Oxytocin
Clinical data
Pronunciation/ˌɒksɪˈtsɪn/
Physiological data
Source tissuespituitary gland
Target tissueswide spread
Receptorsoxytocin receptor
Antagonistsatosiban
Precursoroxytocin/neurophysin I prepropeptide
Metabolismliver and other oxytocinases
Pharmacokinetic data
Protein binding30%
Metabolismliver and other oxytocinases
Elimination half-life1–6 min (IV)
~2 h (intranasal)[1][2]
ExcretionBiliary and kidney
Identifiers
  • 1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-L-prolyl-L-leucylglycinamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.045 Edit this at Wikidata
Chemical and physical data
FormulaC43H66N12O12S2
Molar mass1007.19 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@@H]1NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](N)CSSC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC1=O)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O
  • InChI=1S/C43H66N12O12S2/c1-5-22(4)35-42(66)49-26(12-13-32(45)57)38(62)51-29(17-33(46)58)39(63)53-30(20-69-68-19-25(44)36(60)50-28(40(64)54-35)16-23-8-10-24(56)11-9-23)43(67)55-14-6-7-31(55)41(65)52-27(15-21(2)3)37(61)48-18-34(47)59/h8-11,21-22,25-31,35,56H,5-7,12-20,44H2,1-4H3,(H2,45,57)(H2,46,58)(H2,47,59)(H,48,61)(H,49,66)(H,50,60)(H,51,62)(H,52,65)(H,53,63)(H,54,64)/t22-,25-,26-,27-,28-,29-,30-,31-,35-/m0/s1 checkY
  • Key:XNOPRXBHLZRZKH-DSZYJQQASA-N checkY
  (verify)

Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary.[3] It plays a role in social bonding, reproduction, childbirth, and the period after childbirth.[4] Oxytocin is released into the bloodstream as a hormone in response to sexual activity and during labour.[5][6] It is also available in pharmaceutical form. In either form, oxytocin stimulates uterine contractions to speed up the process of childbirth. In its natural form, it also plays a role in bonding with the baby and milk production.[6][7] Production and secretion of oxytocin is controlled by a positive feedback mechanism, where its initial release stimulates production and release of further oxytocin. For example, when oxytocin is released during a contraction of the uterus at the start of childbirth, this stimulates production and release of more oxytocin and an increase in the intensity and frequency of contractions. This process compounds in intensity and frequency and continues until the triggering activity ceases. A similar process takes place during lactation and during sexual activity.

Oxytocin is derived by enzymatic splitting from the peptide precursor encoded by the human OXT gene. The deduced structure of the active nonapeptide is:

Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2.

Etymology

The term "oxytocin" derives from the Greek "ὠκυτόκος" (ōkutókos), based on ὀξύς (oxús), meaning “sharp” or "swift", and τόκος (tókos), meaning “childbirth”.[8][9] The adjective form is "oxytocic", which refers to medicines which stimulate uterine contractions, to speed up the process of childbirth.

History

The uterine-contracting properties of the principle that would later be named oxytocin were discovered by British pharmacologist Henry Hallett Dale in 1906,[10][11] and its milk ejection property was described by Ott and Scott in 1910[12] and by Schafer and Mackenzie in 1911.[13]

In the 1920s, oxytocin and vasopressin were isolated from pituitary tissue and given their current names.

Oxytocin‘s molecular structure was determined in 1952.[14] In the early 1950s, American biochemist Vincent du Vigneaud found that oxytocin is made up of nine amino acids, and he identified its amino acid sequence, the first polypeptide hormone to be sequenced.[15] In 1953, du Vigneaud carried out the synthesis of oxytocin, the first polypeptide hormone to be synthesized.[16][17][18] Du Vigneaud was awarded the Nobel Prize in 1955 for his work.[19]

Further work on different synthetic routes for oxytocin, as well as the preparation of analogues of the hormone (e.g. 4-deamido-oxytocin) was performed in the following decade by Iphigenia Photaki.[20]

Biochemistry

OXT
Identifiers
AliasesOXT, OT, OT-NPI, OXT-NPI, oxytocin/neurophysin I prepropeptide
External IDsOMIM: 167050 MGI: 97453 HomoloGene: 55494 GeneCards: OXT
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000915

NM_011025

RefSeq (protein)

NP_000906

NP_035155

Location (UCSC)Chr 20: 3.07 – 3.07 MbChr 2: 130.58 – 130.58 Mb
PubMed search[23][24]
Wikidata
View/Edit HumanView/Edit Mouse

Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain.[25] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.[26]

Biosynthesis

The biosynthesis of the different forms of OT
The biosynthesis of the different forms of OT

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[27][28][29] This precursor protein also includes the oxytocin carrier protein neurophysin I.[30] The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).[31]

The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[32] Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.[33]

Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase.[34][35] Other oxytocinases are also known to exist.[34][36] Amastatin, bestatin (ubenimex), leupeptin, and puromycin have been found to inhibit the enzymatic degradation of oxytocin, though they also inhibit the degradation of various other peptides, such as vasopressin, met-enkephalin, and dynorphin A.[36][37][38][39]

Neural sources

In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei,[40] and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate neurons in the nucleus accumbens, a brain structure where oxytocin receptors are expressed.[41] The endocrine effects of hormonal oxytocin and the cognitive or behavioral effects of oxytocin neuropeptides are thought to be coordinated through its common release through these collaterals.[41] Oxytocin is also produced by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[42] Depending on the species, oxytocin receptor-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis.

