You are on page 1of 13

European Journal of Endocrinology (1997) 137 559–571

ISSN 0804-4643

REVIEW

Oxytocin in the human – regulation of derivations and
destinations
John J Evans
University Department of Obstetrics and Gynaecology, Christchurch School of Medicine, Christchurch, New Zealand
(Correspondence should be addressed to J J Evans, University Department of Obstetrics and Gynaecology, Christchurch Women’s Hospital, Private Bag
4711, Christchurch, New Zealand)

Introduction
Those of us who study physiology are tempted to hope
that the experimental perturbations which we induce
affect only the organ which has ensnared our interest.
This review uses physiological systems which incorporate oxytocin as models to indicate some of the ways in
which departure from such investigative paradise
occurs, and also to discuss some of the implications of
a physiology which uses one compound in several
distinct roles.
The dual activities of oxytocin, on the uterus and on
the mammary gland, for some time constituted the
complete portfolio of the peptide’s functions in biology
(1). However, now no longer is consideration of
oxytocin confined to its two traditional roles. Investigations of oxytocin have demonstrated that oxytocin
participates in a wide variety of activities in dispersed
regions of the body, and is an element of the physiology
of both sexes. Oxytocin is involved with sex, pain and
moods, and its sites of action include the thymus, the
ovary, and the pancreas.
After the oxytocic activity and the milk ejecting
activity of the posterior pituitary gland were recognised,
a nonapeptide was found to be responsible for the
effects. The structure of the compound was established
(2, 3) and oxytocin was the first peptide hormone to be
purified and synthesised, and available for pharmacologically defined studies. Modern molecular biology has
provided information of the oxytocin system (Fig. 1).
The oxytocin gene has been mapped to 20p13 (4)
although the nature of the regulatory elements critical
to cell-specific expression of the oxytocin gene are still
ill-defined (5). The molecular structure of the oxytocin
receptor has been characterised (6) and the gene has
been localised to 3p25–3p26 (7–9). It is assumed
that oxytocin has evolved by duplication of an ancestor
gene which oxytocin and vasopressin have in common.
The vasopressin/oxytocin prohormone ancestor was
present in Archaemetazoa, from which vertebrates and
invertebrates diverged 600 million years ago (10, 11).
This review is designed first to serve as a reminder
that a compound can affect multiple entities, secondly
to consider some of the processes which control
interaction between physiological units, and thirdly to
᭧ 1997 Society of the European Journal of Endocrinology

point to the multifaceted effects, including alterations of
behaviour, a pathological change can have. A variety of
control mechanisms which are incorporated into
oxytocin systems are summarised in Table 1 and
corresponding examples indicated in the text by upper
case letters (A–O). This review considers effects induced
by oxytocin which have been observed in human
studies, which after all is the ultimate target of most
projects, with only occasional reference to antecedent
animal investigations. Although animal studies have
suggested several activities for oxytocin which are not
discussed in this review it is necessary to note that there
are some functions of oxytocin which are species
specific. Examples are the apparently opposite effects of
oxytocin on adrenocorticotrophin (ACTH) in humans
(in which oxytocin is reported to be inhibitory) and in
rats (in which oxytocin is stimulatory); another is the
differences in the temporal profile of oxytocin in the
cerebrospinal fluid (CSF) of humans and rats; a third is
the distribution of oxytocin binding sites in the brain.

The brain
The hypothalamus is the traditionally recognised
primary site of oxytocin synthesis. Studies of the
human hypothalamus have shown the presence of
neurones which contain immunoreactive oxytocin and
oxytocin mRNA. The organisation of the neurones is
similar to that in other mammals (12). Also oxytocin
has been detected in several extrahypothalamic areas of
the brain (13, 14). Regulating agents for oxytocin (e.g.
opioids, neurotransmitters, products of the gonads and
thyroid) act via receptors on oxytocin-containing
neurones. Only some neurones possess the receptors
and thus there is a selectivity of oxytocin activation at the
transcriptional level (Table 1, A) (15, 16). Further control
might be exacted in post-transcriptional processing in the
production of polyA tail size of oxytocin mRNA, which
correlates to oxytocin mRNA accumulation (Table 1, B)
(17). The effect is possibly a result of enhanced mRNA
stability and increased half life and also modified
translational efficiency.
In addition oxytocin has been measured in CSF
of humans and exhibits a time-dependent rhythm,

although the presence of an oxytocin-like peptide is a complicating factor (21). white areas adjacent to the solid bars indicate 50 untranslated regions of exons. Other factors are also potential participants in oxytocin regulation. There is substantial evidence that nursing is a potent stimulus for oxytocin release from the neurohypophysis (26. The release of oxytocin from the neurohypophysis is partly modulated by the reproductive endocrine environment (19. Solid bars indicate exons. 27). Sex differences in oxytocin receptor distribution. the brain stem and the spinal cord (18). Some oxytocin receptors are transient and present only during infancy or during maturation. some are regulated by gonadal steroids and some are present constantly (24). The regions encoding the membrane-spanning domains are represented by closed boxes and numbered. the limbic system. The regions encoding extracellular and intracellular domains are shown by hatched boxes. Lactation and the breast One of the traditional activities of oxytocin is in lactation.) although such does not occur in the blood. an effect enhanced by opioid antagonist.560 J J Evans EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 Figure 1 Schematic depictions of the organisation of the oxytocin gene and the oxytocin receptor gene. with permission. (i) The oxytocin receptor gene. From the hypothalamus oxytocin is transported to the posterior pituitary gland. consistent with a role of these compounds in oxytocin neurosecretion (23). C). with permission. A differential control of receptors apparently occurs in brain (Table 1. (Adapted and redrawn from reference 7. (A) Organisation of the oxytocin gene. These include angiotensin-II which increases oxytocin release. are apparently linked to regulation mediated by gonadal steroids (25). Exons are represented by the closed boxes and numbered. (ii) The structure of oxytocin receptor cDNA. Binding of oxytocin in the brain of the human is present in regions which suggest oxytocin-mediated modulation might be involved in sensory. which has implications for genderspecific processes. Pro-opiomelanocortin-derived peptides have been detected in the neurohypophysis of the human. The reflex which elicits . the main source of oxytocin detected in the periphery during lactation and parturition. The transcriptional orientation of prepro-oxytocin-neurophysin-I (50 OT) and prepro-vasopressin-neurophysin-II (50 AVP) is indicated. autonomic and motor processing mechanisms and other basal ganglia-related functions (24). indicating involvement of an opioid mechanism (22). (Adapted and redrawn from reference 135.) (B) Organisation of the oxytocin receptor gene. 20). The oxytocin in CSF is probably derived from neurones which extend to the third ventricle. The translation start (ATG) and termination sites (TGA) are indicated.

