Oxytocin

Not to be confused with Oxycontin.
Oxytocin
Clinical data
Pronunciation /ˌɒksᵻˈtoʊsɪn/
Trade names Pitocin
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: A
Routes of
administration		 Intranasal, IV, IM
ATC code H01BB02 (WHO)
Legal status
Legal status
Pharmacokinetic data
Protein binding 30%
Metabolism liver and other oxytocinases
Biological half-life 1–6 min (IV)
~2 h (intranasal)[1][2]
Excretion Biliary and kidney
Identifiers
CAS Number 50-56-6 YesY
PubChem (CID) 439302
IUPHAR/BPS 2174
DrugBank DB00107 YesY
ChemSpider 388434 YesY
UNII 1JQS135EYN YesY
KEGG D00089 YesY
ChEBI CHEBI:7872 YesY
ChEMBL CHEMBL395429 YesY
ECHA InfoCard 100.000.045
Chemical and physical data
Formula C43H66N12O12S2
Molar mass 1007.19 g/mol
3D model (Jmol) Interactive image
  (verify)

Oxytocin (Oxt) is a hormone, neuropeptide, and medication.[3][4] As a medication, it is used to cause contraction of the uterus in order to start labor or increase the speed of labor, and to stop bleeding following delivery.[3] For this purpose, it is given by injection either into a muscle or into a vein.[3]

The use of oxytocin as a medication can result in excessive contraction of the uterus that can cause distress in an unborn baby. Common side effects in the mother include nausea and a slow heart rate. Serious side effects include water intoxication with an excessive dose and uterus rupture. Allergic reactions may also occur.[3]

Oxytocin is normally produced by the paraventricular nucleus of the hypothalamus and released by the posterior pituitary.[5] It plays a role in social bonding, sexual reproduction in both sexes, and during and after childbirth.[6] Oxytocin is released into the bloodstream as a hormone in response to stretching of the cervix and uterus during labor and with stimulation of the nipples from breastfeeding.[7] This helps with birth, bonding with the baby, and milk production.[7][8]

Oxytocin was discovered in 1952.[9] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[10] As of 2014, the wholesale cost in the developing world is US$0.1–0.56 per dose.[11]

Physiological effects

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 that requires magnesium and cholesterol. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.

Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors.[12]

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.[13] 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.

Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security when in the company of the mate.[20] This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Research has also demonstrated that oxytocin can decrease anxiety and protect against stress, particularly in combination with social support.[21]
Empathy in healthy males has been shown to be increased after intranasal oxytocin[45][46] This is most likely due to the effect of oxytocin in enhancing eye gaze.[47] There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy.[48]
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.[58] 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.[59] Murphy et al. (1987), studying men, found oxytocin levels were raised throughout sexual arousal with no acute increase at orgasm.[60] 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".[61]

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. Consequently, oxytocin is often referred to as the “love hormone".[80] 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.[81] 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.[82]

Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust faster than individuals who do not receive oxytocin.[82] 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.[55] 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.[81]

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.[82][83] 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.[83]

It has also been shown that testosterone directly suppresses oxytocin in mice.[84] 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.[45]

Mood and depression

Oxytocin produces antidepressant-like effects in animal models of depression,[85] and a deficit of it may be involved in the pathophysiology of depression in humans.[86] 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.[87] 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.[88] (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.)[88] 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.[89][90]

Sildenafil has been found to enhance electrically evoked oxytocin release from the pituitary gland.[85] In accordance, the drug shows oxytocin-dependent antidepressant-like effects in animals, and it has proposed that sildenafil may hold promise as a potential antidepressant in humans.[85]

Medical uses

An intravenous infusion of oxytocin is used to induce labor and to support labor in case of slow childbirth. It is unclear whether a high dose is better than a standard dose for labor induction. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release. The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors; this drug is registered in many countries to suppress premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this purpose (ritodrine, salbutamol, and terbutaline).[91]

Side effects

Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon.[92] The following maternal events have been reported:[92]

Excessive dosage or long-term administration (over a period of 24 hours or longer) have been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.

