Pulses Of Oxytocin Research Articles

Sensory Stimulation of Oxytocin Release Is Associated With Stress Management and Maternal Care.

It has been shown that various types of stress initiate different physiological and neuroendocrine disorders. Oxytocin (OT) is mainly produced in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. Hypothalamic OT has antistress effects and attenuates the hypothalamic–pituitary–adrenal (HPA) axis. One mechanism behind the antistress effects of OT is mediated through the inhibition from GABAA receptors on corticotropin-releasing factor (CRF) expression at the PVN. Various manual therapies such as acupuncture, transcutaneous electrical nerve stimulation (TENS), and massage initiate the stimulation of somatosensory neurons of the body. It is well-known that TENS simulates OT expression, while it inhibits CRF expression at the PVN following chronic stress loading in rodents. Upregulation of OT expression at the hypothalamus is activated by the somatosensory stimulation, which is mediated via the spinothalamic pathway (the connection between the spinal cord and hypothalamus). Thus, somatosensory stimulation is beneficial in treating stress-associated symptoms. Hypothalamic OT is associated with the social behaviors, including maternal care and affiliation. Childhood neglect and/or child abuse are severely responsible for deleterious long-term effects on the cognitive/social activity and behavioral development. At parturition, a profound amount of OT is released into the systemic circulation in response to vaginal and cervical stimulation caused by the body of fetus, which induces the onset of maternal behavior. Peridural anesthesia effectively impairs the sensitivity to vaginal and cervical stimulation at parturition. OT levels in cerebrospinal fluid is significantly reduced following peridural anesthesia. The vaginal delivery mothers had significantly more OT pulses than the caesarian section (CS) mothers. Due to low levels of endogenous OT, maternal behavior could be interrupted by epidural anesthesia and CS at parturition because of the reduction of the usual sensory input from the genitalia.

Maternal plasma levels of oxytocin during breastfeeding-A systematic review.

IntroductionOxytocin is a key hormone in breastfeeding. No recent review on plasma levels of oxytocin in response to breastfeeding is available.Materials and methodsSystematic literature searches on breastfeeding induced oxytocin levels were conducted 2017 and 2019 in PubMed, Scopus, CINAHL, and PsycINFO. Data on oxytocin linked effects and effects of medical interventions were included if available.ResultsWe found 29 articles that met the inclusion criteria. All studies had an exploratory design and included 601 women. Data were extracted from the articles and summarised in tables. Breastfeeding induced an immediate and short lasting (20 minutes) release of oxytocin. The release was pulsatile early postpartum (5 pulses/10 minutes) and coalesced into a more protracted rise as lactation proceeded. Oxytocin levels were higher in multiparous versus primiparous women. The number of oxytocin pulses during early breastfeeding was associated with greater milk yield and longer duration of lactation and was reduced by stress. Breastfeeding-induced oxytocin release was associated with elevated prolactin levels; lowered ACTH and cortisol (stress hormones) and somatostatin (a gastrointestinal hormone) levels; enhanced sociability; and reduced anxiety, suggesting that oxytocin induces physiological and psychological adaptations in the mother. Mechanical breast pumping, but not bottle-feeding was associated with oxytocin and prolactin release and decreased stress levels. Emergency caesarean section reduced oxytocin and prolactin release in response to breastfeeding and also maternal mental adaptations. Epidural analgesia reduced prolactin and mental adaptation, whereas infusions of synthetic oxytocin increased prolactin and mental adaptation. Oxytocin infusion also restored negative effects induced by caesarean section and epidural analgesia.ConclusionsOxytocin is released in response to breastfeeding to cause milk ejection, and to induce physiological changes to promote milk production and psychological adaptations to facilitate motherhood. Stress and medical interventions during birth may influence these effects and thereby adversely affect the initiation of breastfeeding.

Maternal plasma levels of oxytocin during physiological childbirth \u2013 a systematic review with implications for uterine contractions and central actions of oxytocin

BackgroundOxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies.MethodsAn a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects.ResultsBasal levels of oxytocin increased 3–4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum.Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin.ConclusionsPlasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother’s brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Oxytocin secretion is pulsatile in men and is related to social-emotional functioning