such as act at the PVN (neurotransmitter-mediated) or the ovary (hormonal). e. It seemed that the oxytocin-induced rise was by a pathway independent of opioids. 35) (see below). J The blood–brain barrier. e. D) then some of the regulation of the downstream processes which control the response to oxytocin can be under the modulation of oxytocin itself. Lactating women were observed to have a blunted ACTH and cortisol and glucose responses to exercise stress but oxytocin levels did not differ and were therefore probably not a factor in this exercise-induced modification (36). consistent with observations that oxytocin suppresses ACTH (34. oxytocin release (28) is activated before the tactile stimulus of suckling occurs. E Alteration in receptor number by other hormones. Post receptor D Pattern of delivery to affect response. and at high doses of oxytocin cAMP was increased (30). N Composite requirements for activation of target gene. or that it stimulates cancer . The relationship of oxytocin to the breast led to the question of whether there is a connection between oxytocin activity and breast cancer. Suckling is associated with a prompt decline in plasma cortisol. (3) controls which rely on separation of systems into biological compartments. In vitro studies clearly demonstrated a responsivity of breast tissue to oxytocin. pulsatile delivery to the breast during lactation. The upper case letters reference the control mechanisms to some examples in the text. which elicits an oxytocin response. (2) Target Interaction at oxytocin receptor C Changes in receptors due to developmental stage in the brain. a process which involves oxytocin (see below).g.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 561 Table 1 Potential control mechanisms in oxytocin-mediated systems. However there might have been modulatory processes activated by oxytocin secreted from magnocellular nuclei into central. although other studies suggest that it is without effect (39).g. opioids. whereas the ethanol inhibition partially involved opioid peptides (37). The sensitivity of the tissue is modulated by the endocrine environment and the breast is most responsive to oxytocin during the post partum period (31). Oxytocin induced a dose– response increase in intracellular Ca2þ with a peakplateau pattern. The table is divided into three categories: (1) controls exerted at the site of oxytocin production. G Receptor subtype. having tissue-specific function. by steroids in the uterus during pregnancy. One of the most well known examples is the priming effect of pulsatile gonadotrophin-releasing hormone and the desensitising effect of continuous exposure of gonadotrophs to this peptide. Conversely lactation suppresses the stress axis. It has been observed that oxytocin inhibits growth of breast cancer cells (38). biochemical-initiated stimuli also affect the oxytocin response. Stimulation of the breast by electrical impulses caused contractions of the uterus at term which followed or were concomitant with an increase in oxytocin (32). A study reported a reduction in the oxytocin response associated with breast feeding when stresses of arithmetic or noise were provided (33). in the ovary or pituitary of females. B mRNA polyA tail length to modify post-transcriptional control. M Target cell-dependent coupling to G-proteins. has been utilised to delay or suppress uterine contractions. L Cyclical alterations in tissue composition.g. e. and oversees a pulsatile pattern of secretion (29). In addition uterine contractions have been reported during breast feeding (27). (3) Compartmentalisation I Paracrine autocrine system constraints.g. as mentioned above. H Different type of stimulus. mediating pathways. has been proposed as a means of clinically inducing contraction at term. e. e. Because the delivery pattern of stimulatory hormone can profoundly affect the response of the target cells (Table 1. K Different forms of oxytocin inducing distinct effects. Consideration of the two traditional targets of oxytocin provides an illustration. suggesting a site of action. Ethanol. In fact breast stimulation. Nevertheless the lactation–stress connection apparently consists of more than oxytocin and ACTH. O Tissue-specific activation of target response. (2) controls at the target site. in non-pregnant women ethanol inhibited the oxytocin rise induced by breast stimulation. F Interaction by regulating agents with the intracellular response to oxytocin. Other. The involvement of oxytocin in several physiological entities. orally in one of its palatable forms or intravenously.g. An interaction between lactation and other systems besides the uterus have also been observed. Mothers know that during feeding a quiet place is optimum. by steroids. raises the possibility that a response to a specific stimulus can interfere in a physiologically distinct system. receptors for oestradiol. (1) Production A Modulation of receptors of regulating agents. In fact oxytocin receptors and oxytocin receptor mRNA have been found in breast cancer tissue.

In addition. Oxytocin receptors are present in the pregnant myometrium. human endothelin receptor exhibits a splice variant with possibly distinct functions (57). However oxytocin might have an indirect effect on breast cancer development. Oxytocin receptor mRNA is heterogeneously expressed in the tissue. E). Oxytocin stimulates contraction of myoepithelial cells in nonpregnant women and so possibly aids elimination of carcinogens generated by superoxide free radicals. are able to remain quiescent in spite of occasionally raised oxytocin levels. 2). The latter results suggested a role of oxytocin in increasing uterine activity during menstruation (52). F). 49). suggesting a biological function of oxytocin during the EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 menstrual cycle (50). The relationships illustrate the possibility of regulatory (in this case steroidal) processes interacting with an oxytocin-targeted system (Table 1. oestrogens) which are responsible for up-regulating oxytocin receptor numbers. Oxytocin decreased follicle-stimulating hormone (FSH)-stimulated oestradiol . Treatment with clomiphene increased the concentrations to normal (51). In addition an interaction between progesterone and oxytocin in their effects on the contractile activity of human myometrium has been observed (45). It appears therefore that oxytocin participates in the network which constitutes the functioning of endometrial glandular cell function. The uterus The pregnant uterus is one of the traditional targets of oxytocin and at around the onset of labour uterine sensitivity to oxytocin markedly increases.g. Interestingly. Thus modulation of oxytocin receptor is an effective control mechanism (Table 1. but the uterus is still refractory at this time. Examples abound in endocrinology. The participation of oxytocin receptors in uterine function has led to investigations of the use of oxytocin antagonists in premature labour (47) and also in amelioration of dysmenorrhoea (48). the uterus) having receptors for modulating agents (e. It must be remembered that parturition involves a complex series of processes. 54) and by analogy there might be cases where oxytocin can control its own receptor. particularly in the human. also increasing during pregnancy reaching a peak after the onset of labour. The involvement of oxytocin in stimulating contractility in labour is by G-protein-mediated processes which activate phospholipase C and mobilise calcium. At the target cell. Binding studies also found a higher concentration at midcycle (51) in contrast to another investigation which observed a rise in receptor density in the late luteal phase and during menstruation. In the case of the response of the myometrium to oxytocin. the control of oxytocin receptors provides a means of modulating oxytocin-mediated effects. a process which is probably dependent on prostaglandin F2a (PGF2a ) (46). There seemed to be a higher concentration of receptor mRNA in the glandular epithelial cells at the time of ovulation. in view of the interaction between oxytocin and the stress axis. it has been observed that there is a synergism between oxytocin and corticotrophinreleasing hormone (CRH) in the contractile response of the myometrium. Conversely granulosa cells respond to oxytocin (Fig. 44). For example there is a relatively large amount of oxytocin receptor mRNA expression at 32 weeks’ gestation.562 J J Evans growth (40). In addition other hormones regulate their own receptors (53. In a more recently emerged model. receptor protein increases during the course of pregnancy (42). Oxytocin receptors are also present in the nonpregnant human uterus but the concentrations are much less than during pregnancy (42. the interaction of oxytocin with its receptor being only one of them. It is possible that part of the process of development of pregnancy involves interaction of oxytocin with the uterus and it has been observed that in subfertile patients the concentration of endometrial oxytocin binding sites is less than in normal women. It seems that the presence of oestradiol is an important factor in enhancing the response of the myometrium to oxytocin. 60).g. Distinct subtypes which are differentially regulated provides for separate activities of the same hormone. Granulosa cells Granulosa cells of the ovarian follicle synthesise oxytocin and secrete it when stimulated with human chorionic gonadotrophin (hCG) (59. Another means of regulation is illustrated by angiotensin-II which alters expression of its own receptor subtype in a tissue-specific manner (58). facilitating phospholipase C activation at a post-receptor level (43. is yet far from clear. human pituitary adenylate cyclase activating polypeptide receptor exhibits splice variants which coupled to dual signal transduction cascades to elicit possibly tissue-specific responses (56). Hence the effect of oxytocin in this context remains uncertain. there appears to be multiple sites for regulation and possible interaction with other receptors (43). G). The existence of subtypes of oxytocin receptors has been postulated (55) but the situation. one of which is the sister hormone of oxytocin. There is also potential for regulation of oxytocin activity using receptor type (Table 1. It has thence been proposed that activities which promote oxytocin levels are protective (41). The ovary Oxytocin and oxytocin receptors have been detected in the ovary which provides a clear illustration of the increasingly recognised need to expand considerations of oxytocin activity into non-traditional areas. vasopressin. Organs (e. The function of oxytocin on the nonpregnant uterus is therefore yet to be resolved.