During pregnancy, increased uterine motility has led to decreased heart rate, cardiac arrhythmia, seizures, brain damage, death in the fetus/neonate:[92]

Administration

Oxytocin is destroyed in the gastrointestinal tract, so it is not active orally and must be administered by injection or as nasal spray. The compound has a half-life of typically about three minutes in the blood when given intravenously. Peripherally administered (e.g., intravenous) peptides like oxytocin cross the blood-brain-barrier very poorly, although very small amounts (< 1%) do appear to enter the central nervous system in humans when given via this route.[93] In contrast to peripheral administration, when administered intranasally via a nasal spray, oxytocin reliably crosses the blood–brain barrier and exhibits psychoactive effects in humans.[94][95] In addition, also unlike the case of peripheral administration, intranasal oxytocin has a central duration of at least 2.25 hours and as long as 4 hours.[1][2] In likely relation to this fact, endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels.[93]

Structure

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.[96] Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin is the equivalent of about 2 μg of pure peptide.

While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was recently reported 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).[97] 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. [98] Ren et al. identified a variant further, Phe2-OT in howler monkeys. [99]

The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is also known as the octapeptide "oxytocin disulfide" (oxidized form), but oxytocin also exists as a reduced straight-chain (non-cyclic) dithiol nonapeptide called oxytoceine.[100] 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.[101]

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.[96] A table showing the sequences of members of the vasopressin/oxytocin superfamily and the species expressing them is present in the vasopressin article. Oxytocin and vasopressin were isolated and their total synthesis reported in 1954,[102] 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."[103]

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.

Synthesis, storage, release, and metabolism

OXT
Identifiers
Aliases OXT, OT, OT-NPI, OXT-NPI, oxytocin/neurophysin I prepropeptide
External IDs OMIM: 167050 HomoloGene: 55494 GeneCards: OXT
Orthologs
Species Human Mouse
Entrez

5020

n/a

Ensembl

ENSG00000101405

n/a

UniProt

P01178

n/a

RefSeq (mRNA)

NM_000915

n/a

RefSeq (protein)

NP_000906.1

n/a

Location (UCSC) Chr 20: 3.07 – 3.07 Mb n/a
PubMed search [104] n/a
Wikidata
View/Edit Human

The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene.[105][106][107] This precursor protein also includes the oxytocin carrier protein neurophysin I.[108] 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).[109]

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.[110] 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.[111]

Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase.[112][113] Other oxytocinases are also known to exist.[112][114] 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.[114][115][116][117]

Neural sources

In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei, 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 oxytocin receptors in the nucleus accumbens.[13] The peripheral hormonal and behavioral brain effects of oxytocin are thought to be coordinated through its common release through these collaterals.[13] Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord.[118] 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

Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum [119][120] and the placenta,[121] in males in the testicles' interstitial cells of Leydig,[122] the retina,[123] the adrenal medulla,[124] the thymus[125] and the pancreas.[126] The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these different 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.[127]

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 F2α to cause regression of the corpus luteum.

Miscellaneous

Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain.[128] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.[87]

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,[129] 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).[49]

History

The word oxytocin was coined from the term oxytocic. Greek ὀξύς, oxys, and τόκος, tokos, meaning "quick birth")

Its uterine-contracting properties were discovered by British pharmacologist Sir Henry Hallett Dale in 1906.[130] And its milk ejection property was described by Ott and Scott in 1910[131] and by Schafer and Mackenzie in 1911.[132]

Oxytocin became the first polypeptide hormone to be sequenced[133] or synthesized.[134][135][136] Du Vigneaud was awarded the Nobel Prize in 1955 for his work.[137]

Research

Oxytocin nasal sprays were studied as a method to stimulate expression of breast milk for mothers with preterm infants.[138]

The trust-inducing property of oxytocin might help those with social anxiety and depression,[45] but with the potential for abuse with confidence tricks[139][140] and military applications.[141] The use of oxytocin in relationship counseling was investigated in 2007, as research had shown the hormone could both enhance trust and improve people's ability to interpret the emotions of others correctly.[142]

Society and culture

Brand names

Synthetic oxytocin is sold as proprietary medication under the trade names Pitocin and Syntocinon, and as generic oxytocin.

References

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