The hypothalamic hormone oxytocin (OXT) plays an important role in a range of physiological processes and social-emotional functioning in both sexes. In women, physiological stimuli, such as suckling and parturition, result in pulsatile release of OXT into the peripheral circulation via the posterior pituitary gland. However, data regarding OXT secretory patterns in men during a state of rest are limited. Further, the relationship between secretory dynamics of OXT and emotional measures has never been evaluated. We hypothesized a pulsatile pattern of OXT secretion in men, and explored the relationship between OXT secretory patterns and social-emotional functioning. MethodsDeconvolution analysis was performed on serum OXT levels obtained every 5min over a period of 10h in 5 healthy normal weight men. Area under the curve (AUC), average OXT values, and pulse characteristics [pulse number, inter-pulse interval, pulse height and mass (area under each pulse)] were calculated. State Adult Attachment Measure (SAAM) assessed types of human attachment. Interpersonal Support Evaluation List (ISEL) assessed perception of social support. Toronto Alexithymia Scale (TAS-20) measured the ability to express and identify one’s own emotions. ResultsMean age was 22.8±1.2years, and BMI was 21.7±0.4kg/m2 (mean±SEM). Assuming a basal secretion of zero and a half life of five to seven minutes, we demonstrated the following: OXT AUC: 5421±1331pg/ml, mean OXT level: 9.1pg/ml, mean pulse number: 22±3/10hr, mean pulse height: 1.81±0.48pg/ml, mean pulse mass: 30.34±10.29pg/ml and mean inter-pulse interval: 27±4min. The SAAM Avoidant scale correlated negatively with mean OXT pulse height (r=−0.90, p=0.04) and pulse mass (r=−0.95, p=0.01). The ISEL Belonging score correlated positively with OXT AUC (r=0.89, p=0.04) and average OXT (r=0.93, p=0.02). ISEL Appraisal score also had a positive association with mean OXT pulse height (r=0.99, p=0.0006) and pulse mass (r=0.98, p=0.003). Finally, ISEL total score had a significant correlation with average OXT values (r=0.90, p=0.04). While none of the subjects had a score in the alexithymia range, TAS-20 Difficulty describing feelings score had an inverse correlation with OXT pulse height (r=−0.96, p=0.01) and pulse mass (r=−0.99, p=0.001). TAS-20 total score also had an inverse correlation with OXT pulse height (r=−0.94, p=0.02) and pulse mass (r=−0.96, p=0.009). ConclusionWe demonstrate a pulsatile pattern of peripheral OXT secretion in healthy men at rest. Subjects with lower OXT pulse height and pulse mass had a more avoidant style of attachment, felt less supported, and expressed greater difficulty in describing their feelings. Our findings support the concept that OXT is a key mediator of social-emotional functioning. Future studies to determine causality are warranted.

The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats.

Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk‐ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto‐excites the neurones to fire action potentials in co‐ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre‐term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane‐anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 μg/kg of F792, and the milk‐ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 μg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling‐ and oxytocin‐induced burst‐firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 μg/kg i.v., F792 acted only peripherally, blocking the milk‐ejecting actions of oxytocin, but not the burst‐firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide antagonist.

Maintenance or regression of the corpus luteum during multiple decisive periods of bovinepregnancy

In ruminants, there are specific times during the estrous cycle or pregnancy when the corpus luteum (CL) may undergo regression. This review has attempted to summarize the physiological and cellular mechanisms involved in CL regression or maintenance during four distinct periods. The first period is near day 7 when animals that are ovulating after a period of low circulating progesterone (P4), such as first pubertal ovulation or first postpartum ovulation, are at risk of having a premature increase in Prostaglandin F2α (PGF) secreted from the uterus resulting in early CL regression and a short estrous cycle. The second period is when normal luteolysis occurs at day 18-25 of the cycle or when the CL is rescued by interferon-tau secreted by the elongating embryo. The uterine mechanisms that determine the timing of this luteolysis or the prevention of luteolysis have been generally defined. Induction and activation of endometrial E2 receptors result in induction of endometrial oxytocin receptors that can now be activated by normal pulses of oxytocin. Of particular importance is the observation that the primary mechanisms are only activated through local (ipsilateral) and not a systemic route due to transfer of PGF from the uterine vein to the ovarian artery. In addition at the CL level, studies are providing definition to the cellular and molecular mechanisms that are activated in response to uterine PGF pulses or pregnancy. The third period that is discussed occurs in the second month of pregnancy (day 28-60) when undefined mechanisms result in CL maintenance of an ipsilateral CL but regression of a contralateral (opposite side from pregnancy) CL. The final period that is discussed is regression of the CL just prior to parturition. Although, cortisol from the fetus appears to be the primary initiator of luteolysis, PGF seems to be the final signal that causes regression of the CL. Thus, in all four periods, regression of the CL is likely to be caused by the direct actions of PGF that is secreted from the uterus. The uterine mechanisms that result in secretion of PGF seem to be normally inhibited during the early luteal phase, making short luteal phases not a normal event, and are altered during early pregnancy (day 18-25) resulting in prevention of luteolysis. During much of pregnancy, the mechanisms that cause PGF secretion from the uterus in response to oxytocin are intact but luteolysis does not normally occur, perhaps due to lack of efficient utero-ovarian transfer of PGF.