oxytocin stimulated oestradiol production which stimulated progesterone release but in addition oxytocin had a direct inhibitory effect on progesterone secretion (68). and possibly has a role in testicular steroidogenesis. hypothalamo–neurohypophyseal axis and say the ovary) (Table 1.) release from cells with suitable characteristics (61). with PGF2a in the luteolytic control of the CL (69) perhaps in a manner analogous to that observed in other species. This together with data from studies in other model systems strongly suggest participation by oxytocin in male reproductive physiology (74). Similarly the control mechanisms acting on the peripheral organs selectively do not affect oxytocin in the neurohypophysis and so when there is stimulation of release from a peripheral site of production then there is no concomitant increase in circulating oxytocin from the neurohypophysis. Oxytocin appears to interact. hCG. 65). Cumulus In the cumulus expression of both oxytocin genes and oxytocin receptor genes have been detected (64. I). although there is evidence for an autocrine/ paracrine oxytocinergic system in the Leydig cell compartment (73). In addition oxytocin receptors have been detected (66. 76). Involvement of oxytocin in communication between human thymic epithelial cells and immature T cells in the development of immune tolerance has been suggested (77). It has been suggested that oxytocin thereby modulates the functions of cumulus cells in a paracrine or autocrine manner and perhaps participates in fertilisation and early embryonic development. Thus the stimuli associated with lactation predicate activation of only certain systems which act to increase oxytocin at the brain and release oxytocin from storage in the neurohypophysis and will not target release or synthesis from say granulosa cells. Evidence for mRNA transcription has been obtained in the human testis although at a relatively low level.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 Figure 2 Effect of oxytocin on progesterone release. acting via Gaq. The thymus induces central T-cell tolerance by clonal deletion of selfreactive T cells. Co. H). The biological significance of oxytocin in the testes is therefore uncertain (72). The ovary provides a well documented example of an extrahypothalamic site of oxytocin production. Indeed . locally. However the CL responds to oxytocin in a complex manner and the role(s) of oxytocin with regard to the human CL are yet to be defined. This appears to be achieved by imprinting molecular self-identity in the thymus. increased inositol phosphate formation and intracellular Ca2þ (63). 563 is therefore apparently the potential for oxytocin to act on cells to increase or decrease metabolite function depending on cellular state. Oxytocin increased intracellular Ca2þ in granulosalutein cells in culture and increased hCG-stimulated progesterone release (62). 67). basal release. Oxytocin. modified and reproduced with permission.g. Results of 24 h incubation of granulosa-lutein cells with oxytocin and hCG performed on culture day 5. In young CL. Distinct types of control (neurohumoral versus hormonal) regulate oxytocin synthesis and release at the different sites (e. 10 000 IU/l. being observed in higher amounts in testes with maturation arrest (71). The testis Oxytocin has been detected in extracts of the human testis (70). The results suggest that locally produced oxytocin induces effects through ligand–receptor interaction. There The thymus The importance of the roles of oxytocin in reproductive function (both physiological and behavioural) implies that immune recognition of the oxytocin self-antigen is necessary. The presence of both oxytocin secretion and oxytocininduced responses reveal the capacity for an autocrine regulatory mechanism. In the several oxytocin systems which are paracrine/ autocrine there is no delivery of significant levels of oxytocin into the peripheral circulation and to the anatomically separated systems. Thus the response is anatomically constrained to a tissue. OT. by the use of paracrine/autocrine physiological units which localise the stimulus and immediate effects (Table 1. oxytocin (10 nmol/l). Large amounts of oxytocin are necessary to have a secondary effect because of the efficiency of metabolism and the consequent short half life of oxytocin. and the CL synthesises oxytocin (60). Oxytocin is present and synthesised locally in the thymus (75.11 and Gi-mediated phospholipase C activation. Corpus luteum Oxytocin has also been detected in the corpus luteum (CL) (66). (From reference 62.

The evidence that oxytocin impairs some memory-related tasks has led to suggestions that it has a role in the forgetting of delivery pain in mothers.saline. although there was no correlation between oxytocin levels and cognitive performance (88).. Oxytocin seems to be more definitively defined as a self molecule than vasopressin. Nevertheless the effects of administering oxytocin on behaviour is often modest. Levels of circulating oxytocin change during sexual activity (78. Also oxytocin action during sexual activity partly perhaps involves its effects on behaviours. The results suggested there was temporary impairing. . perhaps reflecting the broad spectrum of oxytocin action (89). The effect of naloxone on plasma oxytocin levels at orgasm in eight healthy men. An immune disequilibrium such as that of post partum seems to be partly induced by hypersecretion of oxytocin which activates an immune response. is also implicated in modulation of behaviours. In sexual activity The range of activities of oxytocin is emphasised by its apparent role also in sexual activity. 79) (Fig.564 J J Evans some immune pathologies can be explained by thymic oxytocin being involved in T cell positive selection and activation. besides having effects which can be monitored biochemically. This is an illustration that within the orbit of a particular behaviour.. and oxytocin might serve as a neuromodulator and affect cerebral neurones responsible for the cognitive feelings of orgasm.. There have been several investigations of the role of oxytocin in children with obsessive-compulsive disorder (OCD). i. Oxytocin rises following ingestion of oral contraceptives. reproduced with permission. In addition levels of circulating oxytocin have a correlation with personality measures in women.e. The possibility that raised oxytocin levels during parturition alter cognition was investigated. although a causal relationship was not demonstrated. This view is not universally held. 3). was observed. baseline values. B2. This aspect of oxytocin’s involvement illustrates two categories of its activities – an observable physiological factor and also an effect on less easily monitored mood Figure 3 Orgasm increases oxytocin levels. —— naloxone. Indeed the involvement of oxytocin acting as a neuropeptide in psychology has been the subject of several investigations (83). The wide variety of observed effects has led to the suggestion that oxytocin has a general effect on cortical arousal rather than a specific effect limited to a certain stage of information processing (86). Such a barrier can also act as a component in the regulation of responses to oxytocin by compartmentalising the potential targets (Table 1. and/or may sensitise cerebral neurones associated with pelvic floor striated muscle contractions (80). 82). in sexual arousal. since peripheral levels do not necessarily reflect levels at the pertinent neurones in the brain. There is however a blood– brain barrier which makes such measurements of disputable value. and a consequent effect on mental activities has been speculated (20). (From reference 136. Additionally oxytocin attenuated learning processes (85). However oxytocin administration decreased fatigue. J). Psychological changes during sexual arousal have been reported to correspond to changes in oxytocin (81. but interestingly only in women with high emotionality reactivity (90). Treatment with clomipramine improved symptoms in OCD children and increased oxytocin levels in the CSF (although the correlation of quantitative changes was . B1. oxytocin. and some results suggest a subtype of OCD based on hypothalamo–neurohypophyseal dysfunction (91). anger and anxiety (84) and vigour (85). Values have been logarithmically transformed and are expressed as a percentage of the mean. sexual responses. The correlation was weak. in this case the muscles in the genital–pelvic area. In behaviours As we have noted above. A response to noise stress. resulting in an increase in oxytocin levels. there is the opportunity for oxytocin to coordinate at least some of the diverse components of the biological activity. Oxytocin given intranasally to Vietnam veterans suffering from post-traumatic stress disorder reduced their response to combat imagery. The results were consistent with the predicted specific inhibitory effect of oxytocin on memory retrieval and conditioned responding rather than on non-specific arousal (87).) EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 aspects. In addition oxytocin might be involved prior to coitus. It is possible that at least some of oxytocin’s role in this context is related to its well known ability to stimulate contraction of smooth muscles. a conclusion which is reached partly by examination of some pathologies such as an autoimmune aggression against vasopressin-producing neurones which results in central diabetes insipidus (76).

