 weeks after parturition, PPD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Blood samples for plasma OXT assessment were collected in the third trimester. Following the literature, participants with postpartum EPDS scores of 10 or more were regarded as being at risk for PPD development (rPPD group). In a logistic regression analysis, plasma OXT was included as a potential predictor for being at risk for PPD. Results were controlled for prepartal EPDS score, sociodemographic and birth-outcome variables. Plasma OXT concentration in mid-pregnancy significantly predicted PPD symptoms at 2 weeks postpartum. Compared with the no-risk-for-PPD group, the rPPD group was characterized by lower plasma OXT concentrations. To our knowledge, this is the first study to show an association between prepartal plasma OXT concentration and postpartal symptoms of PPD in humans. Assuming a causal relationship, enhancing OXT release during pregnancy could serve as a potential target in prepartum PPD prevention, and help to minimize adverse effects of PPD on the mother-child relationship.

Defective oxytocin function: a clue to understanding the cause of autism?

The autism spectrum disorders are a group of conditions with neurobehavioral impairment affecting approximately 0.6% of children. The clinical presentation is complex and the etiology is largely unknown, although a major role of genetic factors is widely accepted. A number of genetic studies led to the identification of genes and/or copy number variants whose alterations are associated with autism, but no specific factor has been found so far to be responsible for a substantial proportion of cases. Epigenetic modifications may also play a role, as demonstrated by the occurrence of autism in genetic conditions caused by mutations in imprinted genes or regions.The article by Gregory et al. published this month in BMC Medicine, reports on genomic and epigenetic alterations of OXTR, the gene encoding the receptor for oxytocin. The involvement of this gene was suggested by its deletion in an autistic patient. The subsequent analysis of a group of unrelated autistic subjects did not show an OXTR deletion, but rather hypermethylation of the gene promoter, with a reduced mRNA expression.These findings address two major points of the current debate on the etiology and pathogenesis of autism: the role of oxytocin, known to be involved in modeling human behavior, and the possible involvement of epigenetic mechanisms. The nature of this epigenetic dysregulation is unknown but, if proved to be true, might explain the failure to identify sequence alterations in a host of candidate genes. Practical implications of these findings may be forthcoming, however not before extension and validation on a larger scale have confirmed their value.See the associated research paper by Gregory et al: http://www.biomedcentral.com/1741-7015/7/62.