Oxytocin-Stimulated NFAT Transcriptional Activation in Human Myometrial Cells

Oxytocin (OXT) is a peptide hormone that binds the OXT receptor on myometrial cells, initiating an intracellular signaling cascade, resulting in accumulation of intracellular calcium and smooth muscle contraction. In other systems, an elevation of intracellular Ca2+ stimulates nuclear translocation of the transcription factor, nuclear factor of activated T cells (NFAT), which is transcriptionally active in arterial and ileal smooth muscle. Here we have investigated the role of NFAT in the mechanism of action of OXT. Human myometrial cells expressed all five NFAT isoforms (NFATC1–C4 and -5). Myometrial cells were transduced with a recombinant adenovirus expressing a NFATC1-EFP reporter, and a semi-automated imaging system was used to monitor effects of OXT on reporter localization in live cells. OXT induced a concentration-dependent nuclear translocation of NFATC1-EFP in a reversible manner, which was inhibited by OXT antagonists and calcineurin inhibitors. Pulsatile stimulation with OXT caused intermittent, pulse-frequency-dependent, nuclear translocation of NFATC1-EFP, which was more efficient than sustained stimulation. OXT induced nuclear translocation of endogenous NFAT that was transcriptionally active, because OXT stimulated activity of a NFAT-response element-luciferase reporter and induced calcineurin-NFAT dependent expression of RGS2, RCAN1, and PTGS2 (COX2) mRNA. Furthermore, OXT-dependent transcription was dependent on protein neosynthesis; cycloheximide abolished RGS2 transcription but augmented RCAN1 and COX2 transcriptional readouts. This study identifies a novel signaling mechanism within the myometrium, whereby calcineurin-NFAT signaling mediates OXT-induced transcriptional activity. Furthermore, we show NFATC1-EFP is responsive to pulses of OXT, a mechanism by which myometrial cells could decode OXT pulse frequency.

Emergent Synchronous Bursting of Oxytocin Neuronal Network

When young suckle, they are rewarded intermittently with a let-down of milk that results from reflex secretion of the hormone oxytocin; without oxytocin, newly born young will die unless they are fostered. Oxytocin is made by magnocellular hypothalamic neurons, and is secreted from their nerve endings in the pituitary in response to action potentials (spikes) that are generated in the cell bodies and which are propagated down their axons to the nerve endings. Normally, oxytocin cells discharge asynchronously at 1–3 spikes/s, but during suckling, every 5 min or so, each discharges a brief, intense burst of spikes that release a pulse of oxytocin into the circulation. This reflex was the first, and is perhaps the best, example of a physiological role for peptide-mediated communication within the brain: it is coordinated by the release of oxytocin from the dendrites of oxytocin cells; it can be facilitated by injection of tiny amounts of oxytocin into the hypothalamus, and it can be blocked by injection of tiny amounts of oxytocin antagonist. Here we show how synchronized bursting can arise in a neuronal network model that incorporates basic observations of the physiology of oxytocin cells. In our model, bursting is an emergent behaviour of a complex system, involving both positive and negative feedbacks, between many sparsely connected cells. The oxytocin cells are regulated by independent afferent inputs, but they interact by local release of oxytocin and endocannabinoids. Oxytocin released from the dendrites of these cells has a positive-feedback effect, while endocannabinoids have an inhibitory effect by suppressing the afferent input to the cells.

Effect of the environment on the physiology of the sow during late pregnancy, farrowing and early lactation