It is possible that this very complexity is a safeguard against an inappropriate adrenal response to a rise in oxytocin which was unrelated to a stress stimulus. 104). Stimulated responses have also been suppressed. When oxytocin was administered to women under other conditions there was no detectable effect on LH (103.g. In men oxytocin has been observed to increase FSH (105). However clinical treatment with intranasal oxytocin did not produce a reduction in the obsessive or compulsive behaviours (93). 565 Prolactin Prolactin is often associated with oxytocin in lactation although there is little data indicating an endocrinological link in humans. being active at at least two sites. reducing the chance of inappropriate oxytocin-mediated effect. growth factors. L) (107). and oxytocin metabolites.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 negative) (92). Oxytocin has been detected also in the adrenal medulla (113). Gonadotrophins There are also several observations of oxytocin modifying gonadotrophin secretion in animals (100. Thus oxytocin is involved at not just one site in the integrated modulation of cortisol concentrations.g. Investigations in which ACTH rises were not sensitive to oxytocin have also been reported (98. This observation tempts speculation that there is thus illustrated an oxytocin-mediated link between a physiology (ovulation) and a behaviour (sexual activity). 99). 112) of target genes enable a stimulatory complex to include other components (besides oxytocin) to be present necessarily for an effect by oxytocin to be observed (Table 1. Oxytocin reduced ACTH which was stimulated by insulin-induced hypoglycaemia. In the case of tissues which have a changing constitution. COOH-terminal extended forms. such as the pituitary during the ovulatory cycle and the ovary in which cells are transformed from granulosal to luteal. suggesting one reason for its detection might be related to lowered clearance (94). Oxytocin rises in hypoglycaemia and is modulated by glucocorticoids . In women oxytocin advanced the luteinising hormone (LH) surge when administered in the preovulatory period (102). Thus functional sequelae of activation of oxytocin receptors can be modified by the properties which arose from differentiation of the target cell. e. Composite regulatory elements which mediate tissuespecific expression (109. and these different forms of oxytocin can have specific roles (Table 1. In humans oxytocin seems to act reciprocally with vasopressin which is a stimulator of ACTH release. 109) (Table 1. of the target cell (108. but seems not to have a similar effect in the male (97). by vasopressin (96) or by CRH (97). The physiological modulation of stress is thus a complex network of endocrine control mechanisms. Oxytocin is thus able to influence anterior pituitary hormones as a hypothalamic regulating factor. The anterior pituitary gland In addition to hypothalamic oxytocin following the well known neurosecretory pathway to the neurohypophysis there have been suggestions that some also reaches the anterior pituitary lobe via the hypothalamo–pituitary portal vasculature. Oxytocin caused a dose–response reduction of ACTH in men (95). In addition to native oxytocin there are derived forms of the peptide. 101). Thus for oxytocin activity to be manifest at any particular site. N). K). including the complement of second messengers. 111. then extra stage-dependent controls will be operative (Table 1. other components (e. In the human female oxytocin increased thyrotrophin-releasing hormone-induced prolactin release. Possibly oxytocin stimulates pancreatic A-cell secretion. although not all investigators have noted such an effect (106). The variation in population of cell types determines that the pituitary responses of LH and prolactin to oxytocin will not be consistent over all times. A receptor can differentially couple to G-proteins depending on the characteristics. These other factors will be controlled by processes specific to the target and so indirectly regulate oxytocin action. ACTH Regulation of ACTH by oxytocin and involvement in the stress response has been indicated from animal studies. The enzymes which catalyse the formation of the forms may contribute to modulation of biological activities (15). one of the regulating hormones. Therefore the contribution of oxytocin changes to the development of OCD is still uncertain. N-alpha acetyl oxytocin. In addition oxytocin probably also increases insulin and glucagon (114) although apparently not under all circumstances (115). steroids) must act on the target too. an adrenal site of oxytocin action has also been detected (110). M). The adrenal Although oxytocin is believed to affect cortisol via ACTH. enhances hepatic glucose and has a direct glycogenolytic effect. One form (a little larger than native oxytocin) is induced by oestrogen and detected in the peripheral circulation and observed in patients with end-stage renal failure. involving several hormones with oxytocin. particularly in the context of behavioural functioning (15). The pancreas There is also an oxytocin component in glycaemic control.

at say the pancreas or ovary. from an oxytocin-producing unit.. and a pathology which affects oxytocin has the potential to have a wide range of sequelae. It is possible that oxytocin might be involved in improving the impaired glucose counterregulation in these patients (119).1 .1 -). it EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 can be noted that examples of hormonally mediated responses are provided by cells of the granulosa and the pancreas which. Oxytocin release is similarly modulated by local controls. 4).) . Feeding There have been suggestions from animal studies that oxytocin affects appetite. a specific physiological increase in oxytocin. Such a connection has not Figure 4 Oxytocin and insulin-induced hypoglycaemia. (Table 1. Effect of naloxone (3 mg iv) (. The oxytocin response to insulin was enhanced in obese but not normal men by the opioid antagonist naloxone. The regulation of receptors to these activating stimuli are responsive to local conditions. does not lead to a similar response at all potential production sites. such is not the case in women (118). There seems also to be sexual dimorphism in the regulation. These results provide another illustration of the interactive nature of oxytocin-mediated biological systems. Fat cells Oxytocin stimulates H2O2 generation in fat cells by a signal transduction mechanism. suggesting that there is abnormal activity of endogenous opioids in obese men (117) (Fig.566 J J Evans (116). This activity of oxytocin on fat cells is a further reminder that oxytocin has a diverse range of targets. The possibility of a paracrine role for oxytocin in the pancreas is suggested by the presence of the peptide in tissue (120). reproduced with permission. (From reference 117. plasma vasopressin (AVP) and oxytocin (OT) levels in ten obese men and eight normal men. or naloxone followed by insulin (. In considering control processes at a tissue level. are activated to produce oxytocin. The oxytocin rise in response to insulin is reduced in obese men. The oxytocin release in response to hypoglycaemia is exaggerated in patients with Type-I diabetes. in suitable circumstances. It is worth noticing that a stimulus which elicits.15 IU/kg) (——).. insulin (0. The H2O2 produced might participate in the regulation of fat cell differentiation and maintenance of the differentiated state (121). such that although endogenous opioids modulate oxytocin release during insulin-induced hypoglycaemia in men. including in this case insulin and opioids together with oxytocin. O). Thus oxytocin production is indirectly regulated by control mechanisms targeted to particular tissues.-) on blood glucose.