In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.

Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.

Non-neural sources

Endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels.[43]

Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum[44][45] and the placenta;[46] in males in the testicles' interstitial cells of Leydig;[47] and in both sexes in the retina,[48] the adrenal medulla,[49] the thymus[50] and the pancreas.[51] The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these diverse tissues.

Male

The Leydig cells in some species have been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.[52]

Female

Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandin F to cause regression of the corpus luteum.[53]

Evolution

Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are usually located close to each other (less than 15,000 bases apart) on the same chromosome, and are transcribed in opposite directions (however, in fugu,[54] the homologs are further apart and transcribed in the same direction).

The two genes are believed to result from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomata (modern members of the Agnatha).[55]

Biological function

Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor, OT-R, which requires magnesium and cholesterol and is expressed in myometrial cells.[56] It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.[57]

Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, in-group bias, situational lack of honesty, autism, and maternal behaviors.[11]

Physiological

The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. The behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland, or that are collaterals from them.[41] Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem, although the distribution differs markedly between species.[57] Furthermore, the distribution of these receptors changes during development and has been observed to change after parturition in the montane vole.[57]

In a study measuring oxytocin serum levels in women before and after sexual stimulation, the author suggests it serves an important role in sexual arousal. This study found genital tract stimulation resulted in increased oxytocin immediately after orgasm.[64] Another study reported increases of oxytocin during sexual arousal could be in response to nipple/areola, genital, and/or genital tract stimulation as confirmed in other mammals.[65] Murphy et al. (1987), studying men, found that plasma oxytocin levels remain unchanged during sexual arousal, but that levels increase sharply after ejaculation, returning to baseline levels within 30 minutes. In contrast, vasopressin was increased during arousal but returned to baseline at the time of ejaculation. The study concludes that (in males) vasopressin is secreted during arousal, while oxytocin is only secreted after ejaculation.[66] A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted these changes "may simply reflect contractile properties on reproductive tissue".[67]

Psychological

Bonding

In the prairie vole, oxytocin released into the brain of the female during sexual activity is important for forming a pair bond with her sexual partner. Vasopressin appears to have a similar effect in males.[76] Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after a five to 24 minute petting session. This possibly plays a role in the emotional bonding between humans and dogs.[77]

Oxytocin is not only correlated with the preferences of individuals to associate with members of their own group, but it is also evident during conflicts between members of different groups. During conflict, individuals receiving nasally administered oxytocin demonstrate more frequent defense-motivated responses toward in-group members than out-group members. Further, oxytocin was correlated with participant desire to protect vulnerable in-group members, despite that individual's attachment to the conflict.[83] Similarly, it has been demonstrated that when oxytocin is administered, individuals alter their subjective preferences in order to align with in-group ideals over out-group ideals.[84] These studies demonstrate that oxytocin is associated with intergroup dynamics. Further, oxytocin influences the responses of individuals in a particular group to those of another group. The in-group bias is evident in smaller groups; however, it can also be extended to groups as large as one's entire country leading toward a tendency of strong national zeal. A study done in the Netherlands showed that oxytocin increased the in-group favoritism of their nation while decreasing acceptance of members of other ethnicities and foreigners.[85] People also show more affection for their country's flag while remaining indifferent to other cultural objects when exposed to oxytocin.[86] It has thus been hypothesized that this hormone may be a factor in xenophobic tendencies secondary to this effect. Thus, oxytocin appears to affect individuals at an international level where the in-group becomes a specific "home" country and the out-group grows to include all other countries.

Drugs

Fear and anxiety

Oxytocin is typically remembered for the effect it has on prosocial behaviors, such as its role in facilitating trust and attachment between individuals.[92][qualify evidence] However, oxytocin has a more complex role than solely enhancing prosocial behaviors. There is consensus that oxytocin modulates fear and anxiety; that is, it does not directly elicit fear or anxiety.[93] Two dominant theories explain the role of oxytocin in fear and anxiety. One theory states that oxytocin increases approach/avoidance to certain social stimuli and the second theory states that oxytocin increases the salience of certain social stimuli, causing the animal or human to pay closer attention to socially relevant stimuli.[94]

Nasally administered oxytocin has been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses).[95] Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala.[96][97] Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude.[98] Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust more quickly than individuals who do not receive oxytocin.[94][qualify evidence] Facial expressions of disgust are evolutionarily linked to the idea of contagion. Thus, oxytocin increases the salience of cues that imply contamination, which leads to a faster response because these cues are especially relevant for survival. In another study, after administration of oxytocin, individuals displayed an enhanced ability to recognize expressions of fear compared to the individuals who received the placebo.[99] Oxytocin modulates fear responses by enhancing the maintenance of social memories. Rats that are genetically modified to have a surplus of oxytocin receptors display a greater fear response to a previously conditioned stressor. Oxytocin enhances the aversive social memory, leading the rat to display a greater fear response when the aversive stimulus is encountered again.[93]