We investigated the effect of two types of housing on the duration of farrowing and the physiology of sows before and after farrowing. We assigned 20 sows (PEN) to farrowing pens (210 cm × 335 cm) enriched with straw bedding and 18 sows (CRATE) were placed in farrowing crates (80 cm × 210 cm) with no bedding material. We sampled the animals during period A (from day −5 before farrowing to day +1 of lactation) and during period B (from days +2 to +5 of lactation). We took daily venous blood samples for progesterone measurements and four salivary samples per day (at 09:00, 11:00, 13:00 and 15:00) for cortisol determination. In addition, intensive blood sampling was performed in 18 catheterised sows (9 PEN and 9 CRATE) to determine the level of oxytocin during farrowing. The treatment had no effect on litter size, piglet mortality at birth and weaning, growth of the piglets between days 1 and 5 of life. We found no significant difference in the cortisol concentration between the two groups during period A ( p = 0.36). Significant difference was found in period B, where the CRATE group had a higher concentration of cortisol than the PEN group ( p = 0.03). Progesterone concentration did not differ between the two groups ( p = 0.80). The duration of farrowing was on average 93 min longer in the CRATE sows ( n = 15), with a mean of 311 ± 35 min (mean ± S.D.), than in the PEN sows ( n = 19), with a mean of 218 ± 24 min ( p = 0.03). In addition, the mean interval between each piglet expulsion was longer in the CRATE group ( n = 11), with a mean of 25 ± 4 min, than in the PEN group ( n = 15) with a mean of 16 ± 2 min ( p = 0.05). During farrowing, the post-expulsion oxytocin pulses average tended to be higher in the PEN group (77.6 ± 47.6 ng/ml) than in the CRATE group (38.1 ± 24.6 pg/ml) ( p = 0.08). The concentration of oxytocin strongly affected the duration of farrowing ( p < 0.001). In conclusion, this study showed that the environment influences the physiology of the sow during farrowing and early lactation.

The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy

Oxytocin secretion from the posterior pituitary gland is increased during parturition, stimulated by the uterine contractions that forcefully expel the fetuses. Since oxytocin stimulates further contractions of the uterus, which is exquisitely sensitive to oxytocin at the end of pregnancy, a positive feedback loop is activated. The neural pathway that drives oxytocin neurons via a brainstem relay has been partially characterised, and involves A2 noradrenergic cells in the brainstem. Until close to term the responsiveness of oxytocin neurons is restrained by neuroactive steroid metabolites of progesterone that potentiate GABA inhibitory mechanisms. As parturition approaches, and this inhibition fades as progesterone secretion collapses, a central opioid inhibitory mechanism is activated that restrains the excitation of oxytocin cells by brainstem inputs. This opioid restraint is the predominant damper of oxytocin cells before and during parturition, limiting stimulation by extraneous stimuli, and perhaps facilitating optimal spacing of births and economical use of the store of oxytocin accumulated during pregnancy. During parturition, oxytocin cells increase their basal activity, and hence oxytocin secretion increases. In addition, the oxytocin cells discharge a burst of action potentials as each fetus passes through the birth canal. Each burst causes the secretion of a pulse of oxytocin, which sharply increases uterine tone; these bursts depend upon auto-stimulation by oxytocin released from the dendrites of the magnocellular neurons in the supraoptic and paraventricular nuclei. With the exception of the opioid mechanism that emerges to restrain oxytocin cell responsiveness, the behavior of oxytocin cells and their inputs in pregnancy and parturition is explicable from the effects of hormones of pregnancy (relaxin, estrogen, progesterone) on pre-existing mechanisms, leading through relative quiescence at term inter alia to net increase in oxytocin storage, and reduced auto-inhibition by nitric oxide generation. Cyto-architectonic changes in parturition, involving evident retraction of glial processes between oxytocin cells so they get closer together, are probably a response to oxytocin neuron activation rather than being essential for their patterns of firing in parturition.

Effect of finadyne on oestradiol-induced ovarian oxytocin and uterine PGF2alpha secretory systems on day 15 after oestrus in ovarian autotransplanted ewes

This study was undertaken to determine whether induction of ovarian oxytocin after oestradiol treatment on day 15 after oestrus is mediated through prostaglandin secretion by blocking prostaglandin synthesis using finadyne, an inhibitor of the cyclo-oxygenase pathway. Nine ewes with ovarian autotransplants were assigned randomly to receive an i.m. injection of either oestradiol benzoate (50 microg) in peanut oil ( n= 5) or oestradiol benzoate plus finadyne (2.2 mg kg (-1)) ( n= 4) at 3 h intervals starting at the time of oestradiol injection. Blood samples were collected from the ovarian and contralateral jugular veins at 30 min intervals for 6 h before and at 15 min intervals for up to 9 h after the oestradiol and finadyne injections. The secretion rate of ovarian progesterone remained high in all ewes, thus indicating the presence of a functional corpus luteum. Peripheral oestradiol concentrations were significantly (P < 0.001) higher during the 9 h after oestradiol injection in both groups. None of the oestradiol-finadyne-treated ewes showed significant pulses in either ovarian oxytocin secretion or release of the prostaglandin F(2alpha) metabolite 13,14-dihydro-15-keto PGF(2alpha) (PGFM) after injections. In ewes treated with oestradiol only, at least one detectable pulse of ovarian oxytocin and jugular PGFM was observed with mean +/- SEM amplitude of 17.7 +/- 7.29 ng min (-1) and 237.18 +/- 43.13 pg ml (-1), respectively. The areas under the curve for ovarian oxytocin and jugular PGFM pulses were significantly increased after oestradiol treatment. These findings demonstrate that initiation of the arachidonic acid cascade is important for the secretion of oxytocin after oestrogen treatment.