However in Prader–Willi syndrome (PWS). Interactions of oxytocin-mediated systems have been recognised in speculations regarding clinical symptoms in some pathologies. The results are consistent with oxytocin being a satiety hormone. In fact the variability of experimental results between different studies has been assigned at least partly to the different conditions of the experiments (86). Possibly a lack of peripheral oxytocin contributes to the diabetes mellitus and intolerance to glucose in PWS subjects.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 567 probably via a mechanism involving opiates (125). as was noted above. a connection between a physiology (pain) and a behaviour (anxiousness) noticed in a condition with a lack of oxytocin was thus postulated. there is a reduction in important oxytocin neurones going to brain stem nuclei. occasionally observed increased appetite. In another area. However not all side effects of oxytocin hypersecretion are unwelcome. Administration of oxytocin reduced back pains. 131). however. The role of oxytocin in depression is uncertain although perturbations have been reported. 5). In underweight women with restricting anorexia CSF oxytocin levels were low. It has been suggested that the sedation effects of breast feeding are due primarily to oxytocin. On the other hand there was a reduction of plasma oxytocin concentration in another group of depressed patients (133).) . uncertain information of the additional factors which modify the behavioural responses. The review considered the relationship between the various activities of oxytocin and the manner in which Figure 5 Oxytocin (OXT) neurones in Prader–Willi syndrome. Number of oxytocin-expressing neurones in the PVN of 27 controls (A) and 5 PWS patients (B). It is speculated that the low levels might be a reflection of low food intake and thus the women have enhanced retention of cognitive distortion of the consequences of food intake. and this peptide might form the basis of an anti-stress treatment (134). (From reference 123. There is. Oxytocin was not affected in a study in which normal subjects who consumed a large meal were administered cholecystokinin which slows gastric emptying and decreases food intake (122). circumstances will modulate the effect of oxytocin at the cellular level to produce a greater or lesser effect. Oxytocin in non-basal states been definitively established in humans. a reduction in total cell number in the PVN and a reduction in oxytocin neurones of the PVN (123) (Fig. There is also indirect evidence for oxytocin being involved in Alzheimer’s disease in which there is a selective degeneration of the basal nucleus of Meynert and changes in oxytocin levels in certain areas of brain and CSF (130. and depression. There was an increase in oxytocin immunoreactive neurones in the PVN of patients with symptoms of depression (132). There was a reduction in volume of the paraventricular nucleus (PVN). The involvement of oxytocin in behavioural activities implies that certain pathologies will have behavioural corollaries. a disease characterised by insatiable hunger producing gross obesity. It has also been noted that low oxytocin levels are present in children with recurrent abdominal pain. The reduced number of oxytocin neurones in PWS babies possibly partly explains the frequency of perinatal problems during delivery since there is suboptimal fetal oxytocin at labour (123). There is therefore a further example of an interaction between a biologically induced modulation and behavioural sequelae. Pain perception Conclusion Among its activities oxytocin seems to reduce pain. However a causal effect has not been demonstrated. In AIDS (127) and also in Parkinson’s disease (128) there are decreases in the PVN oxytocin-producing neurones which can possibly account for certain of the characteristics of patients. it is likely that for a behavioural response. The perturbation in oxytocin may be significant in influencing the clinical symptoms including the behaviour associated with this condition (124). In passing it is noted that children with recurrent abdominal pain are often anxious with increased muscular tension. alterations in secretion of oxytocin are believed to account for some of the symptoms associated with a subtype of OCD (129). However as with physiological responses. and oxytocin apparently activates contrary effects (126). reproduced with permission. These can include impotence.

Quan R & Knoll JHM. Burbach JPH. Eds R Caldeyro-Barcia and H Heller. 5 Gainer H. Jeong S-W. Forsling M & A vasopressin is influenced by ovarian steroid replacement in women. Circulating oxytocin and Bossmar T. British Medical Bulletin 1955 11 151–155. Advances in Experimental Medicine and Biology 1995 395 1–8. Saji F. Immunohistochemistry of vasopressin. Obstetrics and Gynecology 1994 84 259–262. Seitz PK. The sequence of amino acids in oxytocin with a proposal for the structure of oxytocin. POMC-derived peptide immunoreactivity in neural lobe axons of the human pituitary. Adan RAH & de Bree FM. Evolution of the vasopressin/oxytocin superfamily: Characterization of a cDNA encoding a vasopressin-related precursor from the mollusc Lymnaea stagnalis. 11 Mohr E & Richter D. Weindl A. Stock S. Ives KL. Annals of the New York Academy of Sciences 1992 652 1–13. Silber M & Unva¨s-Moberg K. Swan JM. Dubois-Dauphin M. Kikuchi T et al. The human oxytocin gene promoter is regulated by estrogens. Khayat H. Leake RD. Peptides 1993 14 857–860. Robinson ICAF. Journal of Clinical Endocrinology and Metabolism 1980 51 836–839. Annals of the New York Academy of Sciences 1993 689 50–58. The synthesis of an octapeptide amide with the hormonal activity of oxytocin. Molecular characterization of a cloned human oxytocin receptor. Barberis C & Jard S. Rossor MN & Iversen LL. Smit AB. Katsoyannis PG & Gordon S. Journal of Reproductive Medicine 1993 38 438–442. Ali LA & Azoury RS. Annals of the New York Academy of Sciences 1992 652 29–38. Spallanzani R. Endocrinology 1993 133 1116–1124. Other processes can modulate the production of oxytocin which occurs downstream from different physiological regulatory activation. 1961. Houston MJ & Howie PW. 10 van Kesteren RE. Price DL & Young WS III. The effect of nursing on neurohypophyseal hormone and prolactin secretion in human subjects. British Medical Journal 1983 286 257–259. Amico JA. 12 Sukhov RR. Genomics 1995 26 623–625. Brain Research 1984 291 111–117. and so have a generality beyond those of this particular peptide. Those control mechanisms relating to oxytocin will also be applicable to a wide variety of other physiological systems. Oxytocin release and plasma anterior pituitary and gonadal hormones in women during lactation. Some extra-uterine actions of oxytocin. Irahara M & Aono T. Neuroendocrinology 1991 53 209–213. de With ND. Urbanek M. Electrical breast stimulation oxytocin prolactin and uterine response. Geraerts WPM & Joosse J. Cigarini C. EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 14 15 16 17 18 19 20 References 1 Pickford M. Tenicela R. Johnson AE. Wahi RS & Fuchs F. Dean M & Goldman D. Distribution development and species differences. Journal of Clinical Endocrinology and Metabolism 1981 52 678–683. Journal of Clinical Endocrinology and Metabolism 1983 57 947–951. oxytocin and neurophysin in the 21 22 23 24 25 26 27 28 29 30 31 32 33 34 hypothalamus and extrahypothalamic regions of the human and primate brain. Journal of Clinical Biochemistry 1990 11 6098–6103. 8 Michelini S. Journal of Biological Chemistry 1994 269 32451–32456. American Journal of Obstetrics and Gynecology 1964 89 626–634. 6 Kimura T. Cross BA. A timedependent peak of oxytocin exists in cerebrospinal fluid but not in plasma of humans. Structural organisation of the human oxytocin receptor gene. Journal of Comparative Neurology 1993 337 295–306. Tribollet E. Vasopressin and oxytocin gene expression in the human hypothalamus. Amico JA. Sala NL. In Oxytocin. Influence of psychological stress on suckling-induced pulsatile oxytocin release. Ressler C & Trippett S. Aspects of evolution expression and subcellular mRNA distribution. Battey J & Hansmann I. Uedo T. Sayigh R. Bacchi-Modena A. Witt DM & Chin H. Neurobiology 1992 89 4593–4597. Dreifuss JJ. Azuma C. The oxytocin receptor gene (OXTR) localizes to human chromosome 3p25 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids. Rajaraman S et al. The posterior pituitary gland in relation to reproduction and lactation. Seoud MA-F. Finn FM & Robinson AG. 3 du Vigneaud V. Coiro V & Chiodera P. Jenkins JS. Chiodera P. Ervin MG. Neuroendocrinology 1992 55 269–275. 2 du Vigneaud V. Manning AB. Inoue T. Johnston J & Robinson AG. McNeilly AS. Dawood MY. Molecular and Cellular Endocrinology 1989 65 59–62. Elevated plasma levels of oxytocin in women taking low-dose oral contraceptives. Journal of Clinical Endocrinology and Metabolism 1985 60 5–12. Zingg HH & Lefebvre DL. 9 Simmons CF. oxytocin and neurophysins in the human brain and spinal cord. The investigation of oxytocin provides a general framework of study in which it can be noted that a peptide hormone can have several distinct actions. Alboni A et al. Khan-Dawood FS. Dirks RW. 7 Inoue T. Salvarani C. Polymorphism and genetic mapping of the human oxytocin receptor gene on chromosome 3. Naloxone increases the angiotensin II stimulated rise of arginine vasopressin and oxytocin secretion in man. Yokoyama Y. Cooper KM. Clancy TE. 13 Sofroniew MV. Kikuchi T et al. Vasopressin. The milk-ejecting effect induced by oxytocin and vasopressin during human pregnancy. Ang VTY. Coirini H. Takemura M. Acta Obstetrica et Gynecologica Scandinavica 1995 74 544–548. Regulation of oxytocin gene expression and forms of oxytocin in the brain. and that the interrelationships between the actions result in sometimes unexpected effects. Makino Y. 4 Rao VVNG. Journal of Biological Chemistry 1953 205 949–957. Relationship between plasma profiles of oxytocin . Roberts CW. The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. It is necessary to have some means of regulation so that there is not a tidal wave of oxytocin-initiated events whenever oxytocin is needed physiologically for a response. Release of oxytocin and prolactin in response to suckling. Fisher DA. Cytogenetics and Cell Genetics 1992 61 271–273. A novel oxytocin-like and vasotocin-like peptide in human plasma after administration of estrogen. Some regulatory processes can modulate the responsivity to oxytocin. Inazawa J. Walker LC. Hawthorn J. Ishizuka J. Strategies for cell biological studies in oxytocinergic neurons.568 J J Evans they are related in the body’s physiology. Rance NE. Hypothalamic neuropeptide genes. Oxytocin receptors in the central nervous system. Richard S & Zingg HH. Parathyroid hormone-related peptide production and action in myoepithelial cell line derived from normal human breast. Townsend CM. Kimura T. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1995 60 183–197. Acta Histochemica 1981 24 (Suppl) 79–95. Oxytocin mRNA: increase of polyadenylate tail size during pregnancy and lactation. Weitzman RE. Chronwall BM & Millington WR. Oxford: Pergamon Press. Acta Obstetrica Gynecologica Scandinavica 1989 68 75–78. ˚ kerlund M. Schrell U & Wetzstein R. Lo¨ffler C. Journal of the American Chemical Society 1953 75 4879–4880. Takemura M. pp 68–79. European Journal of Endocrinology 1994 131 385–390. that the selective actions require differential modulatory mechanisms. Ressler C. Sex differences in the regulation of oxytocin receptors by ovarian steroids in the ventromedial hypothalamus of the rat. Schumacher M & McEwen BS.