Mood and depression

Oxytocin produces antidepressant-like effects in animal models of depression,[100] and a deficit of it may be involved in the pathophysiology of depression in humans.[101] The antidepressant-like effects of oxytocin are not blocked by a selective antagonist of the oxytocin receptor, suggesting that these effects are not mediated by the oxytocin receptor.[26] In accordance, unlike oxytocin, the selective non-peptide oxytocin receptor agonist WAY-267,464 does not produce antidepressant-like effects, at least in the tail suspension test.[102] In contrast to WAY-267,464, carbetocin, a close analogue of oxytocin and peptide oxytocin receptor agonist, notably does produce antidepressant-like effects in animals.[102] As such, the antidepressant-like effects of oxytocin may be mediated by modulation of a different target, perhaps the vasopressin V1A receptor where oxytocin is known to weakly bind as an agonist.[103][104]

Sildenafil enhances electrically evoked oxytocin release from the pituitary gland.[100] In accordance, it may have promise as an antidepressant.[100]

Sex differences

It has been shown that oxytocin differentially affects males and females. Females who are administered oxytocin are overall faster in responding to socially relevant stimuli than males who received oxytocin.[94][105] Additionally, after the administration of oxytocin, females show increased amygdala activity in response to threatening scenes; however, males do not show increased amygdala activation. This phenomenon can be explained by looking at the role of gonadal hormones, specifically estrogen, which modulate the enhanced threat processing seen in females. Estrogen has been shown to stimulate the release of oxytocin from the hypothalamus and promote receptor binding in the amygdala.[105]

It has also been shown that testosterone directly suppresses oxytocin in mice.[106] This has been hypothesized to have evolutionary significance. With oxytocin suppressed, activities such as hunting and attacking invaders would be less mentally difficult as oxytocin is strongly associated with empathy.[107]

Social

Chemistry

Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons)
Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons)

Oxytocin is a peptide of nine amino acids (a nonapeptide) in the sequence cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide (Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2); its C-terminus has been converted to a primary amide and a disulfide bridge joins the cysteine moieties.[131] Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin is the equivalent of 1.68 μg of pure peptide.[132]

While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was reported in 2011 in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation (thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine).[133] Since this original Lee et al. paper, two other laboratories have confirmed Pro8-OT and documented additional oxytocin structural variants in this primate taxon. Vargas-Pinilla et al. sequenced the coding regions of the OXT gene in other genera in new world primates and identified the following variants in addition to Leu8- and Pro8-OT: Ala8-OT, Thr8-OT, and Val3/Pro8-OT.[134] Ren et al. identified a variant further, Phe2-OT in howler monkeys.[135]

The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is the oxidized octapeptide oxytocin disulfide, but oxytocin also exists as a reduced straight-chain (non-cyclic) dithiol nonapeptide called oxytoceine.[136] It has been theorized that oxytoceine may act as a free radical scavenger, as donating an electron to a free radical allows oxytoceine to be re-oxidized to oxytocin via the dehydroascorbate / ascorbate redox couple.[137]

Recent advances in analytical instrumental techniques highlighted the importance of liquid chromatography (LC) coupled with mass spectrometry (MS) for measuring oxytocin levels in various samples derived from biological sources. Most of these studies optimized the oxytocin quantification in electrospray ionization (ESI) positive mode, using [M+H]+ as the parent ion at mass-to-charge ratio (m/z) 1007.4 and the fragment ions as diagnostic peaks at m/z 991.0,[138] m/z 723.2[139] and m/z 504.2.[140] These important ion selections paved the way for the development of current methods of oxytocin quantification using MS instrumentation.

The structure of oxytocin is very similar to that of vasopressin. Both are nonapeptides with a single disulfide bridge, differing only by two substitutions in the amino acid sequence (differences from oxytocin bolded for clarity): Cys – Tyr – Phe – Gln – Asn – Cys – Pro – Arg – Gly – NH2.[131] Oxytocin and vasopressin were isolated and their total synthesis reported in 1954,[141] work for which Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry with the citation: "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."[142]

Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone and dynorphin, for example, that act locally. The magnocellular neurosecretory cells that make oxytocin are adjacent to magnocellular neurosecretory cells that make vasopressin. These are large neuroendocrine neurons which are excitable and can generate action potentials.[143]

In popular culture

"Oxytocin" is the name of the fifth song on Billie Eilish's second album Happier Than Ever.

In the novel The Fireman by Joe Hill, the hormone plays a role in neutralizing the danger posed by an infectious spore that causes a condition known as Dragonscale. If the spore enters an oxytocin-rich environment, it will enter a dormant state instead of causing its host to undergo spontaneous human combustion.

The formula for Oxytocin is displayed as written on the fingers of Nina Zilli and appears in the opening shot of her video for "Sola".

See also

References

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