Effect of finadyne on oestradiol-induced ovarian oxytocin and uterine PGF2alpha secretory systems on day 15 after oestrus in ovarian autotransplanted ewes.

This study was undertaken to determine whether induction of ovarian oxytocin after oestradiol treatment on day 15 after oestrus is mediated through prostaglandin secretion by blocking prostaglandin synthesis using finadyne, an inhibitor of the cyclo-oxygenase pathway. Nine ewes with ovarian autotransplants were assigned randomly to receive an i.m. injection of either oestradiol benzoate (50 microg) in peanut oil ( n= 5) or oestradiol benzoate plus finadyne (2.2 mg kg (-1)) ( n= 4) at 3 h intervals starting at the time of oestradiol injection. Blood samples were collected from the ovarian and contralateral jugular veins at 30 min intervals for 6 h before and at 15 min intervals for up to 9 h after the oestradiol and finadyne injections. The secretion rate of ovarian progesterone remained high in all ewes, thus indicating the presence of a functional corpus luteum. Peripheral oestradiol concentrations were significantly (P < 0.001) higher during the 9 h after oestradiol injection in both groups. None of the oestradiol-finadyne-treated ewes showed significant pulses in either ovarian oxytocin secretion or release of the prostaglandin F(2alpha) metabolite 13,14-dihydro-15-keto PGF(2alpha) (PGFM) after injections. In ewes treated with oestradiol only, at least one detectable pulse of ovarian oxytocin and jugular PGFM was observed with mean +/- SEM amplitude of 17.7 +/- 7.29 ng min (-1) and 237.18 +/- 43.13 pg ml (-1), respectively. The areas under the curve for ovarian oxytocin and jugular PGFM pulses were significantly increased after oestradiol treatment. These findings demonstrate that initiation of the arachidonic acid cascade is important for the secretion of oxytocin after oestrogen treatment.

Uterine Contractile Activity Stimulates Supraoptic Neurons in Term Pregnant Rats Via a Noradrenergic Pathway

Oxytocin secretion is important for the normal progress of parturition in the rat. We tested the hypotheses that contractions of the uterus before pup delivery activate oxytocin neurons, and that they do so via a noradrenergic projection. In anesthetized 22-day (term) pregnant rats, iv oxytocin pulses enhanced both uterine contractile activity and the firing rate of oxytocin and vasopressin neurons in the supraoptic nucleus, and these were significantly correlated. The same oxytocin treatment also increased the expression of Fos in both the supraoptic nucleus and the nucleus of the tractus solitarius, but not in 21-day pregnant or virgin rats. In five of eight rats on the day of expected parturition, noradrenaline release in the supraoptic nucleus (sampled by microdialysis) exhibited sudden peaks during oxytocin administration, seen in only one of nine rats given vehicle pulses. Noradrenaline release was significantly greater in rats that went into labor or gave birth to a pup than in rats not in labor. In rats infused with the α1-noradrenergic receptor antagonist, benoxathian, into the supraoptic nucleus before and during iv oxytocin administration, Fos expression in supraoptic neurons was significantly less than that in vehicle controls. Thus, at term pregnancy, uterine contractions activate both oxytocin and vasopressin neurons in the SON, and this activation involves a noradrenergic pathway.

Uterine contractile activity stimulates supraoptic neurons in term pregnant rats via a noradrenergic pathway.

Oxytocin secretion is important for the normal progress of parturition in the rat. We tested the hypotheses that contractions of the uterus before pup delivery activate oxytocin neurons, and that they do so via a noradrenergic projection. In anesthetized 22-day (term) pregnant rats, i.v. oxytocin pulses enhanced both uterine contractile activity and the firing rate of oxytocin and vasopressin neurons in the supraoptic nucleus, and these were significantly correlated. The same oxytocin treatment also increased the expression of Fos in both the supraoptic nucleus and the nucleus of the tractus solitarius, but not in 21-day pregnant or virgin rats. In five of eight rats on the day of expected parturition, noradrenaline release in the supraoptic nucleus (sampled by microdialysis) exhibited sudden peaks during oxytocin administration, seen in only one of nine rats given vehicle pulses. Noradrenaline release was significantly greater in rats that went into labor or gave birth to a pup than in rats not in labor. In rats infused with the alpha(1)-noradrenergic receptor antagonist, benoxathian, into the supraoptic nucleus before and during iv oxytocin administration, Fos expression in supraoptic neurons was significantly less than that in vehicle controls. Thus, at term pregnancy, uterine contractions activate both oxytocin and vasopressin neurons in the SON, and this activation involves a noradrenergic pathway.