Kuhn W & Wuttke W. Oxytocin receptors in nonpregnant human uterus. Rezapour M. Mechanisms regulating oxytocin receptor coupling to phospholipase C in rat and human myometrium. Endocrinology 1990 127 2990–2996. Clauser E. Oxytocin inhibits proliferation of human breast cancer cell lines. Makimura N. Behrens O. Teutsch B. Coiro V. Kimura T. Peat ML. Bussenot I. Regulatory Peptides 1984 8 141–146. Garde SV & Sheth AR. Regulatory Peptides 1993 45 187–191. ontogeny and localization by in vitro and in vivo autoradiography. Gene expressions of oxytocin and oxytocin receptor in cumulus cells of human ovary. Teichmann A. Link H. The effect of oxytocin on oestradiol-17b and testosterone secretion by cultured human granulosa cells. Qian A. American Journal of Obstetrics and Gynecology 1990 163 1961–1967. Sapino A. Cassoni P. Dalkin AC. Takemura M. Furuya K. Haisenleder DJ. Ishikawa N. Porter DG & Pickering BT. Mitsui C. Imaizumi E et al. Amico JA. Murakami M. Journal of Endocrinology 1995 147 525–532. Human Reproduction 1988 3 479–483. Carter CS & Gold PW. Journal of Endocrinology 1994 142 345–352. Obstetrics and Gynaecology 1993 82 532–538. Murrell TG. Quartero HWP. Yang J. Pullen M & Nambi P. Virchows Archiv 1994 425 467–472. Swann RW. Toffoletti F et al. Conchon S. . Vangsted A. Journal of Biological Chemistry 1996 41 25300–25307. The role of oxytocin and vasopressin in the A initiation of preterm and term labour as well as primary dysmenorrhoea. Vianello B et al. Mayerhofer A. Jenkins JS.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 and adrenocorticotrophic hormone during suckling or breast stimulation in women. Mechanism of GnRH action in gonadotrophs. North L. Mehta MK. Suckling-induced attenuation of plasma cortisol concentrations in postpartum lactating women. Fuchs A-R. Identification of oxytocin and vasopressin in the testis and in adrenal tissue. Goodwin TM. Pisegna JR & Wank SA. Journal of Endocrinology 1997 153 49–59. The pharmokinetics of the oxytocin antagonist atosiban in pregnant women with preterm uterine contractions. Journal of Clinical Endocrinology and Metabolism 1985 60 37–41. Antitachyphylactic effects of progesterone and oxytocin on term human myometrial contractile activity in vitro. Inoue T. Fry CH & Kierse MJNC. Endocrinology 1996 137 548–554. Alboni A. Guillou M-D. Kimura T. Inoue T et al. Coombes RC & Luqmani YA. Sterzik K. Two oxytocin-binding site subtypes in rat kidney: pharmacological characterisation. Ivanisevic M. Tokuoka S. Hormone Research 1994 41 (Suppl 1) 41–47. EuropeFinner GN. Fu X. Nomura S. Journal of Biological Chemistry 1996 29 17267–17274. Plevrakis I. Journal of Clinical Endocrinology and Metabolism 1992 74 385–392. Arpin-Bott MP. Expression of the oxytocin and vasopressin genes in human and baboon gonadal tissues. Bianconi L. The potential for oxytocin (OT) to prevent breast cancer: a hypothesis. Lopez Bernal A. Phaneuf S. Interaction between oxytocic and prostaglandin F2a in human corpus luteum? Human Reproduction 1995 10 2320–2324. Journal of Clinical Endocrinology and Metabolism 1992 74 306–312. Gramellini D. Journal of Endocrinology 1990 124 R5–R8. Prostaglandins 1991 42 137–150. Elshourbagy NA. Europe-Finner GN. International Journal of Fertility and Menopausal Studies 1995 40 39–46. Monga M et al. Curnow KM. Helmer H. Endocrinology 1996 137 773–779. Furuya K. Tokuoka S et al. Johnston JM & Vagnuccim AH. Giannini S. Acta Endocrinologica 1992 126 213–216. Hormone Research 1991 35 119–123. American Journal of Obstetrics and Gynecology 1995 173 913–917. Anwer K. Plevrakis I. Fantoni G. Parinaud J. Fuchs F & Soloff MS. Ku CY. Bellinger J. Wakasugi E. Human Reproduction 1991 6 774–778. Davies E. Nobunaga T. Azuma C et al. Inhibition by ethanol of the oxytocin response to breast stimulation in normal women and the role of endogenous opioids. Magini A. G protein expression and second messenger formation in human granulosa cells. Postgraduate Medical Journal 1990 66 195–199. Burford GD. Nicholson HD. Hormone Research 1995 44 47–49. Yasin M. Expression and localization of oxytocin receptor gene in human uterine endometrium in relation to the menstrual cycle. Journal of Reproduction and Fertility 1995 104 77–83. Journal of Clinical Endocrinology and Metabolism 1995 80 2954–2959. Oxytocin and vasopressin biding sites in human and bovine arteries. Millar L. Breast Cancer Research and Treatment 1995 35 225–229. Role of prostaglandins and leukotrienes in the synergistic effect of oxytocin and corticotropin-releasing hormone (CRH) on the contraction force in human gestational myometrium. Advances in Experimental Medicine and Biology 1995 395 469–479. Evidence for the presence of pro-oxytocin/neurophysin-converting enzyme in the human ovary. Maas S. Noort WA. Wu H-L. Oxytocin signalling in human myometrium. Fuchs A-R. Cancer Research 1990 50 7882–7886. Clamagirand C. Cigarini C. Clayton RN. Takemura M. Matsuura N. Endocrinology 1993 132 1830–1835. Rath W. Galliven E. ˚ kerlund M. Investigation of the oxytocin receptor expressions in human breast cancer tissue. Endocrinology 1996 137 780–785. Ivell R. Ulmsten U & Ba¨ckstro˝m T. Camier M & Clamagirand C. Symonds EM & Maynard PV. Ito Y. Maggi M. Brackmann B. Baker PN. Endocrine Research 1994 20 79–87. Evidence for dual coupling to adenylate cyclase and phospholipase C. Carrasco MP. Mitsui C. Fiscella A. Altemus M. European Journal of Endocrinology 1996 134 403–411. Bennegard-Eden B. Onoue H. Taylor AH. Silverlight JJ. Journal of Clinical Endocrinology and Metabolism 1993 77 1209–1214. Suppression of hypothalamic–pituitary–adrenal axis responses to stress in lactating women. Angiotensin II receptors: protein and gene structures expression and potential pathological involvements. Freund-Mercier MJ & Stoekel ME. Advances in Experimental Medicine and Biology 1995 395 453– 467. Jarry H. Makimura N. Effect of oxytocin on free intracellular Ca2þ levels and progesterone release by human granulosa-lutein cells. Hamilton CH & Lopez-Bernal A. Ang VTY. A novel biological aspect of ovarian oxytocin: oxytocin gene expression in cumulus/luteal cells and the effect of oxytocin on embryogenesis in fertilized oocytes. Vieitez G & Grandjean H. Anwer K & Dawood MY. Phaneuf S. Clamagirand C & Pontonnier G. Khan-Dawood FS. Interaction of vasopressin and oxytocin with human breast carcinoma cells. Weglein RC & Holland ML. Kobayashi T. Dawood Y & Khan-Dawood F. Asbo´th G et al. Nomura S. Occurrence of FSH inhibin and other hypothalamic–pituitary–intestinal hormones in normal fertility subfertility and tumors of human testes. Sanborn BM. Pituitary activin receptor subtypes and follistatin gene expression 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 569 in female rats: differential regulation by activin and follistatin. Marshall JM. Adamou JE. Sex steroid modulation of neurohypophysial hormone receptors in human nonpregnant myometrium. Cloning and characterization of the signal transduction of four splice variants of the human pituitary adenylate cyclase activating polypeptide receptor. Wen Y. Deuster PA. Kubota Y. Endometrial oxytocin binding sites in normal women and in subfertile patients. Kimura T. Waltisperger E. Gagnon AW. Negro F & Bussolati G. prostaglandin F2a and estradiol within the human corpus luteum. Paracrine actions of oxytocin. Gilrain JT & Marshall JC. Wiemann M & Gratzl M. Expression of oxytocin receptor in human pregnant myometrium. Mizumoto Y. Abrams LS. Lo˝fgren M. Pignatti D et al. Furuya K. Takeda T et al. Grifo J et al. Molecular characterization of a novel human endothelin receptor splice variant. Oxytocin biosynthesis in serum-free cultures of human granulosa cells. Hahlin M & Kindahl H. Bioactive oxytocin in human and baboon corpora lutea. Wathes DC.