Peripheral Pulses of Oxytocin Increase Partner Preferences in Female, but Not Male, Prairie Voles

Centrally administered oxytocin (OT) facilitates social behaviors including the partner preferences that characterize the monogamous social system of prairie voles. In contrast peripherally administered OT generally has been ineffective in influencing central processes including behavior. OT from the posterior pituitary gland is released in pulses into the peripheral circulation. We hypothesized that peripherally administered OT, if delivered in repeated injections mimicking these pulses, would influence behavior. Male and female prairie voles received three subcutaneous injections of OT, a single injection of OT, or isotonic saline. Animals then were placed with an adult member of the opposite sex, designated as a “partner,” for a 1-h period of cohabitation, and subsequently tested for preference for the familiar partner versus a comparable stranger. Females treated with pulses of peripheral OT (1, 5, or 20 μg) displayed a significant preference for the partner compared to control females, while females receiving a lower dose of OT (0.1 μg) or a single injection (20 μg) did not. There was also a significant within-group effect as pulsed OT-treated females spent more time with the partner when compared to the stranger, while control females spent equal amounts of time with the partner and stranger. Peripheral pulses of OT were no longer effective in inducing partner preferences when females were pretreated with a selective OT receptor antagonist, administered either peripherally or centrally. In contrast to females, peripheral treatment with OT did not facilitate the formation of partner preferences in males.

Increased myometrial contracture frequency at 96-140 days accelerates fetal cardiovascular maturation.

Fetal cardiovascular responses to an altered intrauterine environment of increased myometrial contractures induced by oxytocin (OT) pulses to the ewe over the final 50 days of gestation were studied in chronically instrumented sheep. Ewes received saline (Cntl) or long-term OT treatment (LTOT, 600 microU x kg(-1) x min(-1) in 5-min pulses every 20 min) from 96 days gestational age. Fetal baroreflex responses to sodium nitroprusside (SNP) and phenylephrine (PE) were studied at 133 days gestation. OT increased contractures in LTOT ewes. Fetal blood pressure (FBP) was higher, and fetal heart rate (FHR) and slope of daily change in FBP and FHR were lower in LTOT fetuses. Fetal SNP-induced hypotension resulted in a narrow R-R interval variation range in LTOT fetuses; Cntl fetuses showed early breakdown in compensation. Baroreflex response slope during PE-induced fetal hypertension was lower in LTOT than in Cntl fetuses. Although the cortisol-to-ACTH ratio was lower in LTOT fetuses, fetal plasma ACTH and cortisol changes were similar in control and LTOT fetuses. We hypothesize that contracture-induced alterations in the intrauterine environment accelerate fetal cardiovascular development through mild hypoxemia, repetitive fetal pituitary-adrenal stimulation, and/or physical stimulation.

Luteolysis: a neuroendocrine-mediated event.

In many nonprimate mammalian species, cyclical regression of the corpus luteum (luteolysis) is caused by the episodic pulsatile secretion of uterine PGF2alpha, which acts either locally on the corpus luteum by a countercurrent mechanism or, in some species, via the systemic circulation. Hysterectomy in these nonprimate species causes maintenance of the corpora lutea, whereas in primates, removal of the uterus does not influence the cyclical regression of the corpus luteum. In several nonprimate species, the episodic pattern of uterine PGF2alpha secretion appears to be controlled indirectly by the ovarian steroid hormones estradiol-17beta and progesterone. It is proposed that, toward the end of the luteal phase, loss of progesterone action occurs both centrally in the hypothalamus and in the uterus due to the catalytic reduction (downregulation) of progesterone receptors by progesterone. Loss of progesterone action may permit the return of estrogen action, both centrally in the hypothalamus and peripherally in the uterus. Return of central estrogen action appears to cause the hypothalamic oxytocin pulse generator to alter its frequency and produce a series of intermittent episodes of oxytocin secretion. In the uterus, returning estrogen action concomitantly upregulates endometrial oxytocin receptors. The interaction of neurohypophysial oxytocin with oxytocin receptors in the endometrium evokes the secretion of luteolytic pulses of uterine PGF2alpha. Thus the uterus can be regarded as a transducer that converts intermittent neural signals from the hypothalamus, in the form of episodic oxytocin secretion, into luteolytic pulses of uterine PGF2alpha. In ruminants, portions of a finite store of luteal oxytocin are released synchronously by uterine PGF2alpha pulses. Luteal oxytocin in ruminants may thus serve to amplify neural oxytocin signals that are transduced by the uterus into pulses of PGF2alpha. Whether such amplification of episodic PGF2alpha pulses by luteal oxytocin is a necessary requirement for luteolysis in ruminants remains to be determined. Recently, oxytocin has been reported to be produced by the endometrium and myometrium of the sow, mare, and rat. It is possible that uterine production of oxytocin may act as a supplemental source of oxytocin during luteolysis in these species. In primates, oxytocin and its receptor and PGF2alpha and its receptor have been identified in the corpus luteum and/or ovary. Therefore, it is possible that oxytocin signals of ovarian and/or neural origin may be transduced locally at the ovarian level, thus explaining why luteolysis and ovarian cyclicity can proceed in the absence of the uterus in primates. However, it remains to be established whether the intraovarian process of luteolysis is mediated by arachidonic acid and/or its metabolite PGF2alpha and whether the central oxytocin pulse generator identified in nonprimate species plays a mediatory role during luteolysis in primates. Regardless of the mechanism, intraovarian luteolysis in primates (progesterone withdrawal) appears to be the primary stimulus for the subsequent production of endometrial prostaglandins associated with menstruation. In contrast, luteolysis in nonprimate species appears to depend on the prior production of endometrial prostaglandins. In primates, uterine prostaglandin production may reflect a vestigial mechanism that has been retained during evolution from an earlier dependence on uterine prostaglandin production for luteolysis.

Oestrogenic effects of ICI 182,780, a putative anti-oestrogen, on the secretion of oxytocin and prostaglandin F2 alpha during oestrous cycle in the intact ewe.

The effect of ICI 182,780, oestrogen antagonist, on the concentration of oxytocin and uterine PGF2 alpha was investigated in intact Border Leicester Merino cross ewes during the late oestrous cycle. Twelve cyclic ewes (n = 6 per group) were randomly assigned to receive, at 6 h intervals, intra-muscular injection of either peanut oil or ICI 182,780 (1.5 mg kg-1 day-1) in oil for 2 days, starting at 1900 h on day 13 until 1300 h on day 15 post-oestrus. Hourly blood samples were collected via a jugular catheter from 0800 h on day 14 for 37 h and then daily over days 16, 17 and 18 post-oestrus. Peripheral plasma concentrations of oxytocin, the metabolite of prostaglandin F2 alpha, 15-keto-13,14-dihydro-prostaglandin F2 alpha, (PGFM) and progesterone were measured by radioimmunoassay. All ewes treated with ICI 182,780 exhibited functional luteal regression as indicated by a marked reduction in plasma progesterone concentrations to less than 1000 pg/ml over the period of 18-36 h during sampling period on days 14 and 15 of the oestrous cycle. In five of six vehicle-treated ewes, progesterone concentrations declined between day 16 and day 18 post-oestrus. In the remaining control ewe, progesterone concentrations reach less than 1000 pg/ml within 36 h of the commencement of the sampling period. During the frequent sampling period, the number of oxytocin pulses in the ICI 182,780 treated ewes was significantly higher compared to control ewes (2.7 +/- 0.3 vs. 0.8 +/- 0.3). The mean amplitude of oxytocin pulses observed was also greater (70.4 +/- 19.5 pg/ml) in ewes treated with ICI 182,780, but was not significantly different from the control ewes (33.5 +/- 12.9 pg/ml). Oxytocin pulses may however have occurred following the initial two ICI 182,780 injections but before commencing blood sampling. The oxytocin pulses were detected at a mean of 3.2 +/- 0.2 h following each injection with ICI 182,780 during blood sampling. In the ICI 182,780-treated ewes, the pulsatile pattern of plasma PGFM in jugular blood samples over the 37 h sampling period on days 14 and 15 post-oestrus had a higher amplitude (512.9 +/- 158.9 vs 121.7 +/- 78.7 pg/ml) and pulse area (618.1 +/- 183.3 vs 151.5 +/- 102.9 (ph/ml)tau) compared to the vehicle-treated ewes (P < 0.05) respectively.. The average number of PGFM pulses observed per ewe was 3.0 +/- 0.7 in the ICI 182,780-treated group and was significantly (P < 0.02) higher than the number of pulses (0.5 +/- 0.3) observed in ewes treated with vehicle alone. The PGFM pulses were detected at 4.2 +/- 0.6 h following each injection with ICI 182,780 during blood sampling. The percentage of PGFM pulses that occurred coincidently with significant elevation of oxytocin concentrations was 44.4% in ICI 182,780-treated compared to 66.6% in control ewes. We conclude that administration of oestrogen antagonist ICI 182,780 accelerated development of the luteolytic mechanism by enhancing pulsatile secretion of oxytocin and PGFM which suggests that ICI 182,780 acts as an agonist for oxytocin and prostaglandin f2 alpha release in intact ewes when administered at 1.5 mg/kg/day over day 13 to 15 post-oestrus.