Leonard HL. Legros JJ & Franchimont P. Potter et al. Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. somatostatin. Orr SP & Lasko NB. Neuropeptide genes: targets of activitydependent signal transduction. Almkvist O. The thymic repertoire of neuroendocrine self-antigens: physiological implications in T-cell life and death. Maffei ML. 88 Silber M. Journal of Clinical Endocrinology and Metabolism 1980 50 397–400. 87 Pitman RK. Biology of Reproduction 1997 56 416–422. Hormone and Metabolic Research 1989 21 635–637. Evans JJ. Psychological stress of exposure to uncontrollable noise increases plasma oxytocin in high emotionality women. . Evans JJ. Chiodera P & Geenen V. Volpi R. Page SR. Volpi R. Chiodera P. Oxytocin levels and disappearance rate and plasma follicle-stimulating hormone and luteinizing hormone after oxytocin infusion in men. 82 Anderson-Hunt M & Dennerstein L. Journal of Clinical Endocrinology and Metabolism 1984 58 105–109. Marcato A. The effect of oxytocin infusion on adenohypophyseal function in man. British Medical Journal 1994 309 891–892. Archives of General Psychiatry 1994 51 794–803. Oxytocin and prostatic function. Neurohypophyseal peptides and psychopathology. Immunology Today 1996 17 312–317. The effect of oxytocin infusion on adenohypophyseal and adrenal cortical responses to insulin-induced hypoglycaemia. Science 1986 232 508–511. Peptides 1992 13 1083–1085. Evaluation of oxytocin administration on luteinizing hormone and follicle-stimulating hormone response to luteinizing hormonereleasing hormone during the menstrual cycle of normal women. Peptides 1991 12 1385–1391. Ervin MG. Relationships among cardiovascular muscular and oxytocin responses during human sexual activity. Ang VT. Oxytocin does not modify glucagon. Lancet 1968 2 735. Richter D. Amico JA. High pressure liquid chromatographic separation of an oxytocin/arginine vasotocin-like peptide from the plasma of EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 patients with chronic renal failure. ˚ . Archives of Sexual Behaviour 1994 23 59–79. insulin and oxytocin levels in healthy women. Chang W. Dawood MY. Berrettini Wet al. Clinical Endocrinology 1988 29 257–264. Defresne M-P & Boniver J. Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder. Ang VTY. Ylikorkala O. Life Sciences 1990 47 57–65. Acta Endocrinologica 1989 121 41–45. 81 Carter CS.or calcitonin-induced ACTH-cortisol rise in humans. Chiodera P & Demey-Ponsart E. British Medical Journal 1994 309 929. Bianconi L. Potential for modulation of pituitary hormone secretion in rats. Finn FM. Temporary peripartal impairment in memory and attention and its possible relation to oxytocin concentration. Thymic neurohypophysial-related peptides and T cell selection. Clinical Endocrinology 1990 32 307–313. Kuphal D. Gonadotrophin-releasing activity of neurohypophysial hormones: I. 79 Herbert J. Peptides 1991 12 1399–1406. Rabinovitch S. Serum-gonadotrophins after oxytocin in man. Vasopressin and oxytocin do not influence early sensory processing but affect mood and activation in man. Richardson DW & Winters SJ. Hull ML. Peptides 1996 17 721–728. Legros JJ. Journal of Endocrinology 1990 125 425–432. Changes in cerebrospinal fluid neurochemistry during treatment of obsessive compulsive disorder with clomipramine. Regulatory Peptides 1993 45 273– 278. Increased female sexual response after oxytocin. Pignatti D et al. 86 Fehm-Wolfsdorf G & Born J.570 J J Evans 73 Einspanier A & Ivell R. Zhou W. Robinson G & Evans JJ. Coiro V. Rubinow DR. 93 den Boer JA & Westenberg HGM. 94 Amico JA. Behavioural effects of neurohypophyseal peptides in healthy volunteers: 10 years of research. Millette CF & Kilpatrick DL. Gynecological and Obstetrical Investigation 1995 40 217–221. Camellini L & Rossi G. Fehm HL. An activation function in pit-1 required selectively for synergistic transcription. Baudrihaye M. Stable transfection of GH3 cells with rat gonadotropin-releasing hormone receptor complementary deoxyribonucleic acid results in expression of a receptor coupled to cyclic adenosine 30 50 monophosphate-dependent prolactin release via a G-protein. Journal of Psychosomatic Research 1993 37 581–588. 83 Legros JJ. Reid RA. Journal of Biological Chemistry 1995 270 26497–26504. Rettew DC. 76 Geenan V. 80 Carmichael MS. Journal of Clinical Endocrinology and Metabolism 1982 55 1035–1039. Fertility and Sterility 1984 42 396–399. Dose– response relationship between plasma oxytocin and cortisol and adrenocorticotropin concentrations during oxytocin infusion in normal men. Pre-ovulatory oxytocin administration promotes the onset of the luteinizing hormone surge in human females. Oxytocin in obsessive compulsive disorder. Braun D. 92 Altemus M. Cavazzini U. 84 Pietrowsky R. MacArthur L & Eiden L. Advances in Experimental Medicine and Biology 1995 395 529–538. Doll Jr RB. Heckert LL. Oxytocin and oxytocin receptor expression in reproductive tissues of the male marmoset monkey. 91 Swedo SE. Raval PJ. 74 Nicholson HD & Jenkin L. Kruesi MJP. Geenen V. Journal of Clinical Endocrinology and Metabolism 1985 60 644–650. Nussey SS. Kaiser UB. Inhibitory influence of exogenous oxytocin on adrenocorticotropin secretion in normal human subjects. Chiodera P. Robert F. The effect of oxytocin administration upon the pulsatile secretion of luteinizing hormone in humans. Chin WB & Conn PM. Legros JJ. Ek S & Nilsonne A relationships between personality traits and plasma gastrin cholecystokinin. Inhibitory action of exogenous oxytocin on plasma cortisol in normal human subjects: evidence of action at the adrenal level. 78 Anderson-Hunt M & Dennerstein L. Franchimont P. Arn I. Transcription factor Sp1 is expressed by three different developmentally regulated messenger ribonucleic acids in mouse spermatogenic cells. Smitz S & von Frenckell R. Hormone Research 1992 37 16–21. Oxytocin has a role in gonadotrophin regulation in rats. Schultz K & Nilson JH. Warburton VL. Psychiatry Research 1993 48 107–117. Jackson R. 77 Martens H. Neuroscience and Behavioural Reviews 1992 16 131–144. Persengiev SP. Dixen J & Davidson JM. Endocrinology 1996 137 638–646. White A. Leonard HL. Legros JJ. Neuroendocrinology 1988 48 204– 206. Oxytocin and female sexuality. Page SR. The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus. Benhida A et al. Goxe B & Geenen V. Legros J-J. Pauschinger P & Born J. Listwak SJ. Benny PS & Aickin DR. Journal of Endocrinology 1989 122 99–106. 90 Sanders G. Vandersmissen E. Swedo SE. Janovick JA. Oxytocin and sexual behaviour. Oxytocin and sexual behaviour. Hijman R & Van Ree JM. Archives of General Psychiatry 1992 49 29–36. The 89 Uvna¨s-Moberg K. Peptides 1992 13 461–468. Journal of Biological Chemistry 1996 271 17733– 17738. Cormann-Goffin N. 75 Geenen V. Jonsson C-O. Jenkins JS & White A. Theill LE. Martens H. Trivedi D & Gupta R. Fisher DA et al. Robinson G & Catt KJ. Freillicher J & Lightman SL. Baxter JD & Schaufele F. 85 Bruins J. Human Reproduction 1995 10 2266–2269. Leake RD. Psychoneuroendocrinology 1990 15 47–58. Different composite regulatory elements direct expression of the human a subunit gene to pituitary and placenta. Larsson B & Uvna¨s-Moberg K. Nussey SS & Jenkins JS. Chiodera P. Endocrinology 1994 135 315–320. Effect of a single dose of desglycinamide-[Arg8] vasopressin or oxytocin on cognitive processes in young healthy subjects.

Portegies P. Hofman MA. Purba JS & Hofman MA. Cavazzini U et al. 120 Amico JA. Journal of Clinical Endocrinology and Metabolism 1989 68 688–692. 132 Purba JS. Oxytocin in Alzheimer’s disease: postmortem brain levels. 119 Fisher BM. Marrazzo G. Science 1982 215 1237–1238. Neurohypophysial secretion to insulin-induced hypoglycemia and its regulation by endogenous opioids in women. Checkley SA. American Journal of Psychiatry 1990 147 882–886. 114 Paolisso G. Lesem MD. 123 Swaab DF. 131 Mazurek MF. The effect of oxytocin on the plasma glucagon response to insulin-induced hypoglycaemia in man. Bower M. Pauls DL et al. Baylis PH. De Riu S. Haagendijk WJ. Carney D & Battey J. Acta Endocrinologica 1990 122 467–471. Archives of General Psychiatry 1996 53 137–143. Brain 1993 116 795–809. Hofman MA & Swaab DF. Price DL. Inhibitory effect of dexamethasone on the oxytocin in response to insulin-induced hypoglycaemia in normal men. Davoli C. 122 Miaskiewicz SL. Journal of Endocrinological Investigation 1990 13 757–763. Papadia C et al. Seckl JR & Lightman SL. Neurohypophyseal secretion in response to cholecystokinin but not meal-induced gastric distension in humans. 128 Purba JS. Journal of Clinical Endocrinology and Metabolism 1995 80 573–579. Journal of Endocrinological Investigation 1992 15 459–463. Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system. 133 Frasch A. Journal of Clinical Endocrinology and Metabolism 1984 58 688–691. 126 Alfve´n G. Steiger A & Jirikowski GF. Bird ED & Martin JB. Journal of Biological Chemistry 1985 260 10236–10241. 115 Page SR. Castelli A. American Journal of Medical Sciences 1988 296 303–307. Coyle JT & DeLong MR. Advances in Experimental Medicine and Biology 1995 395 257–258. Stricker EM & Verbalis JG. Increased number of vasopressin. Effects of oxytocin upon the endocrine pancreas secretion and glucose turnover in normal man. Hofman MA & Swaab DF. Goodman WK. Price LH. Brandt HA. Speroni G. Increase by naloxone of arginine vasopressin and oxytocin responses to insulin-induced hypoglycemia in obese men. 136 Murphy MR. Journal of Clinical Endocrinology and Metabolism 1989 68 837–843. Finn FM & Haldar J. Sgambato S. Zetzsche T. 124 Demitrack MA. Acta Paediatrica 1994 83 1076–1080. Bianconi L. Capretti L. Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder. Biochemical Journal 1995 307 543– 548. Spine 1994 19 867–871. 571 125 Yang J. Archives of General Psychiatry 1994 51 782–792. Pizza G. 121 Krieger-Brauer HI & Kather H. de la Torre B & Uvna¨s-Moberg K. Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader–Willi Syndrome: a study of five cases. Received 6 May 1997 Accepted 5 August 1997 . The stimulus-sensitive H202generating system present in human fat-cell plasma membranes is multireceptor-linked and under antagonistic control by hormones and cytokines. Thornton S & Frier BM. Clark AW. 130 Whitehouse PJ. Oxytocin and vasopressin are present in human and rat pancreas. Naloxone inhibits oxytocin release at orgasm in man. 118 Johnson MR. Volpi R. Listwak SJ. Giugliano D et al. Caiazza A. Struble RG. CSF oxytocin in anorexia nervosa and bulimia nervosa: clinical and pathophysiologic considerations. Neurology 1987 37 1001–1003. Reduction of plasma oxytocin levels in patients suffering from major depression. Journal of Clinical Endocrinology and Metabolism 1990 71 1056–1058. Jimerson DC & Gold PW. Oxytocin and behaviour. Seckl JR & Lightman SL. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Acta Endocrinologica 1990 123 504–510. Diabete et Metabolisme 1990 16 248–252. 135 Sausville E. 116 Chiodera P. Ang VTY. 127 Purba JS.Oxytocin in the human EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 113 Ang VTT & Jenkins JS. Marchesi C. North WG. Jackson R & Nussey SS. Depressed concentrations of oxytocin and cortisol in children with recurrent abdominal pain of non-organic origin. Beal MF. Troost D & Swaab DF. Annals of Medicine 1994 26 315–317.and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Chappell PB. Neurology 1994 44 84–89. Decreased number of oxytocin neurons in the paraventricular nucleus of the human hypothalamus in AIDS. Neurohypophysial hormones in the adrenal medulla. 129 Leckman JF. The human vasopressin gene is linked to the oxytocin gene and is selectively expressed in a cultured lung cancer cell line. Arginine vasopressin and oxytocin responses to insulin-induced hypoglycemia in type 1 (insulin-dependent) diabetes. 134 Uvna¨s-Moberg K. 117 Coiro V. Decreased number of oxytocin-immunoreactive neurons in the paraventricular nucleus of the hypothalamus in Parkinson’s disease.