Concentrations of oxytocin in the intercavernous sinus of mares during luteolysis: temporal relationship with concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha.

The reproductive tracts of nine thoroughbred mares were examined by ultrasound to determine the day of ovulation (day 0). Mares were fitted with intercavernous sinus cannulae on the day before the start of sample collection of pituitary venous effluent rich in oxytocin. Intercavernous sinus blood samples were collected for at least 36 h at 5 min intervals beginning at noon on day 13 (n = 2), day 15 (n = 5) or day 16 (n = 2) after ovulation. Concentrations of oxytocin and 13,14-dihydro-15-keto prostaglandin F2 alpha (PGFM) in plasma were determined by radioimmunoassay. Three high-magnitude surges of PGFM (> 1 ng ml-1) were found in these samples. Three high magnitude pulses of oxytocin (> 200 pg ml-1) were also observed, one associated with each of the PGFM surges. In each of these cases, the oxytocin pulse appeared to follow or coincide with the onset of the PGFM surge. Lower magnitude pulses of both hormones were detected throughout the bleeding period in every mare. The average interval between these pulses was 122.3 min for oxytocin and 121.0 min for PGFM. The interval between pulses for individual mares varied from 90 to 199 min for oxytocin, and from 87 to 213 min for PGFM. However, there was no correlation between PGFM and oxytocin pulse intervals among mares. Within each mare, there was no discernable association between low magnitude pulses of oxytocin and PGFM. From these data, it was concluded that high-magnitude surges of PGF2 alpha are associated with similar surges of oxytocin from the posterior pituitary gland, and that PGF2 alpha may induce their secretion. The posterior pituitary gland also appears to secrete oxytocin in a pulsatile manner at a frequency of approximately 1 pulse every 2 h but these pulses do not appear to be associated with the low magnitude pulses of PGF2 alpha secreted from the uterus.

Stimulation of ovarian oxytocin secretion and uterine prostaglandin release by exogenous progesterone early in the cycle of the ovarian auto-transplanted ewe.

The present study was undertaken to determine whether the administration of progesterone, early in the oestrous cycle, had an influence on ovarian oxytocin secretion and on peripheral concentrations of the prostaglandin F2 alpha metabolite 13,14-dihydro-15-keto PGF2 alpha (PGFM) in the ovarian auto-transplanted ewe. Twelve ewes with ovarian auto-transplants (n = 6 per group) were randomly assigned to receive an i.m. injection of progesterone (12.5 mg) or vehicle, twice a day, on days 1, 2 and 3 of the oestrous cycle. Beginning on day 7, blood samples were collected at intervals of 1 h from the ovarian and contralateral jugular veins for up to 70 h. Ovarian oxytocin secretion rate and jugular concentrations of PGFM and progesterone were determined by radioimmunoassay. The number of ewes that showed pulses of both ovarian oxytocin and PGFM was significantly (P < 0.05) greater in progesterone-treated ewes than in control ewes. In progesterone-treated ewes, the average number of ovarian oxytocin pulses per ewe was 9.66 +/- 5.5 (mean +/- SD) and the interval between pulses was 7.18 +/- 5.8 h. The mean amplitude and amount of oxytocin released, as calculated by the area under the curve of ovarian oxytocin pulses, were 6.27 +/- 1.98 ng min-1 and (10.05 +/- 8.91 ng min-1)tau, respectively (where tau is the number of hours between the last time point before and the first time point after a significant increase in hormone concentration was detected by the Pulsar program). The mean amplitude and area under the curve of PGFM pulses were 317.22 +/- 5.65 pg ml-1 and (383.36 +/- 1.77 pg ml-1)tau, respectively. The average number of pulses of plasma PGFM observed per ewe was 5.8 +/- 1.9 and interpulse interval for plasma PGFM pulses was 10.32 +/- 8.7 h between day 7 and day 9 after oestrus. These data indicate that administration of progesterone during the first 3 days of the oestrous cycle results in the premature release of ovarian oxytocin and uterine prostaglandin F2 alpha.